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Sample records for combining pre-calculated molecular

  1. Training software using virtual-reality technology and pre-calculated effective dose data.

    Science.gov (United States)

    Ding, Aiping; Zhang, Di; Xu, X George

    2009-05-01

    This paper describes the development of a software package, called VR Dose Simulator, which aims to provide interactive radiation safety and ALARA training to radiation workers using virtual-reality (VR) simulations. Combined with a pre-calculated effective dose equivalent (EDE) database, a virtual radiation environment was constructed in VR authoring software, EON Studio, using 3-D models of a real nuclear power plant building. Models of avatars representing two workers were adopted with arms and legs of the avatar being controlled in the software to simulate walking and other postures. Collision detection algorithms were developed for various parts of the 3-D power plant building and avatars to confine the avatars to certain regions of the virtual environment. Ten different camera viewpoints were assigned to conveniently cover the entire virtual scenery in different viewing angles. A user can control the avatar to carry out radiological engineering tasks using two modes of avatar navigation. A user can also specify two types of radiation source: Cs and Co. The location of the avatar inside the virtual environment during the course of the avatar's movement is linked to the EDE database. The accumulative dose is calculated and displayed on the screen in real-time. Based on the final accumulated dose and the completion status of all virtual tasks, a score is given to evaluate the performance of the user. The paper concludes that VR-based simulation technologies are interactive and engaging, thus potentially useful in improving the quality of radiation safety training. The paper also summarizes several challenges: more streamlined data conversion, realistic avatar movement and posture, more intuitive implementation of the data communication between EON Studio and VB.NET, and more versatile utilization of EDE data such as a source near the body, etc., all of which needs to be addressed in future efforts to develop this type of software.

  2. SIMAP--a comprehensive database of pre-calculated protein sequence similarities, domains, annotations and clusters.

    Science.gov (United States)

    Rattei, Thomas; Tischler, Patrick; Götz, Stefan; Jehl, Marc-André; Hoser, Jonathan; Arnold, Roland; Conesa, Ana; Mewes, Hans-Werner

    2010-01-01

    The prediction of protein function as well as the reconstruction of evolutionary genesis employing sequence comparison at large is still the most powerful tool in sequence analysis. Due to the exponential growth of the number of known protein sequences and the subsequent quadratic growth of the similarity matrix, the computation of the Similarity Matrix of Proteins (SIMAP) becomes a computational intensive task. The SIMAP database provides a comprehensive and up-to-date pre-calculation of the protein sequence similarity matrix, sequence-based features and sequence clusters. As of September 2009, SIMAP covers 48 million proteins and more than 23 million non-redundant sequences. Novel features of SIMAP include the expansion of the sequence space by including databases such as ENSEMBL as well as the integration of metagenomes based on their consistent processing and annotation. Furthermore, protein function predictions by Blast2GO are pre-calculated for all sequences in SIMAP and the data access and query functions have been improved. SIMAP assists biologists to query the up-to-date sequence space systematically and facilitates large-scale downstream projects in computational biology. Access to SIMAP is freely provided through the web portal for individuals (http://mips.gsf.de/simap/) and for programmatic access through DAS (http://webclu.bio.wzw.tum.de/das/) and Web-Service (http://mips.gsf.de/webservices/services/SimapService2.0?wsdl).

  3. Combination of metformin with chemotherapeutic drugs via different molecular mechanisms.

    Science.gov (United States)

    Peng, Mei; Darko, Kwame Oteng; Tao, Ting; Huang, Yanjun; Su, Qiongli; He, Caimei; Yin, Tao; Liu, Zhaoqian; Yang, Xiaoping

    2017-03-01

    Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits. Interestingly, metformin experiences a diversity of molecular mechanisms when it combines different chemotherapeutic drugs. For example, AMPK/mTOR signaling pathway activation plays a major role when it combines with hormone modulating drugs. In contrast, suppression of HIF-1, p-gp and MRP1 protein expression is its main mechanism when metformin combines with anti-metabolites. Furthermore, when combining of metformin with antibiotics, inhibition of oxidative stress and inflammatory signaling pathway becomes a novel pharmaceutical mechanism for its cardio-protective effect. Induction of apoptotic mitochondria and nucleus could be the major player for the synergistic effect of its combination with cisplatin. In contrast, down-regulation of lipoprotein or cholesterol synthesis might be the undefined molecular base when metformin combines with taxane. Thus, deep exploration of molecular mechanisms of metformin with these different drugs is critical to understand its synergistic effect and help for personalized administration. In this mini-review, detailed molecular mechanisms of these combinations are discussed and summarized. This work will promote better understanding of molecular mechanisms of metformin and provide precise targets to identify specific patient groups to achieve satisfactory treatment efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Clinical effects of low-molecular-weight heparin combined with ...

    African Journals Online (AJOL)

    Purpose: To explore the clinical effects of low-molecular-weight heparin (LMWH) combined with ulinastatin (UTI) in children with acute pancreatitis. Methods: In total, 560 patients with severe acute pancreatitis treated at Binzhou People's Hospital,. Shandong, China, from April 2012 to June 2014 were enrolled in this study.

  5. Low molecular weight salts combined with fluorinated solvents for electrolytes

    Science.gov (United States)

    Tikhonov, Konstantin; Yip, Ka Ki; Lin, Tzu-Yuan; Lei, Norman; Guerrero-Zavala, Guillermo; Kwong, Kristie W.

    2015-11-10

    Provided are electrochemical cells and electrolytes used to build such cells. An electrolyte includes at least one salt having a molecular weight less than about 250. Such salts allow forming electrolytes with higher salt concentrations and ensure high conductivity and ion transport in these electrolytes. The low molecular weight salt may have a concentration of at least about 0.5M and may be combined with one or more other salts, such as linear and cyclic imide salts and/or methide salts. The concentration of these additional salts may be less than that of the low molecular weight salt, in some embodiments, twice less. The additional salts may have a molecular weight greater than about 250. The electrolyte may also include one or more fluorinated solvents and may be capable of maintaining single phase solutions at between about -30.degree. C. to about 80.degree. C.

  6. A Molecular Description of Flexibility in an Antibody Combining Site

    Science.gov (United States)

    Zimmermann, Jörg; Romesberg, Floyd E.; Brooks, Charles L.; Thorpe, Ian F.

    2010-01-01

    Mature antibodies (Abs) that are exquisitely specific for virtually any foreign molecule may be produced by affinity maturation of naïve (or germline) Ab. However, the finite number of germline Ab available suggests that, in contrast to mature Ab, germline Ab must be broadly polyspecific so that they are able to recognize a wide range of ligands. Thus, affinity maturation must play a role mediating Ab specificity. One biophysical property that distinguishes polyspecificity from specificity is protein flexibility; a flexible combining site is able to adopt different conformations that recognize different foreign molecules (or antigens), while a rigid combining site is locked into a conformation that is specific for a given antigen. Recent studies (Proc. Natl. Acad. Sci. USA 104:8821–8826, 2007) have examined, at the atomic level, the structural properties that mediate changes in flexibility at four stages of affinity maturation in the 4-4-20 Ab. These studies employed molecular dynamics simulations to reveal a network of residue interactions that mediate the flexibility changes accompanying maturation. The flexibility of the Ab combining sites in these molecular systems was originally measured using 3-pulse photon echo spectroscopy (3PEPS). The present investigation extends this work by providing a concrete link between structural properties of the Ab molecules and features of the spectroscopic measurements used to characterize their flexibility. Results obtained from the simulations are in good qualitative agreement with the experimental measurements and indicate that the spectroscopic signal is sensitive to protein dynamics distributed throughout the entire combining site. Thus, the simulations provide a molecular level interpretation of the changes induced by affinity maturation of the Ab. The results suggest that 3PEPS spectroscopy in combination with molecular dynamics simulations can provide a detailed description of protein dynamics and, in this case, how

  7. Combining configurational energies and forces for molecular force field optimization

    Science.gov (United States)

    Vlcek, Lukas; Sun, Weiwei; Kent, Paul R. C.

    2017-10-01

    While quantum chemical simulations have been increasingly used as an invaluable source of information for atomistic model development, the high computational expenses typically associated with these techniques often limit thorough sampling of the systems of interest. It is therefore of great practical importance to use all available information as efficiently as possible, and in a way that allows for consistent addition of constraints that may be provided by macroscopic experiments. Here we propose a simple approach that combines information from configurational energies and forces generated in a molecular dynamics simulation to increase the effective number of samples. Subsequently, this information is used to optimize a molecular force field by minimizing the statistical distance similarity metric. We illustrate the methodology on an example of a trajectory of configurations generated in equilibrium molecular dynamics simulations of argon and water and compare the results with those based on the force matching method.

  8. Computer aided molecular design with combined molecular modeling and group contribution

    DEFF Research Database (Denmark)

    Harper, Peter Mathias; Gani, Rafiqul; Kolar, Petr

    1999-01-01

    and on the availability of suitable models for property prediction. A new CAMD methodology that addresses this issue by combining molecular modeling techniques with a traditional CAMD approach is presented. The new method includes a new molecular/atomic structure generation algorithm, a large collection of property...... estimation methods, and, a link to molecular modelling tools. Application of the new CAMD method is highlighted through two industrial examples. (C) 1999 Elsevier Science B.V. All rights reserved.......Computer-aided molecular design (CAMD) provides a means for determining molecules or mixtures of molecules (CAMMD) having a desirable set of physicochemical properties. The application range of CAMD is restricted due to limitations on the complexity of the generated molecular structures...

  9. Studies of bicalutamide-excipients interaction by combination of molecular docking and molecular dynamics simulation.

    Science.gov (United States)

    Li, Caixia; Wang, Jie-Xin; Le, Yuan; Chen, Jian-Feng

    2013-06-03

    While the effects of hydrophilic excipients in enhancing the dissolution rate of water-insoluble drugs have been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. In this work, a combination of docking calculations and MD simulations was applied to investigate the molecular interactions between bicalutamide (BIC) and each of three excipients: lactose (LAC), hydroxypropyl methylcellulose (HPMC), and mannitol (MAN). The calculated results indicated that BIC interacted with HPMC and MAN mainly by Lennard-Jones (LJ) interactions but with LAC mainly by Coulomb (Coul) interactions. There was no hydrogen bond formed between BIC and excipient. It was shown that BIC/LAC had the biggest total solvent accessible surface area with the biggest hydrophilic area and formed the most hydrogen bonds between excipient and water. In addition to the structure analyses, BIC/LAC had both the lowest interaction energy between BIC and excipient and the lowest interaction energy between BIC/excipient and water. All these led to the best dissolution performance of BIC/LAC, which could correspond to the experimental results of dissolution test. The present study suggests that a combination of docking calculations and MD simulations, which aims at complementing the experimental work, could provide a molecular insight into the interaction between drug and excipient. It also holds the great potential to simplify the optimization process of drug delivery system and reduce both time and costs.

  10. Combining molecular dynamics with mesoscopic Green's function reaction dynamics simulations.

    Science.gov (United States)

    Vijaykumar, Adithya; Bolhuis, Peter G; ten Wolde, Pieter Rein

    2015-12-07

    In many reaction-diffusion processes, ranging from biochemical networks, catalysis, to complex self-assembly, the spatial distribution of the reactants and the stochastic character of their interactions are crucial for the macroscopic behavior. The recently developed mesoscopic Green's Function Reaction Dynamics (GFRD) method enables efficient simulation at the particle level provided the microscopic dynamics can be integrated out. Yet, many processes exhibit non-trivial microscopic dynamics that can qualitatively change the macroscopic behavior, calling for an atomistic, microscopic description. We propose a novel approach that combines GFRD for simulating the system at the mesoscopic scale where particles are far apart, with a microscopic technique such as Langevin dynamics or Molecular Dynamics (MD), for simulating the system at the microscopic scale where reactants are in close proximity. This scheme defines the regions where the particles are close together and simulated with high microscopic resolution and those where they are far apart and simulated with lower mesoscopic resolution, adaptively on the fly. The new multi-scale scheme, called MD-GFRD, is generic and can be used to efficiently simulate reaction-diffusion systems at the particle level.

  11. Medicinal plant phytochemicals and their inhibitory activities against pancreatic lipase: molecular docking combined with molecular dynamics simulation approach

    OpenAIRE

    Ahmed, Bilal; Ali Ashfaq, Usman; Mirza, Muhammad Usman

    2017-01-01

    Obesity is the worst health risk worldwide, which is linked to a number of diseases. Pancreatic lipase is considered as an affective cause of obesity and can be a major target for controlling the obesity. The present study was designed to find out best phytochemicals against pancreatic lipase through molecular docking combined with molecular dynamics (MD) simulation. For this purpose, a total of 3770 phytochemicals were docked against pancreatic lipase and ranked them on the basis of binding ...

  12. Novel Molecular Insights into the Combination Treatment of Acromegaly

    NARCIS (Netherlands)

    S.E. Franck (Sanne)

    2017-01-01

    markdownabstractIn chapter 2 of this thesis we have confirmed that LA-SSA in combination with PEGV as a treatment modality for acromegaly still appears to be highly effective, after almost a decade of experience in the Rotterdam cohort (n=112). Normalization of IGF-I levels occurred in 97% of the

  13. Combining optimal control theory and molecular dynamics for protein folding.

    Directory of Open Access Journals (Sweden)

    Yaman Arkun

    Full Text Available A new method to develop low-energy folding routes for proteins is presented. The novel aspect of the proposed approach is the synergistic use of optimal control theory with Molecular Dynamics (MD. In the first step of the method, optimal control theory is employed to compute the force field and the optimal folding trajectory for the Cα atoms of a Coarse-Grained (CG protein model. The solution of this CG optimization provides an harmonic approximation of the true potential energy surface around the native state. In the next step CG optimization guides the MD simulation by specifying the optimal target positions for the Cα atoms. In turn, MD simulation provides an all-atom conformation whose Cα positions match closely the reference target positions determined by CG optimization. This is accomplished by Targeted Molecular Dynamics (TMD which uses a bias potential or harmonic restraint in addition to the usual MD potential. Folding is a dynamical process and as such residues make different contacts during the course of folding. Therefore CG optimization has to be reinitialized and repeated over time to accomodate these important changes. At each sampled folding time, the active contacts among the residues are recalculated based on the all-atom conformation obtained from MD. Using the new set of contacts, the CG potential is updated and the CG optimal trajectory for the Cα atoms is recomputed. This is followed by MD. Implementation of this repetitive CG optimization-MD simulation cycle generates the folding trajectory. Simulations on a model protein Villin demonstrate the utility of the method. Since the method is founded on the general tools of optimal control theory and MD without any restrictions, it is widely applicable to other systems. It can be easily implemented with available MD software packages.

  14. Improvement of cancer immunotherapy by combining molecular targeted therapy

    Directory of Open Access Journals (Sweden)

    Yutaka eKawakami

    2013-05-01

    Full Text Available In human cancer cells, a constitutive activation of MAPK, STAT3, β-catenin, and various other signaling pathways triggers multiple immunosuppressive cascades. These cascades result in the production of immunosuppressive molecules (e.g. TGF-β, IL-10, IL-6, VEGF, and CCL2 and induction of immunosuppressive immune cells (e.g. regulatory T cells, tolerogenic dendritic cells, and myeloid derived suppressor cells. Consequently, immunosuppressive conditions are formed in tumor-associated microenvironments, including the tumor and sentinel lymph nodes. Some of these cancer-derived cytokines and chemokines impair immune cells and render them immunosuppressive via the activation of signaling molecules, such as STAT3, in the immune cells. Thus, administration of signal inhibitors may inhibit the multiple immunosuppressive cascades by acting simultaneously on both cancer and immune cells at the key regulatory points in the cancer-immune network. Since common signaling pathways are involved in manifestation of several hallmarks of cancer, including cancer cell proliferation/survival, invasion/metastasis, and immunosuppression, targeting these shared signaling pathways in combination with immunotherapy may be a promising strategy for cancer treatment.

  15. Combining Radiation Epidemiology With Molecular Biology-Changing From Health Risk Estimates to Therapeutic Intervention.

    Science.gov (United States)

    Abend, Michael; Port, Matthias

    2016-08-01

    The authors herein summarize six presentations dedicated to the key session "molecular radiation epidemiology" of the ConRad meeting 2015. These presentations were chosen in order to highlight the promise when combining conventional radiation epidemiology with molecular biology. Conventional radiation epidemiology uses dose estimates for risk predictions on health. However, combined with molecular biology, dose-dependent bioindicators of effect hold the promise to improve clinical diagnostics and to provide target molecules for potential therapeutic intervention. One out of the six presentations exemplified the use of radiation-induced molecular changes as biomarkers of exposure by measuring stabile chromosomal translocations. The remaining five presentations focused on molecular changes used as bioindicators of the effect. These bioindicators of the effect could be used for diagnostic purposes on colon cancers (genomic instability), thyroid cancer (CLIP2), or head and neck squamous cell cancers. Therapeutic implications of gene expression changes were examined in Chernobyl thyroid cancer victims and Mayak workers.

  16. Mushroom Emergence Detected by Combining Spore Trapping with Molecular Techniques.

    Science.gov (United States)

    Castaño, Carles; Oliva, Jonàs; Martínez de Aragón, Juan; Alday, Josu G; Parladé, Javier; Pera, Joan; Bonet, José Antonio

    2017-07-01

    Obtaining reliable and representative mushroom production data requires time-consuming sampling schemes. In this paper, we assessed a simple methodology to detect mushroom emergence by trapping the fungal spores of the fruiting body community in plots where mushroom production was determined weekly. We compared the performance of filter paper traps with that of funnel traps and combined these spore trapping methods with species-specific quantitative real-time PCR and Illumina MiSeq to determine the spore abundance. Significantly more MiSeq proportional reads were generated for both ectomycorrhizal and saprotrophic fungal species using filter traps than were obtained using funnel traps. The spores of 37 fungal species that produced fruiting bodies in the study plots were identified. Spore community composition changed considerably over time due to the emergence of ephemeral fruiting bodies and rapid spore deposition (lasting from 1 to 2 weeks), which occurred in the absence of rainfall events. For many species, the emergence of epigeous fruiting bodies was followed by a peak in the relative abundance of their airborne spores. There were significant positive relationships between fruiting body yields and spore abundance in time for five of seven fungal species. There was no relationship between fruiting body yields and their spore abundance at plot level, indicating that some of the spores captured in each plot were arriving from the surrounding areas. Differences in fungal detection capacity by spore trapping may indicate different dispersal ability between fungal species. Further research can help to identify the spore rain patterns for most common fungal species. IMPORTANCE Mushroom monitoring represents a serious challenge in economic and logistical terms because sampling approaches demand extensive field work at both the spatial and temporal scales. In addition, the identification of fungal taxa depends on the expertise of experienced fungal taxonomists

  17. Relationship of carbohydrate molecular spectroscopic features in combined feeds to carbohydrate utilization and availability in ruminants

    Science.gov (United States)

    Zhang, Xuewei; Yu, Peiqiang

    To date, there is no study on the relationship between carbohydrate (CHO) molecular structures and nutrient availability of combined feeds in ruminants. The objective of this study was to use molecular spectroscopy to reveal the relationship between CHO molecular spectral profiles (in terms of functional groups (biomolecular, biopolymer) spectral peak area and height intensity) and CHO chemical profiles, CHO subfractions, energy values, and CHO rumen degradation kinetics of combined feeds of hulless barley with pure wheat dried distillers grains with solubles (DDGS) at five different combination ratios (hulless barley to pure wheat DDGS: 100:0, 75:25, 50:50, 25:75, 0:100). The molecular spectroscopic parameters assessed included: lignin biopolymer molecular spectra profile (peak area and height, region and baseline: ca. 1539-1504 cm-1); structural carbohydrate (STCHO, peaks area region and baseline: ca. 1485-1186 cm-1) mainly associated with hemi- and cellulosic compounds; cellulosic materials peak area (centered at ca. 1240 cm-1 with region and baseline: ca. 1272-1186 cm-1); total carbohydrate (CHO, peaks area region and baseline: ca. 1186-946 cm-1). The results showed that the functional groups (biomolecular, biopolymer) in the combined feeds are sensitive to the changes of carbohydrate chemical and nutrient profiles. The changes of the CHO molecular spectroscopic features in the combined feeds were highly correlated with CHO chemical profiles, CHO subfractions, in situ CHO rumen degradation kinetics and fermentable organic matter supply. Further study is needed to investigate possibility of using CHO molecular spectral features as a predictor to estimate nutrient availability in combined feeds for animals and quantify their relationship.

  18. Nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs.

    Science.gov (United States)

    Huang, Wei; Chen, Liqing; Kang, Lin; Jin, Mingji; Sun, Ping; Xin, Xin; Gao, Zhonggao; Bae, You Han

    2017-06-01

    Anticancer therapy has always been a vital challenge for the development of nanomedicine. Repeated single therapeutic agent may lead to undesirable and severe side effects, unbearable toxicity and multidrug resistance due to complex nature of tumor. Nanomedicine-based combination anticancer therapy can synergistically improve antitumor outcomes through multiple-target therapy, decreasing the dose of each therapeutic agent and reducing side effects. There are versatile combinational anticancer strategies such as chemotherapeutic combination, nucleic acid-based co-delivery, intrinsic sensitive and extrinsic stimulus combinational patterns. Based on these combination strategies, various nanocarriers and drug delivery systems were engineered to carry out the efficient co-delivery of combined therapeutic agents for combination anticancer therapy. This review focused on illustrating nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs for synergistically improving anticancer efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Identification and characterization of tebuconazole transformation products in soil by combining suspect screening and molecular typology.

    Science.gov (United States)

    Storck, Veronika; Lucini, Luigi; Mamy, Laure; Ferrari, Federico; Papadopoulou, Evangelia S; Nikolaki, Sofia; Karas, Panagiotis A; Servien, Remi; Karpouzas, Dimitrios G; Trevisan, Marco; Benoit, Pierre; Martin-Laurent, Fabrice

    2016-01-01

    Pesticides generate transformation products (TPs) when they are released into the environment. These TPs may be of ecotoxicological importance. Past studies have demonstrated how difficult it is to predict the occurrence of pesticide TPs and their environmental risk. The monitoring approaches mostly used in current regulatory frameworks target only known ecotoxicologically relevant TPs. Here, we present a novel combined approach which identifies and categorizes known and unknown pesticide TPs in soil by combining suspect screening time-of-flight mass spectrometry with in silico molecular typology. We used an empirical and theoretical pesticide TP library for compound identification by both non-target and target time-of-flight (tandem) mass spectrometry, followed by structural proposition through a molecular structure correlation program. In silico molecular typology was then used to group TPs according to common molecular descriptors and to indirectly elucidate their environmental parameters by analogy to known pesticide compounds with similar molecular descriptors. This approach was evaluated via the identification of TPs of the triazole fungicide tebuconazole occurring in soil during a field dissipation study. Overall, 22 empirical and 12 yet unknown TPs were detected, and categorized into three groups with defined environmental properties. This approach combining suspect screening time-of-flight mass spectrometry with molecular typology could be extended to other organic pollutants and used to rationalize the choice of TPs to be investigated towards a more comprehensive environmental risk assessment scheme. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. A Penalized Linear and Nonlinear Combined Conjugate Gradient Method for the Reconstruction of Fluorescence Molecular Tomography

    OpenAIRE

    Shang Shang; Jing Bai; Xiaolei Song; Hongkai Wang; Jaclyn Lau

    2007-01-01

    Conjugate gradient method is verified to be efficient for nonlinear optimization problems of large-dimension data. In this paper, a penalized linear and nonlinear combined conjugate gradient method for the reconstruction of fluorescence molecular tomography (FMT) is presented. The algorithm combines the linear conjugate gradient method and the nonlinear conjugate gradient method together based on a restart strategy, in order to take advantage of the two kinds of conjugate gradient methods and...

  1. Aquifer vulnerability to pesticide pollution - Combining soil, land-use and aquifer properties with molecular descriptors

    Science.gov (United States)

    Worrall, F.; Kolpin, D.W.

    2004-01-01

    This study uses an extensive survey of herbicides in groundwater across the midwest United States to predict occurrences of a range of compounds across the region from a combination of their molecular properties and the properties of the catchment of a borehole. The study covers 100 boreholes and eight pesticides. For each of the boreholes its catchment the soil, land-use and aquifer properties were characterized. Discriminating boreholes where pollution occurred from those where no pollution occurred gave a model that was 74% correct with organic carbon content, percentage sand content and depth to the water table being significant properties of the borehole catchment. Molecular topological descriptors as well as Koc, solubility and half-life were used to characterize each compound included in the study. Inclusion of molecular properties makes it possible to discriminate between occurrence and non-occurrence of each compound in each well. The best-fit model combines: organic carbon content, percentage sand content and depth to the water table with molecular descriptors representing molecular size, molecular branching and functional group composition of the herbicides.

  2. A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

    NARCIS (Netherlands)

    Springer, Simeon; Wang, Yuxuan; Dal Molin, Marco; Masica, David L.; Jiao, Yuchen; Kinde, Isaac; Blackford, Amanda; Raman, Siva P.; Wolfgang, Christopher L.; Tomita, Tyler; Niknafs, Noushin; Douville, Christopher; Ptak, Janine; Dobbyn, Lisa; Allen, Peter J.; Klimstra, David S.; Schattner, Mark A.; Schmidt, C. Max; Yip-Schneider, Michele; Cummings, Oscar W.; Brand, Randall E.; Zeh, Herbert J.; Singhi, Aatur D.; Scarpa, Aldo; Salvia, Roberto; Malleo, Giuseppe; Zamboni, Giuseppe; Falconi, Massimo; Jang, Jin-Young; Kim, Sun-Whe; Kwon, Wooil; Hong, Seung-Mo; Song, Ki-Byung; Kim, Song Cheol; Swan, Niall; Murphy, Jean; Geoghegan, Justin; Brugge, William; Fernandez-del Castillo, Carlos; Mino-Kenudson, Mari; Schulick, Richard; Edil, Barish H.; Adsay, Volkan; Paulino, Jorge; van Hooft, Jeanin; Yachida, Shinichi; Nara, Satoshi; Hiraoka, Nobuyoshi; Yamao, Kenji; Hijioka, Susuma; van der Merwe, Schalk; Goggins, Michael; Canto, Marcia Irene; Ahuja, Nita; Hirose, Kenzo; Makary, Martin; Weiss, Matthew J.; Cameron, John; Pittman, Meredith; Eshleman, James R.; Diaz, Luis A.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Karchin, Rachel; Hruban, Ralph H.; Vogelstein, Bert; Lennon, Anne Marie

    2015-01-01

    The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. We performed a multi-center, retrospective

  3. 78 FR 21128 - Molecular Diagnostic Instruments With Combined Functions; Draft Guidance for Industry and Food...

    Science.gov (United States)

    2013-04-09

    ... HUMAN SERVICES Food and Drug Administration Molecular Diagnostic Instruments With Combined Functions; Draft Guidance for Industry and Food and Drug Administration Staff; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the...

  4. Electron-phonon scattering from Green’s function transport combined with molecular dynamics

    DEFF Research Database (Denmark)

    Markussen, Troels; Palsgaard, Mattias Lau Nøhr; Stradi, Daniele

    2017-01-01

    We present a conceptually simple method for treating electron-phonon scattering and phonon limited mobilities. By combining Green’s function based transport calculations and molecular dynamics, we obtain a temperature dependent transmission from which we evaluate the mobility. We validate our...

  5. Medicinal plant phytochemicals and their inhibitory activities against pancreatic lipase: molecular docking combined with molecular dynamics simulation approach.

    Science.gov (United States)

    Ahmed, Bilal; Ali Ashfaq, Usman; Usman Mirza, Muhammad

    2017-04-26

    Obesity is the worst health risk worldwide, which is linked to a number of diseases. Pancreatic lipase is considered as an affective cause of obesity and can be a major target for controlling the obesity. The present study was designed to find out best phytochemicals against pancreatic lipase through molecular docking combined with molecular dynamics (MD) simulation. For this purpose, a total of 3770 phytochemicals were docked against pancreatic lipase and ranked them on the basis of binding affinity. Finally, 10 molecules (Kushenol K, Rosmarinic acid, Reserpic acid, Munjistin, Leachianone G, Cephamycin C, Arctigenin, 3-O-acetylpadmatin, Geniposide and Obtusin) were selected that showed strong bonding with the pancreatic lipase. MD simulations were performed on top five compounds using AMBER16. The simulated complexes revealed stability and ligands remained inside the binding pocket. This study concluded that these finalised molecules can be used as drug candidate to control obesity.

  6. Combined multi-pharmacophore, molecular docking and molecular dynamic study for discovery of promising MTH1 inhibitors

    Science.gov (United States)

    Dai, Duoqian; Zhou, Lu; Zhu, Xiaohong; You, Rong; Zhong, Liangliang

    2017-06-01

    MutT homolog 1 (MTH1), a nudix phosphohydrolase enzyme participates in the process of repairing of DNA damage by hydrolyzing oxidized deoxy-ribonucleoside triphosphate in cancer cells, is regarded as a potential target for anticancer therapy. In order to seek for promising inhibitor of MTH1, structured-based pharmacophore and 3D-QSAR pharmacophore hypotheses combine with the ADMET analysis and Lipinski's rule of five were used for screening the public molecules libraries (Asinex, Ibscreen and Natural). Then molecular docking studies were performed on screened hits via various docking programs (Glide SP, GOLD and Glide XP), five molecules with three scaffolds were picked out as potential inhibitors against MTH1. Eventually, 20 ns molecular dynamics simulation was implemented on the potential inhibitors. The RMSD (Root Mean Square Deviation) values were used to illustrate bind stability between potential molecules and MTH1. Therefore, the five hits may be considered as promising MTH1 inhibitors by all above studies.

  7. Evaluation of RTV as a Moldable Matrix When Combined With Molecular Sieve and Organic Hydrogen Getter

    Energy Technology Data Exchange (ETDEWEB)

    Knight, J. A.

    2011-12-01

    This work was undertaken in an effort to develop a combined RTV 615/3Å molecular sieve/DEB molded component. A molded RTV 615/3Å molecular sieve component is currently in production, and an RTV 615/DEB component was produced in the past. However, all three materials have never before been combined in a single production part, and this is an opportunity to create a new component capable of being molded to shape, performing desiccation, and hydrogen gettering. This analysis looked at weapons system parameters and how they might influence part design. It also looked at material processing and how it related to mixing, activating a dessicant, and hydrogen uptake testing.

  8. Shock waves simulated using the dual domain material point method combined with molecular dynamics

    Science.gov (United States)

    Zhang, Duan Z.; Dhakal, Tilak R.

    2017-04-01

    In this work we combine the dual domain material point method with molecular dynamics in an attempt to create a multiscale numerical method to simulate materials undergoing large deformations with high strain rates. In these types of problems, the material is often in a thermodynamically nonequilibrium state, and conventional constitutive relations or equations of state are often not available. In this method, the closure quantities, such as stress, at each material point are calculated from a molecular dynamics simulation of a group of atoms surrounding the material point. Rather than restricting the multiscale simulation in a small spatial region, such as phase interfaces, or crack tips, this multiscale method can be used to consider nonequilibrium thermodynamic effects in a macroscopic domain. This method takes the advantage that the material points only communicate with mesh nodes, not among themselves; therefore molecular dynamics simulations for material points can be performed independently in parallel. The dual domain material point method is chosen for this multiscale method because it can be used in history dependent problems with large deformation without generating numerical noise as material points move across cells, and also because of its convergence and conservation properties. To demonstrate the feasibility and accuracy of this method, we compare the results of a shock wave propagation in a cerium crystal calculated using the direct molecular dynamics simulation with the results from this combined multiscale calculation.

  9. Combined Analysis of Extant Rhynchonellida (Brachiopoda) Using Morphological and Molecular Data.

    Science.gov (United States)

    Bapst, David W; Schreiber, Holly A; Carlson, Sandra J

    2017-05-08

    Independent molecular and morphological phylogenetic analyses have often produced discordant results for certain groups which, for fossil-rich groups, raises the possibility that morphological data might mislead in those groups for which we depend upon morphology the most. Rhynchonellide brachiopods, with more than 500 extinct genera but only 19 extant genera represented today, provide an opportunity to explore the factors that produce contentious phylogenetic signal across datasets, as previous phylogenetic hypotheses generated from molecular sequence data bear little agreement with those constructed using morphological characters. Using a revised matrix of 66 morphological characters, and published ribosomal DNA sequences, we performed a series of combined phylogenetic analyses to identify conflicting phylogenetic signals. We completed a series of parsimony-based and Bayesian analyses, varying the data used, the taxa included, and the models used in the Bayesian analyses. We also performed simulation-based sensitivity analyses to assess whether the small size of the morphological data partition relative to the molecular data influenced the results of the combined analyses. In order to compare and contrast a large number of phylogenetic analyses and their resulting summary trees, we developed a measure for the incongruence between two topologies, and simultaneously ignore any differences in phylogenetic resolution. Phylogenetic hypotheses generated using only morphological characters differed amongst each other, and with previous analyses, while molecular-only and combined Bayesian analyses produced extremely similar topologies. Characters historically associated with traditional classification in the Rhynchonellida have very low consistency indices on the topology preferred by the combined Bayesian analyses. Overall, this casts doubt on the use of morphological systematics to resolve relationships among the crown rhynchonellide brachiopods. However, expanding our

  10. Consolidating Molecular Logic with New Solid-Bound YES and PASS 1 Gates and Their Combinations.

    Science.gov (United States)

    McKinney, Bernadine O F; Daly, Brian; Yao, Chaoyi; Schroeder, Marc; de Silva, A Prasanna

    2017-07-05

    Proton-driven YES and PASS 1 molecular logic tags based on anthracene and 4-aminonaphthalimide fluorophores, emitting blue and green, respectively, are employed on amino-terminated polyethylene glycol-polystyrene and aminopropyl silica particles. The (YES+PASS 1) logic combination is also a distinguishable tag in both colours. The scope of such tags is delineated. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Molecular modelling on small molecular CDK2 inhibitors: an integrated approach using a combination of molecular docking, 3D-QSAR and pharmacophore modelling.

    Science.gov (United States)

    Yuan, H; Liu, H; Tai, W; Wang, F; Zhang, Y; Yao, S; Ran, T; Lu, S; Ke, Z; Xiong, X; Xu, J; Chen, Y; Lu, T

    2013-10-01

    Cyclin-dependent kinase 2 (CDK2) has been identified as an important target for developing novel anticancer agents. Molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and pharmacophore modelling were combined with the ultimate goal of studying the structure-activity relationship of CDK2 inhibitors. The comparative molecular similarity indices analysis (CoMSIA) model constructed based on a set of 3-aminopyrazole derivatives as CDK2 inhibitors gave statistically significant results (q (2) = 0.700; r (2) = 0.982). A HypoGen pharmacophore model, constructed using diverse CDK2 inhibitors, also showed significant statistics ([Formula: see text]Cost = 61.483; RMSD = 0.53; Correlation coefficient = 0.98). The small residues and error values between the estimated and experimental activities of the training and test set compounds proved their strong capability of activity prediction. The structural insights obtained from these two models were consistent with each other. The pharmacophore model summarized the important pharmacophoric features required for protein-ligand binding. The 3D contour maps in combination with the comprehensive pharmacophoric features helped to better interpret the structure-activity relationship. The results will be beneficial for the discovery and design of novel CDK2 inhibitors. The simplicity of this approach provides expansion to its applicability in optimizing other classes of small molecular CDK2 inhibitors.

  12. The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas

    Directory of Open Access Journals (Sweden)

    Tina eDasgupta

    2013-05-01

    Full Text Available Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent or refractory pediatric brain tumors, radiation therapy (XRT is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in low-grade gliomas is being exploited with targeted inhibitors. These agents are also being combined with XRT to increase their efficacy. In this review, we discuss novel agents targeting three different pathways in low-grade gliomas, and their potential combination with XRT. B-Raf is a kinase in the Ras/Raf/MAPK kinase pathway, which is integral to cellular division, survival and metabolism. In low-grade pediatric gliomas, point mutations in BRAF (BRAF V600E or a BRAF fusion mutation (KIAA1549:BRAF causes overactivation of the MEK/MAPK pathway. Pre-clinical data shows cooperation between XRT and tagrgeted inhibitors of BRAF V600E, and MEK and mTOR inhibitors in the gliomas with the BRAF fusion. A second important signaling cascade in pediatric glioma pathogenesis is the PI3 kinase (PI3K/mTOR pathway. Dual PI3K/mTOR inhibitors are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis. Several inhibitors of immunomodulators are currently being evaluated in in clinical trials for the treatment of recurrent or refractory pediatric central nervous system (CNS tumors. In summary, combinations of these targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. We summarize the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. Parallels are drawn to adult gliomas, and the molecular mechanisms underlying the efficacy of these agents is discussed

  13. Molecular landscape of acquired resistance to targeted therapy combinations in BRAF mutant colorectal cancer

    Science.gov (United States)

    Oddo, Daniele; Sennott, Erin M.; Barault, Ludovic; Valtorta, Emanuele; Arena, Sabrina; Cassingena, Andrea; Filiciotto, Genny; Marzolla, Giulia; Elez, Elena; van Geel, Robin M.J.M.; Bartolini, Alice; Crisafulli, Giovanni; Boscaro, Valentina; Godfrey, Jason T.; Buscarino, Michela; Cancelliere, Carlotta; Linnebacher, Michael; Corti, Giorgio; Truini, Mauro; Siravegna, Giulia; Grasselli, Julieta; Gallicchio, Margherita; Bernards, René; Schellens, Jan H.M.; Tabernero, Josep; Engelman, Jeffrey A.; Sartore-Bianchi, Andrea; Bardelli, Alberto; Siena, Salvatore; Corcoran, Ryan B.; Di Nicolantonio, Federica

    2016-01-01

    Summary Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF mutant resistant cell line models across seven different clinically-relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1. These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. In order to identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF mutant colorectal cancer. PMID:27312529

  14. A Combined Experimental and Molecular Dynamics Study of Iodide-Based Ionic Liquid and Water Mixtures.

    Science.gov (United States)

    Nickerson, Stella D; Nofen, Elizabeth M; Chen, Haobo; Ngan, Miranda; Shindel, Benjamin; Yu, Hongyu; Dai, Lenore L

    2015-07-16

    Iodide-based ionic liquids have been widely employed as iodide sources in electrolytes for applications utilizing the triiodide/iodide redox couple. While adding a low-viscosity solvent such as water to ionic liquids can greatly enhance their usefulness, mixtures of highly viscous iodide-containing ILs with water have never been studied. This paper investigates, for the first time, mixtures of water and the ionic liquid 1-butyl-3-methylimidazolium iodide ([BMIM][I]) through a combined experimental and molecular dynamics study. The density, melting point, viscosity, and conductivity of these mixtures were measured by experiment. The composition region below 50% water by mole was found to differ dramatically from the region above 50% water, with trends in density and melting point differing before and after that point. Water was found to have a profound effect on viscosity and conductivity of the IL, and the effect of hydrogen bonding was discussed. Molecular dynamics simulations representing the same mixture compositions were performed. Molecular ordering was observed, as were changes in this ordering corresponding to water content. Molecular ordering was related to the experimentally measured mixture properties, providing a possible explanation for the two distinct composition regions identified by experiment.

  15. Combining fossil and molecular data to date the diversification of New World Primates.

    Science.gov (United States)

    Schrago, C G; Mello, B; Soares, A E R

    2013-11-01

    Recent methodological advances in molecular dating associated with the growing availability of sequence data have prompted the study of the evolution of New World Anthropoidea in recent years. Motivated by questions regarding historical biogeography or the mode of evolution, these works aimed to obtain a clearer scenario of Platyrrhini origins and diversification. Although some consensus was found, disputed issues, especially those relating to the evolutionary affinities of fossil taxa, remain. The use of fossil taxa for divergence time analysis is traditionally restricted to the provision of calibration priors. However, new analytical approaches have been developed that incorporate fossils as terminals and, thus, directly assign ages to the fossil tips. In this study, we conducted a combined analysis of molecular and morphological data, including fossils, to derive the timescale of New World anthropoids. Differently from previous studies that conducted total-evidence analysis of molecules and morphology, our approach investigated the morphological clock alone. Our results corroborate the hypothesis that living platyrrhines diversified in the last 20 Ma and that Miocene Patagonian fossils compose an independent evolutionary radiation that diversified in the late Oligocene. When compared to the node ages inferred from the molecular timescale, the inclusion of fossils augmented the precision of the estimates for nodes constrained by the fossil tips. We show that morphological data can be analysed using the same methodological framework applied in relaxed molecular clock studies. © 2013 The Authors. Journal of Evolutionary Biology © 2013 European Society For Evolutionary Biology.

  16. Magnetic nanoparticles in fluid environment: combining molecular dynamics and Lattice-Boltzmann

    Science.gov (United States)

    Melenev, Petr

    2017-06-01

    Hydrodynamic interactions between magnetic nanoparticles suspended in the Newtonian liquid are accounted for using a combination of the lattice Boltzmann method and molecular dynamics simulations. Nanoparticle is modelled by the system of molecular dynamics material points (which form structure resembles raspberry) coupled to the lattice Boltzmann fluid. The hydrodynamic coupling between the colloids is studied by simulations of the thermo-induced rotational diffusion of two raspberry objects. It was found that for the considered range of model parameters the approaching of the raspberries leads to slight retard of the relaxation process. The presence of the weak magnetic dipolar interaction between the objects leads to modest decrease of the relaxation time and the extent of the acceleration of the diffusion is intensified along with magnetic forces.

  17. Iron Oxide Nanoradiomaterials: Combining Nanoscale Properties with Radioisotopes for Enhanced Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Juan Pellico

    2017-01-01

    Full Text Available The combination of the size-dependent properties of nanomaterials with radioisotopes is emerging as a novel tool for molecular imaging. There are numerous examples already showing how the controlled synthesis of nanoparticles and the incorporation of a radioisotope in the nanostructure offer new features beyond the simple addition of different components. Among the different nanomaterials, iron oxide-based nanoparticles are the most used in imaging because of their versatility. In this review, we will study the different radioisotopes for biomedical imaging, how to incorporate them within the nanoparticles, and what applications they can be used for. Our focus is directed towards what is new in this field, what the nanoparticles can offer to the field of nuclear imaging, and the radioisotopes hybridized with nanomaterials for use in molecular imaging.

  18. Controllable production of low molecular weight heparins by combinations of heparinase I/II/III.

    Science.gov (United States)

    Wu, Jingjun; Zhang, Chong; Mei, Xiang; Li, Ye; Xing, Xin-Hui

    2014-01-30

    Enzymatic depolymerization of heparin by heparinases is promising for production of low molecular weight heparins (LMWHs) as anticoagulants, due to its mild reaction conditions and high selectivity. Here, different heparinase combinations were used to depolymerize heparin. Heparinase I and heparinase II can depolymerize heparin more efficiently than heparinase III, respectively, but heparinase III was the best able to protect the anticoagulant activities of LMWHs. Heparinase III and heparinase I/II combinations were able to efficiently depolymerize heparin to LMWHs with higher anticoagulant activity than the LMWHs produced by the respective heparinase I and heparinase II. HepIII and HepI is the best combination for maintaining high anti-IIa activity (75.7 ± 4.21 IU/mg) at the same Mw value. Furthermore, considering both the changes in molecular weight and anticoagulant activity, the action patterns of heparinase I and heparinase II were found not to follow the exolytic and processive depolymerizing mechanism from the reducing end of heparin. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Combining differential expression, chromosomal and pathway analyses for the molecular characterization of renal cell carcinoma.

    Science.gov (United States)

    Furge, Kyle A; Dykema, Karl; Petillo, David; Westphal, Michael; Zhang, Zhongfa; Kort, Eric J; Teh, Bin Tean

    2007-06-01

    Using high-throughput gene-expression profiling technology, we can now gain a better understanding of the complex biology that is taking place in cancer cells. This complexity is largely dictated by the abnormal genetic makeup of the cancer cells. This abnormal genetic makeup can have profound effects on cellular activities such as cell growth, cell survival and other regulatory processes. Based on the pattern of gene expression, or molecular signatures of the tumours, we can distinguish or subclassify different types of cancers according to their cell of origin, behaviour, and the way they respond to therapeutic agents and radiation. These approaches will lead to better molecular subclassification of tumours, the basis of personalized medicine. We have, to date, done whole-genome microarray gene-expression profiling on several hundreds of kidney tumours. We adopt a combined bioinformatic approach, based on an integrative analysis of the gene-expression data. These data are used to identify both cytogenetic abnormalities and molecular pathways that are deregulated in renal cell carcinoma (RCC). For example, we have identified the deregulation of the VHL-hypoxia pathway in clear-cell RCC, as previously known, and the c-Myc pathway in aggressive papillary RCC. Besides the more common clear-cell, papillary and chromophobe RCCs, we are currently characterizing the molecular signatures of rarer forms of renal neoplasia such as carcinoma of the collecting ducts, mixed epithelial and stromal tumours, chromosome Xp11 translocations associated with papillary RCC, renal medullary carcinoma, mucinous tubular and spindle-cell carcinoma, and a group of unclassified tumours. Continued development and improvement in the field of molecular profiling will better characterize cancer and provide more accurate diagnosis, prognosis and prediction of drug response.

  20. Modern dose-finding designs for cancer phase I trials drug combinations and molecularly targeted agents

    CERN Document Server

    Hirakawa, Akihiro; Daimon, Takashi; Matsui, Shigeyuki

    2018-01-01

    This book deals with advanced methods for adaptive phase I dose-finding clinical trials for combination of two agents and molecularly targeted agents (MTAs) in oncology. It provides not only methodological aspects of the dose-finding methods, but also software implementations and practical considerations in applying these complex methods to real cancer clinical trials. Thus, the book aims to furnish researchers in biostatistics and statistical science with a good summary of recent developments of adaptive dose-finding methods as well as providing practitioners in biostatistics and clinical investigators with advanced materials for designing, conducting, monitoring, and analyzing adaptive dose-finding trials. The topics in the book are mainly related to cancer clinical trials, but many of those topics are potentially applicable or can be extended to trials for other diseases. The focus is mainly on model-based dose-finding methods for two kinds of phase I trials. One is clinical trials with combinations of tw...

  1. Combining Coarse-Grained Protein Models with Replica-Exchange All-Atom Molecular Dynamics

    Directory of Open Access Journals (Sweden)

    Andrzej Koliński

    2013-05-01

    Full Text Available We describe a combination of all-atom simulations with CABS, a well-established coarse-grained protein modeling tool, into a single multiscale protocol. The simulation method has been tested on the C-terminal beta hairpin of protein G, a model system of protein folding. After reconstructing atomistic details, conformations derived from the CABS simulation were subjected to replica-exchange molecular dynamics simulations with OPLS-AA and AMBER99sb force fields in explicit solvent. Such a combination accelerates system convergence several times in comparison with all-atom simulations starting from the extended chain conformation, demonstrated by the analysis of melting curves, the number of native-like conformations as a function of time and secondary structure propagation. The results strongly suggest that the proposed multiscale method could be an efficient and accurate tool for high-resolution studies of protein folding dynamics in larger systems.

  2. Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology.

    Science.gov (United States)

    van der Kamp, Marc W; Mulholland, Adrian J

    2013-04-23

    Computational enzymology is a rapidly maturing field that is increasingly integral to understanding mechanisms of enzyme-catalyzed reactions and their practical applications. Combined quantum mechanics/molecular mechanics (QM/MM) methods are important in this field. By treating the reacting species with a quantum mechanical method (i.e., a method that calculates the electronic structure of the active site) and including the enzyme environment with simpler molecular mechanical methods, enzyme reactions can be modeled. Here, we review QM/MM methods and their application to enzyme-catalyzed reactions to investigate fundamental and practical problems in enzymology. A range of QM/MM methods is available, from cheaper and more approximate methods, which can be used for molecular dynamics simulations, to highly accurate electronic structure methods. We discuss how modeling of reactions using such methods can provide detailed insight into enzyme mechanisms and illustrate this by reviewing some recent applications. We outline some practical considerations for such simulations. Further, we highlight applications that show how QM/MM methods can contribute to the practical development and application of enzymology, e.g., in the interpretation and prediction of the effects of mutagenesis and in drug and catalyst design.

  3. Combination of anti-hypertensive drugs: a molecular dynamics simulation study.

    Science.gov (United States)

    Yousefpour, Abbas; Modarress, Hamid; Goharpey, Fatemeh; Amjad-Iranagh, Sepideh

    2017-05-01

    The anti-hypertensive drugs amlodipine, atenolol and lisinopril, in ordinary and PEGylated forms, with different combined-ratios, were studied by molecular dynamics simulations using GROMACS software. Twenty simulation systems were designed to evaluate the interactions of drug mixtures with a dimyristoylphosphatidylcholine (DMPC) lipid bilayer membrane, in the presence of water molecules. In the course of simulations, various properties of the systems were investigated, including drug location, diffusion and mass distribution in the membrane; drug orientation; the lipid chain disorder as a result of drug penetration into the DMPC membrane; the number of hydrogen bonds; and drug surface area. According to the results obtained, combined drugs penetrate deeper into the DMPC lipid bilayer membrane, and the lipid chains remain ordered. Also, the combined PEGylated drugs, at a combination ratio of 1:1:1, enhance drug penetration into the DMPC membrane, reduce drug agglomeration, orient the drug in a proper angle for easy penetration into the membrane, and decrease undesirable lipotoxicity due to distorted membrane self-assembly and thickness. Graphical abstract ᅟ.

  4. A modern approach to rotiferan phylogeny: combining morphological and molecular data.

    Science.gov (United States)

    Sørensen, Martin V; Giribet, Gonzalo

    2006-08-01

    The phylogeny of selected members of the phylum Rotifera is examined based on analyses under parsimony direct optimization and Bayesian inference of phylogeny. Species of the higher metazoan lineages Acanthocephala, Micrognathozoa, Cycliophora, and potential outgroups are included to test rotiferan monophyly. The data include 74 morphological characters combined with DNA sequence data from four molecular loci, including the nuclear 18S rRNA, 28S rRNA, histone H3, and the mitochondrial cytochrome c oxidase subunit I. The combined molecular and total evidence analyses support the inclusion of Acanthocephala as a rotiferan ingroup, but do not support the inclusion of Micrognathozoa and Cycliophora. Within Rotifera, the monophyletic Monogononta is sister group to a clade consisting of Acanthocephala, Seisonidea, and Bdelloidea-for which we propose the name Hemirotifera. We also formally propose the inclusion of Acanthocephala within Rotifera, but maintaining the name Rotifera for the new expanded phylum. Within Monogononta, Gnesiotrocha and Ploima are also supported by the data. The relationships within Ploima remain unstable to parameter variation or to the method of phylogeny reconstruction and poorly supported, and the analyses showed that monophyly was questionable for the families Dicranophoridae, Notommatidae, and Brachionidae, and for the genus Proales. Otherwise, monophyly was generally supported for the represented ploimid families and genera.

  5. Spectroscopic impact on protein and carbohydrate inherent molecular structures of barley, oat and corn combined with wheat DDGS

    OpenAIRE

    Abeysekara, S.; Damiran, D.; Yu, P.

    2011-01-01

    The objectives of this experiment were to use non-invasive and non-destructive infrared molecular spectroscopy as a novel approach to explore and identify protein and carbohydrate molecular structure spectral features of DDGS (dried distillers grain solubles from wheat, Triticum aestivum) and its combinations with barley (Hordeum vulgare), corn (Zea mays) and oat (Avena sativa). The spectral parameters assessed in this study included amides, protein molecular structures of α-helix and β-sheet...

  6. Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

    Science.gov (United States)

    Oddo, Daniele; Sennott, Erin M; Barault, Ludovic; Valtorta, Emanuele; Arena, Sabrina; Cassingena, Andrea; Filiciotto, Genny; Marzolla, Giulia; Elez, Elena; van Geel, Robin M J M; Bartolini, Alice; Crisafulli, Giovanni; Boscaro, Valentina; Godfrey, Jason T; Buscarino, Michela; Cancelliere, Carlotta; Linnebacher, Michael; Corti, Giorgio; Truini, Mauro; Siravegna, Giulia; Grasselli, Julieta; Gallicchio, Margherita; Bernards, René; Schellens, Jan H M; Tabernero, Josep; Engelman, Jeffrey A; Sartore-Bianchi, Andrea; Bardelli, Alberto; Siena, Salvatore; Corcoran, Ryan B; Di Nicolantonio, Federica

    2016-08-01

    Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1 These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504-15. ©2016 AACR. ©2016 American Association for Cancer Research.

  7. A Hybrid approach to molecular continuum processes combiningGaussian basis functions and the discrete variable representation

    Energy Technology Data Exchange (ETDEWEB)

    Rescigno, Thomas N.; Horner, Daniel A.; Yip, Frank L.; McCurdy,C. William

    2005-08-29

    Gaussian basis functions, routinely employed in molecular electronic structure calculations, can be combined with numerical grid-based functions in a discrete variable representation to provide an efficient method for computing molecular continuum wave functions. This approach, combined with exterior complex scaling, obviates the need for slowly convergent single-center expansions, and allows one to study a variety of electron-molecule collision problems. The method is illustrated by computation of various bound and continuum properties of H2+.

  8. Optical signatures of molecular dissymmetry: combining theory with experiments to address stereochemical puzzles.

    Science.gov (United States)

    Mukhopadhyay, Parag; Wipf, Peter; Beratan, David N

    2009-06-16

    quadrupole and magnetic dipole perturbations by the electromagnetic field. Moreover, OR arises from a combination of nearly canceling contributions to the electronic response. Indeed, the challenge posed by the chiroptical properties delayed the advent of even qualitatively accurate descriptions for some chiroptical signatures until the past decade when, for example, prediction of the observed sign of experimental OR became accessible to theory. The computation of chiroptical signatures, in close coordination with synthesis and spectroscopy, provides a powerful framework to diagnose and interpret the dissymmetry of chemical structures and molecular assemblies. Chiroptical theory now produces new schemes to elucidate structure, to describe the specific molecular sources of chiroptical signatures, and to assist in our understanding of how dissymmetry is templated and propagated in the condensed phase.

  9. An Exploration of Molecular Correlates Relevant to Radiation Combined Skin-Burn Trauma.

    Directory of Open Access Journals (Sweden)

    Aminul Islam

    Full Text Available Exposure to high dose radiation in combination with physical injuries such as burn or wound trauma can produce a more harmful set of medical complications requiring specialist interventions. Currently these interventions are unavailable as are the precise biomarkers needed to help both accurately assess and treat such conditions. In the present study, we tried to identify and explore the possible role of serum exosome microRNA (miRNA signatures as potential biomarkers for radiation combined burn injury (RCBI.Female B6D2F1/J mice were assigned to four experimental groups (n = 6: sham control (SHAM, burn injury (BURN, radiation injury (RI and combined radiation skin burn injury (CI. We performed serum multiplex cytokine analysis and serum exosome miRNA expression profiling to determine novel miRNA signatures and important biological pathways associated with radiation combined skin-burn trauma.Serum cytokines, IL-5 and MCP-1, were significantly induced only in CI mice (p<0.05. From 890 differentially expressed miRNAs identified, microarray analysis showed 47 distinct miRNA seed sequences significantly associated with CI mice compared to SHAM control mice (fold change ≥ 1.2, p<0.05. Furthermore, only two major miRNA seed sequences (miR-690 and miR-223 were validated to be differentially expressed for CI mice specifically (fold change ≥ 1.5, p<0.05.Serum exosome miRNA signature data of adult mice, following RCBI, provides new insights into the molecular and biochemical pathways associated with radiation combined skin-burn trauma in vivo.

  10. Polydopamine Nanoparticles as a Versatile Molecular Loading Platform to Enable Imaging-guided Cancer Combination Therapy.

    Science.gov (United States)

    Dong, Ziliang; Gong, Hua; Gao, Min; Zhu, Wenwen; Sun, Xiaoqi; Feng, Liangzhu; Fu, Tingting; Li, Yonggang; Liu, Zhuang

    2016-01-01

    Cancer combination therapy to treat tumors with different therapeutic approaches can efficiently improve treatment efficacy and reduce side effects. Herein, we develop a theranostic nano-platform based on polydopamine (PDA) nanoparticles, which then are exploited as a versatile carrier to allow simultaneous loading of indocyanine green (ICG), doxorubicin (DOX) and manganese ions (PDA-ICG-PEG/DOX(Mn)), to enable imaging-guided chemo & photothermal cancer therapy. In this system, ICG acts as a photothermal agent, which shows red-shifted near-infrared (NIR) absorbance and enhanced photostability compared with free ICG. DOX, a model chemotherapy drug, is then loaded onto the surface of PDA-ICG-PEG with high efficiency. With Mn(2+) ions intrinsically chelated, PDA-ICG-PEG/DOX(Mn) is able to offer contrast under T1-weighted magnetic resonance (MR) imaging. In a mouse tumor model, the MR imaging-guided combined chemo- & photothermal therapy achieves a remarkable synergistic therapeutic effect compared with the respective single treatment modality. This work demonstrates that PDA nanoparticles could serve as a versatile molecular loading platform for MR imaging guided combined chemo- & photothermal therapy with minimal side effects, showing great potential for cancer theranostics.

  11. On the cluster composition of supercritical water combining molecular modeling and vibrational spectroscopic data.

    Science.gov (United States)

    Tassaing, T; Garrain, P A; Bégué, D; Baraille, I

    2010-07-21

    The present study is aimed at a detailed analysis of supercritical water structure based on the combination of experimental vibrational spectra as well as molecular modeling calculations of isolated water clusters. We propose an equilibrium cluster composition model where supercritical water is considered as an ideal mixture of small water clusters (n=1-3) at the chemical equilibrium and the vibrational spectra are expected to result from the superposition of the spectra of the individual clusters, Thus, it was possible to extract from the decomposition of the midinfrared spectra the evolution of the partition of clusters in supercritical water as a function of density. The cluster composition predicted by this model was found to be quantitatively consistent with the near infrared and Raman spectra of supercritical water analyzed using the same procedure. We emphasize that such methodology could be applied to determine the portion of cluster in water in a wider thermodynamic range as well as in more complex aqueous supercritical solutions.

  12. Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies

    Directory of Open Access Journals (Sweden)

    Antonella Bisio

    2017-06-01

    Full Text Available A number of low molecular weight heparin (LMWH products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic and pharmacodynamics differences. While enoxaparin has been extensively investigated, little information is available regarding the LMWH dalteparin. The present study is focused on the detailed structural characterization of Fragmin® by LC-MS and NMR applied both to the whole drug and to its enzymatic products. For a more in-depth approach, size homogeneous octasaccharide and decasaccharide components together with their fractions endowed with high or no affinity toward antithrombin were also isolated and their structural profiles characterized. The combination of different analytical strategies here described represents a useful tool for the assessment of batch-to-batch structural variability and for comparative evaluation of structural features of biosimilar products.

  13. Combined molecular and spin dynamics simulation of bcc iron with lattice vacancies

    Science.gov (United States)

    Mudrick, Mark; Eisenbach, Markus; Perera, Dilina; Stocks, G. Malcolm; Landau, David P.

    2017-11-01

    Using an atomistic model that treats both translational and spin degrees of freedom, we have performed combined molecular and spin dynamics simulations to study dynamic properties of BCC iron with varying vacancy concentrations. Atomic interactions are described by an empirical many-body potential while spin interactions are handled with a Heisenberg-like Hamiltonian with a coordinate dependent exchange interaction. By calculating the Fourier transform of spatial and temporal correlation functions, vibrational and magnetic excitations have been studied. The creation of vacancies in the material has shown splitting of the characteristic transverse spin-wave excitations, indicating the production of additional excitation modes. By merging two vacancies to form a nearest neighbor pair, we find that these modes become more distinct. Investigation of longitudinal spin-wave excitations reveals interactions between constituent components of the split transverse excitations.

  14. Multiscale simulations of anisotropic particles combining molecular dynamics and Green's function reaction dynamics.

    Science.gov (United States)

    Vijaykumar, Adithya; Ouldridge, Thomas E; Ten Wolde, Pieter Rein; Bolhuis, Peter G

    2017-03-21

    The modeling of complex reaction-diffusion processes in, for instance, cellular biochemical networks or self-assembling soft matter can be tremendously sped up by employing a multiscale algorithm which combines the mesoscopic Green's Function Reaction Dynamics (GFRD) method with explicit stochastic Brownian, Langevin, or deterministic molecular dynamics to treat reactants at the microscopic scale [A. Vijaykumar, P. G. Bolhuis, and P. R. ten Wolde, J. Chem. Phys. 143, 214102 (2015)]. Here we extend this multiscale MD-GFRD approach to include the orientational dynamics that is crucial to describe the anisotropic interactions often prevalent in biomolecular systems. We present the novel algorithm focusing on Brownian dynamics only, although the methodology is generic. We illustrate the novel algorithm using a simple patchy particle model. After validation of the algorithm, we discuss its performance. The rotational Brownian dynamics MD-GFRD multiscale method will open up the possibility for large scale simulations of protein signalling networks.

  15. Multiscale simulations of anisotropic particles combining molecular dynamics and Green's function reaction dynamics

    Science.gov (United States)

    Vijaykumar, Adithya; Ouldridge, Thomas E.; ten Wolde, Pieter Rein; Bolhuis, Peter G.

    2017-03-01

    The modeling of complex reaction-diffusion processes in, for instance, cellular biochemical networks or self-assembling soft matter can be tremendously sped up by employing a multiscale algorithm which combines the mesoscopic Green's Function Reaction Dynamics (GFRD) method with explicit stochastic Brownian, Langevin, or deterministic molecular dynamics to treat reactants at the microscopic scale [A. Vijaykumar, P. G. Bolhuis, and P. R. ten Wolde, J. Chem. Phys. 143, 214102 (2015)]. Here we extend this multiscale MD-GFRD approach to include the orientational dynamics that is crucial to describe the anisotropic interactions often prevalent in biomolecular systems. We present the novel algorithm focusing on Brownian dynamics only, although the methodology is generic. We illustrate the novel algorithm using a simple patchy particle model. After validation of the algorithm, we discuss its performance. The rotational Brownian dynamics MD-GFRD multiscale method will open up the possibility for large scale simulations of protein signalling networks.

  16. Combining molecular dynamics and an electrodiffusion model to calculate ion channel conductance

    Science.gov (United States)

    Wilson, Michael A.; Nguyen, Thuy Hien; Pohorille, Andrew

    2014-12-01

    Establishing the relation between the structures and functions of protein ion channels, which are protein assemblies that facilitate transmembrane ion transport through water-filled pores, is at the forefront of biological and medical sciences. A reliable way to determine whether our understanding of this relation is satisfactory is to reproduce the measured ionic conductance over a broad range of applied voltages. This can be done in molecular dynamics simulations by way of applying an external electric field to the system and counting the number of ions that traverse the channel per unit time. Since this approach is computationally very expensive we develop a markedly more efficient alternative in which molecular dynamics is combined with an electrodiffusion equation. This alternative approach applies if steady-state ion transport through channels can be described with sufficient accuracy by the one-dimensional diffusion equation in the potential given by the free energy profile and applied voltage. The theory refers only to line densities of ions in the channel and, therefore, avoids ambiguities related to determining the surface area of the channel near its endpoints or other procedures connecting the line and bulk ion densities. We apply the theory to a simple, model system based on the trichotoxin channel. We test the assumptions of the electrodiffusion equation, and determine the precision and consistency of the calculated conductance. We demonstrate that it is possible to calculate current/voltage dependence and accurately reconstruct the underlying (equilibrium) free energy profile, all from molecular dynamics simulations at a single voltage. The approach developed here applies to other channels that satisfy the conditions of the electrodiffusion equation.

  17. Combined, solid-state molecular property and gamma spectrometers for CBRNE detection

    Science.gov (United States)

    Rogers, Ben; Grate, Jay; Pearson, Brett; Gallagher, Neal; Wise, Barry; Whitten, Ralph; Adams, Jesse

    2013-05-01

    Nevada Nanotech Systems, Inc. (Nevada Nano) has developed a multi-sensor solution to Chemical, Biological, Radiological, Nuclear and Explosives (CBRNE) detection that combines the Molecular Property Spectrometer™ (MPS™)—a micro-electro-mechanical chip-based technology capable of measuring a variety of thermodynamic and electrostatic molecular properties of sampled vapors and particles—and a compact, high-resolution, solid-state gamma spectrometer module for identifying radioactive materials, including isotopes used in dirty bombs and nuclear weapons. By conducting multiple measurements, the system can provide a more complete characterization of an unknown sample, leading to a more accurate identification. Positive identifications of threats are communicated using an integrated wireless module. Currently, system development is focused on detection of commercial, military and improvised explosives, radioactive materials, and chemical threats. The system can be configured for a variety of CBRNE applications, including handheld wands and swab-type threat detectors requiring short sample times, and ultra-high sensitivity detectors in which longer sampling times are used. Here we provide an overview of the system design and operation and present results from preliminary testing.

  18. Perspectives on the design of clinical trials combining transarterial chemoembolization and molecular targeted therapy.

    Science.gov (United States)

    Hsu, Chiun; Po-Ching-Liang; Morita, Satoshi; Hu, Fu-Chang; Cheng, Ann-Lii

    2012-11-01

    Transarterial chemoembolization (TACE) moderately prolongs the survival of patients with intermediate-stage hepatocellular carcinoma. Molecular targeted therapy (MTT) may improve the efficacy of TACE. However, the findings of clinical trials evaluating the efficacy of a combination of TACE and MTT are conflicting. We hypothesized that this disparity can be prevented using alternative study designs. In this review, we classify the pertinent issues of study designs into five domains: primary endpoints, patients, TACE procedures, timing of randomization, and drug administration. Furthermore, we discuss the methods for increasing the success rate by minimizing potentially confounding factors within these five domains. Transarterial chemoembolization (TACE) is the current standard therapy for patients with Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) [1, 2, 3]. The survival benefit of TACE is supported by the results of meta-analysis of clinical trials comparing TACE with other conservative treatments in patients with inoperable HCC [4]. The results showed that the median survival of patients improved from approximately 16 to 20 months following TACE [4, 5]. Although advances in TACE techniques and the use of new embolization agents may improve the efficacy of TACE [6, 7], other approaches are needed to further improve the outcome in HCC patients treated using TACE. Molecular targeted therapy (MTT) has improved the survival of patients with advanced-stage HCC [5, 8]. Therefore, combining MTT and TACE may additionally improve the survival in patients with intermediate-stage HCC. Many molecular targeted agents (MTA) are currently undergoing evaluation in randomized trials (table 1). However, the designs of these trials differ significantly. The results of two trials combining sorafenib and TACE were recently reported. Both trials failed to demonstrate a therapeutic benefit of the combination therapy for time to tumor progression

  19. Combining phylogenomics and fossils in higher-level squamate reptile phylogeny: molecular data change the placement of fossil taxa.

    Science.gov (United States)

    Wiens, John J; Kuczynski, Caitlin A; Townsend, Ted; Reeder, Tod W; Mulcahy, Daniel G; Sites, Jack W

    2010-12-01

    Molecular data offer great potential to resolve the phylogeny of living taxa but can molecular data improve our understanding of relationships of fossil taxa? Simulations suggest that this is possible, but few empirical examples have demonstrated the ability of molecular data to change the placement of fossil taxa. We offer such an example here. We analyze the placement of snakes among squamate reptiles, combining published morphological data (363 characters) and new DNA sequence data (15,794 characters, 22 nuclear loci) for 45 living and 19 fossil taxa. We find several intriguing results. First, some fossil taxa undergo major changes in their phylogenetic position when molecular data are added. Second, most fossil taxa are placed with strong support in the expected clades by the combined data Bayesian analyses, despite each having >98% missing cells and despite recent suggestions that extensive missing data are problematic for Bayesian phylogenetics. Third, morphological data can change the placement of living taxa in combined analyses, even when there is an overwhelming majority of molecular characters. Finally, we find strong but apparently misleading signal in the morphological data, seemingly associated with a burrowing lifestyle in snakes, amphisbaenians, and dibamids. Overall, our results suggest promise for an integrated and comprehensive Tree of Life by combining molecular and morphological data for living and fossil taxa.

  20. The breakthrough curve combination for xenon sampling dynamics in a carbon molecular sieve column.

    Science.gov (United States)

    Shu-jiang, Liu; Zhan-ying, Chen; Yin-zhong, Chang; Shi-lian, Wang; Qi, Li; Yuan-qing, Fan; Huai-mao, Jia; Xin-jun, Zhang; Yun-gang, Zhao

    2015-01-21

    In the research of xenon sampling and xenon measurements, the xenon breakthrough curve plays a significant role in the xenon concentrating dynamics. In order to improve the theoretical comprehension of the xenon concentrating procedure from the atmosphere, the method of the breakthrough curve combination for sampling techniques should be developed and investigated under pulse injection conditions. In this paper, we describe a xenon breakthrough curve in a carbon molecular sieve column, the combination curve method for five conditions is shown and debated in detail; the fitting curves and the prediction equations are derived in theory and verified by the designed experiments. As a consequence, the curves of the derived equations are in good agreement with the fitting curves by tested. The retention times of the xenon in the column are 61.2, 42.2 and 23.5 at the flow rate of 1200, 1600 and 2000 mL min(-1), respectively, but the breakthrough times are 51.4, 38.6 and 35.1 min.

  1. A simple method to combine multiple molecular biomarkers for dichotomous diagnostic classification

    Directory of Open Access Journals (Sweden)

    Amin Manik A

    2006-10-01

    Full Text Available Abstract Background In spite of the recognized diagnostic potential of biomarkers, the quest for squelching noise and wringing in information from a given set of biomarkers continues. Here, we suggest a statistical algorithm that – assuming each molecular biomarker to be a diagnostic test – enriches the diagnostic performance of an optimized set of independent biomarkers employing established statistical techniques. We validated the proposed algorithm using several simulation datasets in addition to four publicly available real datasets that compared i subjects having cancer with those without; ii subjects with two different cancers; iii subjects with two different types of one cancer; and iv subjects with same cancer resulting in differential time to metastasis. Results Our algorithm comprises of three steps: estimating the area under the receiver operating characteristic curve for each biomarker, identifying a subset of biomarkers using linear regression and combining the chosen biomarkers using linear discriminant function analysis. Combining these established statistical methods that are available in most statistical packages, we observed that the diagnostic accuracy of our approach was 100%, 99.94%, 96.67% and 93.92% for the real datasets used in the study. These estimates were comparable to or better than the ones previously reported using alternative methods. In a synthetic dataset, we also observed that all the biomarkers chosen by our algorithm were indeed truly differentially expressed. Conclusion The proposed algorithm can be used for accurate diagnosis in the setting of dichotomous classification of disease states.

  2. Diagnosis of Strongyloides stercoralis by morphological characteristics combine with molecular biological methods.

    Science.gov (United States)

    Wang, Li-Fu; Xu, Lian; Luo, Shi-Qi; Xie, Hui; Chen, Wei; Wu, Zhong-Dao; Sun, Xi

    2017-04-01

    Strongyloidiasis is one of the neglected tropical diseases caused by infection with the nematode Strongyloides genus and distributed worldwide. Strongyloidiasis can be fatal in immunosuppressed patients induced hyperinfection or disseminated strongyloidiasis. Unfortunately, until now, due to the unspecific clinical symptom in infected individuals and the low sensitivity diagnosis of strongyloidiasis, many patients were misdiagnosed every year. Furthermore, the larvae of the Strongyloides stercoralis (S. stercoralis) is similar to other nematodes such as hookworm, Trichostrongylus increased the difficulty of diagnosis. In this case, the patient is a 63-year-old male person, who had a nearly 30 years medical history of asthma and emphysema, and 4-5-year medical history of diabetes. The sputum examination found some parasite larvae, then we identify the larvae using clinical observation and morphological characteristics combine with examined cytochrome oxidase subunit 1 (COX1) and 18S rRNA genes by PCR, sequence analysis and finally classified by phylogenetic analysis, the larvae were diagnosed as S. stercoralis. Our results showed that diagnosis with strongyloidiasis by morphological characteristics combine with molecular biological methods can improve the sensitive of diagnosis and provide a final diagnosis for the disease in the clinics.

  3. Aspirin and low-molecular weight heparin combination therapy effectively prevents recurrent miscarriage in hyperhomocysteinemic women.

    Directory of Open Access Journals (Sweden)

    Pratip Chakraborty

    Full Text Available The management of recurrent pregnancy loss (RPL still remains a great challenge, and women with polycystic ovarian syndrome (PCOS are at a greater risk for spontaneous abortion. Treatment with low-molecular-weight heparin (LMWH has become an accepted treatment option for women with RPL; however, the subgroup of women, who are likely to respond to LMWH, has not been precisely identified. The present study evaluated the efficacy of LMWH with reference to PCOS and associated metabolic phenotypes including hyperhomocysteinemia (HHcy, insulin resistance (IR and obesity. This prospective observational study was conducted at Institute of Reproductive Medicine, Kolkata, India. A total of 967 women with history of 2 or more consecutive first trimester abortions were screened and 336 were selected for the study. The selected patients were initially divided on the basis of presence or absence of PCOS, while subsequent stratification was based on HHcy, IR and/or obesity. The subjects had treatment with aspirin during one conception cycle and aspirin-LMWH combined anticoagulant therapy for the immediate next conception cycle, if the first treated cycle was unsuccessful. Pregnancy salvage was the sole outcome measure. The overall rate of pregnancy salvage following aspirin therapy was 43.15%, which was mostly represented by normohomocysteinemic women, while the salvage rate was lower in the HHcy populations irrespective of the presence or absence of PCOS, IR, or obesity. By contrast, aspirin-LMWH combined therapy could rescue 66.84% pregnancies in the aspirin-failed cases. Logistic regression analyses showed that HHcy remained a significant factor in predicting salvage rates in the PCOS, IR, and obese subpopulations controlled for other confounding factors. With regard to pregnancy salvage, combined anticoagulant therapy with aspirin and LMWH conferred added benefit to those with HHcy phenotype.

  4. Using combined morphological, allometric and molecular approaches to identify species of the genus Raillietiella (Pentastomida.

    Directory of Open Access Journals (Sweden)

    Crystal Kelehear

    Full Text Available Taxonomic studies of parasites can be severely compromised if the host species affects parasite morphology; an uncritical analysis might recognize multiple taxa simply because of phenotypically plastic responses of parasite morphology to host physiology. Pentastomids of the genus Raillietiella are endoparasitic crustaceans primarily infecting the respiratory system of carnivorous reptiles, but also recorded from bufonid anurans. The delineation of pentastomids at the generic level is clear, but the taxonomic status of many species is not. We collected raillietiellids from lungs of the invasive cane toad (Rhinella marina, the invasive Asian house gecko (Hemidactylus frenatus, and a native tree frog (Litoria caerulea in tropical Australia, and employed a combination of genetic analyses, and traditional and novel morphological methods to clarify their identity. Conventional analyses of parasite morphology (which focus on raw values of morphological traits revealed two discrete clusters in terms of pentastome hook size, implying two different species of pentastomes: one from toads and a tree frog (Raillietiella indica and another from lizards (Raillietiella frenatus. However, these clusters disappeared in allometric analyses that took pentastome body size into account, suggesting that only a single pentastome taxon may be involved. Our molecular data revealed no genetic differences between parasites in toads versus lizards, confirming that there was only one species: R. frenatus. This pentastome (previously known only from lizards clearly is also capable of maturing in anurans. Our analyses show that the morphological features used in pentastomid taxonomy change as the parasite transitions through developmental stages in the definitive host. To facilitate valid descriptions of new species of pentastomes, future taxonomic work should include both morphological measurements (incorporating quantitative measures of body size and hook bluntness and

  5. Multiscale simulations of patchy particle systems combining Molecular Dynamics, Path Sampling and Green's Function Reaction Dynamics

    Science.gov (United States)

    Bolhuis, Peter

    Important reaction-diffusion processes, such as biochemical networks in living cells, or self-assembling soft matter, span many orders in length and time scales. In these systems, the reactants' spatial dynamics at mesoscopic length and time scales of microns and seconds is coupled to the reactions between the molecules at microscopic length and time scales of nanometers and milliseconds. This wide range of length and time scales makes these systems notoriously difficult to simulate. While mean-field rate equations cannot describe such processes, the mesoscopic Green's Function Reaction Dynamics (GFRD) method enables efficient simulation at the particle level provided the microscopic dynamics can be integrated out. Yet, many processes exhibit non-trivial microscopic dynamics that can qualitatively change the macroscopic behavior, calling for an atomistic, microscopic description. The recently developed multiscale Molecular Dynamics Green's Function Reaction Dynamics (MD-GFRD) approach combines GFRD for simulating the system at the mesocopic scale where particles are far apart, with microscopic Molecular (or Brownian) Dynamics, for simulating the system at the microscopic scale where reactants are in close proximity. The association and dissociation of particles are treated with rare event path sampling techniques. I will illustrate the efficiency of this method for patchy particle systems. Replacing the microscopic regime with a Markov State Model avoids the microscopic regime completely. The MSM is then pre-computed using advanced path-sampling techniques such as multistate transition interface sampling. I illustrate this approach on patchy particle systems that show multiple modes of binding. MD-GFRD is generic, and can be used to efficiently simulate reaction-diffusion systems at the particle level, including the orientational dynamics, opening up the possibility for large-scale simulations of e.g. protein signaling networks.

  6. Shared and unique responses of plants to multiple individual stresses and stress combinations: physiological and molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Prachi ePandey

    2015-09-01

    Full Text Available In field conditions, plants are often simultaneously exposed to multiple biotic and abiotic stresses resulting in substantial yield loss. Plants have evolved various physiological and molecular adaptations to protect themselves under stress combinations. Emerging evidences suggest that plant responses to a combination of stresses are unique from individual stress responses. In addition, plants exhibit shared responses which are common to individual stresses and stress combination. In this review, we provide an update on the current understanding of both unique and shared responses. Specific focus of this review is on heat-drought stress as a major abiotic stress combination and, drought-pathogen and heat-pathogen as examples of abiotic-biotic stress combinations. We also comprehend the current understanding of molecular mechanisms of cross talk in relation to shared and unique molecular responses for plant survival under stress combinations. Thus, the knowledge of shared responses of plants from individual stress studies and stress combinations can be utilized to develop varieties with broad spectrum stress tolerance.

  7. Shared and unique responses of plants to multiple individual stresses and stress combinations: physiological and molecular mechanisms.

    Science.gov (United States)

    Pandey, Prachi; Ramegowda, Venkategowda; Senthil-Kumar, Muthappa

    2015-01-01

    In field conditions, plants are often simultaneously exposed to multiple biotic and abiotic stresses resulting in substantial yield loss. Plants have evolved various physiological and molecular adaptations to protect themselves under stress combinations. Emerging evidences suggest that plant responses to a combination of stresses are unique from individual stress responses. In addition, plants exhibit shared responses which are common to individual stresses and stress combination. In this review, we provide an update on the current understanding of both unique and shared responses. Specific focus of this review is on heat-drought stress as a major abiotic stress combination and, drought-pathogen and heat-pathogen as examples of abiotic-biotic stress combinations. We also comprehend the current understanding of molecular mechanisms of cross talk in relation to shared and unique molecular responses for plant survival under stress combinations. Thus, the knowledge of shared responses of plants from individual stress studies and stress combinations can be utilized to develop varieties with broad spectrum stress tolerance.

  8. Synergistic effects of combining morphological and molecular data in resolving the phylogeny of butterflies and skippers

    Science.gov (United States)

    Wahlberg, Niklas; Braby, Michael F; Brower, Andrew V.Z; de Jong, Rienk; Lee, Ming-Min; Nylin, Sören; Pierce, Naomi E; Sperling, Felix A.H; Vila, Roger; Warren, Andrew D; Zakharov, Evgueni

    2005-01-01

    Phylogenetic relationships among major clades of butterflies and skippers have long been controversial, with no general consensus even today. Such lack of resolution is a substantial impediment to using the otherwise well studied butterflies as a model group in biology. Here we report the results of a combined analysis of DNA sequences from three genes and a morphological data matrix for 57 taxa (3258 characters, 1290 parsimony informative) representing all major lineages from the three putative butterfly super-families (Hedyloidea, Hesperioidea and Papilionoidea), plus out-groups representing other ditrysian Lepidoptera families. Recently, the utility of morphological data as a source of phylogenetic evidence has been debated. We present the first well supported phylogenetic hypothesis for the butterflies and skippers based on a total-evidence analysis of both traditional morphological characters and new molecular characters from three gene regions (COI, EF-1α and wingless). All four data partitions show substantial hidden support for the deeper nodes, which emerges only in a combined analysis in which the addition of morphological data plays a crucial role. With the exception of Nymphalidae, the traditionally recognized families are found to be strongly supported monophyletic clades with the following relationships: (Hesperiidae+(Papilionidae+(Pieridae+(Nymphalidae+(Lycaenidae+Riodinidae))))). Nymphalidae is recovered as a monophyletic clade but this clade does not have strong support. Lycaenidae and Riodinidae are sister groups with strong support and we suggest that the latter be given family rank. The position of Pieridae as the sister taxon to nymphalids, lycaenids and riodinids is supported by morphology and the EF-1α data but conflicted by the COI and wingless data. Hedylidae are more likely to be related to butterflies and skippers than geometrid moths and appear to be the sister group to Papilionoidea+Hesperioidea. PMID:16048773

  9. Assessing the viability of bacterial species in drinking water by combined cellular and molecular analyses.

    Science.gov (United States)

    Kahlisch, Leila; Henne, Karsten; Gröbe, Lothar; Brettar, Ingrid; Höfle, Manfred G

    2012-02-01

    The question which bacterial species are present in water and if they are viable is essential for drinking water safety but also of general relevance in aquatic ecology. To approach this question we combined propidium iodide/SYTO9 staining ("live/dead staining" indicating membrane integrity), fluorescence-activated cell sorting (FACS) and community fingerprinting for the analysis of a set of tap water samples. Live/dead staining revealed that about half of the bacteria in the tap water had intact membranes. Molecular analysis using 16S rRNA and 16S rRNA gene-based single-strand conformation polymorphism (SSCP) fingerprints and sequencing of drinking water bacteria before and after FACS sorting revealed: (1) the DNA- and RNA-based overall community structure differed substantially, (2) the community retrieved from RNA and DNA reflected different bacterial species, classified as 53 phylotypes (with only two common phylotypes), (3) the percentage of phylotypes with intact membranes or damaged cells were comparable for RNA- and DNA-based analyses, and (4) the retrieved species were primarily of aquatic origin. The pronounced difference between phylotypes obtained from DNA extracts (dominated by Betaproteobacteria, Bacteroidetes, and Actinobacteria) and from RNA extracts (dominated by Alpha-, Beta-, Gammaproteobacteria, Bacteroidetes, and Cyanobacteria) demonstrate the relevance of concomitant RNA and DNA analyses for drinking water studies. Unexpected was that a comparable fraction (about 21%) of phylotypes with membrane-injured cells was observed for DNA- and RNA-based analyses, contradicting the current understanding that RNA-based analyses represent the actively growing fraction of the bacterial community. Overall, we think that this combined approach provides an interesting tool for a concomitant phylogenetic and viability analysis of bacterial species of drinking water.

  10. Relaxation dynamics of lysozyme in solution under pressure: Combining molecular dynamics simulations and quasielastic neutron scattering

    Energy Technology Data Exchange (ETDEWEB)

    Calandrini, V. [Centre de Biophysique Moleculaire, Rue Charles Sadron, 45071 Orleans (France); Synchrotron Soleil, L' Orme de Merisiers, B.P. 48, 91192 Gif-sur-Yvette (France); Hamon, V. [Centre de Biophysique Moleculaire, Rue Charles Sadron, 45071 Orleans (France); Hinsen, K. [Centre de Biophysique Moleculaire, Rue Charles Sadron, 45071 Orleans (France); Synchrotron Soleil, L' Orme de Merisiers, B.P. 48, 91192 Gif-sur-Yvette (France); Calligari, P. [Centre de Biophysique Moleculaire, Rue Charles Sadron, 45071 Orleans (France); Institut Laue-Langevin, 6 Rue Jules Horowitz, B.P. 156, 38042 Grenoble (France); Laboratoire Leon Brillouin, CEA Saclay, 91191 Gif-sur-Yvette (France); Bellissent-Funel, M.-C. [Laboratoire Leon Brillouin, CEA Saclay, 91191 Gif-sur-Yvette (France); Kneller, G.R. [Centre de Biophysique Moleculaire, Rue Charles Sadron, 45071 Orleans (France); Synchrotron Soleil, L' Orme de Merisiers, B.P. 48, 91192 Gif-sur-Yvette (France)], E-mail: kneller@cnrs-orleans.fr

    2008-04-18

    This paper presents a study of the influence of non-denaturing hydrostatic pressure on the relaxation dynamics of lysozyme in solution, which combines molecular dynamics simulations and quasielastic neutron scattering experiments. We compare results obtained at ambient pressure and at 3 kbar. Experiments have been performed at pD 4.6 and at a protein concentration of 60 mg/ml. For both pressures we checked the monodispersity of the protein solution by small angle neutron scattering. To interpret the simulation results and the experimental data, we adopt the fractional Ornstein-Uhlenbeck process as a model for the internal relaxation dynamics of the protein. On the experimental side, global protein motions are accounted for by the model of free translational diffusion, neglecting the much slower rotational diffusion. We find that the protein dynamics in the observed time window from about 1 to 100 ps is slowed down under pressure, while its fractal characteristics is preserved, and that the amplitudes of the motions are reduced by about 20%. The slowing down of the relaxation is reduced with increasing q-values, where more localized motions are seen.

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

    Science.gov (United States)

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

    2018-02-14

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

  12. A combined laser-induced breakdown and Raman spectroscopy Echelle system for elemental and molecular microanalysis

    Energy Technology Data Exchange (ETDEWEB)

    Hoehse, Marek [BAM Federal Institute for Materials Research and Testing, Richard-Willstaetter Str. 11, D-12489 Berlin (Germany); Mory, David [LTB Lasertechnik Berlin, Rudower Chaussee 29, 12489 Berlin (Germany); Florek, Stefan [ISAS - Institute for Analytical Science, Albert-Einstein-Str. 9, D-12489 Berlin (Germany); Weritz, Friederike [BAM Federal Institute for Materials Research and Testing, Richard-Willstaetter Str. 11, D-12489 Berlin (Germany); Gornushkin, Igor, E-mail: igor.gornushkin@bam.d [BAM Federal Institute for Materials Research and Testing, Richard-Willstaetter Str. 11, D-12489 Berlin (Germany); Panne, Ulrich [BAM Federal Institute for Materials Research and Testing, Richard-Willstaetter Str. 11, D-12489 Berlin (Germany); Humboldt Universitaet zu Berlin, Chemistry Department, Brook-Taylor-Strasse 2, D-12489 Berlin (Germany)

    2009-11-15

    Raman and laser-induced breakdown spectroscopy is integrated into a single system for molecular and elemental microanalyses. Both analyses are performed on the same approx 0.002 mm{sup 2} sample spot allowing the assessment of sample heterogeneity on a micrometric scale through mapping and scanning. The core of the spectrometer system is a novel high resolution dual arm Echelle spectrograph utilized for both techniques. In contrast to scanning Raman spectroscopy systems, the Echelle-Raman spectrograph provides a high resolution spectrum in a broad spectral range of 200-6000 cm{sup -1} without moving the dispersive element. The system displays comparable or better sensitivity and spectral resolution in comparison to a state-of-the-art scanning Raman microscope and allows short analysis times for both Raman and laser induced breakdown spectroscopy. The laser-induced breakdown spectroscopy performance of the system is characterized by ppm detection limits, high spectral resolving power (15,000), and broad spectral range (290-945 nm). The capability of the system is demonstrated with the mapping of heterogeneous mineral samples and layer by layer analysis of pigments revealing the advantages of combining the techniques in a single unified set-up.

  13. A combined experimental and mathematical approach for molecular-based optimization of irinotecan circadian delivery.

    Directory of Open Access Journals (Sweden)

    Annabelle Ballesta

    2011-09-01

    Full Text Available Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular profile. As a proof of concept we optimized exposure of Caco-2 colon cancer cells to irinotecan (CPT11, a cytotoxic drug approved for the treatment of colorectal cancer. CPT11 was bioactivated into SN38 and its efflux was mediated by ATP-Binding-Cassette (ABC transporters in Caco-2 cells. After cell synchronization with a serum shock defining Circadian Time (CT 0, circadian rhythms with a period of 26 h 50 (SD 63 min were observed in the mRNA expression of clock genes REV-ERBα, PER2, BMAL1, the drug target topoisomerase 1 (TOP1, the activation enzyme carboxylesterase 2 (CES2, the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1, and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2. DNA-bound TOP1 protein amount in presence of CPT11, a marker of the drug PD, also displayed circadian variations. A mathematical model of CPT11 molecular pharmacokinetics-pharmacodynamics (PK-PD was designed and fitted to experimental data. It predicted that CPT11 bioactivation was the main determinant of CPT11 PD circadian rhythm. We then adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. We considered exposure schemes in the form of an initial concentration of CPT11 given at a particular CT, over a duration ranging from 1 to 27 h. For any dose of CPT11, optimal exposure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1h30 to 1h50 before the nadir of CPT11 bioactivation rhythm in

  14. Treating electrostatics with Wolf summation in combined quantum mechanical and molecular mechanical simulations.

    Science.gov (United States)

    Ojeda-May, Pedro; Pu, Jingzhi

    2015-11-07

    The Wolf summation approach [D. Wolf et al., J. Chem. Phys. 110, 8254 (1999)], in the damped shifted force (DSF) formalism [C. J. Fennell and J. D. Gezelter, J. Chem. Phys. 124, 234104 (2006)], is extended for treating electrostatics in combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. In this development, we split the QM/MM electrostatic potential energy function into the conventional Coulomb r(-1) term and a term that contains the DSF contribution. The former is handled by the standard machinery of cutoff-based QM/MM simulations whereas the latter is incorporated into the QM/MM interaction Hamiltonian as a Fock matrix correction. We tested the resulting QM/MM-DSF method for two solution-phase reactions, i.e., the association of ammonium and chloride ions and a symmetric SN2 reaction in which a methyl group is exchanged between two chloride ions. The performance of the QM/MM-DSF method was assessed by comparing the potential of mean force (PMF) profiles with those from the QM/MM-Ewald and QM/MM-isotropic periodic sum (IPS) methods, both of which include long-range electrostatics explicitly. For ion association, the QM/MM-DSF method successfully eliminates the artificial free energy drift observed in the QM/MM-Cutoff simulations, in a remarkable agreement with the two long-range-containing methods. For the SN2 reaction, the free energy of activation obtained by the QM/MM-DSF method agrees well with both the QM/MM-Ewald and QM/MM-IPS results. The latter, however, requires a greater cutoff distance than QM/MM-DSF for a proper convergence of the PMF. Avoiding time-consuming lattice summation, the QM/MM-DSF method yields a 55% reduction in computational cost compared with the QM/MM-Ewald method. These results suggest that, in addition to QM/MM-IPS, the QM/MM-DSF method may serve as another efficient and accurate alternative to QM/MM-Ewald for treating electrostatics in condensed-phase simulations of chemical reactions.

  15. Combining an Elastic Network With a Coarse-Grained Molecular Force Field : Structure, Dynamics, and Intermolecular Recognition

    NARCIS (Netherlands)

    Periole, Xavier; Cavalli, Marco; Marrink, Siewert-Jan; Ceruso, Marco A.

    Structure-based and physics-based coarse-grained molecular force fields have become attractive approaches to gain mechanistic insight into the function of large biomolecular assemblies. Here, we study how both approaches can be combined into a single representation, that we term ELNEDIN. In this

  16. Combining Classical and Molecular Approaches Elaborates on the Complexity of Mechanisms Underpinning Anterior Regeneration

    Science.gov (United States)

    Evans, Deborah J.; Owlarn, Suthira; Tejada Romero, Belen; Chen, Chen; Aboobaker, A. Aziz

    2011-01-01

    The current model of planarian anterior regeneration evokes the establishment of low levels of Wnt signalling at anterior wounds, promoting anterior polarity and subsequent elaboration of anterior fate through the action of the TALE class homeodomain PREP. The classical observation that decapitations positioned anteriorly will regenerate heads more rapidly than posteriorly positioned decapitations was among the first to lead to the proposal of gradients along an anteroposterior (AP) axis in a developmental context. An explicit understanding of this phenomenon is not included in the current model of anterior regeneration. This raises the question what the underlying molecular and cellular basis of this temporal gradient is, whether it can be explained by current models and whether understanding the gradient will shed light on regenerative events. Differences in anterior regeneration rate are established very early after amputation and this gradient is dependent on the activity of Hedgehog (Hh) signalling. Animals induced to produce two tails by either Smed-APC-1(RNAi) or Smed-ptc(RNAi) lose anterior fate but form previously described ectopic anterior brain structures. Later these animals form peri-pharyngeal brain structures, which in Smed-ptc(RNAi) grow out of the body establishing a new A/P axis. Combining double amputation and hydroxyurea treatment with RNAi experiments indicates that early ectopic brain structures are formed by uncommitted stem cells that have progressed through S-phase of the cell cycle at the time of amputation. Our results elaborate on the current simplistic model of both AP axis and brain regeneration. We find evidence of a gradient of hedgehog signalling that promotes posterior fate and temporarily inhibits anterior regeneration. Our data supports a model for anterior brain regeneration with distinct early and later phases of regeneration. Together these insights start to delineate the interplay between discrete existing, new, and then

  17. Combining classical and molecular approaches elaborates on the complexity of mechanisms underpinning anterior regeneration.

    Directory of Open Access Journals (Sweden)

    Deborah J Evans

    Full Text Available The current model of planarian anterior regeneration evokes the establishment of low levels of Wnt signalling at anterior wounds, promoting anterior polarity and subsequent elaboration of anterior fate through the action of the TALE class homeodomain PREP. The classical observation that decapitations positioned anteriorly will regenerate heads more rapidly than posteriorly positioned decapitations was among the first to lead to the proposal of gradients along an anteroposterior (AP axis in a developmental context. An explicit understanding of this phenomenon is not included in the current model of anterior regeneration. This raises the question what the underlying molecular and cellular basis of this temporal gradient is, whether it can be explained by current models and whether understanding the gradient will shed light on regenerative events. Differences in anterior regeneration rate are established very early after amputation and this gradient is dependent on the activity of Hedgehog (Hh signalling. Animals induced to produce two tails by either Smed-APC-1(RNAi or Smed-ptc(RNAi lose anterior fate but form previously described ectopic anterior brain structures. Later these animals form peri-pharyngeal brain structures, which in Smed-ptc(RNAi grow out of the body establishing a new A/P axis. Combining double amputation and hydroxyurea treatment with RNAi experiments indicates that early ectopic brain structures are formed by uncommitted stem cells that have progressed through S-phase of the cell cycle at the time of amputation. Our results elaborate on the current simplistic model of both AP axis and brain regeneration. We find evidence of a gradient of hedgehog signalling that promotes posterior fate and temporarily inhibits anterior regeneration. Our data supports a model for anterior brain regeneration with distinct early and later phases of regeneration. Together these insights start to delineate the interplay between discrete existing, new

  18. Combining molecular modeling with experimental methodologies: mechanism of membrane permeation and accumulation of ofloxacin.

    Science.gov (United States)

    Fresta, Massimo; Guccione, Salvatore; Beccari, Andrea R; Furneri, Pio M; Puglisi, Giovanni

    2002-12-01

    The interaction between ofloxacin, as a model drug of the fluoroquinolone class, and biomembranes was examined as the possible initial step in a transmembrane diffusion process. Dipalmitoylphosphatidylcholine was used for the preparation of biomembrane models. The influence of environmental conditions and protonation on molecular physicochemical behavior, and hence on the membrane interaction, was investigated by differential scanning calorimetry (DSC). This technique has been shown to be very effective in the interpretation of interactions of drug microspeciations with biomembranes. These findings suggest that the interaction occurred owing to ionic and hydrophobic forces showing how the passage through the membrane is mainly favored in the pH interval 6-7.4. It was demonstrated that a pH gradient through model membranes may be responsible for a poorly homogeneous distribution of ofloxacin (or other related fluoroquinolones), which justifies the in vivo accumulation properties of this drug. DSC experiments, which are in agreement with computational data, also showed that the complexing capability of ofloxacin with regard to Mg(++) or Ca(++) may govern the drug entrance into bacterial cells before the DNA Girase inhibition and could ensure the formation of hydrophobic and more fluid phospholipid domains on the surface of the model membrane. These regions are more permeable with regard to various solutes, as well as ofloxacin, allowing a so-called 'self-promoted entrance pathway'. The combination of experimental methodologies with computational data allowed a further rationalization of the results and opened new perspectives into the mechanism of action of ofloxacin, namely its interaction with lipid bilayers and drug-divalent cation complex formation, which might be extended to the entire fluoroquinolone class. Ofloxacin accumulation within Escherichia coli ATCC 25922 was measured as a function of time. Also in this example, the environmental conditions influenced

  19. Molecular beacon probes combined with amplification by NASBA enable homogeneous, real-time detection of RNA

    NARCIS (Netherlands)

    Leone, G.; Schijndel, van H.; Gemen, van B.; Kramer, F.R.; Schoen, C.D.

    1998-01-01

    Molecular beacon probes can be employed in a NASBA amplicon detection system to generate a specific fluorescent signal concomitantly with amplification. A molecular beacon, designed to hybridize within the target sequence, was introduced into NASBA reactions that amplify the genomic RNA of potato

  20. A new African fossil caprin and a combined molecular and morphological Bayesian phylogenetic analysis of caprini (Mammalia: Bovidae).

    Science.gov (United States)

    Bibi, F; Vrba, E; Fack, F

    2012-09-01

    Given that most species that have ever existed on Earth are extinct, no evolutionary history can ever be complete without the inclusion of fossil taxa. Bovids (antelopes and relatives) are one of the most diverse clades of large mammals alive today, with over a hundred living species and hundreds of documented fossil species. With the advent of molecular phylogenetics, major advances have been made in the phylogeny of this clade; however, there has been little attempt to integrate the fossil record into the developing phylogenetic picture. We here describe a new large fossil caprin species from ca. 1.9-Ma deposits from the Middle Awash, Ethiopia. To place the new species phylogenetically, we perform a Bayesian analysis of a combined molecular (cytochrome b) and morphological (osteological) character supermatrix. We include all living species of Caprini, the new fossil species, a fossil takin from the Pliocene of Ethiopia (Budorcas churcheri), and the insular subfossil Myotragus balearicus. The combined analysis demonstrates successful incorporation of both living and fossil species within a single phylogeny based on both molecular and morphological evidence. Analysis of the combined supermatrix produces superior resolution than with either the molecular or morphological data sets considered alone. Parsimony and Bayesian analyses of the data set are also compared and shown to produce similar results. The combined phylogenetic analysis indicates that the new fossil species is nested within Capra, making it one of the earliest representatives of this clade, with implications for molecular clock calibration. Geographical optimization indicates no less than four independent dispersals into Africa by caprins since the Pliocene. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

  1. Combining Pickering Emulsion Polymerization with Molecular Imprinting to Prepare Polymer Microspheres for Selective Solid-Phase Extraction of Malachite Green

    Directory of Open Access Journals (Sweden)

    Weixin Liang

    2017-08-01

    Full Text Available Malachite green (MG is currently posing a carcinogenic threat to the safety of human lives; therefore, it is highly desirable to develop an effective method for fast trace detection of MG. Herein, for the first time, this paper presents a systematic study on polymer microspheres, being prepared by combined Pickering emulsion polymerization and molecular imprinting, to detect and purify MG. The microspheres, molecularly imprinted with MG, show enhanced adsorption selectivity to MG, despite a somewhat lowered adsorption capacity, as compared to the counterpart without molecular imprinting. Structural features and adsorption performance of these microspheres are elucidated by different characterizations and kinetic and thermodynamic analyses. The surface of the molecularly imprinted polymer microspheres (M-PMs exhibits regular pores of uniform pore size distribution, endowing M-PMs with impressive adsorption selectivity to MG. In contrast, the microspheres without molecular imprinting show a larger average particle diameter and an uneven porous surface (with roughness and a large pore size, causing a lower adsorption selectivity to MG despite a higher adsorption capacity. Various adsorption conditions are investigated, such as pH and initial concentration of the solution with MG, for optimizing the adsorption performance of M-PMs in selectively tackling MG. The adsorption kinetics and thermodynamics are deeply discussed and analyzed, so as to provide a full picture of the adsorption behaviors of the polymer microspheres with and without the molecular imprinting. Significantly, M-PMs show promising solid-phase extraction column applications for recovering MG in a continuous extraction manner.

  2. High-throughput SNP genotyping: combining tag SNPs and molecular beacons

    CSIR Research Space (South Africa)

    Barreiro, LB

    2009-10-01

    Full Text Available In the last decade, molecular beacons have emerged to become a widely used tool in the multiplex typing of single nucleotide polymorphisms (SNPs). Improvements in detection technologies in instrumentation and chemistries to label these probes have...

  3. Diagnosis of human granulocytic anaplasmosis in Belgium by combining molecular and serological methods

    Directory of Open Access Journals (Sweden)

    M. Hing

    2014-11-01

    Full Text Available We report here one new, hospitalized case of Anaplasma phagocytophilum in Belgium. The clinical presentation of anaplasmosis, its treatment and the molecular and serological relevant laboratory methods are briefly developed.

  4. Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

    Science.gov (United States)

    Tvaroška, Igor

    2015-02-11

    Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial. These methods allow the modeling of enzymatic reactions by using quantum mechanical methods for the calculation of the electronic structure of the active site models and treating the remaining enzyme environment by faster molecular mechanics methods. Herein, the application of QM/MM methods to glycosyltransferase catalyzed reactions is reviewed, and the insight from modeling of glycosyl transfer into the mechanisms and transition states structures of both inverting and retaining glycosyltransferases are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Combining NMR and Molecular Dynamics Studies for Insights into the Allostery of Small GTPase–Protein Interactions

    Science.gov (United States)

    Zhang, Liqun; Bouguet-Bonnet, Sabine; Buck, Matthias

    2014-01-01

    Combinations of experimentally derived data from nuclear magnetic resonance spectroscopy and analyses of molecular dynamics trajectories increasingly allow us to obtain a detailed description of the molecular mechanisms by which proteins function in signal transduction. This chapter provides an introduction into these two methodologies, illustrated by example of a small GTPase–effector interaction. It is increasingly becoming clear that new insights are provided by the combination of experimental and computational methods. Understanding the structural and protein dynamical contributions to allostery will be useful for the engineering of new binding interfaces and protein functions, as well as for the design/in silico screening of chemical agents that can manipulate the function of small GTPase–protein interactions in diseases such as cancer. PMID:22052494

  6. Impact of chemotherapy with S-1 and oxaliplatin (SOX) in combination with molecular-targeting agents on colorectal liver metastases.

    Science.gov (United States)

    Watanabe, Kazuhiro; Kawahara, Hidejiro; Enomoto, Hiroya; Toyama, Yoichi; Akiba, Tadashi; Yanaga, Katsuhiko

    2013-09-01

    The aim of this study was to evaluate the impact of chemotherapy with molecular-targeting agents on liver metastases from colorectal cancer. Six patients with synchronous colorectal liver metastases who underwent hepatectomy after chemotherapy with S-1 and oxaliplatin (SOX) between January 2010 and December 2011 at the Department of Surgery, Kashiwa Hospital, the Jikei University School of Medicine were enrolled. Two patients received only SOX as chemotherapy, while the others received SOX in combination with one of the three molecular-targeting agents, bevacizumab, cetuximab, and panitumumab. In the two patients who received SOX alone, liver metastases completely disappeared at more than six months after starting chemotherapy as shown by computed tomographic (CT) scan. However, malignant cells were diffusely detected by pathological examination at the site of liver metastases, as detected by CT scan before chemotherapy. In the other four patients who received SOX in combination with molecular targets, the size of liver metastases appeared unchanged at three months after limited chemotherapy by CT scan. Pathologically, few malignant cells were detected, only at the borderline of the tumor, while most tumor cells inside the tumor were necrotized and been replaced by fibroconnective tissue. Molecular-targeting agents may induce tumor necrosis rapidly from inside the tumor, which might not be detected by CT scan before surgery.

  7. Multi-scale calculation based on dual domain material point method combined with molecular dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Dhakal, Tilak Raj [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-02-27

    This dissertation combines the dual domain material point method (DDMP) with molecular dynamics (MD) in an attempt to create a multi-scale numerical method to simulate materials undergoing large deformations with high strain rates. In these types of problems, the material is often in a thermodynamically non-equilibrium state, and conventional constitutive relations are often not available. In this method, the closure quantities, such as stress, at each material point are calculated from a MD simulation of a group of atoms surrounding the material point. Rather than restricting the multi-scale simulation in a small spatial region, such as phase interfaces, or crack tips, this multi-scale method can be used to consider non-equilibrium thermodynamic e ects in a macroscopic domain. This method takes advantage that the material points only communicate with mesh nodes, not among themselves; therefore MD simulations for material points can be performed independently in parallel. First, using a one-dimensional shock problem as an example, the numerical properties of the original material point method (MPM), the generalized interpolation material point (GIMP) method, the convected particle domain interpolation (CPDI) method, and the DDMP method are investigated. Among these methods, only the DDMP method converges as the number of particles increases, but the large number of particles needed for convergence makes the method very expensive especially in our multi-scale method where we calculate stress in each material point using MD simulation. To improve DDMP, the sub-point method is introduced in this dissertation, which provides high quality numerical solutions with a very small number of particles. The multi-scale method based on DDMP with sub-points is successfully implemented for a one dimensional problem of shock wave propagation in a cerium crystal. The MD simulation to calculate stress in each material point is performed in GPU using CUDA to accelerate the

  8. Theoretical Characterization of the Spectral Density of the Water-Soluble Chlorophyll-Binding Protein from Combined Quantum Mechanics/Molecular Mechanics Molecular Dynamics Simulations.

    Science.gov (United States)

    Rosnik, Andreana M; Curutchet, Carles

    2015-12-08

    Over the past decade, both experimentalists and theorists have worked to develop methods to describe pigment-protein coupling in photosynthetic light-harvesting complexes in order to understand the molecular basis of quantum coherence effects observed in photosynthesis. Here we present an improved strategy based on the combination of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations and excited-state calculations to predict the spectral density of electronic-vibrational coupling. We study the water-soluble chlorophyll-binding protein (WSCP) reconstituted with Chl a or Chl b pigments as the system of interest and compare our work with data obtained by Pieper and co-workers from differential fluorescence line-narrowing spectra (Pieper et al. J. Phys. Chem. B 2011, 115 (14), 4042-4052). Our results demonstrate that the use of QM/MM MD simulations where the nuclear positions are still propagated at the classical level leads to a striking improvement of the predicted spectral densities in the middle- and high-frequency regions, where they nearly reach quantitative accuracy. This demonstrates that the so-called "geometry mismatch" problem related to the use of low-quality structures in QM calculations, not the quantum features of pigments high-frequency motions, causes the failure of previous studies relying on similar protocols. Thus, this work paves the way toward quantitative predictions of pigment-protein coupling and the comprehension of quantum coherence effects in photosynthesis.

  9. Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

    Science.gov (United States)

    Eide, Christopher A.; Kaempf, Andy; Khanna, Vishesh; Savage, Samantha L.; Rofelty, Angela; English, Isabel; Ho, Hibery; Pandya, Ravi; Bolosky, William J.; Poon, Hoifung; Deininger, Michael W.; Collins, Robert; Swords, Ronan T.; Watts, Justin; Pollyea, Daniel A.; Medeiros, Bruno C.; Traer, Elie; Tognon, Cristina E.; Mori, Motomi; Druker, Brian J.; Tyner, Jeffrey W.

    2017-01-01

    Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies. PMID:28784769

  10. Selective extraction of triazine herbicides based on a combination of membrane assisted solvent extraction and molecularly imprinted solid phase extraction.

    Science.gov (United States)

    Chimuka, Luke; van Pinxteren, Manuela; Billing, Johan; Yilmaz, Ecevit; Jönsson, Jan Åke

    2011-02-04

    A selective extraction technique based on the combination of membrane assisted solvent extraction and molecularly imprinted solid phase extraction for triazine herbicides in food samples was developed. Simazine, atrazine, prometon, terbumeton, terbuthylazine and prometryn were extracted from aqueous food samples into a hydrophobic polypropylene membrane bag containing 1000μL of toluene as the acceptor phase along with 100mg of MIP particles. In the acceptor phase, the compounds were re-extracted onto MIP particles. The extraction technique was optimised for the type of organic acceptor solvent, amount of molecularly imprinted polymers particles in the organic acceptor phase, extraction time and addition of salt. Toluene as the acceptor phase was found to give higher triazine binding onto MIP particles compared to hexane and cyclohexane. Extraction time of 120min and 100mg of MIP were found to be optimum parameters. Addition of salt increased the extraction efficiency for more polar triazines. The selectivity of the technique was demonstrated by extracting spiked cow pea and corn extracts where clean chromatograms were obtained compared to only membrane assisted solvent extraction or only molecularly imprinted solid phase extraction. The study revealed that this combination may be a simple way of selectively extracting compounds in complex samples. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Concepts for the Formation of Molecular Nanostructures: Self-Assembly and SPM Manipulation -- A Combined Approach.

    Science.gov (United States)

    Jung, Thomas A.

    1996-03-01

    We(Work performed in collaboration with J.K. Gimzewski and R. R. Schlittler, IBM Rüschlikon, and C. Joachim and Hao Tang, CNRS Toulouse,) (Supported by the BBW of Switzerland through the ESPRIT basic research program PRONANO (8523). ) demonstrate the controlled generation of molecular nanostructures based on specific chemical synthesis and well-controlled epitaxial growth. Such structures, assembled in parallel by growth kinetics, can be modified selectively by manipulating individual molecules using different modes of the scanning tunneling microscope. The influence of molecular structure on such properties as mobility, conformational adaptation to the substrate, and the current/voltage (I/V) characteristic are compared for porphyrin molecules with different substituents. Numerical simulations are related to experimentally accessible parameters. The resulting rules and concepts are to be generalized and applied to the design of nanostructures having more specific functional properties.

  12. Molecular modeling studies on series of Btk inhibitors using docking, structure-based 3D-QSAR and molecular dynamics simulation: a combined approach.

    Science.gov (United States)

    Balasubramanian, Pavithra K; Balupuri, Anand; Cho, Seung Joo

    2016-03-01

    Bruton tyrosine kinase (Btk) is a non-receptor tyrosine kinase. It is a crucial component in BCR pathway and expressed only in hematopoietic cells except T cells and Natural killer cells. BTK is a promising target because of its involvement in signaling pathways and B cell diseases such as autoimmune disorders and lymphoma. In this work, a combined molecular modeling study of molecular docking, 3D-QSAR and molecular dynamic (MD) simulation were performed on a series of 2,5-diaminopyrimidine compounds as inhibitors targeting Btk kinase to understand the interaction and key residues involved in the inhibition. A structure based CoMFA (q (2) = 0.675, NOC = 5, r (2) = 0.961) and COMSIA (q (2) = 0.704, NOC = 6, r (2) = 0.962) models were developed from the conformation obtained by docking. The developed models were subjected to various validation techniques such as leave-five-out, external test set, bootstrapping, progressive sampling and rm (2) metrics and found to have a good predictive ability in both internal and external validation. Our docking results showed the important residues that interacts in the active site residues in inhibition of Btk kinase. Furthermore, molecular dynamics simulation was employed to study the stability of the docked conformation and to investigate the binding interactions in detail. The MD simulation analyses identified several important hydrogen bonds with Btk, including the gatekeeper residue Thr474 and Met477 at the hinge region. Hydrogen bond with active site residues Leu408 and Arg525 were also recognized. A good correlation between the MD results, docking studies and the contour map analysis are observed. This indicates that the developed models are reliable. Our results from this study can provide insights in the designing and development of more potent Btk kinase inhibitors.

  13. Combining differential expression, chromosomal and pathway analyses for the molecular characterization of renal cell carcinoma

    OpenAIRE

    Furge, Kyle A; Dykema, Karl; Petillo, David; Westphal, Michael; Zhang, Zhongfa; Eric J. Kort; Teh, Bin Tean

    2007-01-01

    Using high-throughput gene-expression profiling technology, we can now gain a better understanding of the complex biology that is taking place in cancer cells. This complexity is largely dictated by the abnormal genetic makeup of the cancer cells. This abnormal genetic makeup can have profound effects on cellular activities such as cell growth, cell survival and other regulatory processes. Based on the pattern of gene expression, or molecular signatures of the tumours, we can distinguish or s...

  14. Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Yuwei Wang

    2017-01-01

    Full Text Available The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR, are the main endocrine therapies for prostate cancer (PCa. But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.

  15. Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists.

    Science.gov (United States)

    Wang, Yuwei; Han, Rui; Zhang, Huimin; Liu, Hongli; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2017-01-01

    The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR), are the main endocrine therapies for prostate cancer (PCa). But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.

  16. Combined Molecular Algorithms for the Generation, Equilibration and Topological Analysis of Entangled Polymers: Methodology and Performance

    Directory of Open Access Journals (Sweden)

    Nikos Ch. Karayiannis

    2009-11-01

    Full Text Available We review the methodology, algorithmic implementation and performance characteristics of a hierarchical modeling scheme for the generation, equilibration and topological analysis of polymer systems at various levels of molecular description: from atomistic polyethylene samples to random packings of freely-jointed chains of tangent hard spheres of uniform size. Our analysis focuses on hitherto less discussed algorithmic details of the implementation of both, the Monte Carlo (MC procedure for the system generation and equilibration, and a postprocessing step, where we identify the underlying topological structure of the simulated systems in the form of primitive paths. In order to demonstrate our arguments, we study how molecular length and packing density (volume fraction affect the performance of the MC scheme built around chain-connectivity altering moves. In parallel, we quantify the effect of finite system size, of polydispersity, and of the definition of the number of entanglements (and related entanglement molecular weight on the results about the primitive path network. Along these lines we approve main concepts which had been previously proposed in the literature.

  17. Prediction of binding poses to FXR using multi-targeted docking combined with molecular dynamics and enhanced sampling

    Science.gov (United States)

    Bhakat, Soumendranath; Åberg, Emil; Söderhjelm, Pär

    2017-10-01

    Advanced molecular docking methods often aim at capturing the flexibility of the protein upon binding to the ligand. In this study, we investigate whether instead a simple rigid docking method can be applied, if combined with multiple target structures to model the backbone flexibility and molecular dynamics simulations to model the sidechain and ligand flexibility. The methods are tested for the binding of 35 ligands to FXR as part of the first stage of the Drug Design Data Resource (D3R) Grand Challenge 2 blind challenge. The results show that the multiple-target docking protocol performs surprisingly well, with correct poses found for 21 of the ligands. MD simulations started on the docked structures are remarkably stable, but show almost no tendency of refining the structure closer to the experimentally found binding pose. Reconnaissance metadynamics enhances the exploration of new binding poses, but additional collective variables involving the protein are needed to exploit the full potential of the method.

  18. Evaluation of quantitative PCR combined with PMA treatment for molecular assessment of microbial water quality.

    Science.gov (United States)

    Gensberger, Eva Theres; Polt, Marlies; Konrad-Köszler, Marianne; Kinner, Paul; Sessitsch, Angela; Kostić, Tanja

    2014-12-15

    Microbial water quality assessment currently relies on cultivation-based methods. Nucleic acid-based techniques such as quantitative PCR (qPCR) enable more rapid and specific detection of target organisms and propidium monoazide (PMA) treatment facilitates the exclusion of false positive results caused by DNA from dead cells. Established molecular assays (qPCR and PMA-qPCR) for legally defined microbial quality parameters (Escherichia coli, Enterococcus spp. and Pseudomonas aeruginosa) and indicator organism group of coliforms (implemented on the molecular detection of Enterobacteriaceae) were comparatively evaluated to conventional microbiological methods. The evaluation of an extended set of drinking and process water samples showed that PMA-qPCR for E. coli, Enterococcus spp. and P. aeruginosa resulted in higher specificity because substantial or complete reduction of false positive signals in comparison to qPCR were obtained. Complete compliance to reference method was achieved for E. coli PMA-qPCR and 100% specificity for Enterococcus spp. and P. aeruginosa in the evaluation of process water samples. A major challenge remained in sensitivity of the assays, exhibited through false negative results (7-23%), which is presumably due to insufficient sample preparation (i.e. concentration of bacteria and DNA extraction), rather than the qPCR limit of detection. For the detection of the indicator group of coliforms, the evaluation study revealed that the utilization of alternative molecular assays based on the taxonomic group of Enterobacteriaceae was not adequate. Given the careful optimization of the sensitivity, the highly specific PMA-qPCR could be a valuable tool for rapid detection of hygienic parameters such as E. coli, Enterococcus spp. and P. aeruginosa. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Mapping Molecular Function to Biological Nanostructure: Combining Structured Illumination Microscopy with Fluorescence Lifetime Imaging (SIM + FLIM

    Directory of Open Access Journals (Sweden)

    Frederik Görlitz

    2017-07-01

    Full Text Available We present a new microscope integrating super-resolved imaging using structured illumination microscopy (SIM with wide-field optically sectioned fluorescence lifetime imaging (FLIM to provide optical mapping of molecular function and its correlation with biological nanostructure below the conventional diffraction limit. We illustrate this SIM + FLIM capability to map FRET readouts applied to the aggregation of discoidin domain receptor 1 (DDR1 in Cos 7 cells following ligand stimulation and to the compaction of DNA during the cell cycle.

  20. Accurate molecular structure and spectroscopic properties for nucleobases: A combined computational - microwave investigation of 2-thiouracil as a case study

    Science.gov (United States)

    Puzzarini, Cristina; Biczysko, Malgorzata; Barone, Vincenzo; Peña, Isabel; Cabezas, Carlos; Alonso, José L.

    2015-01-01

    The computational composite scheme purposely set up for accurately describing the electronic structure and spectroscopic properties of small biomolecules has been applied to the first study of the rotational spectrum of 2-thiouracil. The experimental investigation was made possible thanks to the combination of the laser ablation technique with Fourier Transform Microwave spectrometers. The joint experimental – computational study allowed us to determine accurate molecular structure and spectroscopic properties for the title molecule, but more important, it demonstrates a reliable approach for the accurate investigation of isolated small biomolecules. PMID:24002739

  1. A remarkable hematological and molecular response pattern in a patient with polycythemia vera during combination therapy with simvastatin and alendronate

    Directory of Open Access Journals (Sweden)

    Anders Lindholm Sørensen

    2016-01-01

    Full Text Available We report a 57-year old man with polycythemia vera, who had a remarkable hematological and molecular response during treatment with simvastatin and alendronate. The patient was treated with this combination for 56 months, and during this period the patient has been in complete hematological remission. The JAK2-V617F allele burden has dropped from 64% to sustained values below 20%, and follow-up bone marrow biopsies have revealed no change in PV features, without any regular cytoreductive treatment.

  2. Caffeine and sulfadiazine interact differently with human serum albumin: A combined fluorescence and molecular docking study

    Science.gov (United States)

    Islam, Mullah Muhaiminul; Sonu, Vikash K.; Gashnga, Pynsakhiat Miki; Moyon, N. Shaemningwar; Mitra, Sivaprasad

    2016-01-01

    The interaction and binding behavior of the well-known drug sulfadiazine (SDZ) and psychoactive stimulant caffeine (CAF) with human serum albumin (HSA) was monitored by in vitro fluorescence titration and molecular docking calculations under physiological condition. The quenching of protein fluorescence on addition of CAF is due to the formation of protein-drug complex in the ground state; whereas in case of SDZ, the experimental results were explained on the basis of sphere of action model. Although both these compounds bind preferentially in Sudlow's site 1 of the protein, the association constant is approximately two fold higher in case of SDZ (∼4.0 × 104 M-1) in comparison with CAF (∼9.3 × 102 M-1) and correlates well with physico-chemical properties like pKa and lipophilicity of the drugs. Temperature dependent fluorescence study reveals that both SDZ and CAF bind spontaneously with HSA. However, the binding of SDZ with the protein is mainly governed by the hydrophobic forces in contrast with that of CAF; where, the interaction is best explained in terms of electrostatic mechanism. Molecular docking calculation predicts the binding of these drugs in different location of sub-domain IIA in the protein structure.

  3. Restorable piezochromism phenomenon in an AIE molecular crystal: combined synchronous Raman scattering.

    Science.gov (United States)

    Liu, Liqun; Wang, Kai; Deng, Jian; Zhang, Zhe; Wang, Yan; Ma, Yuguang

    2017-02-22

    Many AIE active molecules have been designed and synthesized, and have been found to possess many interesting characteristics. In recent years, research into AIE crystals has increased, and it has been clearly shown that the piezochromic effect of AIE crystals depends on their structure. While most of the related research has given qualitative results, to quantitatively reveal molecular conditions under different pressure conditions, crystals of an AIE material (2Z,2'Z)-3,3'-(1,4-phenylene)bis(2-(naphthalen-2-yl)acrylonitrile) were investigated by synchronous Raman scattering and fluorescence spectroscopies. The molecular structure of the crystal changed during the process of pressurizing and then depressurizing under hydrostatic pressure, and a 142 nm red-shift value was observed in the emission spectrum of the PBNA crystal. The crystal was transformed into a new phase when the pressure was above 1.03 GPa and returned to the original phase when the pressure was decreased. The unique restorable phase transformation process of the crystal of this AIE active material could be used for erasable optical information storage and stress sensing devices.

  4. Design of a Gd-DOTA-phthalocyanine conjugate combining MRI contrast imaging and photosensitization properties as a potential molecular theranostic.

    Science.gov (United States)

    Aydın Tekdaş, Duygu; Garifullin, Ruslan; Şentürk, Berna; Zorlu, Yunus; Gundogdu, Umut; Atalar, Ergin; Tekinay, Ayse B; Chernonosov, Alexander A; Yerli, Yusuf; Dumoulin, Fabienne; Guler, Mustafa O; Ahsen, Vefa; Gürek, Ayşe Gül

    2014-01-01

    The design and synthesis of a phthalocyanine--Gd-DOTA conjugate is presented to open the way to novel molecular theranostics, combining the properties of MRI contrast imaging with photodynamic therapy. The rational design of the conjugate integrates isomeric purity of the phthalocyanine core substitution, suitable biocompatibility with the use of polyoxo water-solubilizing substituents, and a convergent synthetic strategy ended by the use of click chemistry to graft the Gd-DOTA moiety to the phthalocyanine. Photophysical and photochemical properties, contrast imaging experiments and preliminary in vitro investigations proved that such a combination is relevant and lead to a new type of potential theranostic agent. © 2014 The American Society of Photobiology.

  5. Magnetic materials at finite temperatures: thermodynamics and combined spin and molecular dynamics derived from first principles calculations

    Energy Technology Data Exchange (ETDEWEB)

    Eisenbach, Markus [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Perera, Meewanage Dilina N. [Univ. of Georgia, Athens, GA (United States). Center for Simulational Physics; Landau, David P [Univ. of Georgia, Athens, GA (United States). Center for Simulational Physics; Nicholson, Don M. [Univ. of North Carolina, Asheville, NC (United States). Dept. of Physics; Yin, Junqi [Univ. of Tennessee, Knoxville, TN (United States). National Inst. for Computational Sciences; Brown, Greg [Florida State Univ., Tallahassee, FL (United States). Dept. of Physics

    2015-01-01

    We present a unified approach to describe the combined behavior of the atomic and magnetic degrees of freedom in magnetic materials. Using Monte Carlo simulations directly combined with first principles the Curie temperature can be obtained ab initio in good agreement with experimental values. The large scale constrained first principles calculations have been used to construct effective potentials for both the atomic and magnetic degrees of freedom that allow the unified study of influence of phonon-magnon coupling on the thermodynamics and dynamics of magnetic systems. The MC calculations predict the specific heat of iron in near perfect agreement with experimental results from 300K to above Tc and allow the identification of the importance of the magnon-phonon interaction at the phase-transition. Further Molecular Dynamics and Spin Dynamics calculations elucidate the dynamics of this coupling and open the potential for quantitative and predictive descriptions of dynamic structure factors in magnetic materials using first principles-derived simulations.

  6. A Combination of 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies of Benzimidazole-Quinolinone Derivatives as iNOS Inhibitors

    Directory of Open Access Journals (Sweden)

    Peixun Liu

    2012-09-01

    Full Text Available Inducible Nitric Oxide Synthase (iNOS has been involved in a variety of diseases, and thus it is interesting to discover and optimize new iNOS inhibitors. In previous studies, a series of benzimidazole-quinolinone derivatives with high inhibitory activity against human iNOS were discovered. In this work, three-dimensional quantitative structure-activity relationships (3D-QSAR, molecular docking and molecular dynamics (MD simulation approaches were applied to investigate the functionalities of active molecular interaction between these active ligands and iNOS. A QSAR model with R2 of 0.9356, Q2 of 0.8373 and Pearson-R value of 0.9406 was constructed, which presents a good predictive ability in both internal and external validation. Furthermore, a combined analysis incorporating the obtained model and the MD results indicates: (1 compounds with the proper-size hydrophobic substituents at position 3 in ring-C (R3 substituent, hydrophilic substituents near the X6 of ring-D and hydrophilic or H-bond acceptor groups at position 2 in ring-B show enhanced biological activities; (2 Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485 are key amino acids in the active pocket, and activities of iNOS inhibitors are consistent with their capability to alter the position of these important residues, especially Glu371 and Thr370. The results provide a set of useful guidelines for the rational design of novel iNOS inhibitors.

  7. MOLECULAR SYSTEMATICS OF IRIDACEAE: A COMBINED ANALYSIS OF FOUR PLASTID DNA SEQUENCE MATRICES

    Directory of Open Access Journals (Sweden)

    M.W. CHASE

    2000-01-01

    Full Text Available Iridaceae are one of the largest families of Lilianae and probably also among the best studied families of monocotyledons. To further evaluate generic, tribal and subfamilial relationships, we have produced four plastid DNA data sets for 57 genera of Iridaceae plus outgroups: rps4, rbcL (both protein coding genes, and the trnL intron snd the trnL-F inter-gene spacer. All four matrices produce highly congruent, although not identical trees, and we thus analysed them in a combined analysis, which produced a highly resolved and well supported topology. In each of the individual trees, some genera or groups of genera are misplaced relative to Goldblatt’s and Rudall’s morphological cladistic studies, but the combined analysis produced a pattern much more similar to these previous ideas of relationships. In the combined tree, all subfamilies were resolved as monophyletic clades, except Nivenioideae, which formed a grade in which Ixioideae were embedded. The achlorophyllous Geosiris (sometimes referred to Geosiridaceae or Burmanniaceae fell within the nivenioid grade. Most of the tribes are monophyletic, except for Ixieae, Watsonieae and Sisyrinchieae, but the topology within Ixioideae is not strongly supported due to extremely low levels of sequence divergence. Isophysis is sister to the rest of the family, and Diplarrhena falls in a well supported position as sister to Irideae/Sisyrinchieae/Tigridieae/Mariceae; Bobartia of Sisyrinchieae is supported as a member of Irideae.

  8. Modeling the adsorption of PAH mixture in silica nanopores by molecular dynamic simulation combined with machine learning.

    Science.gov (United States)

    Sui, Hong; Li, Lin; Zhu, Xinzhe; Chen, Daoyi; Wu, Guozhong

    2016-02-01

    The persistence of polycyclic aromatic hydrocarbons (PAHs) in contaminated soils is largely controlled by their molecular fate in soil pores. The adsorption and diffusion of 16 PAHs mixture in silica nanopore with diameter of 2.0, 2.5, 3.0 and 3.5 nm, respectively, were characterized by adsorption energy, mean square displacement, free surface area and free volume fraction using molecular dynamic (MD) simulation. Results suggested that PAHs adsorption in silica nanopores was associated with diffusion process while competitive sorption was not the dominant mechanism in context of this study. The partial least squares (PLS) regression and machine learning (ML) methods (i.e. support vector regression, M5 decision tree and multilayer perceptrons) were used to correlate the adsorption energy with the pore diameter and PAH properties (number of carbon atoms, aromatic ring number, boiling point, molecular weight, octanol-water partition coefficient, octanol-organic carbon partition coefficient, solvent accessible area, solvent accessible volume and polarization). Results indicated that the PAH adsorption could not be predicted by linear regression as the R(2)Y and Q(2)Y coefficients of PLS analysis was 0.375 and 0.199, respectively. The nonlinearity was well recognized by ML with correlation coefficient up to 0.9. Overall, the combination of MD simulation and ML approaches can assist in interpreting the sequestration of organic contaminants in the soil nanopores. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Production of Medium Chain Fatty Acids by Yarrowia lipolytica: Combining Molecular Design and TALEN to Engineer the Fatty Acid Synthase.

    Science.gov (United States)

    Rigouin, Coraline; Gueroult, Marc; Croux, Christian; Dubois, Gwendoline; Borsenberger, Vinciane; Barbe, Sophie; Marty, Alain; Daboussi, Fayza; André, Isabelle; Bordes, Florence

    2017-10-20

    Yarrowia lipolytica is a promising organism for the production of lipids of biotechnological interest and particularly for biofuel. In this study, we engineered the key enzyme involved in lipid biosynthesis, the giant multifunctional fatty acid synthase (FAS), to shorten chain length of the synthesized fatty acids. Taking as starting point that the ketoacyl synthase (KS) domain of Yarrowia lipolytica FAS is directly involved in chain length specificity, we used molecular modeling to investigate molecular recognition of palmitic acid (C16 fatty acid) by the KS. This enabled to point out the key role of an isoleucine residue, I1220, from the fatty acid binding site, which could be targeted by mutagenesis. To address this challenge, TALEN (transcription activator-like effector nucleases)-based genome editing technology was applied for the first time to Yarrowia lipolytica and proved to be very efficient for inducing targeted genome modifications. Among the generated FAS mutants, those having a bulky aromatic amino acid residue in place of the native isoleucine at position 1220 led to a significant increase of myristic acid (C14) production compared to parental wild-type KS. Particularly, the best performing mutant, I1220W, accumulates C14 at a level of 11.6% total fatty acids. Overall, this work illustrates how a combination of molecular modeling and genome-editing technology can offer novel opportunities to rationally engineer complex systems for synthetic biology.

  10. Adaptive frozen orbital treatment for the fragment molecular orbital method combined with density-functional tight-binding.

    Science.gov (United States)

    Nishimoto, Yoshio; Fedorov, Dmitri G

    2018-02-14

    The exactly analytic gradient is derived and implemented for the fragment molecular orbital (FMO) method combined with density-functional tight-binding (DFTB) using adaptive frozen orbitals. The response contributions which arise from freezing detached molecular orbitals on the border between fragments are computed by solving Z-vector equations. The accuracy of the energy, its gradient, and optimized structures is verified on a set of representative inorganic materials and polypeptides. FMO-DFTB is applied to optimize the structure of a silicon nano-wire, and the results are compared to those of density functional theory and experiment. FMO accelerates the DFTB calculation of a boron nitride nano-ring with 7872 atoms by a factor of 406. Molecular dynamics simulations using FMO-DFTB applied to a 10.7 μm chain of boron nitride nano-rings, consisting of about 1.2 × 10 6 atoms, reveal the rippling and twisting of nano-rings at room temperature.

  11. [The study of dynamics of clinical and molecular phenotypes in the generalized form of myasthenia with optimized and combined treatment].

    Science.gov (United States)

    Drozd, O A; Efremov, V V; Romantsov, M G; Sarvilina, I V

    2013-01-01

    The aim of the study was the research of clinical and molecular phenotypes in the generalized form of myasthenia with optimized treantment, which includes the application of basic mode of the treatment and meglumine sodium succinate, and also the combined mode of the treatment, which includes the mode of the treatment and meglumine sodium succinate and ozonotherapy. The most epressed improvement of indicators of the clinical and neurologic status (the eliminaton of motoring breakdown, eye movement disrders, the weaknesses of mimic, respiratory and chewing muscles, bulbar syndrome, the doubling in eye and ptosis, pharyngeal violations and increase in volume of movement of eyes) was observed in the group of patients receiving the combined therapy. The reduction of the epressiveness of the defeat of the neuromotor device and the decrement of the amplitude of the various degree of M-answer in patients with myasthenla is revealed in the application of the combined therapy in the comparison with the application of the basic and optimized therapy. For the first time we have investigaed the dynamics of the intensity of the expression of specfic peptides and proteins in blood serum in patients with the application of basic therapy, reamberin and ozonotherapy, which have allowed to open the new mechanisms of the efficiency ofthe combined therapy of the disease.

  12. Water interactions with condensed organic phases: a combined experimental and theoretical study of molecular-level processes

    Science.gov (United States)

    Johansson, Sofia M.; Kong, Xiangrui; Thomson, Erik S.; Papagiannakopoulos, Panos; Pettersson, Jan B. C.; Lovrić, Josip; Toubin, Céline

    2016-04-01

    Water uptake on aerosol particles modifies their chemistry and microphysics with important implications for air quality and climate. A large fraction of the atmospheric aerosol consists of organic aerosol particles or inorganic particles with condensed organic components. Here, we combine laboratory studies using the environmental molecular beam (EMB) method1 with molecular dynamics (MD) simulations to characterize water interactions with organic surfaces in detail. The over-arching aim is to characterize the mechanisms that govern water uptake, in order to guide the development of physics-based models to be used in atmospheric modelling. The EMB method enables molecular level studies of interactions between gases and volatile surfaces at near ambient pressure,1 and the technique may provide information about collision dynamics, surface and bulk accommodation, desorption and diffusion kinetics. Molecular dynamics simulations provide complementary information about the collision dynamics and initial interactions between gas molecules and the condensed phase. Here, we focus on water interactions with condensed alcohol phases that serve as highly simplified proxies for systems in the environment. Gas-surface collisions are in general found to be highly inelastic and result in efficient surface accommodation of water molecules. As a consequence, surface accommodation of water can be safely assumed to be close to unity under typical ambient conditions. Bulk accommodation is inefficient on solid alcohol and the condensed materials appear to produce hydrophobic surface structures, with limited opportunities for adsorbed water to form hydrogen bonds with surface molecules. Accommodation is significantly more efficient on the dynamic liquid alcohol surfaces. The results for n-butanol (BuOH) are particularly intriguing where substantial changes in water accommodation taking place over a 10 K interval below and above the BuOH melting point.2 The governing mechanisms for the

  13. Correction: An integrated anti-arrhythmic target network of compound Chinese medicine Wenxin Keli revealed by combined machine learning and molecular pathway analysis.

    Science.gov (United States)

    Wang, Taiyi; Lu, Ming; Du, Qunqun; Yao, Xi; Zhang, Peng; Chen, Xiaonan; Xie, Weiwei; Li, Zheng; Ma, Yuling; Zhu, Yan

    2017-09-26

    Correction for 'An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis' by Taiyi Wang et al., Mol. BioSyst., 2017, 13, 1018-1030.

  14. Utilizing a combination of molecular and spatial tools to assess the effect of a public health intervention.

    Science.gov (United States)

    Muellner, P; Marshall, J C; Spencer, S E F; Noble, A D; Shadbolt, T; Collins-Emerson, J M; Midwinter, A C; Carter, P E; Pirie, R; Wilson, D J; Campbell, D M; Stevenson, M A; French, N P

    2011-12-01

    Until recently New Zealand had one of the highest rates of human campylobacteriosis reported by industrialized countries. Since the introduction of a range of control measures in the poultry production chain a reduction in human cases of around 50% has been observed nationwide. To inform risk managers a combination of spatial, temporal and molecular tools - including minimum spanning trees, risk surfaces, rarefaction analysis and dynamic source attribution modelling - was used in this study to formally evaluate the reduction in disease risk that occurred after the implementation of control measures in the poultry industry. Utilizing data from a sentinel surveillance site in the Manawatu region of New Zealand, our analyses demonstrated a reduction in disease risk attributable to a reduction in the number of poultry-associated campylobacteriosis cases. Before the implementation of interventions poultry-associated cases were more prevalent in urban than rural areas, whereas for ruminant-associated cases the reverse was evident. In addition to the overall reduction in prevalence, this study also showed a stronger intervention effect in urban areas where poultry sources were more dominant. Overall a combination of molecular and spatial tools has provided evidence that the interventions aimed at reducing Campylobacter contamination of poultry were successful in reducing poultry-associated disease and this will inform the development of future control strategies. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice

    Directory of Open Access Journals (Sweden)

    Yu-Qin Chen

    2015-01-01

    Full Text Available Objective: This work was aimed at studying the inhibitory activity of metformin combined with the commonly used chemotherapy drug cisplatin in human lung cancer xenografts in nude mice. We also examined the combined effects of these drugs on the molecular expression of survivin, matrix metalloproteinase-2 (MMP-2, vascular endothelial growth factor-C (VEGF-C, and vascular endothelial growth factorreceptor-3 (VEGFR-3 to determine the mechanism of action and to explore the potential applications of the new effective drug therapy in lung cancer. Materials and Methods: The nude mice model of lung cancer xenografts was established, and mice were randomly divided into the metformin group, the cisplatin group, the metformin + cisplatin group, and the control group. The animals were killed 42 days after drug administration, and the tumor tissues were then sampled to detect the messenger ribonucleic acid (mRNA and protein expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR. Results: The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the cisplatin group and the combined treatment group were lower than that in the control group (P < 0.05. In the metformin group, the expression of MMP-2 protein and mRNA was lower than that in the control group (P < 0.05. The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the combined treatment group were lower than that in the cisplatin group and the metformin group (P < 0.05. Conclusions: Metformin inhibited the expression of MMP-2, cisplatin and the combined treatment inhibited the expression of survivin, MMP-2, VEGF-C, and VEGFR-3, and the combined treatment of metformin with cisplatin resulted in enhanced anti-tumor efficacy.

  16. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate

    Energy Technology Data Exchange (ETDEWEB)

    Saldanha, Sabita N., E-mail: sabivan@uab.edu [Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294 (United States); Department of Biological Sciences, Alabama State University, Montgomery, AL 36104 (United States); Kala, Rishabh [Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294 (United States); Tollefsbol, Trygve O., E-mail: trygve@uab.edu [Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294 (United States); Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Comprehensive Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

    2014-05-15

    Bioactive compounds are considered safe and have been shown to alter genetic and epigenetic profiles of tumor cells. However, many of these changes have been reported at molecular concentrations higher than physiologically achievable levels. We investigated the role of the combinatorial effects of epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, and sodium butyrate (NaB), a dietary microbial fermentation product of fiber, in the regulation of survivin, which is an overexpressed anti-apoptotic protein in colon cancer cells. For the first time, our study showed that the combination treatment induced apoptosis and cell cycle arrest in RKO, HCT-116 and HT-29 colorectal cancer cells. This was found to be regulated by the decrease in HDAC1, DNMT1, survivin and HDAC activity in all three cell lines. A G2/M arrest was observed for RKO and HCT-116 cells, and G1 arrest for HT-29 colorectal cancer cells for combinatorial treatment. Further experimentation of the molecular mechanisms in RKO colorectal cancer (CRC) cells revealed a p53-dependent induction of p21 and an increase in nuclear factor kappa B (NF-κB)-p65. An increase in double strand breaks as determined by gamma-H2A histone family member X (γ-H2AX) protein levels and induction of histone H3 hyperacetylation was also observed with the combination treatment. Further, we observed a decrease in global CpG methylation. Taken together, these findings suggest that at low and physiologically achievable concentrations, combinatorial EGCG and NaB are effective in promoting apoptosis, inducing cell cycle arrest and DNA-damage in CRC cells. - Highlights: • EGCG and NaB as a combination inhibits colorectal cancer cell proliferation. • The combination treatment induces DNA damage, G2/M and G1 arrest and apoptosis. • Survivin is effectively down-regulated by the combination treatment. • p21 and p53 expressions are induced by the combination treatment. • Epigenetic proteins DNMT1 and HDAC1 are

  17. Mechanistic Insights into Molecular Targeting and Combined Modality Therapy for Aggressive, Localized Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Alan eDal Pra

    2016-02-01

    Full Text Available Radiation therapy (RT is one of the mainstay treatments for prostate cancer (PCa. The potentially curative approaches can provide satisfactory results for many patients with non-metastatic PCa; however, a considerable number of individuals may present disease recurrence and die from the disease. Exploiting the rich molecular biology of PCa will provide insights into how the most resistant tumor cells can be eradicated to improve treatment outcomes. Important for this biology-driven individualized treatment is a robust selection procedure. The development of predictive biomarkers for RT efficacy is therefore of utmost importance for a clinically exploitable strategy to achieve tumor-specific radiosensitization. This review highlights the current status and possible opportunities in the modulation of four key processes to enhance radiation response in PCa by targeting the: I. androgen signaling pathway; II. hypoxic tumor cells and regions; III. DNA damage response (DDR pathway; and IV. abnormal extra/intra-cell signaling pathways. In addition, we discuss how and which patients should be selected for biomarker-based clinical trials exploiting and validating these targeted treatment strategies with precision RT to improve cure rates in non-indolent, localized PCa.

  18. A system for combined three-dimensional morphological and molecular analysis of thick tissue specimens

    Energy Technology Data Exchange (ETDEWEB)

    Fernandez-Gonzalez, Rodrigo; Jones, Arthur; Garcia-Rodriguez, Enrique; Yuan Chen, Ping; Idica, Adam; Lockett, Stephen J.; Barcellos-Hoff, Mary Helen; Ortiz-de-Solorzano, Carlos

    2002-04-25

    We present a new system for simultaneous morphological and molecular analysis of thick tissue samples. The system is composed of a computer assisted microscope and a JAVA-based image display, analysis and visualization program that allows acquisition, annotation, meaningful storage, three-dimensional reconstruction and analysis of structures of interest in thick sectioned tissue specimens. We describe the system in detail and illustrate its use by imaging, reconstructing and analyzing two complete tissue blocks which were differently processed and stained. One block was obtained from a ductal carcinoma in situ (DCIS) lumpectomy specimen and stained alternatively with Hematoxilyn and Eosin (H&E), and with a counterstain and fluorescence in situ hybridization (FISH) to the ERB-B2 gene. The second block contained a fully sectioned mammary gland of a mouse, stained for Histology with H&E. We show how the system greatly reduces the amount of interaction required for the acquisition and analysis and is therefore suitable for studies that require morphologically driven, wide scale (e.g., whole gland) analysis of complex tissue samples or cultures.

  19. Estimating the Phanerozoic history of the Ascomycota lineages: combining fossil and molecular data.

    Science.gov (United States)

    Beimforde, Christina; Feldberg, Kathrin; Nylinder, Stephan; Rikkinen, Jouko; Tuovila, Hanna; Dörfelt, Heinrich; Gube, Matthias; Jackson, Daniel J; Reitner, Joachim; Seyfullah, Leyla J; Schmidt, Alexander R

    2014-09-01

    The phylum Ascomycota is by far the largest group in the fungal kingdom. Ecologically important mutualistic associations such as mycorrhizae and lichens have evolved in this group, which are regarded as key innovations that supported the evolution of land plants. Only a few attempts have been made to date the origin of Ascomycota lineages by using molecular clock methods, which is primarily due to the lack of satisfactory fossil calibration data. For this reason we have evaluated all of the oldest available ascomycete fossils from amber (Albian to Miocene) and chert (Devonian and Maastrichtian). The fossils represent five major ascomycete classes (Coniocybomycetes, Dothideomycetes, Eurotiomycetes, Laboulbeniomycetes, and Lecanoromycetes). We have assembled a multi-gene data set (18SrDNA, 28SrDNA, RPB1 and RPB2) from a total of 145 taxa representing most groups of the Ascomycota and utilized fossil calibration points solely from within the ascomycetes to estimate divergence times of Ascomycota lineages with a Bayesian approach. Our results suggest an initial diversification of the Pezizomycotina in the Ordovician, followed by repeated splits of lineages throughout the Phanerozoic, and indicate that this continuous diversification was unaffected by mass extinctions. We suggest that the ecological diversity within each lineage ensured that at least some taxa of each group were able to survive global crises and rapidly recovered. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Determination of cadmium at ultra-trace levels by CPE-molecular fluorescence combined methodology

    Energy Technology Data Exchange (ETDEWEB)

    Talio, Maria Carolina [Instituto de Quimica de San Luis (INQUISAL-CONICET), Chacabuco y Pedernera, 5700 San Luis (Argentina); Luconi, Marta O. [Area de Quimica Analitica, Facultad de Quimica, Bioquimica y Farmacia, Universidad Nacional de San Luis, San Luis (Argentina); Masi, Adriana N. [Area de Bromatologia- Ensayo y Valoracion de Medicamentos, Facultad de Quimica, Bioquimica y Farmacia, Universidad Nacional de San Luis, San Luis (Argentina); Instituto de Quimica de San Luis (INQUISAL-CONICET), Chacabuco y Pedernera, 5700 San Luis (Argentina); Fernandez, Liliana P., E-mail: lfernand@unsl.edu.ar [Area de Quimica Analitica, Facultad de Quimica, Bioquimica y Farmacia, Universidad Nacional de San Luis, San Luis (Argentina); Instituto de Quimica de San Luis (INQUISAL-CONICET), Chacabuco y Pedernera, 5700 San Luis (Argentina)

    2009-10-15

    A highly sensitive micelle-mediated extraction methodology for the preconcentration and determination of trace levels of cadmium by molecular fluorescence has been developed. Metal was complexed with o-phenanthroline (o-phen) and eosin (eo) at pH 7.6 in buffer Tris medium and quantitatively extracted into a small volume of surfactant-rich phase of PONPE 7.5 after centrifugating. The chemical variables affecting cloud point extraction (CPE) were evaluated and optimized. The RSD for six replicates of cadmium determinations at 0.84 {mu}g L{sup -1} level was 1.17%. The linearity range using the preconcentration system was between 2.79 x 10{sup -3} {mu}g L{sup -1} and 2.81 {mu}g L{sup -1} with a correlation coefficient of 0.99. Under the optimal conditions, it obtained a LOD of 8.38 x 10{sup -4} {mu}g L{sup -1} and LOQ of 2.79 x 10{sup -3} {mu}g L{sup -1}. The method presented good sensitivity and selectivity and was applied to the determination of trace amounts of cadmium in commercially bottled mineral water, tap water and water well samples with satisfactory results. The proposed method is an innovative application of CPE-luminescence to metal analysis comparable in sensitivity and accuracy with atomic spectroscopies.

  1. Microscopic Rate Constants of Crystal Growth from Molecular Dynamic Simulations Combined with Metadynamics

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    Dániel Kozma

    2012-01-01

    Full Text Available Atomistic simulation of crystal growth can be decomposed into two steps: the determination of the microscopic rate constants and a mesoscopic kinetic Monte Carlo simulation. We proposed a method to determine kinetic rate constants of crystal growth. We performed classical molecular dynamics on the equilibrium liquid/crystal interface of argon. Metadynamics was used to explore the free energy surface of crystal growth. A crystalline atom was selected at the interface, and it was displaced to the liquid phase by adding repulsive Gaussian potentials. The activation free energy of this process was calculated as the maximal potential energy density of the Gaussian potentials. We calculated the rate constants at different interfacial structures using the transition state theory. In order to mimic real crystallization, we applied a temperature difference in the calculations of the two opposite rate constants, and they were applied in kinetic Monte Carlo simulation. The novelty of our technique is that it can be used for slow crystallization processes, while the simple following of trajectories can be applied only for fast reactions. Our method is a possibility for determination of elementary rate constants of crystal growth that seems to be necessary for the long-time goal of computer-aided crystal design.

  2. Combining morphometrics with molecular taxonomy: how different are similar foliose keratose sponges from the Australian tropics?

    Science.gov (United States)

    Abdul Wahab, M A; Fromont, J; Whalan, S; Webster, N; Andreakis, N

    2014-04-01

    Sponge taxonomy can be challenging as many groups exhibit extreme morphological plasticity induced by local environmental conditions. Foliose keratose sponges of the sub-family Phyllospongiinae (Dictyoceratida, Thorectidae: Strepsichordaia, Phyllospongia and Carteriospongia) are commonly found in intertidal and subtidal habitats of the Indo-Pacific. Lacking spicules, these sponges can be difficult to differentiate due to the lack of reliable morphological characters for species delineation. We use molecular phylogenies inferred from the nuclear Internal Transcribed Spacer 2 region (ITS2) and morphometrics (19 characters; 52 character states) to identify evolutionarily significant units (ESUs; sensu Moritz) within foliose Phyllosponginiids collected from seven geographic locations across tropical eastern and Western Australia. The ITS2 topology was congruent with the tree derived from Bayesian inference of discrete morphological characters supporting expected taxonomic relationships at the genus level and the identification of five ESUs. However, phylogenies inferred from the ITS2 marker revealed multiple sequence clusters, some of which were characterised by distinct morphological features and specific geographic ranges. Our results are discussed in light of taxonomic incongruences within this study, hidden sponge diversity and the role of vicariant events in influencing present day distribution patterns. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Anion recognition by azophenol thiourea-based chromogenic sensors: a combined DFT and molecular dynamics investigation.

    Science.gov (United States)

    Wong, Ming Wah; Xie, Huifang; Kwa, Soo Tin

    2013-01-01

    The relative binding affinities of several anions towards 2-nitroazophenol thiourea-based receptors were studied using density functional theory (DFT) in the gas phase and in chloroform solvent via PCM calculations. Both receptors have five distinctive NH and OH hydrogen donor atoms. All receptor-anion complexes are characterized by five intermolecular hydrogen bonds. The binding free energies are strongly influenced by a dielectric medium, and the solvation effect alters the trend of anion binding to the receptor. The calculated order of anion binding affinity for the receptor in chloroform, H2PO4->AcO->F->Cl->HSO4->NO3-, is in excellent accord with experimental findings. The overall order of binding affinity is attributed to the basicity of the anion, the effect of solvation, and the number of proton acceptors available. Calculations of the NMR and UV-vis spectra strongly support the experimental characterization of the receptor-anion complexes. Explicit solvent molecular dynamics simulations of selected receptor-anion complexes were also carried out. Analysis of the structural descriptors revealed that the anions were strongly bound within the binding pocket via hydrogen-bonding interactions to the five receptor protons throughout the simulation.

  4. Integrative taxonomy: Combining morphological, molecular and chemical data for species delineation in the parthenogenetic Trhypochthonius tectorum complex (Acari, Oribatida, Trhypochthoniidae

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    Weigmann Gerd

    2011-02-01

    Full Text Available Abstract Background There is a long-standing controversial about how parthenogenetic species can be defined in absence of a generally accepted species concept for this reproductive mode. An integrative approach was suggested, combining molecular and morphological data to identify distinct monophyletic entities. Using this approach, speciation of parthenogenetic lineages was recently demonstrated for groups of bdelloid rotifers and oribatid mites. Trhypochthonius tectorum, an oribatid mite from the entirely parthenogenetic desmonomatan family Trhypochthoniidae, is traditionally treated as a single species in Central Europe. However, two new morphological lineages were recently proposed for some Austrian populations of T. tectorum, and were described as novel subspecies (T. silvestris europaeus or form (T. japonicus forma occidentalis. We used the morphological and morphometrical data which led to this separation, and added mitochondrial and nuclear DNA sequences and the chemical composition of complex exocrine oil gland secretions to test this taxonomical hypothesis. This is the first attempt to combine these three types of data for integrative taxonomical investigations of oribatid mites. Results We show that the previous European species T. tectorum represents a species complex consisting of three distinct lineages in Austria (T.tectorum, T. silvestris europaeus and T. japonicus forma occidentalis, each clearly separated by morphology, oil gland secretion profiles and mitochondrial cox1 sequences. This diversification happened in the last ten million years. In contrast to these results, no variation among the lineages was found in the nuclear 18S rDNA. Conclusions Our approach combined morphological, molecular and chemical data to investigate diversity and species delineation in a parthenogenetic oribatid mite species complex. To date, hypotheses of a general oribatid mite phylogeny are manifold, and mostly based on single-method approaches

  5. Molecular properties from combined QM/MM methods. I. Analytical second derivative and vibrational calculations

    Science.gov (United States)

    Cui, Qiang; Karplus, Martin

    2000-01-01

    Analytical second derivatives for combined QM/MM calculations have been formulated and implemented in the CHARMM program interfaced with the ab initio quantum mechanical GAMESS and CADPAC programs. This makes possible evaluation of vibrational frequencies and infrared intensities in large systems that cannot be treated effectively by QM or MM alone; examples are polarizable molecules in solution and substrates or transition states in enzymes. Test calculations on a number of systems, including formamide in water, butanol, a model transition state structure for triosephosphate isomerase and the active site model of myoglobin, show that the MM description of the environment can capture much of its polarization effects on the QM region. Thus the implementation of analytical second derivatives within the QM/MM framework has considerable potential for the study of large systems.

  6. Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity

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    Petitjean Michel

    2009-08-01

    Full Text Available Abstract Background Virtual screening methods are now well established as effective to identify hit and lead candidates and are fully integrated in most drug discovery programs. Ligand-based approaches make use of physico-chemical, structural and energetics properties of known active compounds to search large chemical libraries for related and novel chemotypes. While 2D-similarity search tools are known to be fast and efficient, the use of 3D-similarity search methods can be very valuable to many research projects as integration of "3D knowledge" can facilitate the identification of not only related molecules but also of chemicals possessing distant scaffolds as compared to the query and therefore be more inclined to scaffolds hopping. To date, very few methods performing this task are easily available to the scientific community. Results We introduce a new approach (LigCSRre to the 3D ligand similarity search of drug candidates. It combines a 3D maximum common substructure search algorithm independent on atom order with a tunable description of atomic compatibilities to prune the search and increase its physico-chemical relevance. We show, on 47 experimentally validated active compounds across five protein targets having different specificities, that for single compound search, the approach is able to recover on average 52% of the co-actives in the top 1% of the ranked list which is better than gold standards of the field. Moreover, the combination of several runs on a single protein target using different query active compounds shows a remarkable improvement in enrichment. Such Results demonstrate LigCSRre as a valuable tool for ligand-based screening. Conclusion LigCSRre constitutes a new efficient and generic approach to the 3D similarity screening of small compounds, whose flexible design opens the door to many enhancements. The program is freely available to the academics for non-profit research at: http://bioserv.rpbs.univ-paris-diderot.fr/LigCSRre.html.

  7. A diagnostic algorithm combining clinical and molecular data distinguishes Kawasaki disease from other febrile illnesses

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    Ling Xuefeng B

    2011-12-01

    Full Text Available Abstract Background Kawasaki disease is an acute vasculitis of infants and young children that is recognized through a constellation of clinical signs that can mimic other benign conditions of childhood. The etiology remains unknown and there is no specific laboratory-based test to identify patients with Kawasaki disease. Treatment to prevent the complication of coronary artery aneurysms is most effective if administered early in the course of the illness. We sought to develop a diagnostic algorithm to help clinicians distinguish Kawasaki disease patients from febrile controls to allow timely initiation of treatment. Methods Urine peptidome profiling and whole blood cell type-specific gene expression analyses were integrated with clinical multivariate analysis to improve differentiation of Kawasaki disease subjects from febrile controls. Results Comparative analyses of multidimensional protein identification using 23 pooled Kawasaki disease and 23 pooled febrile control urine peptide samples revealed 139 candidate markers, of which 13 were confirmed (area under the receiver operating characteristic curve (ROC AUC 0.919 in an independent cohort of 30 Kawasaki disease and 30 febrile control urine peptidomes. Cell type-specific analysis of microarrays (csSAM on 26 Kawasaki disease and 13 febrile control whole blood samples revealed a 32-lymphocyte-specific-gene panel (ROC AUC 0.969. The integration of the urine/blood based biomarker panels and a multivariate analysis of 7 clinical parameters (ROC AUC 0.803 effectively stratified 441 Kawasaki disease and 342 febrile control subjects to diagnose Kawasaki disease. Conclusions A hybrid approach using a multi-step diagnostic algorithm integrating both clinical and molecular findings was successful in differentiating children with acute Kawasaki disease from febrile controls.

  8. [Xanthinuria type 1 in a woman with arthralgias: a combined clinical and molecular genetic investigation].

    Science.gov (United States)

    Därr, Roland Wolfgang; Lenzner, Steffen; Eggermann, Thomas; Därr, Wolfgang Hermann

    2016-04-01

    A 53-year old woman with recurrent polyarthralgias, negative test results in a recent rheumatologic work-up and an unmeasurably low uric acid serum concentration presented for suspected IgM paraproteinemia. Physical examination, abdominal ultrasound and routine laboratory test results were unremarkable. Repeat determination confirmed a markedly decreased uric acid (UA) serum concentration. Urinary xanthine and hypoxanthine concentrations were increased by 14-fold and 7.5-fold, respectively. Fractional urinary UA excretion was not increased and the allopurinol loading test was normal. Sequencing of the xanthine dehydrogenase (XDH) gene revealed the pathogenic deletion c.641delC in the homozygous state. Segregation analysis showed that the patient's mother and her two adult sons were carriers of the mutation but not a half-sister and a half-brother of her deceased father. There was no evidence of parental consanguinity. These results established xanthinuria type 1 as the cause of the patient's recurrent polyarthralgias due to a previously unreported homozygosity for the known mutation c.641delC of the XDH gene. The patient was advised to adhere to a low-purine diet and to ensure an increased daily fluid-intake of at least 2.5 l. She has since remained symptom free. Markedly lowered serum uric acid concentrations are a hallmark of xanthinuria and of hereditary renal hypouricemia, and in the absence of severe hepatic failure or evidence of an untoward drug effect should raise suspicion of these diseases. A targeted diagnostic work-up should then be initiated and factitious hypouricemia due to IgM paraproteinemia considered only in the case of equivocal test results. Molecular-genetic characterization and segregation analysis will ultimately establish the underlying genotype. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Chitosan Combined with Molecular Beacon for Mir-155 Detection and Imaging in Lung Cancer

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    Hai-Zhen Zhu

    2014-09-01

    Full Text Available Lung cancer is the major cause of cancer-related deaths worldwide, thus developing effective methods for its early diagnosis is urgently needed. In recent years, microRNAs (miRNAs, miR have been reported to play important roles in carcinogenesis and have become potential biomarkers for cancer diagnosis and treatment. Molecular beacon (MB technology is a universal technology to detect DNA/RNA expression in living cells. As a natural polymers, chitosan (CS nanoparticles could be used as a carrier for safe delivery of nucleic acid. In this study, we developed a probe using nanoparticles of miR-155 MB self assembled with CS (CS-miR-155 MB to image the expression of miR-155 in cancer cells. Hybridization assay showed that the locked nucleic acid (LAN modified miR-155 MB could target miR-155 effectively and sensitively. The miR-155 MB self-assembly with CS nanoparticles formed stable complexes at the proper weight ratio. The CS nanoparticles showed higher fluorescence intensity and transfection efficiency than the lipid-based formulation transfection agent by confocal microscopy and flow cytometry analysis. The CS-MB complexes were found to be easily synthesized and exhibited strong enzymatic stability, efficient cellular uptake, high target selectivity and biocompatibility. The CS-MB complexes can also be applied in other cancers just by simply changing for a targeted miRNA highly expressed in those cancer cells. Therefore, it is a promising vehicle used for detecting miRNA expression in living cells.

  10. Molecular insight into atypical instability behavior of fixed-dose combination containing amlodipine besylate and losartan potassium.

    Science.gov (United States)

    Handa, Tarun; Jhajra, Shalu; Bhagat, Shweta; Bharatam, P V; Chakraborti, Asit K; Singh, Saranjit

    2017-03-20

    Combination therapy with the use of fixed-dose combinations (FDCs) is evincing increasing interest of prescribers, manufacturers and even regulators, evidently due to the primary benefit of improved patient compliance. However, owing to potential of drug-drug interaction, FDCs require closer scrutiny with respect to their physical and chemical stability. Accordingly, the purpose of the present study was to explore stability behavior of a popular antihypertensive combination of amlodipine besylate (AML) and losartan potassium (LST). Physical mixtures of the two drugs and multiple marketed formulations were stored under accelerated conditions of temperature and humidity (40°C/75% RH) in a stability chamber and samples were withdrawn after 1 and 3 months. The physical changes were observed visibly, while chemical changes were monitored by HPLC employing a method that could separate the two drugs and all other components present. The combination revealed strong physical instability and also chemical degradation of AML in the presence of LST. Interestingly, three isomeric interaction products of AML were formed in the combination, which otherwise were reported in the literature to be generated on exposure of AML free base above its melting point. The same unusual products were even formed when multiple marketed FDCs were stored under accelerated conditions outside their storage packs. However, these were absent when AML alone was stored in the same studied conditions. Therefore, reasons for physical and chemical incompatibility and the mechanism of degradation of AML in the presence of LST were duly explored at the molecular level. The outcomes of the study are expected to help in development of stable FDCs of the two drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice.

    Science.gov (United States)

    Chen, Yu-Qin; Chen, Gang

    2015-01-01

    This work was aimed at studying the inhibitory activity of metformin combined with the commonly used chemotherapy drug cisplatin in human lung cancer xenografts in nude mice. We also examined the combined effects of these drugs on the molecular expression of survivin, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor-C (VEGF-C), and vascular endothelial growth factor receptor-3 (VEGFR-3) to determine the mechanism of action and to explore the potential applications of the new effective drug therapy in lung cancer. The nude mice model of lung cancer xenografts was established, and mice were randomly divided into the metformin group, the cisplatin group, the metformin + cisplatin group, and the control group. The animals were killed 42 days after drug administration, and the tumor tissues were then sampled to detect the messenger ribonucleic acid (mRNA) and protein expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the cisplatin group and the combined treatment group were lower than that in the control group (P metformin group, the expression of MMP-2 protein and mRNA was lower than that in the control group (P metformin group (P Metformin inhibited the expression of MMP-2, cisplatin and the combined treatment inhibited the expression of survivin, MMP-2, VEGF-C, and VEGFR-3, and the combined treatment of metformin with cisplatin resulted in enhanced anti-tumor efficacy.

  12. Barcoding against a paradox? Combined molecular species delineations reveal multiple cryptic lineages in elusive meiofaunal sea slugs

    Science.gov (United States)

    2012-01-01

    meiofauna and accentuates the taxonomic deficit that characterizes meiofauna research. We observe for Pontohedyle slugs a high degree of morphological simplicity and uniformity, which we expect might be a general rule for meiofauna. To tackle cryptic diversity in little explored and hard-to-sample invertebrate taxa, at present, a combined approach seems most promising, such as multi-marker-barcoding (i.e., molecular systematics using mitochondrial and nuclear markers and the criterion of reciprocal monophyly) combined with a minimum consensus approach across independent methods of molecular species delineation to define candidate species. PMID:23244441

  13. Inadequacy of the Lorentz-Berthelot combining rules for accurate predictions of equilibrium properties by molecular simulation

    Science.gov (United States)

    Delhommelle, Jérôme; Millié, Philippe

    Though molecular beam experiments have revealed deficiencies in the Lorentz-Berthelot combining rules, these rules are still used widely to parametrize effective pair potential models or to calculate the thermodynamic properties of mixtures. Gibbs ensemble Monte Carlo and isothermal isobaric Monte Carlo simulations were used to compute the liquid-vapour phase equilibria and the liquid properties of binary mixtures of rare gases modelled by effective pair potentials. Three sets of simple combining rules were tested in this work: the commonly used Lorentz-Berthelot rules, the Kong rules (Kong, J., 1973, J. chem. Phys., 59, 2464) and the Waldman-Hagler rules (Waldman, M., and Hagler, A. T., 1993, J. comput. Chem., 14, 1077). These three sets of rules do not require any additional parameter. It is shown that: (1) the choice of a set of combining rules has a significant effect on the thermodynamic properties, (2) using the Lorentz-Berthelot rules yields significant deviations from experiment and (3) the Kong rules provide a much better description of the mixture properties both for coexistence curves and liquid properties. We therefore recommend the use of the Kong rules instead of the Lorentz-Berthelot when parametrizing potential models.

  14. Combined single cell AFM manipulation and TIRFM for probing the molecular stability of multilayer fibrinogen matrices

    Energy Technology Data Exchange (ETDEWEB)

    Christenson, W. [Department of Physics, Arizona State University, Tempe, AZ 85287 (United States); Center for Biological Physics, Arizona State University, Tempe, AZ 85287 (United States); Yermolenko, I. [Department of Physics, Arizona State University, Tempe, AZ 85287 (United States); School of Life Sciences, Arizona State University, Tempe, AZ 85287 (United States); Plochberger, B. [Department of Physics, Arizona State University, Tempe, AZ 85287 (United States); Camacho-Alanis, F.; Ros, A. [Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 (United States); Ugarova, T.P. [School of Life Sciences, Arizona State University, Tempe, AZ 85287 (United States); Ros, R., E-mail: Robert.Ros@asu.edu [Department of Physics, Arizona State University, Tempe, AZ 85287 (United States); Center for Biological Physics, Arizona State University, Tempe, AZ 85287 (United States)

    2014-01-15

    Adsorption of fibrinogen on various surfaces produces a nanoscale multilayer matrix, which strongly reduces the adhesion of platelets and leukocytes with implications for hemostasis and blood compatibility of biomaterials. The nonadhesive properties of fibrinogen matrices are based on their extensibility, ensuing the inability to transduce strong mechanical forces via cellular integrins and resulting in weak intracellular signaling. In addition, reduced cell adhesion may arise from the weaker associations between fibrinogen molecules in the superficial layers of the matrix. Such reduced stability would allow integrins to pull fibrinogen molecules out of the matrix with comparable or smaller forces than required to break integrin–fibrinogen bonds. To examine this possibility, we developed a method based on the combination of total internal reflection fluorescence microscopy, single cell manipulation with an atomic force microscope and microcontact printing to study the transfer of fibrinogen molecules out of a matrix onto cells. We calculated the average fluorescence intensities per pixel for wild-type HEK 293 (HEK WT) and HEK 293 cells expressing leukocyte integrin Mac-1 (HEK Mac-1) before and after contact with multilayered matrices of fluorescently labeled fibrinogen. For contact times of 500 s, HEK Mac-1 cells show a median increase of 57% of the fluorescence intensity compared to 6% for HEK WT cells. The results suggest that the integrin Mac-1-fibrinogen interactions are stronger than the intermolecular fibrinogen interactions in the superficial layer of the matrix. The low mechanical stability of the multilayer fibrinogen surface may contribute to the reduced cell adhesive properties of fibrinogen-coated substrates. We anticipate that the described method can be applied to various cell types to examine their integrin-mediated adhesion to the extracellular matrices with a variable protein composition. - Highlights: • We present a method combining

  15. Insights into molecular properties of the human monocarboxylate transporter 8 by combining functional with structural information

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    Kleinau Gunnar

    2011-08-01

    Full Text Available Abstract Background The monocarboxylate transporter 8 (MCT8 is a member of the major facilitator superfamily (MFS and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation known as the Allan-Herndon-Dudley syndrome. This syndrome is characterized by abnormally high T3, low/normal T4 serum levels and slightly elevated serum TSH. To date, more than 25 pathogenic mutations in hMCT8 are known and they are valuable indicators of important regions for structural and functional MCT8 properties. Methods We designed a structural human MCT8 model and studied reported pathogenic missense mutations with focus on the estimation of those amino acid positions which are probably sensitive for substrate transport. Furthermore, assuming similarities between determinants of T3 binding observed in the published crystal structure of the thyroid hormone receptor beta occupied by its ligand T3 and the structural MCT8 model, we explore potential T3 binding sites in the MCT8 substrate channel cavity. Results We found that all known pathogenic missense mutations are located exclusively in the transmembrane helices and to a high degree at conserved residues among the MCT family. Furthermore, mutations either of or to prolines/glycines are located mainly at helices 9-12 and are expected to cause steric clashes or structural misfolding. In contrast, several other mutations are close to the potential substrate channel and affected amino acids are likely involved in the switching mechanism between different transporter conformations. Finally, three potential substrate binding sites are predicted for MCT8. Conclusions Naturally occurring mutations of MCT8 provide molecular insights into protein regions important for protein folding, substrate binding and the switching mechanism during substrate transport. Future studies guided by this information should help to clarify structure

  16. Solvatochromic shift of phenol blue in water from a combined Car-Parrinello molecular dynamics hybrid quantum mechanics-molecular mechanics and ZINDO approach.

    Science.gov (United States)

    Murugan, N Arul; Jha, Prakash Chandra; Rinkevicius, Z; Ruud, Kenneth; Agren, Hans

    2010-06-21

    The present work addresses the solvatochromic shift of phenol blue (PB) dye. For this purpose the results of Car-Parrinello molecular dynamics (CPMD) simulations for PB in gas phase are compared with results obtained for PB in water from CPMD hybrid quantum mechanics-molecular mechanics (CPMD-QM/MM) calculations. The absorption spectra were obtained using the intermediate neglect of differential overlap/spectroscopic-configuration interaction (INDO/CIS) method and were calculated for a multitude of configurations of the trajectory. The calculated lambda(max) for PB in gas phase was found to be about 535 nm, which is considerably lower than the lambda(max) reported for PB in nonpolar solvents. Different solvation shells for PB in water have been defined based on the solute-all-atoms and solvent center of mass radial distribution function (g(r(X-O))). The electronic excitation energies for PB computed in the presence of solvent molecules in an increasing number of solvation shells were calculated in a systematic way to evaluate their contributions to the solvatochrmic shift. The inclusion of solvent molecules in the hydration shell yields a lambda(max) of 640 nm, which contributes to almost 78% of the solvatochromic shift. The inclusion of solvent molecules up to 10 A in the g(r(X-O)) rdf yields a lambda(max) of 670 nm which is in good agreement with the experimentally reported value of 654-684 nm. Overall, the present study suggests that the combined CPMD-QM/MM and INDO-CIS approach can be used successfully to model solvatochromic shifts of organic dye molecules.

  17. Peptide-surfactant interactions: A combined spectroscopic and molecular dynamics simulation approach

    Science.gov (United States)

    Roussel, Guillaume; Caudano, Yves; Matagne, André; Sansom, Mark S.; Perpète, Eric A.; Michaux, Catherine

    2018-02-01

    In the present contribution, we report a combined spectroscopic and computational approach aiming to unravel at atomic resolution the effect of the anionic SDS detergent on the structure of two model peptides, the α-helix TrpCage and the β-stranded TrpZip. A detailed characterization of the specific amino acids involved is performed. Monomeric (single molecules) and micellar SDS species differently interact with the α-helix and β-stranded peptides, emphasizing the different mechanisms occurring below and above the critical aggregation concentration (CAC). Below the CAC, the α-helix peptide is fully unfolded, losing its hydrophobic core and its Asp-Arg salt bridge, while the β-stranded peptide keeps its native structure with its four Trp well oriented. Above the CAC, the SDS micelles have the same effect on both peptides, that is, destabilizing the tertiary structure while keeping their secondary structure. Our studies will be helpful to deepen our understanding of the action of the denaturant SDS on peptides and proteins.

  18. Deciphering the molecular basis of wine yeast fermentation traits using a combined genetic and genomic approach.

    Science.gov (United States)

    Ambroset, Chloé; Petit, Maud; Brion, Christian; Sanchez, Isabelle; Delobel, Pierre; Guérin, Cyprien; Chiapello, Hélène; Nicolas, Pierre; Bigey, Frédéric; Dequin, Sylvie; Blondin, Bruno

    2011-09-01

    The genetic basis of the phenotypic diversity of yeast is still poorly understood. Wine yeast strains have specific abilities to grow and ferment under stressful conditions compared with other strains, but the genetic basis underlying these traits is unknown. Understanding how sequence variation influences such phenotypes is a major challenge to address adaptation mechanisms of wine yeast. We aimed to identify the genetic basis of fermentation traits and gain insight into their relationships with variations in gene expression among yeast strains. We combined fermentation trait QTL mapping and expression profiling of fermenting cells in a segregating population from a cross between a wine yeast derivative and a laboratory strain. We report the identification of QTL for various fermentation traits (fermentation rates, nitrogen utilization, metabolites production) as well as expression QTL (eQTL). We found that many transcripts mapped to several eQTL hotspots and that two of them overlapped with QTL for fermentation traits. A QTL controlling the maximal fermentation rate and nitrogen utilization overlapping with an eQTL hotspot was dissected. We functionally demonstrated that an allele of the ABZ1 gene, localized in the hotspot and involved in p-aminobenzoate biosynthesis, controls the fermentation rate through modulation of nitrogen utilization. Our data suggest that the laboratory strain harbors a defective ABZ1 allele, which triggers strong metabolic and physiological alterations responsible for the generation of the eQTL hotspot. They also suggest that a number of gene expression differences result from some alleles that trigger major physiological disturbances.

  19. In situ mechanical and molecular investigations of collagen/apatite biomimetic composites combining Raman spectroscopy and stress-strain analysis.

    Science.gov (United States)

    Chatzipanagis, Konstantinos; Baumann, Christoph G; Sandri, Monica; Sprio, Simone; Tampieri, Anna; Kröger, Roland

    2016-12-01

    We report the design, fabrication and application of a novel micro-electromechanical device coupled to a confocal Raman microscope that enables in situ molecular investigations of micro-fibers under uniaxial tensile load. This device allows for the mechanical study of micro-fibers with diameters in the range between 10 and 100μm and lengths of several hundred micrometers. By exerting forces in the mN range, the device enables an important force range to be accessed between that of atomic force microscopy and macroscopic stress-strain measurement devices. The load is varied using a stiffness-calibrated glass micro-needle driven by a piezo-translator during simultaneous Raman microscopy imaging. The method enables experiments probing the molecular response of micro-fibers to external stress. This set-up was applied to biomimetic non-mineralized and mineralized collagen micro-fibers revealing that above 30% mineralization the proline-related Raman band shows a pronounced response to stress, which is not observed in non-mineralized collagen. This molecular response coincides with a strong increase in the Young's modulus from 0.5 to 6GPa for 0% and 70% mineralized collagen, respectively. Our results are consistent with a progressive interlocking of the collagen triple-helices by apatite nanocrystals as the degree of mineralization increases. Collagen and apatite are the main constituents regulating the mechanical properties of bone. Hence, an improved understanding of the impact of mineralization on these properties is of large interest for the scientific community. This paper presents systematic studies of synthetic collagen microfibers with increasing apatite content and their response to tensile stress by using a novel self-made electromechanical device combined with a Raman spectrometer for molecular level studies. The impact of apatite on the mechanical and molecular response of collagen is evaluated giving important insights into the interaction between the

  20. Combined Campylobacter jejuni and Campylobacter coli Rapid Testing and Molecular Epidemiology in Conventional Broiler Flocks.

    Science.gov (United States)

    Schallegger, G; Muri-Klinger, S; Brugger, K; Lindhardt, C; John, L; Glatzl, M; Wagner, M; Stessl, B

    2016-12-01

    Campylobacter spp. are important causes of bacterial zoonosis, most often transmitted by contaminated poultry meat. From an epidemiological and risk assessment perspective, further knowledge should be obtained on Campylobacter prevalence and genotype distribution in primary production. Consequently, 15 Austrian broiler flocks were surveyed in summer for their thermophilic Campylobacter spp. contamination status. Chicken droppings, dust and drinking water samples were collected from each flock at three separate sampling periods. Isolates were confirmed by PCR and subtyped. We also compared three alternative methods (culture-based enrichment in Bolton broth, culture-independent real-time PCR and a lateral-flow test) for their applicability in chicken droppings. Twelve flocks were found to be positive for thermophilic Campylobacter spp. during the entire sampling period. Seven flocks (46.6%) were contaminated with both, C. jejuni and C. coli, five flocks harboured solely one species. We observed to a majority flock-specific C. jejuni and C. coli genotypes, which dominated the respective flock. Flocks within a distance jejuni genotypes indicating a cross-contamination event via the environment or personnel vectors. Multilocus sequence typing (MLST) of C. jejuni revealed that the majority of isolates were assigned to globally distributed clonal complexes or had a strong link to the human interface (CC ST-446 and ST4373). The combination of techniques poses an advantage over risk assessment studies based on cultures alone, as, in the case of Campylobacter, occurrence of a high variety of genotypes might be present among a broiler flock. We suggest applying the lateral-flow test under field conditions to identify 'high-shedding' broiler flocks at the farm level. Consequently, poultry farmers and veterinarians could improve hygiene measurements and direct sanitation activities, especially during the thinning period. Ultimately, real-time PCR could be applied to quantify

  1. Response of the seagrass Posidonia oceanica to different light environments: Insights from a combined molecular and photo-physiological study.

    Science.gov (United States)

    Dattolo, E; Ruocco, M; Brunet, C; Lorenti, M; Lauritano, C; D'Esposito, D; De Luca, P; Sanges, R; Mazzuca, S; Procaccini, G

    2014-10-01

    Here we investigated mechanisms underlying the acclimation to light in the marine angiosperm Posidonia oceanica, along its bathymetric distribution (at -5 m and -25 m), combining molecular and photo-physiological approaches. Analyses were performed during two seasons, summer and autumn, in a meadow located in the Island of Ischia (Gulf of Naples, Italy), where a genetic distinction between plants growing above and below the summer thermocline was previously revealed. At molecular level, analyses carried out using cDNA-microarray and RT-qPCR, revealed the up-regulation of genes involved in photoacclimation (RuBisCO, ferredoxin, chlorophyll binding proteins), and photoprotection (antioxidant enzymes, xanthophyll-cycle related genes, tocopherol biosynthesis) in the upper stand of the meadow, indicating that shallow plants are under stressful light conditions. However, the lack of photo-damage, indicates the successful activation of defense mechanisms. This conclusion is also supported by several responses at physiological level as the lower antenna size, the higher number of reaction centers and the higher xanthophyll cycle pigment pool, which are common plant responses to high-light adaptation/acclimation. Deep plants, despite the lower available light, seem to be not light-limited, thanks to some shade-adaptation strategies (e.g. higher antenna size, lower Ek values). Furthermore, also at the molecular level there were no signs of stress response, indicating that, although the lower energy available, low-light environments are more favorable for P. oceanica growth. Globally, results of whole transcriptome analysis displayed two distinct gene expression signatures related to depth distribution, reflecting the different light-adaptation strategies adopted by P. oceanica along the depth gradient. This observation, also taking into account the genetic disjunction of clones along the bathymetry, might have important implications for micro-evolutionary processes

  2. Adsorption of TCDD with 1-butyl-3-methylimidazolium dicyanamide ionic liquid: a combined molecular dynamics simulation and quantum chemistry study.

    Science.gov (United States)

    Pan, Wenxiao; Qi, Yuanyuan; Wang, Ruoxi; Han, Zhe; Zhang, Dongju; Zhan, Jinhua

    2013-04-01

    The effective abatement of flue gas emissions, especially polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), is one of the challenging issues in the field of environmental science currently. Imidazolium-based dicyanamide ionic liquids (ILs) were proposed to have potential in controlling the emissions of PCDD/Fs. However, the relevant mechanism at the molecular level still remains unclear. To address this subject, we here present a combined molecular dynamics (MD) simulation and quantum chemical (QM) study on the adsorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener among PCDD/F family, by 1-butyl-3-methylimidazolium dicyanamide IL, a representative imidazolium dicyanoamide ILs, which were demonstrated to possess high capture capability for PCDD/Fs. The MD simulation results show that TCDD molecules can be effectively adsorbed on the IL surface to form a dense layer, but cannot enter the interior of the IL. The results of QM calculations show that the adsorption of TCDDs on the IL surface occurs via intra-molecular hydrogen bond interactions. The calculated interaction energy of the anion with TCDD molecule is two times more than that of the cation, implying that the IL anion dominates the interaction with TCDD molecules, while the cation plays a secondary role. Based on the calculated results, we propose that imidazolium dicyanamide IL films/membranes may be better materials than the corresponding bulk for capturing TCDD. The present theoretical results may be helpful to designing the functional ILs which effectively capture and concentrate PCDD/F compounds. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives.

    Science.gov (United States)

    López-Lira, Claudia; Alzate-Morales, Jans H; Paulino, Margot; Mella-Raipán, Jaime; Salas, Cristian O; Tapia, Ricardo A; Soto-Delgado, Jorge

    2017-06-23

    A combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2LOO ) of .75 and .73 as well as conventional correlation coefficients (R2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity. © 2017 John Wiley & Sons A/S.

  4. Novel restricted access materials combined to molecularly imprinted polymers for selective solid-phase extraction of organophosphorus pesticides from honey.

    Science.gov (United States)

    He, Juan; Song, Lixin; Chen, Si; Li, Yuanyuan; Wei, Hongliang; Zhao, Dongxin; Gu, Keren; Zhang, Shusheng

    2015-11-15

    A novel restricted access materials (RAM) combined to molecularly imprinted polymers (MIPs), using malathion as template molecule and glycidilmethacrylate (GMA) as pro-hydrophilic co-monomer, were prepared for the first time. RAM-MIPs with hydrophilic external layer were characterized by scanning electron microscopy and recognition and selectivity properties were compared with the restricted access materials-non-molecularly imprinted polymers (RAM-NIPs) and unmodified MIPs. RAM-MIPs were used as the adsorbent enclosed in solid phase extraction column and several important extraction parameters were comprehensively optimized to evaluate the extraction performance. Under the optimum extraction conditions, RAM-MIPs exhibited comparable or even higher selectivity with greater extraction capacity toward six kinds of organophosphorus pesticides (including malathion, ethoprophos, phorate, terbufos, dimethoate, and fenamiphos) compared with the MIPs and commercial solid phase extraction columns. The RAM-MIPs solid phase extraction coupled with gas chromatography was successfully applied to simultaneously determine six kinds of organophosphorus pesticides from honey sample. The new established method showed good linearity in the range of 0.01-1.0 μg mL(-1), low limits of detection (0.0005-0.0019 μg mL(-1)), acceptable reproducibility (RSD, 2.26-4.81%, n = 6), and satisfactory relative recoveries (90.9-97.6%). It was demonstrated that RAM-MIPs solid phase extraction with excellent selectivity and restricted access function was a simple, rapid, selective, and effective sample pretreatment method. Copyright © 2015. Published by Elsevier Ltd.

  5. Restrained Proton Indicator in Combined Quantum-Mechanics/Molecular-Mechanics Dynamics Simulations of Proton Transfer through a Carbon Nanotube.

    Science.gov (United States)

    Duster, Adam W; Lin, Hai

    2017-09-14

    Recently, a collective variable "proton indicator" was purposed for tracking an excess proton solvated in bulk water in molecular dynamics simulations. In this work, we demonstrate the feasibility of utilizing the position of this proton indicator as a reaction coordinate to model an excess proton migrating through a hydrophobic carbon nanotube in combined quantum-mechanics/molecular-mechanics simulations. Our results indicate that applying a harmonic restraint to the proton indicator in the bulk solvent near the nanotube pore entrance leads to the recruitment of water molecules into the pore. This is consistent with an earlier study that employed a multistate empirical valence bond potential and a different representation (center of excess charge) of the proton. We attribute this water recruitment to the delocalized nature of the solvated proton, which prefers to be in high-dielectric bulk solvent. While water recruitment into the pore is considered an artifact in the present simulations (because of the artificially imposed restraint on the proton), if the proton were naturally restrained, it could assist in building water wires prior to proton transfer through the pore. The potential of mean force for a proton translocation through the water-filled pore was computed by umbrella sampling, where the bias potentials were applied to the proton indicator. The free energy curve and barrier heights agree reasonably with those in the literature. The results suggest that the proton indicator can be used as a reaction coordinate in simulations of proton transport in confined environments.

  6. Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo.

    Directory of Open Access Journals (Sweden)

    Dieudonné Makaba Mvumbi

    Full Text Available Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo. This study essentially revealed that resistance to chloroquine is still decreasing while polymorphism related to amodiaquine resistance seems to be not present in Democratic Republic of Congo, that three samples, located in the east of the country, harbor Pfmdr1 amplification and that none of the mutations found in South-East Asia correlated with artemisinine resistance have been found in Democratic Republic of Congo. But new mutations have been identified, especially the M476K, occurred in the same position that the M476I previously identified in the F32-ART strain, strongly resistant to artemisinine. Antimalarial first-line treatments currently in use in Democratic Republic of Congo are not associated with emergence of molecular markers of resistance.

  7. Phylogeny and systematic position of Opiliones: a combined analysis of chelicerate relationships using morphological and molecular data

    Science.gov (United States)

    Giribet, Gonzalo; Edgecombe, Gregory D.; Wheeler, Ward C.; Babbitt, Courtney

    2002-01-01

    The ordinal level phylogeny of the Arachnida and the suprafamilial level phylogeny of the Opiliones were studied on the basis of a combined analysis of 253 morphological characters, the complete sequence of the 18S rRNA gene, and the D3 region of the 28S rRNA gene. Molecular data were collected for 63 terminal taxa. Morphological data were collected for 35 exemplar taxa of Opiliones, but groundplans were applied to some of the remaining chelicerate groups. Six extinct terminals, including Paleozoic scorpions, are scored for morphological characters. The data were analyzed using strict parsimony for the morphological data matrix and via direct optimization for the molecular and combined data matrices. A sensitivity analysis of 15 parameter sets was undertaken, and character congruence was used as the optimality criterion to choose among competing hypotheses. The results obtained are unstable for the high-level chelicerate relationships (except for Tetrapulmonata, Pedipalpi, and Camarostomata), and the sister group of the Opiliones is not clearly established, although the monophyly of Dromopoda is supported under many parameter sets. However, the internal phylogeny of the Opiliones is robust to parameter choice and allows the discarding of previous hypotheses of opilionid phylogeny such as the "Cyphopalpatores" or "Palpatores." The topology obtained is congruent with the previous hypothesis of "Palpatores" paraphyly as follows: (Cyphophthalmi (Eupnoi (Dyspnoi + Laniatores))). Resolution within the Eupnoi, Dyspnoi, and Laniatores (the latter two united as Dyspnolaniatores nov.) is also stable to the superfamily level, permitting a new classification system for the Opiliones. c2002 The Willi Hennig Society.

  8. Combined computational and experimental studies of molecular interactions of albuterol sulfate with bovine serum albumin for pulmonary drug nanoparticles

    Directory of Open Access Journals (Sweden)

    Lin SH

    2016-09-01

    Full Text Available Shao-Hui Lin,1 Wei Cui,2 Gui-Ling Wang,1 Shuai Meng,1 Ying-Chun Liu,3 Hong-Wei Jin,4 Liang-Ren Zhang,4 Ying Xie1,4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, 2School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 3Soft Matter Research Center, Department of Chemistry, Zhejiang University, Hangzhou, 4State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China Abstract: Albumin-based nanoparticles (NPs are a promising technology for developing drug-carrier systems, with improved deposition and retention profiles in lungs. Improved understanding of these drug–carrier interactions could lead to better drug-delivery systems. The present study combines computational and experimental methods to gain insights into the mechanism of binding of albuterol sulfate (AS to bovine serum albumin (BSA on the molecular level. Molecular dynamics simulation and surface plasmon resonance spectroscopy were used to determine that there are two binding sites on BSA for AS: the first of which is a high-affinity site corresponding to AS1 and the second of which appears to represent the integrated functions of several low-affinity sites corresponding to AS2, AS3, and AS8. AS1 was the strongest binding site, established via electrostatic interaction with Glu243 and Asp255 residues in a hydrophobic pocket. Hydrogen bonds and salt bridges played a main role in the critical binding of AS1 to BSA, and water bridges served a supporting role. Based upon the interaction mechanism, BSA NPs loaded with AS were prepared, and their drug-loading efficiency, morphology, and -release profiles were evaluated. Successful clinical development of AS-BSA-NPs may improve therapy and prevention of bronchospasm in patients with reversible obstructive airway disease, and thus

  9. Study on the Application of the Combination of TMD Simulation and Umbrella Sampling in PMF Calculation for Molecular Conformational Transitions

    Directory of Open Access Journals (Sweden)

    Qing Wang

    2016-05-01

    Full Text Available Free energy calculations of the potential of mean force (PMF based on the combination of targeted molecular dynamics (TMD simulations and umbrella samplings as a function of physical coordinates have been applied to explore the detailed pathways and the corresponding free energy profiles for the conformational transition processes of the butane molecule and the 35-residue villin headpiece subdomain (HP35. The accurate PMF profiles for describing the dihedral rotation of butane under both coordinates of dihedral rotation and root mean square deviation (RMSD variation were obtained based on the different umbrella samplings from the same TMD simulations. The initial structures for the umbrella samplings can be conveniently selected from the TMD trajectories. For the application of this computational method in the unfolding process of the HP35 protein, the PMF calculation along with the coordinate of the radius of gyration (Rg presents the gradual increase of free energies by about 1 kcal/mol with the energy fluctuations. The feature of conformational transition for the unfolding process of the HP35 protein shows that the spherical structure extends and the middle α-helix unfolds firstly, followed by the unfolding of other α-helices. The computational method for the PMF calculations based on the combination of TMD simulations and umbrella samplings provided a valuable strategy in investigating detailed conformational transition pathways for other allosteric processes.

  10. Subcritical water extraction combined with molecular imprinting technology for sample preparation in the detection of triazine herbicides.

    Science.gov (United States)

    Zhao, Fengnian; Wang, Shanshan; She, Yongxin; Zhang, Chao; Zheng, Lufei; Jin, Maojun; Shao, Hua; Jin, Fen; Du, Xinwei; Wang, Jing

    2017-09-15

    A selective, environmentally friendly, and cost-effective sample extraction method based on a combination of subcritical water extraction (SWE) and molecularly imprinted solid-phase extraction (MISPE) was developed for the determination of eight triazine herbicides in soil samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In SWE, the highest extraction yields of triazine herbicides were obtained under 150°C for 15min using 20% ethanol as the organic modifier. Addition of MIP during SWE increased the extraction efficiency, and using MIP as a selective SPE sorbent improved the enrichment capability. Soil samples were treated with the optimized extraction MIP/SWE-MISPE method and analyzed by LC-MS/MS. The novel technique was then applied to soil samples for the determination of triazine herbicides, and better recoveries (78.9%-101%) were obtained compared with using SWE-MISPE (30%-67%). Moreover, this newly developed method displayed good linearity (R2>0.99) and precision (2.7-9.8%), and low enough detection limits (0.4-3.3μgkg-1). This combination of SWE and MIP technology is a simple, effective and promising method to selectively extract class-specific compounds in complex samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Combined effect of glycine and sea salt on aerosol cloud droplet activation predicted by molecular dynamics simulations.

    Science.gov (United States)

    Sun, Lu; Hede, Thomas; Tu, Yaoquan; Leck, Caroline; Agren, Hans

    2013-10-17

    The present study illustrates the combined effect of organic and inorganic compounds on cloud droplet nucleation and activation processes representative for the marine environment. Amino acids and sea salt are common marine cloud condensation nuclei (CCN) which act as a prerequisite for growth of cloud droplets. The chemical and physical properties of these CCN play a key role for interfacial properties such as surface tension, which is important for the optical properties of clouds and for heterogeneous reactions. However, there is a lack of detailed information and in situ measurements of surface tension of such nanosized droplets. Here we present a study of the combined effect of zwitterionic glycine (ZGLY) and sea salt in nanosized water droplets using molecular dynamics simulations, where particular emphasis is placed on the surface tension for the nanosized droplets. The critical supersaturation is estimated by the Köhler equation. It is found that dissolved sea salt interacts with ZGLY through a water bridge and weakens the hydrogen bonds among ZGLYs, which has a significant effect on both surface tension and water vapor supersaturation. Clusters of glycine mixed with sea salt deliquesce more efficiently and have higher growth factors.

  12. Potential of combining of liquid membranes and molecularly imprinted polymers in extraction of 17beta-estradiol from aqueous samples.

    Science.gov (United States)

    Nemulenzi, Olga; Mhaka, Byron; Cukrowska, Ewa; Ramström, Olof; Tutu, Hlanganani; Chimuka, Luke

    2009-06-01

    The potential of combination of liquid membranes (microporous membrane liquid-liquid extraction) and molecularly imprinted polymers (MIPs) was performed using 17beta-estradiol (E2) as model compound. The model compound was extracted from aqueous sample through a hydrophobic porous membrane that was impregnated with hexane/ethyl acetate (3:2), which also formed part of the acceptor phase. In the acceptor phase, the compound was bound onto MIP particles that were also part of the organic phase. The potential of such combination was optimised for the type and amount of MIP particles in the organic acceptor phase, the extraction time, and the type of organic acceptor solvent. Ultrasound assisted binding of E2 onto MIP particles was also investigated. MIPs prepared by precipitation polymerization were found to be superior to those prepared by bulk polymerization. Increase in the extraction time and the amount of MIP particles in the acceptor phase led to more E2 binding onto the MIP particles. Hexane/ethyl acetate (3:2) as an organic acceptor was found to give higher E2 binding onto MIP particles compared to toluene, diethyl ether, and hexane. Ultrasound was furthermore found to increase the binding of E2 onto MIP particles. The selectivity of the technique was demonstrated by extracting wastewater and where clean chromatograms were obtained compared to liquid membrane extractions (SLMs) alone.

  13. A randomized controlled trial of combined 5-fluorouracil and low-molecular-weight heparin in management of established proliferative vitreoretinopathy.

    Science.gov (United States)

    Charteris, David G; Aylward, G William; Wong, David; Groenewald, Carl; Asaria, Riaz H Y; Bunce, Catey

    2004-12-01

    To determine the efficacy of a combination of 5-fluorouracil and low-molecular-weight heparin (LMWH) to improve the outcome of surgery for established proliferative vitreoretinopathy (PVR). Double-masked, prospective, randomized, placebo-controlled clinical trial. Three tertiary-referral teaching hospital vitreoretinal surgical units. One hundred fifty-seven patients with established PVR (grade C, anterior or posterior) undergoing vitrectomy surgery. All patients underwent vitreoretinal surgery and silicone oil exchange with or without membrane peeling and/or retinectomy. Patients were randomly allocated to perioperative infusion with or without 5-fluorouracil (200 microg/ml) and LMWH (5 IU/ml) in Hartmann's solution for 1 hour. The primary outcome measure was defined as posterior retinal reattachment after removal of silicone oil without any reoperations at 6 months. Secondary outcome measures recorded were posterior retinal reattachment, localized/tractional retinal detachment, visual acuity, macular pucker, hypotony, glaucoma, keratopathy, and cataract. Removal of silicone oil and reoperations were also recorded. Overall, at 6 months 84% of patients had full retinal reattachment and 94% had stable posterior retinal reattachment. There was no significant difference in success in the primary outcome measure (56%, treatment group; 51%, placebo group; P = 0.59) or in secondary outcome measures or rates of complications. Secondary macular pucker occurred less often in the treatment group (6% vs. 17% at 6 months, P = 0.068). A perioperative infusion of combined 5-fluorouracil and LMWH does not significantly increase the success rate of vitreoretinal surgery for established PVR.

  14. Combined effects of low-molecular-weight organic acids on mobilization of arsenic and lead from multi-contaminated soils.

    Science.gov (United States)

    Onireti, Olaronke O; Lin, Chuxia; Qin, Junhao

    2017-03-01

    A batch experiment was conducted to examine the combined effects of three common low-molecular-weight organic acids (LMWOAs) on the mobilization of arsenic and lead in different types of multi-contaminated soils. The capacity of individual LMWOAs (at a same molar concentration) to mobilize soil-borne As and Pb varied significantly. The combination of the organic acids did not make a marked "additive" effect on the mobilization of the investigated three elements. An "antagonistic" effect on element mobilization was clear in the treatments involving oxalic acid for some soils. The acid strength of a LMWOA did not play an important role in controlling the mobilization of elements. While the mobilization of As and Pb was closely associated with the dissolution of soil-borne Fe, soil properties such as original soil pH, organic matter contents and the total amount of the element relative to the total Fe markedly complicated the mobility of that element. Aging led to continual consumption of proton introduced from addition of LMWOAs and consequently caused dramatic changes in solution-borne Fe, which in turn resulted in change in As and Pb in the soil solution though different elements behaved differently. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Effective charges of ionic liquid determined self-consistently through combination of molecular dynamics simulation and density-functional theory.

    Science.gov (United States)

    Ishizuka, Ryosuke; Matubayasi, Nobuyuki

    2017-11-15

    A self-consistent scheme combining the molecular dynamics (MD) simulation and density functional theory (DFT) was recently proposed to incorporate the effects of the charge transfer and polarization of ions into non-poralizable force fields of ionic liquids for improved description of energetics and dynamics. The purpose of the present work is to analyze the detailed setups of the MD/DFT scheme by focusing on how the basis set, exchange-correlation (XC) functional, charge-fitting method or force field for the intramolecular and Lennard-Jones interactions affects the MD/DFT results of 1,3-dimethylimidazolium bis(trifluoromethylsulfonyl) imide ( [C1mim][NTf2]) and 1-ethyl-3-methylimidazolium glycinate ( [C2mim][Gly]). It was found that the double-zeta valence polarized or larger size of basis set is required for the convergence of the effective charge of the ion. The choice of the XC functional was further not influential as far as the generalized gradient approximation is used. The charge-fitting method and force field govern the accuracy of the MD/DFT scheme, on the other hand. We examined the charge-fitting methods of Blöchl, the iterative Hirshfeld (Hirshfeld-I), and REPEAT in combination with Lopes et al.'s force field and general AMBER force field. There is no single combination of charge fitting and force field that provides good agreements with the experiments, while the MD/DFT scheme reduces the effective charges of the ions and leads to better description of energetics and dynamics compared to the original force field with unit charges. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  16. Nanomedicine: nanoparticles, molecular biosensors, and targeted gene/drug delivery for combined single-cell diagnostics and therapeutics

    Science.gov (United States)

    Prow, Tarl W.; Salazar, Jose H.; Rose, William A.; Smith, Jacob N.; Reece, Lisa; Fontenot, Andrea A.; Wang, Nan A.; Lloyd, R. Stephen; Leary, James F.

    2004-07-01

    Next generation nanomedicine technologies are being developed to provide for continuous and linked molecular diagnostics and therapeutics. Research is being performed to develop "sentinel nanoparticles" which will seek out diseased (e.g. cancerous) cells, enter those living cells, and either perform repairs or induce those cells to die through apoptosis. These nanoparticles are envisioned as multifunctional "smart drug delivery systems". The nanosystems are being developed as multilayered nanoparticles (nanocrystals, nanocapsules) containing cell targeting molecules, intracellular re-targeting molecules, molecular biosensor molecules, and drugs/enzymes/gene therapy. These "nanomedicine systems" are being constructed to be autonomous, much like present-day vaccines, but will have sophisticated targeting, sensing, and feedback control systems-much more sophisticated than conventional antibody-based therapies. The fundamental concept of nanomedicine is to not to just kill all aberrant cells by surgery, radiation therapy, or chemotherapy. Rather it is to fix cells, when appropriate, one cell-at-a-time, to preserve and re-build organ systems. When cells should not be fixed, such as in cases where an improperly repaired cell might give rise to cancer cells, the nanomedical therapy would be to induce apoptosis in those cells to eliminate them without the damagin bystander effects of the inflammatory immune response system reacting to necrotic cells or those which have died from trauma or injury. The ultimate aim of nanomedicine is to combine diagnostics and therapeutics into "real-time medicine", using where possible in-vivo cytometry techniques for diagnostics and therapeutics. A number of individual components of these multi-component nanoparticles are already working in in-vitro and ex-vivo cell and tissue systems. Work has begun on construction of integrated nanomedical systems.

  17. Probing of possible olanzapine binding site on human serum albumin: Combination of spectroscopic methods and molecular dynamics simulation

    Energy Technology Data Exchange (ETDEWEB)

    Shahlaei, Mohsen, E-mail: mohsenshahlaei@yahoo.com [Nano drug delivery research Center, Research Center, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Rahimi, Behnoosh [Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Student research committee, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Ashrafi-Kooshk, Mohammad Reza [Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Sadrjavadi, Komail [Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Department of Pharmacognosy and Biotechnology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Khodarahmi, Reza, E-mail: rkhodarahmi@mbrc.ac.ir [Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Department of Pharmacognosy and Biotechnology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of)

    2015-02-15

    Human serum albumin (HSA)-drug binding affinity is one of the major factors that determine the pharmacokinetics, halftime and bioavailability of drugs in various tissues. In the present study, the interaction of olanzapine (OLZ), a thienobenzodiazepine drug, administered for the treatment of schizophrenia and bipolar disorder, with HSA has been studied using spectroscopic methods such as ultraviolet absorbance, fluorescence and FTIR combined with computational procedures. Analyzing of the Stern–Volmer quenching data showed only one primary binding site on HSA with a binding constant of 4.12×10{sup 4} M{sup −1} at 298 K. Thermodynamic analyses showed enthalpy change (ΔH°) and entropy change (ΔS°) were 28.03±3.42 kJ mol{sup −1} and −25.52±11.52 J mol{sup −1} K{sup −1}, respectively. Molecular docking results suggested the hydrophobic residues such as Val{sub 216}, Leu{sub 327}, Ala{sub 350} and polar residues such as Glu{sub 354} play an important role in the drug binding. Decrement in α-helix content of the protein upon OLZ binding was also confirmed by evidences provided by molecular dynamics simulation as well as FTIR spectroscopy. - Highlights: • Leu{sub 327}, Ala{sub 350} as well as hydrophilic residues of HSA play an important role in the binding reaction. • The drug has only one primary binding site on HSA with a binding constant of 4.12×10{sup 4} M{sup −1} at 298 K. • The drug binds near to site I.

  18. Epitope mapping of monoclonal antibody HPT-101: a study combining dynamic force spectroscopy, ELISA and molecular dynamics simulations

    Science.gov (United States)

    Stangner, Tim; Angioletti-Uberti, Stefano; Knappe, Daniel; Singer, David; Wagner, Carolin; Hoffmann, Ralf; Kremer, Friedrich

    2015-12-01

    By combining enzyme-linked immunosorbent assay (ELISA) and optical tweezers-assisted dynamic force spectroscopy (DFS), we identify for the first time the binding epitope of the phosphorylation-specific monoclonal antibody (mAb) HPT-101 to the Alzheimer's disease relevant peptide tau[pThr231/pSer235] on the level of single amino acids. In particular, seven tau isoforms are synthesized by replacing binding relevant amino acids by a neutral alanine (alanine scanning). From the binding between mAb HPT-101 and the alanine-scan derivatives, we extract specific binding parameters such as bond lifetime {τ }0, binding length {x}{ts}, free energy of activation {{Δ }}G (DFS) and affinity constant {K}{{a}} (ELISA, DFS). Based on these quantities, we propose criteria to identify essential, secondary and non-essential amino acids, being representative of the antibody binding epitope. The obtained results are found to be in full accord for both experimental techniques. In order to elucidate the microscopic origin of the change in binding parameters, we perform molecular dynamics (MD) simulations of the free epitope in solution for both its parent and modified form. By taking the end-to-end distance {d}{{E}-{{E}}} and the distance between the α-carbons {d}{{C}-{{C}}} of the phosphorylated residues as gauging parameters, we measure how the structure of the epitope depends on the type of substitution. In particular, whereas {d}{{C}-{{C}}} is sometimes conserved between the parent and modified form, {d}{{E}-{{E}}} strongly changes depending on the type of substitution, correlating well with the experimental data. These results are highly significant, offering a detailed microscopic picture of molecular recognition.

  19. Synthesis of a pH-Sensitive Hetero[4]Rotaxane Molecular Machine that Combines [c2]Daisy and [2]Rotaxane Arrangements.

    Science.gov (United States)

    Waelès, Philip; Riss-Yaw, Benjamin; Coutrot, Frédéric

    2016-05-10

    The synthesis of a novel pH-sensitive hetero[4]rotaxane molecular machine through a self-sorting strategy is reported. The original tetra-interlocked molecular architecture combines a [c2]daisy chain scaffold linked to two [2]rotaxane units. Actuation of the system through pH variation is possible thanks to the specific interactions of the dibenzo-24-crown-8 (DB24C8) macrocycles for ammonium, anilinium, and triazolium molecular stations. Selective deprotonation of the anilinium moieties triggers shuttling of the unsubstituted DB24C8 along the [2]rotaxane units. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. A combination of immunohistochemistry and molecular approaches improves highly sensitive detection of BRAF mutations in papillary thyroid cancer.

    Science.gov (United States)

    Martinuzzi, Claudia; Pastorino, Lorenza; Andreotti, Virginia; Garuti, Anna; Minuto, Michele; Fiocca, Roberto; Bianchi-Scarrà, Giovanna; Ghiorzo, Paola; Grillo, Federica; Mastracci, Luca

    2016-09-01

    The optimal method for BRAF mutation detection remains to be determined despite advances in molecular detection techniques. The aim of this study was to compare, against classical Sanger sequencing, the diagnostic performance of two of the most recently developed, highly sensitive methods: BRAF V600E immunohistochemistry (IHC) and peptide nucleic-acid (PNA)-clamp qPCR. BRAF exon 15 mutations were searched in formalin-fixed paraffin-embedded tissues from 86 papillary thyroid carcinoma using the three methods. The limits of detection of Sanger sequencing in borderline or discordant cases were quantified by next generation sequencing. BRAF mutations were found in 74.4 % of cases by PNA, in 71 % of cases by IHC, and in 64 % of cases by Sanger sequencing. Complete concordance for the three methods was observed in 80 % of samples. Better concordance was observed with the combination of two methods, particularly PNA and IHC (59/64) (92 %), while the combination of PNA and Sanger was concordant in 55 cases (86 %). Sensitivity of the three methods was 99 % for PNA, 94.2 % for IHC, and 89.5 % for Sanger. Our data show that IHC could be used as a cost-effective, first-line method for BRAF V600E detection in daily practice, followed by PNA analysis in negative or uninterpretable cases, as the most efficient method. PNA-clamp quantitative PCR is highly sensitive and complementary to IHC as it also recognizes other mutations besides V600E and it is suitable for diagnostic purposes.

  1. Two-tier approach combining molecular and culture-based techniques for optimized detection of vancomycin-resistant enterococci.

    Science.gov (United States)

    Both, Anna; Franke, Gefion C; Mirwald, Nadine; Lütgehetmann, Marc; Christner, Martin; Klupp, Eva-Maria; Belmar Campos, Cristina; Büttner, Henning; Aepfelbacher, Martin; Rohde, Holger

    2017-08-24

    Given constantly high or even rising incidences of both colonization and infection with vancomycin-resistant enterococci (VRE), timely and accurate identification of carriers in high-risk patient populations is of evident clinical importance. In this study, a two-tier approach consisting of PCR-based screening and cultural confirmation of positive results is compared to the conventional approach solely based on culture on selective media. The 2-tier strategy was highly consistent with the conventional approach, and was found to possess high sensitivity and specificity (93.1% and 100%, respectively). The introduction of the PCR-based combined VRE screening approach significantly (P<0.0001) reduced median overall time to result by 44.3hours. The effect was found to be most pronounced in VRE negative samples. Positive vanA PCR was highly consistent with culture (PPV: 92.0%, 95% CI: 72.5-98.6%, NPV: 99.6%, 95% CI: 98.9-99.6%), thus allowing for preliminary reporting of VRE detection. In contrast, a vanB positive PCR does not allow for preliminary reporting (PPV: 58.5%, 95% CI: 44.2-71.6%, NPV: 99.8%, 95% CI: 99.2-100%). The introduction of a molecular assay for rapid detection of VRE from rectal swabs combined with cultural confirmation proved to be reliable and time saving, especially in a setting of low VRE prevalence and predominance of vanA positive strains. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Combining `OMIC tools and other targeted molecular methods to evaluate iron limitation of diatoms in the Northeast Pacific Ocean.

    Science.gov (United States)

    Chappell, D.; Wallace, J.; Jenkins, B. D.; Powell, K.

    2016-02-01

    Diatoms are an abundant and widespread group of phytoplankton capable of exerting a profound influence on global carbon cycling. It is widely accepted that iron (Fe) controls diatom production in many ocean systems and the Fe stress response has been a focus of research for some time. Assessing the Fe status of natural diatom populations has proven challenging, as diatom species in the same genus may be difficult to distinguish using microscopy and the physiological and molecular responses to Fe stress can vary widely within a genus. A targeted high-throughput sequencing method to characterize the diatom community in field samples has been developed. Additionally, comparative transcriptomics of laboratory experiments with ecologically relevant species have been used to elucidate genes whose expression is tightly coupled to specific limitation scenarios. These two methods have been combined with data mining of the growing database of diatom transcriptomes to develop species-specific markers of physiological status in field populations. Data will be presented on the development and use of these methods to analyze samples collected on field expeditions to the Northeast Pacific Ocean sampling across gradients of Fe.

  3. The combined effect of AGN and supernovae feedback in launching massive molecular outflows in high-redshift galaxies

    Science.gov (United States)

    Biernacki, Pawel; Teyssier, Romain

    2018-01-01

    We have recently improved our model of active galactic nucleus (AGN) by attaching the supermassive black hole (SMBH) to a massive nuclear star cluster (NSC). Here we study the effects of this new model in massive, gas-rich galaxies with several simulations of different feedback recipes with the hydrodynamics code RAMSES. These simulations are compared to a reference simulation without any feedback, in which the cooling halo gas is quickly consumed in a burst of star formation. In the presence of strong supernovae (SN) feedback, we observe the formation of a galactic fountain that regulates star formation over a longer period, but without halting it. If only AGN feedback is considered, as soon as the SMBH reaches a critical mass, strong outflows of hot gas are launched and prevent the cooling halo gas from reaching the disk, thus efficiently halting star formation, leading to the so-called "quenching". If both feedback mechanisms act in tandem, we observe a non-linear coupling, in the sense that the dense gas in the supernovae-powered galactic fountain is propelled by the hot outflow powered by the AGN at much larger radii than without AGN. We argue that these particular outflows are able to unbind dense gas from the galactic halo, thanks to the combined effect of SN and AGN feedback. We speculate that this mechanism occurs at the end of the fast growing phase of SMBH, and is at the origin of the dense molecular outflows observed in many massive high-redshift galaxies.

  4. Counter-ion binding and mobility in the presence of hydrophobic polyions – combining molecular dynamics simulations and NMR

    Directory of Open Access Journals (Sweden)

    Maksym Druchok

    2016-06-01

    Full Text Available Counter-ion binding and mobility in aqueous solutions of partially hydrophobic ionene oligoions is studied here by a combination of all-atomic molecular dynamics (MD simulations and NMR (19F and 81Br nuclei measurements. We present results for 12, 12–ionenes in the presence of different halide ions (F−, Cl−, Br− and I−, as well as their mixtures; the latter allowing us to probe counter-ion selectivity of these oligoions. We consolidate both structural and dynamic information, in particular simulated radial distribution functions and average residence times of counter-ions in the vicinity of ionenes and NMR data in the form of counter-ion chemical shift and self-diffusion coefficients. On one hand, previously reported enthalpy of dilution and mixing measurements show a reverse counter-ion sequence for 12, 12–ionenes with respect to their less hydrophobic 3, 3– and 6, 6– analogues. On the other hand, the current MD and NMR data, reflecting the counter-ion binding tendencies to the ionene chain, give evidence for the same ordering as that observed by MD for 3, 3–ionenes. This is not seen as a contradiction and can be rationalized on the basis of increasing chain hydrophobicity, which has different consequences for enthalpy and ion-binding. The latter is reflecting free energy changes and as such includes both enthalpic and entropic contributions.

  5. Counter-ion binding and mobility in the presence of hydrophobic polyions – combining molecular dynamics simulations and NMR

    Energy Technology Data Exchange (ETDEWEB)

    Druchok, Maksym [Institute for Condensed Matter Physics, Svientsitskii 1, 79011 Lviv (Ukraine); Malikova, Natalie; Rollet, Anne-Laure [Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR 8234, PHENIX, F-75005, Paris (France); Vlachy, Vojko, E-mail: vojko.vlachy@fkkt.uni-lj.si [Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana (Slovenia)

    2016-06-15

    Counter-ion binding and mobility in aqueous solutions of partially hydrophobic ionene oligoions is studied here by a combination of all-atomic molecular dynamics (MD) simulations and NMR ({sup 19}F and {sup 81}Br nuclei) measurements. We present results for 12, 12–ionenes in the presence of different halide ions (F{sup −}, Cl{sup −}, Br{sup −} and I{sup −}), as well as their mixtures; the latter allowing us to probe counter-ion selectivity of these oligoions. We consolidate both structural and dynamic information, in particular simulated radial distribution functions and average residence times of counter-ions in the vicinity of ionenes and NMR data in the form of counter-ion chemical shift and self-diffusion coefficients. On one hand, previously reported enthalpy of dilution and mixing measurements show a reverse counter-ion sequence for 12, 12–ionenes with respect to their less hydrophobic 3, 3– and 6, 6– analogues. On the other hand, the current MD and NMR data, reflecting the counter-ion binding tendencies to the ionene chain, give evidence for the same ordering as that observed by MD for 3, 3–ionenes. This is not seen as a contradiction and can be rationalized on the basis of increasing chain hydrophobicity, which has different consequences for enthalpy and ion-binding. The latter is reflecting free energy changes and as such includes both enthalpic and entropic contributions.

  6. Combined multispectroscopic and molecular dynamics simulation investigation on the interaction between cyclosporine A and β-lactoglobulin.

    Science.gov (United States)

    Mohseni-Shahri, Fatemeh S; Moeinpour, Farid; Malaekeh-Nikouei, Bizhan; Nassirli, Hooriyeh

    2017-02-01

    β-Lactoglobulin (β-LG), the major whey protein in milks of many mammals, has a high affinity for a wide range of compounds. Cyclosporine A (CsA), is an immunosuppressant drug mainly prescribe in organ transplantation to prevent rejection. In this study, the interaction of CsA with β-LG was investigated using various spectroscopic techniques (UV-visible and fluorescence) in an aqueous medium at two temperatures of 298 and 310K in combination with a molecular dynamics simulation study. The titration results indicated that CsA quenched the fluorescence intensity of β-LG through a static mechanism. The binding constants for the binding of CsA to β-LG at two different temperatures 298 and 310K were obtained 1.12×10(5) and 0.87×10(5)M(-1), respectively. Thermodynamic data indicated that the hydrophobic interactions and hydrogen bonds dominate in the binding site. Results of fluorescence resonance energy transfer (FRET) measurements suggest that resonance energy transfer occurs between β-LG and CsA. Moreover, MD simulation results implied that CsA can interact with β-LG, without affecting the secondary structure of β-LG. Experimental and MD simulations data reciprocally supported each other. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest

    Science.gov (United States)

    Arenz, Stefan; Bock, Lars V.; Graf, Michael; Innis, C. Axel; Beckmann, Roland; Grubmüller, Helmut; Vaiana, Andrea C.; Wilson, Daniel N.

    2016-07-01

    Nascent polypeptides can induce ribosome stalling, regulating downstream genes. Stalling of ErmBL peptide translation in the presence of the macrolide antibiotic erythromycin leads to resistance in Streptococcus sanguis. To reveal this stalling mechanism we obtained 3.6-Å-resolution cryo-EM structures of ErmBL-stalled ribosomes with erythromycin. The nascent peptide adopts an unusual conformation with the C-terminal Asp10 side chain in a previously unseen rotated position. Together with molecular dynamics simulations, the structures indicate that peptide-bond formation is inhibited by displacement of the peptidyl-tRNA A76 ribose from its canonical position, and by non-productive interactions of the A-tRNA Lys11 side chain with the A-site crevice. These two effects combine to perturb peptide-bond formation by increasing the distance between the attacking Lys11 amine and the Asp10 carbonyl carbon. The interplay between drug, peptide and ribosome uncovered here also provides insight into the fundamental mechanism of peptide-bond formation.

  8. Study on the molecular interaction of graphene quantum dots with human serum albumin: Combined spectroscopic and electrochemical approaches

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Shan; Qiu, Hangna; Lu, Shuangyan; Zhu, Fawei [College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning 530001 (China); Xiao, Qi, E-mail: qi.xiao@whu.edu.cn [College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning 530001 (China); State Key Laboratory of Virology, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072 (China)

    2015-03-21

    Highlights: • The interactions between GQDs and HSA were systematically investigated. • GQDs could quench the intrinsic fluorescence of HSA via static mode. • The binding site of GQDs was mainly located in site I of HSA. • The potential toxicity of GQDs resulted in the structural damage of HSA. - Abstract: Graphene quantum dots (GQDs) have attracted great attention in biological and biomedical applications due to their super properties, but their potential toxicity investigations are rarely involved. Since few studies have addressed whether GQDs could bind and alter the structure and function of human serum albumin (HSA), the molecular interaction between GQDs and HSA was systematically characterized by the combination of multispectroscopic and electrochemical approaches. GQDs could quench the intrinsic fluorescence of HSA via static mode. The competitive binding fluorescence assay revealed that the binding site of GQDs was site I of HSA. Some thermodynamic parameters suggested that GQDs interacted with HSA mainly through van der Waals interactions and hydrogen bonding interactions, and protonation might also participate in the process. As further revealed by FT-IR spectroscopy and circular dichroism technique, GQDs could cause the global and local conformational change of HSA, which illustrated the potential toxicity of GQDs that resulted in the structural damage of HSA. Electrochemical techniques demonstrated the complex formation between GQDs and HSA. Our results offered insights into the binding mechanism of GQDs with HSA and provided important information for possible toxicity risk of GQDs to human health.

  9. The combination therapy of imatinib and dasatinib achieves long-term molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia

    OpenAIRE

    Zhu, Yu; Pan, Liangqin; Hong, Ming; Liu, Weixing; Qiao, Chun; Li, Jianyong; Qian, Sixuan

    2014-01-01

    Abstract For patients with chronic myeloid leukemia (CML) failing imatinib therapy, second-generation tyrosine kinase inhibitors (TKIs) are recommended. Here, we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib, but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullary toxicity. Our observations suggest that combination of TKIs may provide an additive/...

  10. Ab initio absorption spectrum of NiO combining molecular dynamics with the embedded cluster approach in a discrete reaction field

    NARCIS (Netherlands)

    Domingo, Alex; Rodriguez-Fortea, Antonio; Swart, Marcel; de Graaf, Coen; Broer-Braam, Henderika

    2012-01-01

    We developed a procedure that combines three complementary computational methodologies to improve the theoretical description of the electronic structure of nickel oxide. The starting point is a Car-Parrinello molecular dynamics simulation to incorporate vibrorotational degrees of freedom into the

  11. Possible Peroxo State of the Dicopper Site of Particulate Methane Monooxygenase from Combined Quantum Mechanics and Molecular Mechanics Calculations.

    Science.gov (United States)

    Itoyama, Shuhei; Doitomi, Kazuki; Kamachi, Takashi; Shiota, Yoshihito; Yoshizawa, Kazunari

    2016-03-21

    Enzymatic methane hydroxylation is proposed to efficiently occur at the dinuclear copper site of particulate methane monooxygenase (pMMO), which is an integral membrane metalloenzyme in methanotrophic bacteria. The resting state and a possible peroxo state of the dicopper active site of pMMO are discussed by using combined quantum mechanics and molecular mechanics calculations on the basis of reported X-ray crystal structures of the resting state of pMMO by Rosenzweig and co-workers. The dicopper site has a unique structure, in which one copper is coordinated by two histidine imidazoles and another is chelated by a histidine imidazole and primary amine of an N-terminal histidine. The resting state of the dicopper site is assignable to the mixed-valent Cu(I)Cu(II) state from a computed Cu-Cu distance of 2.62 Å from calculations at the B3LYP-D/TZVP level of theory. A μ-η(2):η(2)-peroxo-Cu(II)2 structure similar to those of hemocyanin and tyrosinase is reasonably obtained by using the resting state structure and dioxygen. Computed Cu-Cu and O-O distances are 3.63 and 1.46 Å, respectively, in the open-shell singlet state. Structural features of the dicopper peroxo species of pMMO are compared with those of hemocyanin and tyrosinase and synthetic dicopper model compounds. Optical features of the μ-η(2):η(2)-peroxo-Cu(II)2 state are calculated and analyzed with TD-DFT calculations.

  12. Combined effect of temperature and ammonia on molecular response and survival of the freshwater crustacean Gammarus pulex.

    Science.gov (United States)

    Henry, Y; Piscart, C; Charles, S; Colinet, H

    2017-03-01

    Freshwater ecosystems are experiencing mounting pressures from agriculture, urbanization, and climate change, which could drastically impair aquatic biodiversity. As nutrient inputs increase and temperatures rise, ammonia (NH 3 ) concentration is likely to be associated with stressful temperatures. To investigate the interaction between NH 3 and temperature on aquatic invertebrate survival, we performed a factorial experiment on the survival and molecular response of Gammarus pulex, with temperature (10, 15, 20, and 25°C) and NH 3 (0, 0.5, 1, 2, 3, and 4mg NH 3 /L) treatments. We observed an unexpected antagonistic interaction between temperature and NH 3 concentration, meaning survival in the 4mg NH 3 /L treatment was higher at 25°C than at the control temperature of 10°C. A toxicokinetic-toxicodynamic (TK-TD) model was built to describe this antagonistic interaction. While the No Effect Concentration showed no significant variation across temperatures, the 50% lethal concentration at the end of the experiment increased from 2.7 (2.1-3.6) at 10°C to 5.5 (3.5- 23.4) mg NH 3 /L at 25°C. Based on qPCR data, we associated these survival patterns to variations in the expression of the hsp70 gene, a generic biomarker of stress. However, though there was a 14-fold increase in hsp70 mRNA expression for gammarids exposed to 25°C compared to controls, NH 3 concentration had no effect on hsp70 mRNA synthesis across temperatures. Our results demonstrate that the effects of combined environmental stressors, like temperature and NH 3 , may strongly differ from simple additive effects, and that stress response to temperature can actually increase resilience to nutrient pollution in some circumstances. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Combination of culture-dependent and culture-independent molecular methods for the determination of lactic microbiota in sucuk.

    Science.gov (United States)

    Kesmen, Z; Yetiman, A E; Gulluce, A; Kacmaz, N; Sagdic, O; Cetin, B; Adiguzel, A; Sahin, F; Yetim, H

    2012-02-15

    In this study, the culture-dependent and culture-independent molecular methods were used for the identification of lactic acid bacteria (LAB) in sucuk a Turkish fermented dry sausage. On the one hand, the PCR-DGGE method targetting the V1 and V3 regions of 16S DNA was applied to DNA that was directly extracted from sucuk samples. On the other hand, rep-PCR fingerprinting was performed for the primary differentiation and grouping of the isolates, and the results were confirmed by sequencing of the 16S rDNA and 16S-23S rDNA intergenic spacer region. As a result of the PCR-DGGE analysis of all the samples, total 8 different lactic acid bacteria were identified, and Lactobacillus sakei, Lactobacillus curvatus and Weissella viridescens were the dominant microbiota among these bacteria. The culture-dependent approach indicated that the majority of the strains belonged to the Lactobacillus genera including Lb. sakei, Lactobacillus plantarum, Lb. curvatus, Lactobacillus brevis, Lactobacillus farciminis and Lactobacillus alimentarius. However, Leuconostoc and Weisella were also detected as minor genera. Again, Lactococcus piscium, Weissella halotolerans, Staphylococcus succinus and the comigrated Staphylococcus piscifermentans/Staphylococcus condimenti/Staphylococcus carnosus group were detected only with the culture-independent method while Lb. plantarum, Leuconostoc mesenteroides and Leuconostoc citreum were identified only by using the culture-dependent method. In the results, it was concluded that the combination of culture-dependent and culture-independent methods was necessary for reliable and detailed investigation of LAB communities in fermented food products. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Simulating a 100 keV cascade in a simplified nuclear glass by a method combining ballistic and classical molecular dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Delaye, J.-M. [Commissariat a l' energie atomique (CEA), Rhone Valley Research Center, DEN/DTCD/SECM/LCLT, BP 17171, 30207 Bagnols-sur-Ceze Cedex (France)]. E-mail: jean-marc.delaye@cea.fr; Ghaleb, D. [Commissariat a l' energie atomique (CEA), Rhone Valley Research Center, DEN/DTCD/SECM/LCLT, BP 17171, 30207 Bagnols-sur-Ceze Cedex (France)

    2006-09-15

    The CoMoD method (combined molecular dynamics) extends the scope of classical molecular dynamics to allow the investigation of energy levels corresponding to actual recoil nuclei with shorter computation times. The results obtained at 100 keV confirm those obtained by classical molecular dynamics at lower energies. After the acceleration of the initial projectile, the glass passes through a depolymerization phase that reaches a maximum before structure recovery. The 100 keV cascade simulated here shows a persistent final depolymerization of about 150 chemical bonds. We also observe a decrease in the atomic density along the primary or secondary projectile path within a radius of 15 A. There does not seem to be any reason that would prevent applying the CoMoD method to other glass or crystalline matrices, although each matrix will require reconfiguration.

  15. Combined 3D-QSAR, molecular docking, molecular dynamics simulation, and binding free energy calculation studies on the 5-hydroxy-2H-pyridazin-3-one derivatives as HCV NS5B polymerase inhibitors.

    Science.gov (United States)

    Yu, Haijing; Fang, Yu; Lu, Xia; Liu, Yongjuan; Zhang, Huabei

    2014-01-01

    The NS5B RNA-dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti-hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5-hydroxy-2H-pyridazin-3-one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D-QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40-ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC50 values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM-PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors. © 2013 John Wiley & Sons A/S.

  16. Organic field-effect transistors as a test-bed for molecular electronics : A combined study with large-area molecular junctions

    NARCIS (Netherlands)

    Asadi, Kamal; Katsouras, Ilias; Harkema, Jan; Gholamrezaie, Fatemeh; Smits, Edsger C. F.; Biscarini, Fabio; Blom, Paul W. M.; de Leeuw, Dago M.

    2012-01-01

    The contact resistance of a transistor using self-assembled monolayer (SAM)-modified source and drain electrodes depends on the SAM tunnel resistance, the height of the injection barrier and the morphology at the contact. To disentangle the different contributions, we have combined here the

  17. Organic field-effect transistors as a test-bed for molecular electronics : a combined study with large-area molecular junctions

    NARCIS (Netherlands)

    Asadi, K.; Katsouras, I.; Harkema, J.; Gholamrezaie, F.; Smits, E.C.P.; Biscarini, F.; Blom b, P.W.M.; Leeuw, D.M. de

    2012-01-01

    The contact resistance of a transistor using self-assembled monolayer (SAM)-modified source and drain electrodes depends on the SAM tunnel resistance, the height of the injection barrier and the morphology at the contact. To disentangle the different contributions, we have combined here the

  18. A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors.

    Science.gov (United States)

    Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal

    2016-11-01

    Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study, pharmacophore and atom-based 3D-QSAR studies were carried out for pyrazolopyridine and quinoline derivatives using Schrödinger suite 2014-3. A four-point pharmacophore model was developed using 74 molecules having pIC50 ranging from 10.1 to 4.5. The best four feature model consists of one hydrogen bond acceptor, two aromatic rings, and one hydrophobic group. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2 )= .9949), cross validation coefficient (Q(2 )= .7291), and Pearson-r (.9107) at six component partial least square factor. The external validation indicated that our QSAR model possessed high predictive power with R(2) value of .88. The generated model was further validated by enrichment studies using the decoy test. Molecular docking, free energy calculation, and molecular dynamics (MD) simulation studies have been performed to explore the putative binding modes of these ligands. A 10-ns MD simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity.

  19. Three-body expansion of the fragment molecular orbital method combined with density-functional tight-binding.

    Science.gov (United States)

    Nishimoto, Yoshio; Fedorov, Dmitri G

    2017-03-15

    The three-body fragment molecular orbital (FMO3) method is formulated for density-functional tight-binding (DFTB). The energy, analytic gradient, and Hessian are derived in the gas phase, and the energy and analytic gradient are also derived for polarizable continuum model. The accuracy of FMO3-DFTB is evaluated for five proteins, sodium cation in explicit solvent, and three isomers of polyalanine. It is shown that FMO3-DFTB is considerably more accurate than FMO2-DFTB. Molecular dynamics simulations for sodium cation in water are performed for 100 ps, yielding radial distribution functions and coordination numbers. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  20. A combination of novel solid-state NMR methods and related software to study molecular assemblies and biomolecules

    NARCIS (Netherlands)

    Gradmann, S.H.E.

    2013-01-01

    Solid-state Nuclear Magnetic Resonance (ssNMR) is a versatile spectroscopic method that can be applied to various samples relevant in life and material science and provides atomic insight into molecular structure, dynamics and assembly. The present thesis describes the diversity and utility of ssNMR

  1. Atomic structure of screw dislocations intersecting the Au(111) surface: A combined scanning tunneling microscopy and molecular dynamics study

    DEFF Research Database (Denmark)

    Engbæk, Jakob; Schiøtz, Jakob; Dahl-Madsen, Bjarke

    2006-01-01

    The atomic-scale structure of naturally occurring screw dislocations intersecting a Au(111) surface has been investigated both experimentally by scanning tunneling microscopy (STM) and theoretically using molecular dynamics (MD) simulations. The step profiles of 166 dislocations were measured using...

  2. The combined effect of salinity and heat reveals a specific physiological, biochemical and molecular response in tomato plants.

    Science.gov (United States)

    Rivero, Rosa M; Mestre, Teresa C; Mittler, Ron; Rubio, Francisco; Garcia-Sanchez, Francisco; Martinez, Vicente

    2014-05-01

    Many studies have described the response mechanisms of plants to salinity and heat applied individually; however, under field conditions some abiotic stresses often occur simultaneously. Recent studies revealed that the response of plants to a combination of two different stresses is specific and cannot be deduced from the stresses applied individually. Here, we report on the response of tomato plants to a combination of heat and salt stress. Interestingly, and in contrast to the expected negative effect of the stress combination on plant growth, our results show that the combination of heat and salinity provides a significant level of protection to tomato plants from the effects of salinity. We observed a specific response of plants to the stress combination that included accumulation of glycine betaine and trehalose. The accumulation of these compounds under the stress combination was linked to the maintenance of a high K(+) concentration and thus a lower Na(+) /K(+) ratio, with a better performance of the cell water status and photosynthesis as compared with salinity alone. Our findings unravel new and unexpected aspects of the response of plants to stress combination and provide a proposed list of enzymatic targets for improving crop tolerance to the abiotic field environment. © 2013 John Wiley & Sons Ltd.

  3. Combinations of alkaloids affecting different molecular targets with the saponin digitonin can synergistically enhance trypanocidal activity against Trypanosoma brucei brucei

    National Research Council Canada - National Science Library

    Krstin, Sonja; Peixoto, Herbenya Silva; Wink, Michael

    2015-01-01

    .... In this study, the potential synergism of mutual combinations of bioactive alkaloids and alkaloids with a membrane-active steroidal saponin, digitonin, was explored with regard to their effect on T. b. brucei...

  4. Quantum Mechanics/Molecular Mechanics Method Combined with Hybrid All-Atom and Coarse-Grained Model: Theory and Application on Redox Potential Calculations.

    Science.gov (United States)

    Shen, Lin; Yang, Weitao

    2016-04-12

    We developed a new multiresolution method that spans three levels of resolution with quantum mechanical, atomistic molecular mechanical, and coarse-grained models. The resolution-adapted all-atom and coarse-grained water model, in which an all-atom structural description of the entire system is maintained during the simulations, is combined with the ab initio quantum mechanics and molecular mechanics method. We apply this model to calculate the redox potentials of the aqueous ruthenium and iron complexes by using the fractional number of electrons approach and thermodynamic integration simulations. The redox potentials are recovered in excellent accordance with the experimental data. The speed-up of the hybrid all-atom and coarse-grained water model renders it computationally more attractive. The accuracy depends on the hybrid all-atom and coarse-grained water model used in the combined quantum mechanical and molecular mechanical method. We have used another multiresolution model, in which an atomic-level layer of water molecules around redox center is solvated in supramolecular coarse-grained waters for the redox potential calculations. Compared with the experimental data, this alternative multilayer model leads to less accurate results when used with the coarse-grained polarizable MARTINI water or big multipole water model for the coarse-grained layer.

  5. Combined role of molecular diffusion, mean streaming and helicity in the eddy diffusivity of short-correlated random flows

    CERN Document Server

    Afonso, Marco Martins; Gama, Sílvio

    2016-01-01

    We analytically investigate the effective-diffusivity tensor of a tracer particle in a fluid flow endowed with a short correlation time. By means of functional calculus and a multiscale expansion, we write down the main contributions to the eddy diffusivity due to each single physical effect and to their interplays. Namely, besides molecular diffusivity and a constant uniform mean streaming, we take into account the possibility for the (incompressible, Gaussian, stationary, homogeneous, isotropic) turbulent fluctuations to break parity invariance. With respect to the classical turbulence-driven diffusivity amplification for delta-correlated flows, we find that the presence of a short temporal correlation induces a diminution even when coupled with such effects, with two principal exceptions. Notably, the diffusivity is --- perturbatively --- enlarged not only by the helical contribution itself, but also by the interference between molecular diffusion and mean flow.

  6. Molecular basis of the structural stability of hemochromatosis factor E: A combined molecular dynamic simulation and GdmCl-induced denaturation study.

    Science.gov (United States)

    Khan, Parvez; Parkash, Amresh; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-03-01

    Hemochromatosis factor E (HFE) is a member of class I MHC family and plays a significant role in the iron homeostasis. Denaturation of HFE induced by guanidinium chloride (GdmCl) was measured by monitoring changes in [θ]222 (mean residue ellipticity at 222 nm), intrinsic fluorescence emission intensity at 346 nm (F346 ) and the difference absorption coefficient at 287 nm (Δε287) at pH 8.0 and 25°C. Coincidence of denaturation curves of these optical properties suggests that GdmCl-induced denaturation (native (N) state ↔ denatured (D) state) is a two-state process. The GdmCl-induced denaturation was found reversible in the entire concentration range of the denaturant. All denaturation curves were analyzed for ΔGD0, Gibbs free energy change associated with the denaturation equilibrium (N state ↔ D state) in the absence of GdmCl, which is a measure of HFE stability. We further performed molecular dynamics simulation for 40 ns to see the effect of GdmCl on the structural stability of HFE. A well defined correlation was established between in vitro and in silico studies. © 2015 Wiley Periodicals, Inc.

  7. Advances in Human Biology: Combining Genetics and Molecular Biophysics to Pave the Way for Personalized Diagnostics and Medicine

    Directory of Open Access Journals (Sweden)

    Emil Alexov

    2014-01-01

    Full Text Available Advances in several biology-oriented initiatives such as genome sequencing and structural genomics, along with the progress made through traditional biological and biochemical research, have opened up a unique opportunity to better understand the molecular effects of human diseases. Human DNA can vary significantly from person to person and determines an individual’s physical characteristics and their susceptibility to diseases. Armed with an individual’s DNA sequence, researchers and physicians can check for defects known to be associated with certain diseases by utilizing various databases. However, for unclassified DNA mutations or in order to reveal molecular mechanism behind the effects, the mutations have to be mapped onto the corresponding networks and macromolecular structures and then analyzed to reveal their effect on the wild type properties of biological processes involved. Predicting the effect of DNA mutations on individual’s health is typically referred to as personalized or companion diagnostics. Furthermore, once the molecular mechanism of the mutations is revealed, the patient should be given drugs which are the most appropriate for the individual genome, referred to as pharmacogenomics. Altogether, the shift in focus in medicine towards more genomic-oriented practices is the foundation of personalized medicine. The progress made in these rapidly developing fields is outlined.

  8. Probing into the Molecular Requirements for Antioxidant Activity in Plant Phenolic Compounds Utilizing a Combined Strategy of PCA and ANN.

    Science.gov (United States)

    Agatonovic-Kustrin, Snezana; Morton, David W; Ristivojevic, Petar

    2017-01-01

    This study investigates molecular structural requirements that are responsible for the antioxidant activity in phenolic compounds. Antioxidant activity of compounds was determined with a 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay. Principal component analysis (PCA) was used to classify phenolic antioxidants according to the key molecular features that contribute to their antioxidant activity. Artificial neutral networks (ANNs) was used to develop a predictive QSAR model. Both models agreed that structural characteristics of phenolic compounds responsible for the antioxidant activity include: (1) number and position of alcohol groups on the aromatic ring; (2) molecular size; (3) flexibility/bulkiness; and (4) water solubility. PCA has classified data into phenolic acids and flavonoids, suggesting two distinct mechanisms of action. ANN has confirmed different mechanisms of action for flavonoids and polyphenolic acids, i.e. breaking of free radical chain reactions by donation of a hydrogen atom to neutralise a free radical and the chelating ability of polyphenolic acids. Although two phenolic acids may have the same relative polarity, their different functional groups may drastically change the nature of their interactions with free radicals, and their antioxidant activity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Structural Studies of Phycobiliproteins from Spirulina: Combining Spectroscopy, Thermodynamics, and Molecular Modeling in an Undergraduate Biochemistry Experiment

    Science.gov (United States)

    Taylor, Ann T. S.; Feller, Scott E.

    2002-12-01

    Molecular modeling provides a powerful mechanism for students to connect molecular-level structural changes with macroscopically observable properties. We describe an experiment that integrates spectroscopy, thermodynamics, and molecular modeling into a single activity examining structural changes in phycobiliproteins upon denaturation with urea. Phycobiliproteins contain a covalently attached chromophore, phycocyanobilin, which is constrained in a planar conformation by the folded protein. Upon denaturation of the protein, the chromophore undergoes a conformational change, leading to a significant alteration of the absorption spectrum. By measuring the absorbance at 625 nm as a function of urea concentration, the free energy of unfolding can be determined. Students determine the dihedral angles in the chromophore and map the contacts between protein and chromophore using Protein Explorer, a structure visualization program freely available on the Internet. The change in absorption wavelength can be related to the difference between the LUMO and HOMO energies, obtained using PC Spartan Pro, for the chromophore in the folded and unfolded phycobiliprotein. This experiment could be used in a physical chemistry class in a curriculum that integrates biochemistry throughout the course work as well as in a traditional biochemistry course. Featured on the Cover

  10. Identification and characterization of contrasting sunflower genotypes to early leaf senescence process combining molecular and physiological studies (Helianthus annuus L.).

    Science.gov (United States)

    López Gialdi, A I; Moschen, S; Villán, C S; López Fernández, M P; Maldonado, S; Paniego, N; Heinz, R A; Fernandez, P

    2016-09-01

    Leaf senescence is a complex mechanism ruled by multiple genetic and environmental variables that affect crop yields. It is the last stage in leaf development, is characterized by an active decline in photosynthetic rate, nutrients recycling and cell death. The aim of this work was to identify contrasting sunflower inbred lines differing in leaf senescence and to deepen the study of this process in sunflower. Ten sunflower genotypes, previously selected by physiological analysis from 150 inbred genotypes, were evaluated under field conditions through physiological, cytological and molecular analysis. The physiological measurement allowed the identification of two contrasting senescence inbred lines, R453 and B481-6, with an increase in yield in the senescence delayed genotype. These findings were confirmed by cytological and molecular analysis using TUNEL, genomic DNA gel electrophoresis, flow sorting and gene expression analysis by qPCR. These results allowed the selection of the two most promising contrasting genotypes, which enables future studies and the identification of new biomarkers associated to early senescence in sunflower. In addition, they allowed the tuning of cytological techniques for a non-model species and its integration with molecular variables. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Molecular simulation study of the specific combination between four kinds of phthalic acid esters and human serum albumin.

    Science.gov (United States)

    Wu, Zhiwei; Yi, Zhongsheng; Dong, Lu; Zhang, Aiqian

    2016-01-01

    The interaction between endocrine disruptor phthalic acid esters (PAEs) and human serum albumin (HSA) was studied by fluorescence spectroscopy and molecular modeling methods. The efficiency of energy transfer and the distance between HSA and PAEs were calculated. The results showed that all of the four kinds of PAEs could quench the intrinsic fluorescence of the HSA, with the mechanisms of static quenching and non-radiative energy transfer. Molecular docking study and thermodynamic analysis revealed that the binding behavior was mainly governed by hydrophobic force. And the results of site marker competitive experiments and modeling method suggested that the four PAEs would mainly bind to the HSA in sub-domain IIIA, which demonstrated that the experimental results could coordinate with the theoretical results. Molecular dynamic simulation (MD) revealed that HSA did have a slight conformational change when it bound with PAEs. It also verified the greater stability of HSA-PAEs complex compared to free protein. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Selective extraction and determination of chlorogenic acids as combined quality markers in herbal medicines using molecularly imprinted polymers based on a mimic template.

    Science.gov (United States)

    Ji, Wenhua; Zhang, Mingming; Yan, Huijiao; Zhao, Hengqiang; Mu, Yan; Guo, Lanping; Wang, Xiao

    2017-12-01

    We describe a solid-phase extraction adsorbent based on molecularly imprinted polymers (MIPs), prepared with use of a mimic template. The MIPs were used for the selective extraction and determination of three chlorogenic acids as combined quality markers for Lonicera japonica and Lianhua qingwen granules. The morphologies and surface groups of the MIPs were assessed by scanning electron microscopy, Brunauer-Emmett-Teller surface area analysis, and Fourier transform infrared spectroscopy. The adsorption isotherms, kinetics, and selectivity of the MIPs were systematically compared with those of non-molecularly imprinted polymers. The MIPs showed high selectivity toward three structurally similar chlorogenic acids (chlorogenic acid, cryptochlorogenic acid, and neochlorogenic acid). A procedure using molecularly imprinted solid-phase extraction coupled with high-performance liquid chromatography was established for the determination of three chlorogenic acids from Lonicera japonica and Lianhua qingwen granules. The recoveries of the chlorogenic acids ranged from 93.1% to 101.4%. The limits of detection and limits of quantification for the three chlorogenic acids were 0.003 mg g-1 and 0.01 mg g-1, respectively. The newly developed method is thus a promising technique for the enrichment and determination of chlorogenic acids from herbal medicines. Graphical Abstract Mimic molecularly imprinted polymers for the selective extraction of chlorogenic acids.

  13. Combining gravimetric and vibrational spectroscopy measurements to quantify first- and second-shell hydration layers in polyimides with different molecular architectures.

    Science.gov (United States)

    Musto, Pellegrino; Mensitieri, Giuseppe; Lavorgna, Marino; Scarinzi, Gennaro; Scherillo, Giuseppe

    2012-02-02

    In-situ Fourier transform infrared (FTIR) measurements have been carried out at different relative pressures of water vapor to study the H(2)O diffusion in three polyimides differing in their molecular structure and fluorine substitution. Spectral data have been analyzed by difference spectroscopy, least-squares curve fitting, and two-dimensional (2D) correlation spectroscopy, which provided molecular level information on the diffusion mechanism. In particular, two distinct water species were identified corresponding, respectively, to the first and second-shell hydration layers. The spectroscopic analysis demonstrated that the relative population of these species is a function of the total water content in the system. A method has been devised to quantify the water concentration in the two hydration layers, based on a combination of spectroscopic and gravimetric data. The results have been compared with those from an earlier spectroscopic approach reported in the literature and based on the analysis of the carbonyl region.

  14. The molecular mechanism of action of aspirin, curcumin and sulforaphane combinations in the chemoprevention of pancreatic cancer.

    Science.gov (United States)

    Thakkar, Arvind; Sutaria, Dhruvitkumar; Grandhi, B Karthik; Wang, Jeffrey; Prabhu, Sunil

    2013-04-01

    Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with ~37,000 deaths each year. The present study evaluated the chemopreventive potential of a combination of aspirin (ASP), curcumin (CUR) and sulforaphane (SFN) in low doses to human pancreatic cancer cells, MIA PaCa-2 and Panc-1. Results demonstrated that low doses of ASP (1 mM), CUR (10 µM) and SFN (5 µM) (ACS) combination reduced cell viability by ~70% (Pmechanisms.

  15. Integrative Taxonomic Study of the Purse Crab Genus Persephona Leach, 1817 (Brachyura: Leucosiidae): Combining Morphology and Molecular Data

    Science.gov (United States)

    Magalhães, Tatiana; Robles, Rafael; Felder, Darryl L.

    2016-01-01

    Marine crabs of the genus Persephona Leach, 1817 are restricted to American waters of the western Atlantic and eastern Pacific Oceans. Subfamilial assignment of this taxon has varied between authors and its species composition remain in question. We conducted a comparative study based on morphology and molecular phylogenetics for all ten recognized species of Persephona, along with Iliacantha hancocki. We tested whether Persephona finneganae, P. lichtensteinii, and P. crinita represent a single species as suggested by some authors; whether specimens identified as P. punctata, P. mediterranea, and P. aquilonaris warrant treatment as separate species; and whether I. hancocki should be regarded as a junior synonym of P. subovata. Diagnostic morphological characters (of the carapace, chelipeds, and third maxillipeds) were used along with gonopod (male first pleopod 1) features and live coloration. The 16S rRNA and the Cytochrome Oxidase I (COI) (DNA barcoding) mitochondrial genes were used as molecular markers. Both morphological and molecular analyses revealed that putative specimens of P. crinita from Brazil and those assigned to P. finneganae were no different from specimens presently assignable to P. lichtensteinii. P. finneganae is regarded as a junior synonym of P. lichtensteinii, and we apply P. crinita only to specimens we examined from the Gulf of Mexico. Specimens from Brazil previously reported as P. crinita are herewith concluded to represent P. lichtensteinii. Additionally, P. townsendi is a junior synonym of P. orbicularis, Iliacantha hancocki is concluded to be a junior synonym of P. subovata, while P. aquilonaris and P. mediterranea are found to represent separate species. On the basis of our revisions, eight species of Persephona are considered valid, and the reported distribution for P. crinita is restricted. PMID:27099956

  16. Analysis of the ITQ-12 zeolite performance in propane-propylene separations using a combination of experiments and molecular simulations

    NARCIS (Netherlands)

    Gutiérrez-Sevillano, J.J.; Dubbeldam, D.; Rey, F.; Valencia, S.; Palomino, M.; Martín-Calvo, A.; Calero, S.

    2010-01-01

    We present a combined computational and experimental approach to evaluate the suitability of the ITQ-12 nanoporous material (ITW) as a propane−propylene separation device. For this, we have computed adsorption and diffusion of propane and propylene in the ITQ-12 zeolite. The propane isotherm is

  17. Host specificity of North American Rhabdias spp. (Nematoda: Rhabdiasidae): combining field data and experimental infections with a molecular phylogeny.

    Science.gov (United States)

    Langford, Gabriel J; Janovy, John

    2013-04-01

    Lungworms of the cosmopolitan genus Rhabdias are among the most common parasites of amphibians and squamate reptiles. The present study used experimental infections, field studies, and a molecular phylogeny to determine the host specificity of 6 Rhabdias spp. that infect snakes and anurans from North America. The molecular phylogeny suggests Rhabdias ranae from Nebraska and Mississippi may represent separate, cryptic species. In addition, the phylogeny strongly supports separate clades for anuran and snake lungworms. Field studies and experimental infections indicate that snake lungworms are generalist snake parasites; however, laboratory experiments also suggest that lizards can be infected under some environmental conditions. Lungworms from anurans were found not to infect salamanders or reptiles, in nature or in the laboratory; anuran lungworm species ranged from strict host specificity, e.g., R. ranae from Nebraska, to relative generalist, e.g., Rhabdias joaquinensis from Nebraska. Overall, host specificity for species of Rhabdias does not provide support for the evolution of progressive specialization over time. For most species of lungworms, host specificity in nature appears to be limited by both ecological and physiological factors, which vary between species and their hosts. Furthermore, some lungworms, e.g., Rhabdias bakeri from Missouri, appear to be tracking host resources instead of host phylogenies, an example of ecological fitting.

  18. Nanopatterning of functional materials by gas phase pattern deposition of self-assembled molecular thin films in combination with electrodeposition.

    Science.gov (United States)

    George, Antony; Maijenburg, A Wouter; Nguyen, Minh Duc; Maas, Michiel G; Blank, Dave H A; ten Elshof, Johan E

    2011-10-18

    We present a general methodology to pattern functional materials on the nanometer scale using self-assembled molecular templates on conducting substrates. A soft lithographic gas phase edge patterning process using poly(dimethylsiloxane) molds was employed to form electrically isolating organosilane patterns of a few nanometer thickness and a line width that could be tuned by varying the time of deposition. Electrodeposition was employed to deposit patterns of Ni and ZnO on these prepatterned substrates. Deposition occurred only on patches of the substrate where no organosilane monolayer was present. The process is simple, inexpensive, and scalable to large areas. We achieved formation of metallic and oxide material patterns with a lateral resolution of 80 nm. © 2011 American Chemical Society

  19. Combined Monte Carlo/torsion-angle molecular dynamics for ensemble modeling of proteins, nucleic acids and carbohydrates.

    Science.gov (United States)

    Zhang, Weihong; Howell, Steven C; Wright, David W; Heindel, Andrew; Qiu, Xiangyun; Chen, Jianhan; Curtis, Joseph E

    2017-05-01

    We describe a general method to use Monte Carlo simulation followed by torsion-angle molecular dynamics simulations to create ensembles of structures to model a wide variety of soft-matter biological systems. Our particular emphasis is focused on modeling low-resolution small-angle scattering and reflectivity structural data. We provide examples of this method applied to HIV-1 Gag protein and derived fragment proteins, TraI protein, linear B-DNA, a nucleosome core particle, and a glycosylated monoclonal antibody. This procedure will enable a large community of researchers to model low-resolution experimental data with greater accuracy by using robust physics based simulation and sampling methods which are a significant improvement over traditional methods used to interpret such data. Published by Elsevier Inc.

  20. Combined experimental powder X-ray diffraction and DFT data to obtain the lowest energy molecular conformation of friedelin

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Djalma Menezes de; Mussel, Wagner da Nova; Duarte, Lucienir Pains; Silva, Gracia Divina de Fatima; Duarte, Helio Anderson; Gomes, Elionai Cassiana de Lima [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Quimica; Guimaraes, Luciana [Universidade Federal de Sao Joao Del-Rei (UFSJ), MG (Brazil). Dept. de Ciencias Naturais; Vieira Filho, Sidney A., E-mail: bibo@ef.ufop.br [Universidade Federal de Ouro Preto (UFOP), MG (Brazil). Dept. de Farmacia

    2012-07-01

    Friedelin molecular conformers were obtained by Density Functional Theory (DFT) and by ab initio structure determination from powder X-ray diffraction. Their conformers with the five rings in chair-chair-chair-boat-boat, and with all rings in chair, are energy degenerated in gas-phase according to DFT results. The powder diffraction data reveals that rings A, B and C of friedelin are in chair, and rings D and E in boat-boat, conformation. The high correlation values among powder diffraction data, DFT and reported single crystal data indicate that the use of conventional X-ray diffractometer can be applied in routine laboratory analysis in the absence of a single-crystal diffractometer. (author)

  1. Combined experimental powder X-ray diffraction and DFT data to obtain the lowest energy molecular conformation of friedelin

    Directory of Open Access Journals (Sweden)

    Djalma Menezes de Oliveira

    2012-01-01

    Full Text Available Friedelin molecular conformers were obtained by Density Functional Theory (DFT and by ab initio structure determination from powder X-ray diffraction. Their conformers with the five rings in chair-chair-chair-boat-boat, and with all rings in chair, are energy degenerated in gas-phase according to DFT results. The powder diffraction data reveals that rings A, B and C of friedelin are in chair, and rings D and E in boat-boat, conformation. The high correlation values among powder diffraction data, DFT and reported single-crystal data indicate that the use of conventional X-ray diffractometer can be applied in routine laboratory analysis in the absence of a single-crystal diffractometer.

  2. Processes underpinning development and maintenance of diversity in rice in West Africa: evidence from combining morphological and molecular markers.

    Directory of Open Access Journals (Sweden)

    Alfred Mokuwa

    Full Text Available We assessed the interplay of artificial and natural selection in rice adaptation in low-input farming systems in West Africa. Using 20 morphological traits and 176 molecular markers, 182 farmer varieties of rice (Oryza spp. from 6 West African countries were characterized. Principal component analysis showed that the four botanical groups (Oryza sativa ssp. indica, O. sativa ssp. japonica, O. glaberrima, and interspecific farmer hybrids exhibited different patterns of morphological diversity. Regarding O. glaberrima, morphological and molecular data were in greater conformity than for the other botanical groups. A clear difference in morphological features was observed between O. glaberrima rices from the Togo hills and those from the Upper Guinea Coast, and among O. glaberrima rices from the Upper Guinea Coast. For the other three groups such clear patterns were not observed. We argue that this is because genetic diversity is shaped by different environmental and socio-cultural selection pressures. For O. glaberrima, recent socio-cultural selection pressures seemed to restrict genetic diversity while this was not observed for the other botanical groups. We also show that O. glaberrima still plays an important role in the selection practices of farmers and resulting variety development pathways. This is particularly apparent in the case of interspecific farmer hybrids where a relationship was found between pericarp colour, panicle attitude and genetic diversity. Farmer varieties are the product of long and complex trajectories of selection governed by local human agency. In effect, rice varieties have emerged that are adapted to West African farming conditions through genotype × environment × society interactions. The diversity farmers maintain in their rice varieties is understood to be part of a risk-spreading strategy that also facilitates successful and often serendipitous variety innovations. We advocate, therefore, that farmers and

  3. Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors.

    Science.gov (United States)

    Bhansali, S G; Kulkarni, V M

    2014-01-01

    Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure-activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good 'leave-one-out' cross validated correlation coefficient (q(2)) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r(2)) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r(2)(pred)) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called 'glutamine-switch', and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure-activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.

  4. Evidence for molecular antagonistic mechanism between mercury and selenium in rice (Oryza sativa L.): A combined study using 1, 2-dimensional electrophoresis and SR-XRF techniques.

    Science.gov (United States)

    Li, Yunyun; Li, Hong; Li, Yu-Feng; Zhao, Jiating; Guo, Jingxia; Wang, Ru; Li, Bai; Zhang, Zhiyong; Gao, Yuxi

    2017-10-16

    Mercury (Hg) is a hazardous chemical in the environment and can accumulate in the food chain. Selenium (Se) is a necessary element for human health and has antagonistic effects on Hg toxicity. In this work, we investigated the effect of Se on Hg containing and Hg-responsive proteins in rice using 1, 2-dimensional electrophoresis combined with SR-XRF techniques. Two weeks old rice seedlings were exposed to Hg and/or Se compounds. After 21days proteins in the rice roots were separated by electrophoresis and their metal contents were determined by X-ray fluorescence to identify Hg and Se responsive biomolecules. The results show that under Hg stress alone Hg is bound to proteins with molecular weights of 15-25kDa. With the addition of Se, a new Hg-containing protein band in the 55-70kDa range was also found, while the content of Hg in the 15-25kDa proteins decreased. Ten and nine new protein spots were identified after adding Se to inorganic Hg and methylmercury exposed roots, respectively. Adding Se regulates the abundance of proteins associated with carbohydrate and energy metabolism, stress response, cell cycle, and DNA replication indicating that these proteins mediate the antagonism of Se against Hg toxicity. This study helps us to better understand the molecular mechanism of Hg tolerance as well as the molecular antagonism between Hg and Se in rice plants. Copyright © 2017 Elsevier GmbH. All rights reserved.

  5. Combined quantum-mechanics/molecular-mechanics dynamics simulation of A-DNA double strands irradiated by ultra-low-energy carbon ions

    Energy Technology Data Exchange (ETDEWEB)

    Ngaojampa, C.; Nimmanpipug, P. [Computer Simulation and Modeling Laboratory (CSML), Department of Chemistry and Center for Innovation Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Yu, L.D., E-mail: yuld@fnrf.science.cmu.ac.t [Plasma and Beam Physics Research Facility, Department of Physics and Materials Science, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Thailand Center of Excellence in Physics, Commission on Higher Education, 328 Si Ayutthaya Road, Bangkok 10400 (Thailand); Anuntalabhochai, S. [Molecular Biology Laboratory, Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Lee, V.S., E-mail: vannajan@gmail.co [Computer Simulation and Modeling Laboratory (CSML), Department of Chemistry and Center for Innovation Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200 (Thailand); Thailand Center of Excellence in Physics, Commission on Higher Education, 328 Si Ayutthaya Road, Bangkok 10400 (Thailand)

    2011-02-15

    In order to promote understanding of the fundamentals of ultra-low-energy ion interaction with DNA, molecular dynamics simulations using combined quantum-mechanics/molecular-mechanics of poly-AT and poly-GC A-DNA double strands irradiated by <200 eV carbon ions were performed to investigate the molecular implications of mutation bias. The simulations were focused on the responses of the DNA backbones and nitrogenous bases to irradiation. Analyses of the root mean square displacements of the backbones and non-hydrogen atoms of base rings of the simulated DNA structure after irradiation revealed a potential preference of DNA double strand separation, dependent on the irradiating energy. The results show that for the backbones, the large difference in the displacement between poly-GC and poly-AT in the initial time period could be the reason for the backbone breakage; for the nitrogenous base pairs, A-T is 30% more sensitive or vulnerable to ion irradiation than G-C, demonstrating a preferential, instead of random, effect of irradiation-induced mutation.

  6. Long-term prognostic value of the combination of EORTC risk group calculator and molecular markers in non-muscle-invasive bladder cancer patients treated with intravesical Bacille Calmette-Guérin

    Directory of Open Access Journals (Sweden)

    Sultan S Alkhateeb

    2011-01-01

    Conclusion: Molecular markers have a long-term prognostic value when combined with EORTC scoring system and they may be used to improve the predictive accuracy of currently existing scoring system. Larger series are needed to confirm these findings.

  7. Combined morphological and molecular data unveils relationships of Pseudobranchiomma (Sabellidae, Annelida) and reveals higher diversity of this intriguing group of fan worms in Australia, including potentially introduced species.

    Science.gov (United States)

    Capa, María; Murray, Anna

    2016-01-01

    Pseudobranchiomma (Sabellidae, Annelida) is a small and heterogeneous group of fan worms found in shallow marine environments and is generally associated with hard substrates. The delineation and composition of this genus is problematic since it has been defined only by plesiomorphic characters that are widely distributed among other sabellids. In this study we have combined morphological and molecular (mitochondrial and nuclear DNA sequences) data to evaluate species diversity in Australia and assess the phylogenetic relationships of these and other related sabellids. Unlike morphological data alone, molecular data and combined datasets suggest monophyly of Pseudobranchiomma. In this study, a new species of Pseudobranchiomma is described and three others are considered as potential unintentional introductions to Australian waters, one of them reported for the first time for the continent. Pseudobranchiomma pallidasp. n. bears 4-6 serrations along the radiolar flanges, lacks radiolar eyes and has uncini with three transverse rows of teeth over the main fang. In the new species the colour pattern as well is characteristic and species specific.

  8. Characterization of angiotensin-I converting enzyme inhibiting peptide from Venerupis philippinarum with nano-liquid chromatography in combination with orbitrap mass spectrum detection and molecular docking

    Science.gov (United States)

    Shi, Lei; Wu, Tizhi; Sheng, Naijuan; Yang, Li; Wang, Qian; Liu, Rui; Wu, Hao

    2017-06-01

    The complexity and diversity of peptide mixture from protein hydrolysates make their characterization difficult. In this study, a method combining nano LC-MS/MS with molecular docking was applied to identifying and characterizing a peptide with angiotensin-I converting enzyme (ACE-I) inhibiting activity from Venerupis philippinarum hydrolysate. Firstly, ethanol supernatant of V. philippinarum hydrolysate was separated into active fractions with chromatographic methods such as ion-exchange chromatography and high performance liquid chromatography in combination. Then seven peptides from active fraction were identified according to the searching result of the MS/MS spectra against protein databases. Peptides were synthesized and subjected to ACE-I-inhibition assay. The peptide NTLTLIDTGIGMTK showed the highest potency with an IC50 of 5.75 μmol L-1. The molecular docking analysis showed that the ACE-I inhibiting peptide NTLTLIDTGIGMTK bond with residues Glu123, Glu403, Arg522, Glu376, Gln281 and Asn285 of ACE-I. Therefore, active peptides could be identified with the present method rather than the traditional purification and identification strategies. It may also be feasible to identify other food-derived peptides which target other enzymes and receptors with the method developed in this study.

  9. A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90α

    Energy Technology Data Exchange (ETDEWEB)

    Mehta, Adi; Shervington, Leroy; Munje, Chinmay; Shervington, Amal, E-mail: aashervington@googlemail.com [Brain Tumour North West, Faculty of Science and Technology, University of Central Lancashire, Preston, PR1 2HE (United Kingdom)

    2011-12-08

    Hsp90α's vital role in tumour survival and progression, together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validates it as a therapeutic target for glioma. Hsp90α was downregulated using the post-transcriptional RNAi strategy (sihsp90α) and a post-translational inhibitor, the benzoquinone antibiotic 17-AAG. Glioblastoma U87-MG and normal human astrocyte SVGp12 were treated with sihsp90α, 17-AAG and concurrent sihsp90α/17-AAG (combined treatment). Both Hsp90α gene silencing and the protein inhibitor approaches resulted in a dramatic reduction in cell viability. Results showed that sihsp90α, 17-AAG and a combination of sihsp90α/17-AAG, reduced cell viability by 27%, 75% and 88% (p < 0.001), respectively, after 72 h. hsp90α mRNA copy numbers were downregulated by 65%, 90% and 99% after 72 h treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG, respectively. The relationship between Hsp90α protein expression and its client Akt kinase activity levels were monitored following treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG. Akt kinase activity was downregulated as a direct consequence of Hsp90α inhibition. Both Hsp90α and Akt kinase levels were significantly downregulated after 72 h. Although, 17-AAG when used as a single agent reduces the Hsp90α protein and the Akt kinase levels, the efficacy demonstrated by combinatorial treatment was found to be far more effective. Combination treatment reduced the Hsp90α protein and Akt kinase levels to 4.3% and 43%, respectively, after 72 h. hsp90α mRNA expression detected in SVGp12 was negligible compared to U87-MG, also, the combination treatment did not compromise the normal cell viability. Taking into account the role of Hsp90α in tumour progression and the involvement of Akt kinase in cell signalling and the anti-apoptotic pathways in tumours, this double targets treatment infers a novel therapeutic strategy.

  10. Molecular characterization of viable Legionella spp. in cooling tower water samples by combined use of ethidium monoazide and PCR.

    Science.gov (United States)

    Inoue, Hiroaki; Fujimura, Reiko; Agata, Kunio; Ohta, Hiroyuki

    2015-01-01

    Viable Legionella spp. in environmental water samples were characterized phylogenetically by a clone library analysis combining the use of ethidium monoazide and quantitative PCR. To examine the diversity of Legionella spp., six cooling tower water samples and three bath water samples were collected and analyzed. A total of 617 clones were analyzed for their 16S rRNA gene sequences and classified into 99 operational taxonomic units (OTUs). The majority of OTUs were not clustered with currently described Legionella spp., suggesting the wide diversity of not-yet-cultured Legionella groups harbored in cooling tower water environments.

  11. Molecular structure and spectroscopic investigations combined with hypoglycemic/anticancer and docking studies of a new barbituric acid derivative

    Science.gov (United States)

    Barakat, Assem; Soliman, Saied M.; Elshaier, Yaseen A. M. M.; Ali, M.; Al-Majid, Abdullah Mohammed; Ghabbour, Hazem A.

    2017-04-01

    The one-pot synthesis reaction of barbituric acid derivative, 1,3-cyclohexandione, and 4-fluorobenzaldehyde in water mediated by NHEt2 as base afforded 4 with excellent yield. The synthesized compound was characterized by spectrophotometric tools as well as X-ray single crystal diffraction technique. The stability of the nine possible isomers of the synthesized compound was studied using the B3LYP method and 6-31G(d,p) basis set. The electronic and spectroscopic properties of the most stable isomer were predicted. The UV-Vis absorption spectrum displayed two bands at 203 and 257 nm in the solvent chloroform. The latter was calculated at 235.6 nm (f = 0.1995) in the gas phase due to H-2→L (42%) and H-1→L+2 (14%) excitations. In solution, using chloroform as a solvent, a slight bathochromic shift to 237.6 nm with an increase in the absorption intensity (f = 0.2898) was predicted. The molecular orbital energy level diagram of this transition band was characterized mainly by π-π* transitions. The 13C and 1H NMR chemical shifts correlated well with the experimental data. The correlations had higher correlation coefficients (R2) when solvent effects were considered. The atomic charges were calculated using natural population analysis and the charged regions were presented using a molecular electrostatic potential (MEP) map. The synthesized compound was examined as a hypoglycemic agent via inhibition of α-glucosidase and β-glucuronidase enzymes. Its inhibitory activity against α-glucosidase was 10 times greater than the inhibitory activity of the standard drug acarbose (IC50 77.9 ± 0.3 μM and 840 ± 1.73 μM, respectively). Moreover, the target compound was evaluated for anticancer activity against MCF-7, H460, 3T3, and Hela cell lines. It demonstrated inhibitory activity against the MCF-7 and H460 cell lines with IC50 5.80 ± 0.12 and 19.6 ± 0.5 μM, respectively, in comparison to doxorubicin. The docking study was performed using the OpenEye program.

  12. Diversity of anoxygenic phototrophic sulfur bacteria in the microbial mats of the Ebro Delta: a combined morphological and molecular approach.

    Science.gov (United States)

    Martínez-Alonso, Maira; Van Bleijswijk, Judith; Gaju, Núria; Muyzer, Gerard

    2005-05-01

    The diversity of purple and green sulfur bacteria in the multilayered sediments of the Ebro Delta was investigated. Specific oligonucleotide primers for these groups were used for the selective amplification of 16S rRNA gene sequences. Subsequently, amplification products were separated by denaturing gradient gel electrophoresis and sequenced, which yielded a total of 32 sequences. Six of the sequences were related to different cultivated members of the green sulfur bacteria assemblage, whereas seven fell into the cluster of marine or halophilic Chromatiaceae. Six sequences were clustered with the family Ectothiorhodospiraceae, three of the six being closely related to chemotrophic bacteria grouped together with Halorhodospira genus, and the other three forming a group related to the genus Ectothiorhodospira. The last thirteen sequences constituted a cluster where no molecular isolate from microbial mats has so far been reported. Our results indicate that the natural diversity in the ecosystem studied has been significantly underestimated in the past and point out the presence of novel species not related to all known purple sulfur bacteria. Furthermore, the detection of green sulfur bacteria, after only an initial step of enrichment, suggests that -- with the appropriate methodology -- several genera, such as Prosthecochloris, could be established as regular members of marine microbial mats.

  13. Stability and Membrane Orientation of the Fukutin Transmembrane Domain: A Combined Multiscale Molecular Dynamics and Circular Dichroism Study

    Science.gov (United States)

    2010-01-01

    The N-terminal domain of fukutin-I has been implicated in the localization of the protein in the endoplasmic reticulum and Golgi Apparatus. It has been proposed to mediate this through its interaction with the thinner lipid bilayers found in these compartments. Here we have employed multiscale molecular dynamics simulations and circular dichroism spectroscopy to explore the structure, stability, and orientation of the short 36-residue N-terminus of fukutin-I (FK1TMD) in lipids with differing tail lengths. Our results show that FK1TMD adopts a stable helical conformation in phosphatidylcholine lipids when oriented with its principal axis perpendicular to the bilayer plane. The stability of the helix is largely insensitive to the lipid tail length, preventing hydrophobic mismatch by virtue of its mobility and ability to tilt within the lipid bilayers. This suggests that changes in FK1TMD tilt in response to bilayer properties may be implicated in the regulation of its trafficking. Coarse-grained simulations of the complex Golgi membrane suggest the N-terminal domain may induce the formation of microdomains in the surrounding membrane through its preferential interaction with 1,2-dipalmitoyl-sn-glycero-3-phosphatidylinositol 4,5-bisphosphate lipids. PMID:21105749

  14. Exploring the possible role of Glu286 in CcO by electrostatic energy computations combined with molecular dynamics.

    Science.gov (United States)

    Woelke, Anna Lena; Galstyan, Gegham; Galstyan, Artur; Meyer, Tim; Heberle, Joachim; Knapp, Ernst-Walter

    2013-10-17

    Cytochrome c oxidase (CcO) is a central enzyme in aerobic life catalyzing the conversion of molecular oxygen to water and utilizing the chemical energy to pump protons and establish an electrochemical gradient. Despite intense research, it is not understood how CcO achieves unidirectional proton transport and avoids short circuiting the proton pump. Within this work, we analyzed the potential role of Glu286 as a proton valve. We performed unconstrained MD simulations of CcO with an explicit membrane for up to 80 ns. Those MD simulations revealed that deprotonated Glu286 (Glu286-) is repelled by the negatively charged propionic acid PRD of heme a3. Thus, it destabilizes a potential linear chain of waters in the hydrophobic cavity connecting Glu286 with PRD and the binuclear center (BNC). Conversely, protonated Glu286 (Glu286H) may remain in an upward position (oriented toward PRD) and can stabilize the connecting linear water chain in the hydrophobic cavity. We calculated the pKa of Glu286 under physiological conditions to be above 12, but this value decreases to about 9 under increased water accessibility of Glu286. The latter value is in accordance with experimental measurements. In the time course of MD simulation, we also observed conformations where Glu286 bridges between water molecules located on both sides (the D channel being connected to the N side and the hydrophobic cavity), which might lead to proton backflow.

  15. A combined crossed molecular beams and theoretical study of the reaction CN + C{sub 2}H{sub 4}

    Energy Technology Data Exchange (ETDEWEB)

    Balucani, Nadia, E-mail: nadia.balucani@unipg.it [Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, Perugia (Italy); Leonori, Francesca; Petrucci, Raffaele [Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, Perugia (Italy); Wang, Xingan [Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, Perugia (Italy); Department of Chemical Physics, University of Science and Technology of China, Hefei 230026 (China); Casavecchia, Piergiorgio [Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, Perugia (Italy); Skouteris, Dimitrios [Scuola Normale Superiore, Pisa (Italy); Albernaz, Alessandra F. [Instituto de Física, Universidade de Brasília, Brasília (Brazil); Gargano, Ricardo [Instituto de Física, Universidade de Brasília, Brasília (Brazil); Departments of Chemistry and Physics, University of Florida, Quantum Theory Project, Gainesville, FL 32611 (United States)

    2015-03-01

    Highlights: • The CN + C{sub 2}H{sub 4} reaction was investigated in crossed beam experiments. • Electronic structure calculations of the potential energy surface were performed. • RRKM estimates qualitatively reproduce the experimental C{sub 2}H{sub 3}NC yield. - Abstract: The CN + C{sub 2}H{sub 4} reaction has been investigated experimentally, in crossed molecular beam (CMB) experiments at the collision energy of 33.4 kJ/mol, and theoretically, by electronic structure calculations of the relevant potential energy surface and Rice–Ramsperger–Kassel–Marcus (RRKM) estimates of the product branching ratio. Differently from previous CMB experiments at lower collision energies, but similarly to a high energy study, we have some indication that a second reaction channel is open at this collision energy, the characteristics of which are consistent with the channel leading to CH{sub 2}CHNC + H. The RRKM estimates using M06L electronic structure calculations qualitatively support the experimental observation of C{sub 2}H{sub 3}NC formation at this and at the higher collision energy of 42.7 kJ/mol of previous experiments.

  16. Combined molecular docking and QSAR study of fused heterocyclic herbicide inhibitors of D1 protein in photosystem II of plants.

    Science.gov (United States)

    Funar-Timofei, Simona; Borota, Ana; Crisan, Luminita

    2017-05-01

    Cinnoline, pyridine, pyrimidine, and triazine herbicides were found be inhibitors of the D1 protein in photosystem II (D1 PSII) electron transport of plants. The photosystem II inhibitory activity of these herbicides, expressed by experimental [Formula: see text] values, was modeled by a docking and quantitative structure-activity relationships study. A conformer ensemble for each of the herbicide structure was generated using the MMFF94s force field. These conformers were further employed in a docking approach, which provided new information about the rational "active conformations" and various interaction patterns of the herbicide derivatives with D1 PSII. The most "active conformers" from the docking study were used to calculate structural descriptors, which were further related to the inhibitory experimental [Formula: see text] values by multiple linear regression (MLR). The dataset was divided into training and test sets according to the partition around medoids approach, taking 27% of the compounds from the entire series for the test set. Variable selection was performed using the genetic algorithm, and several criteria were checked for model performance. WHIM and GETAWAY geometrical descriptors (position of substituents and moieties in the molecular space) were found to contribute to the herbicidal activity. The derived MLR model is statistically significant, shows very good stability and was used to predict the herbicidal activity of new derivatives having cinnoline, indeno[1.2-c]cinnoline-ll-one, triazolo[1,5-a] pyridine, imidazo[1,2-a]pyridine, triazine and triazolo[1,5-a] pyrimidine scaffolds whose experimental inhibitory activity against D1 PSII had not been determined up to now.

  17. The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies.

    Science.gov (United States)

    Lu, Shin-Hua; Wu, Josephine W; Liu, Hsuan-Liang; Zhao, Jian-Hua; Liu, Kung-Tien; Chuang, Chih-Kuang; Lin, Hsin-Yi; Tsai, Wei-Bor; Ho, Yih

    2011-01-21

    Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors. The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R² = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site. The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.

  18. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies

    Directory of Open Access Journals (Sweden)

    Chuang Chih-Kuang

    2011-01-01

    Full Text Available Abstract Background Alzheimer's disease (AD is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. Methods In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5 program based on a set of known AChE inhibitors. Results The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R2 = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site. Conclusions The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.

  19. Combining molecular-marker and chemical analysis of Capparis decidua (Capparaceae) in the Thar Desert of Western Rajasthan (india).

    Science.gov (United States)

    Kumar, Sushil; Sharma, Ramavtar; Kumar, Vinod; Vyas, Govind K; Rathore, Abhishek

    2013-03-01

    The Thar Desert, a very inhospitable place, accommodates only plant species that survive acute drought, unpredictable precipitation, and those can grow in the limited moisture of sandy soils. Capparis decidua is among one of the few plants able to grow well under these conditions. This species is highly exploited and has been naturally taken, as local people use it for various purposes like food, timber and fuel, although, no management or conservation efforts have been established. The present study was conducted in this arid area of Western Rajasthan (India) with the aim to obtain preliminary molecular information about this group of plants. We evaluated diversity among 46 samples of C. decidua using chemical parameters and random amplified polymorphic DNA (RAPD) markers. Fourteen chemical parameters and eight minerals (total 22 variables) of this species fruits were estimated. A total of 14 RAPD primers produced 235 band positions, of which 81.27% were polymorphic. Jaccard's similarity coefficients for RAPD primers ranged from 0.34 to 0.86 with a mean genetic similarity of 0.50. As per observed coefficient of variation, NDF (Neutral Detergent Fiber) content was found to be the most variable trait followed by starch and soluble carbohydrate. The Manhattan dissimilarity coefficient values for chemical parameters ranged between 0.02-0.31 with an average of 0.092. The present study revealed a very low correlation (0.01) between chemical parameters and RAPD-based matrices. The low correlation between chemical- and RAPD-based matrices indicated that the two methods were different and highly variable. The chemical-based diversity will assist in selection of nutritionally rich samples for medicinal purpose, while genetic diversity to face natural challenges and find sustainable ways to promote conservation for future use.

  20. High-resolution modeling of antibody structures by a combination of bioinformatics, expert knowledge, and molecular simulations.

    Science.gov (United States)

    Shirai, Hiroki; Ikeda, Kazuyoshi; Yamashita, Kazuo; Tsuchiya, Yuko; Sarmiento, Jamica; Liang, Shide; Morokata, Tatsuaki; Mizuguchi, Kenji; Higo, Junichi; Standley, Daron M; Nakamura, Haruki

    2014-08-01

    In the second antibody modeling assessment, we used a semiautomated template-based structure modeling approach for 11 blinded antibody variable region (Fv) targets. The structural modeling method involved several steps, including template selection for framework and canonical structures of complementary determining regions (CDRs), homology modeling, energy minimization, and expert inspection. The submitted models for Fv modeling in Stage 1 had the lowest average backbone root mean square deviation (RMSD) (1.06 Å). Comparison to crystal structures showed the most accurate Fv models were generated for 4 out of 11 targets. We found that the successful modeling in Stage 1 mainly was due to expert-guided template selection for CDRs, especially for CDR-H3, based on our previously proposed empirical method (H3-rules) and the use of position specific scoring matrix-based scoring. Loop refinement using fragment assembly and multicanonical molecular dynamics (McMD) was applied to CDR-H3 loop modeling in Stage 2. Fragment assembly and McMD produced putative structural ensembles with low free energy values that were scored based on the OSCAR all-atom force field and conformation density in principal component analysis space, respectively, as well as the degree of consensus between the two sampling methods. The quality of 8 out of 10 targets improved as compared with Stage 1. For 4 out of 10 Stage-2 targets, our method generated top-scoring models with RMSD values of less than 1 Å. In this article, we discuss the strengths and weaknesses of our approach as well as possible directions for improvement to generate better predictions in the future. © 2014 Wiley Periodicals, Inc.

  1. Combining Graphical and Analytical Methods with Molecular Simulations To Analyze Time-Resolved FRET Measurements of Labeled Macromolecules Accurately.

    Science.gov (United States)

    Peulen, Thomas-Otavio; Opanasyuk, Oleg; Seidel, Claus A M

    2017-09-07

    Förster resonance energy transfer (FRET) measurements from a donor, D, to an acceptor, A, fluorophore are frequently used in vitro and in live cells to reveal information on the structure and dynamics of DA labeled macromolecules. Accurate descriptions of FRET measurements by molecular models are complicated because the fluorophores are usually coupled to the macromolecule via flexible long linkers allowing for diffusional exchange between multiple states with different fluorescence properties caused by distinct environmental quenching, dye mobilities, and variable DA distances. It is often assumed for the analysis of fluorescence intensity decays that DA distances and D quenching are uncorrelated (homogeneous quenching by FRET) and that the exchange between distinct fluorophore states is slow (quasistatic). This allows us to introduce the FRET-induced donor decay, εD(t), a function solely depending on the species fraction distribution of the rate constants of energy transfer by FRET, for a convenient joint analysis of fluorescence decays of FRET and reference samples by integrated graphical and analytical procedures. Additionally, we developed a simulation toolkit to model dye diffusion, fluorescence quenching by the protein surface, and FRET. A benchmark study with simulated fluorescence decays of 500 protein structures demonstrates that the quasistatic homogeneous model works very well and recovers for single conformations the average DA distances with an accuracy of FRET-based dynamic structural biology. Finally, we present theories and simulations to assess the accuracy and precision of steady-state and time-resolved FRET measurements in resolving DA distances on the single-molecule and ensemble level and provide a rigorous framework for estimating approximation, systematic, and statistical errors.

  2. Combination Therapy «Metformin + Glimepiride» in Patients with Type 2 Diabetes Mellitus (Molecular Mechanisms for Optimization of the Rehabilitation Effect

    Directory of Open Access Journals (Sweden)

    V.V. Poltorak

    2015-03-01

    Full Text Available This review describes the molecular mechanisms of therapeutic action of the combination of oral antidiabetic drugs «metformin + glimepiride», aimed at the correction of both defects, which determine the development of metabolic abnormalities in type 2 diabetes mellitus, namely, relative insulin deficiency and insulin resistance. The combination of metformin with glimepiride is optimal in terms of therapeutic effects on both molecules, which metabolic hypoactivity determines the metabolic state of insulin resistance, respectively, adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ. In addition, metformin has unique ability to eliminate the phenomenon of «hyperglycemic memory» by increasing the expression and activity of sirtuin-1. On the other hand, the third generation sulfonylurea glimepiride provides a «gentle» stimulation of the β-cells, which maintains the physiological ratio proinsulin/insulin and slows down the development of the phenomenon of β-cell desensitization to physiological and pharmacological stimuli. Glimepiride retains protective phenomenon of ischemic preconditioning and extends the range of therapeutic effect on the pathophysiological components of insulin resistance due to insulin-mimetic and insulin-sensitizing effect, as well as potentiates the beneficial effects of metformin (particularly, via adiponectin. Above mentioned determinated the achievement of optimized therapeutic efficacy of pharmaceutical combination against the background of decreased side effects (reduced dose of glimepiride, metformin.

  3. Adsorption of Zn(II) on the kaolinite(001) surfaces in aqueous environment: A combined DFT and molecular dynamics study

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Qiang; Kong, Xiang-Ping; Zhang, Bao-Hua; Wang, Juan, E-mail: juaner80@163.com

    2017-08-31

    Highlights: • Zn(II) adsorption on two types of neutral kaolinite(001) surfaces is investigated. • Surface “Ou” is found the preferred site for mono- and bi-dentate complexes. • Both Zn(II) and surface oxygen accept electrons from aqua oxygens. • Coupling of O 2p with Zn sp{sup 3}d{sup 2} (or sp{sup 3}) hybridization states is the bonding nature. - Abstract: Adsorption of Zn(II) on two types of neutral (001) surfaces of kaolinite, tetrahedral Si(t) and octahedral Al(o), was studied by means of DFT calculations and classical molecular dynamics simulations. The position and structure for both outer-sphere and mono-/bi-dentate inner-sphere complexes of Zn(II) in aqueous environment were examined, with binding energy and radial distribution function calculated. Outer-sphere complex on the Si(t) surface, monodentate inner-sphere complex of “O{sub u}” (surface oxygen with “upright” hydrogen) site and bidentate complex of “O{sub u}-O{sub u}” site of neighboring Al centers on the Al(o) surface are considered to be the dominant adsorption species. The outer-sphere complex is found six-coordinated with distorted octahedral geometry, while both the inner-sphere complexes exhibit the tetrahedral structure with coordination number of four. Hydrogen bonding interactions between oxygen or hydrogen of the kaolinite(001) surfaces and the aqua ligands of Zn(II) act as the key role for the structure and stability of adsorption complexes. Upon the Mulliken population analysis and partial density of states, both Zn(II) and surface oxygen accept electrons from aqua oxygens, and coupling of O 2p with the sp{sup 3}d{sup 2} or sp{sup 3} hybridization states of Zn(II) is the primary bonding nature of Zn(II) with oxygen in outer- and inner-sphere complexes, respectively.

  4. Hydroxyl-radical footprinting combined with molecular modeling identifies unique features of DNA conformation and nucleosome positioning.

    Science.gov (United States)

    Shaytan, Alexey K; Xiao, Hua; Armeev, Grigoriy A; Wu, Carl; Landsman, David; Panchenko, Anna R

    2017-09-19

    Nucleosomes are the most abundant protein-DNA complexes in eukaryotes that provide compaction of genomic DNA and are implicated in regulation of transcription, DNA replication and repair. The details of DNA positioning on the nucleosome and the DNA conformation can provide key regulatory signals. Hydroxyl-radical footprinting (HRF) of protein-DNA complexes is a chemical technique that probes nucleosome organization in solution with a high precision unattainable by other methods. In this work we propose an integrative modeling method for constructing high-resolution atomistic models of nucleosomes based on HRF experiments. Our method precisely identifies DNA positioning on nucleosome by combining HRF data for both DNA strands with the pseudo-symmetry constraints. We performed high-resolution HRF for Saccharomyces cerevisiae centromeric nucleosome of unknown structure and characterized it using our integrative modeling approach. Our model provides the basis for further understanding the cooperative engagement and interplay between Cse4p protein and the A-tracts important for centromere function. Published by Oxford University Press on behalf of Nucleic Acids Research 2017.

  5. Enhancing crop resilience to combined abiotic and biotic stress through the dissection of physiological and molecular crosstalk

    Directory of Open Access Journals (Sweden)

    Christos eKissoudis

    2014-05-01

    Full Text Available Plants growing in their natural habitats are often challenged simultaneously by multiple stress factors, both abiotic and biotic. Research has so far been limited to responses to individual stresses, and understanding of adaptation to combinatorial stress is limited, but indicative of non-additive interactions. Omics data analysis and functional characterization of individual genes has revealed a convergence of signalling pathways for abiotic and biotic stress adaptation. Taking into account that most data originate from imposition of individual stress factors, this review summarizes these findings in a physiological context, following the pathogenesis timeline and highlighting potential differential interactions occurring between abiotic and biotic stress signalling across the different cellular compartments and at the whole plant level. Potential effects of abiotic stress on resistance components such as extracellular receptor proteins, R-genes and systemic acquired resistance will be elaborated, as well as crosstalk at the levels of hormone, ROS and redox signalling. Breeding targets and strategies are proposed focusing on either manipulation and deployment of individual common regulators such as transcription factors or pyramiding of non- (negatively interacting components such as R-genes with abiotic stress resistance genes. We propose that dissection of broad spectrum stress tolerance conferred by priming chemicals may provide an insight on stress cross regulation and additional candidate genes for improving crop performance under combined stress. Validation of the proposed strategies in lab and field experiments is a first step towards the goal of achieving tolerance to combinatorial stress in crops.

  6. Combining molecular-marker and chemical analysis of Capparis deciduas (Capparaceae in the Thar Desert of Western Rajasthan (India

    Directory of Open Access Journals (Sweden)

    Sushil Kumar

    2013-03-01

    Full Text Available The Thar Desert, a very inhospitable place, accommodates only plant species that survive acute drought, unpredictable precipitation, and those can grow in the limited moisture of sandy soils. Capparis decidua is among one of the few plants able to grow well under these conditions. This species is highly exploited and has been naturally taken, as local people use it for various purposes like food, timber and fuel, although, no management or conservation efforts have been established. The present study was conducted in this arid area of Western Rajasthan (India with the aim to obtain preliminary molecular information about this group of plants. We evaluated diversity among 46 samples of C. decidua using chemical parameters and random amplified polymorphic DNA (RAPD markers. Fourteen chemical parameters and eight minerals (total 22 variables of this species fruits were estimated. A total of 14 RAPD primers produced 235 band positions, of which 81.27% were polymorphic. Jaccard s similarity coefficients for RAPD primers ranged from 0.34 to 0.86 with a mean genetic similarity of 0.50. As per observed coefficient of variation, NDF (Neutral Detergent Fiber content was found to be the most variable trait followed by starch and soluble carbohydrate. The Manhattan dissimilarity coefficient values for chemical parameters ranged between 0.02-0.31 with an average of 0.092. The present study revealed a very low correlation (0.01 between chemical parameters and RAPD-based matrices. The low correlation between chemical- and RAPD-based matrices indicated that the two methods were different and highly variable. The chemical-based diversity will assist in selection of nutritionally rich samples for medicinal purpose, while genetic diversity to face natural challenges and find sustainable ways to promote conservation for future use.El desierto de Thar, un lugar muy inhóspito, alberga sólo a las especies de plantas capaces de resistir a condiciones de sequ

  7. Accelerating Monte Carlo Molecular Simulations Using Novel Extrapolation Schemes Combined with Fast Database Generation on Massively Parallel Machines

    KAUST Repository

    Amir, Sahar Z.

    2013-05-01

    We introduce an efficient thermodynamically consistent technique to extrapolate and interpolate normalized Canonical NVT ensemble averages like pressure and energy for Lennard-Jones (L-J) fluids. Preliminary results show promising applicability in oil and gas modeling, where accurate determination of thermodynamic properties in reservoirs is challenging. The thermodynamic interpolation and thermodynamic extrapolation schemes predict ensemble averages at different thermodynamic conditions from expensively simulated data points. The methods reweight and reconstruct previously generated database values of Markov chains at neighboring temperature and density conditions. To investigate the efficiency of these methods, two databases corresponding to different combinations of normalized density and temperature are generated. One contains 175 Markov chains with 10,000,000 MC cycles each and the other contains 3000 Markov chains with 61,000,000 MC cycles each. For such massive database creation, two algorithms to parallelize the computations have been investigated. The accuracy of the thermodynamic extrapolation scheme is investigated with respect to classical interpolation and extrapolation. Finally, thermodynamic interpolation benefiting from four neighboring Markov chains points is implemented and compared with previous schemes. The thermodynamic interpolation scheme using knowledge from the four neighboring points proves to be more accurate than the thermodynamic extrapolation from the closest point only, while both thermodynamic extrapolation and thermodynamic interpolation are more accurate than the classical interpolation and extrapolation. The investigated extrapolation scheme has great potential in oil and gas reservoir modeling.That is, such a scheme has the potential to speed up the MCMC thermodynamic computation to be comparable with conventional Equation of State approaches in efficiency. In particular, this makes it applicable to large-scale optimization of L

  8. Utilization of low molecular weight organics by soil microorganisms: combination of 13C-labelling with PLFA analysis

    Science.gov (United States)

    Gunina, Anna; Dippold, Michaela; Kuzyakov, Yakov

    2014-05-01

    Microbial metabolisation is the main transformation pathway of low molecular weight organic substances (LMWOS), but detailed knowledge concerning the fate of LMWOS in soils is strongly limited. Considering that various LMWOS classes enter biochemical cycles at different steps, we hypothesise that the percentage of their LMWOS-Carbon (C) used for microbial biomass (MB) production and consequently medium-term stabilisation in soil is different. We traced the three main groups of LMWOS: amino acids, sugars and carboxylic acids, by uniformly labelled 13C-alanine, -glutamate, -glucose, -ribose, -acetate and -palmitate. Incorporation of 13C from these LMWOS into MB (fumigation-extraction method) and into phospholipid fatty acids (PLFAs) (Bligh-Dyer extraction, purification and GC-C-IRMS measurement) was investigated under field conditions 3 d and 10 d after LMWOS application. The activity of microbial utilization of LMWOS for cell membrane construction was estimated by replacement of PLFA-C with 13C. Decomposition of LMWOS-C comprised 20-65% of the total label, whereas incorporation of 13C into MB amounted to 20-50% of initially applied 13C on day three and was reduced to 5-30% on day 10. Incorporation of 13C-labelled LMWOS into MB followed the trend sugars > carboxylic acids > amino acids. Differences in microbial utilisation between LMWOS were observed mainly at day 10. Thus, instead of initial rapid uptake, further metabolism within microbial cells accounts for the individual fate of C from different LMWOS in soils. Incorporation of 13C from each LMWOS into each PLFA occurred, which reflects the ubiquitous ability of all functional microbial groups for LMWOS utilization. The preferential incorporation of palmitate can be attributed to its role as a direct precursor for many fatty acids (FAs) and PLFA formation. Higher incorporation of alanine and glucose compared to glutamate, ribose and acetate reflect the preferential use of glycolysis-derived substances in the FAs

  9. Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy calculation studies.

    Science.gov (United States)

    Zhang, Wen; Qiu, Kai-Xiong; Yu, Fang; Xie, Xiao-Guang; Zhang, Shu-Qun; Chen, Ya-Juan; Xie, Hui-Ding

    2017-10-01

    B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔGbind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC50<50μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs. Copyright © 2017. Published by Elsevier Ltd.

  10. Combined molecular MRI and immuno-spin-trapping for in vivo detection of free radicals in orthotopic mouse GL261 gliomas.

    Science.gov (United States)

    Towner, Rheal A; Smith, Nataliya; Saunders, Debra; De Souza, Patricia Coutinho; Henry, Leah; Lupu, Florea; Silasi-Mansat, Robert; Ehrenshaft, Marilyn; Mason, Ronald P; Gomez-Mejiba, Sandra E; Ramirez, Dario C

    2013-12-01

    Free radicals play a major role in gliomas. By combining immuno-spin-trapping (IST) and molecular magnetic resonance imaging (mMRI), in vivo levels of free radicals were detected within mice bearing orthotopic GL261 gliomas. The nitrone spin trap DMPO (5,5-dimethyl pyrroline N-oxide) was administered prior to injection of an anti-DMPO probe (anti-DMPO antibody covalently bound to a bovine serum albumin (BSA)-Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-biotin MRI contrast agent) to trap tumor-associated free radicals. mMRI detected the presence of anti-DMPO adducts by either a significant sustained increase (pfree radicals from a glioma model. © 2013.

  11. Combined quantum-mechanical molecular mechanics calculations with NWChem and AMBER: Excited state properties of green fluorescent protein chromophore analogue in aqueous solution.

    Science.gov (United States)

    Pirojsirikul, Teerapong; Götz, Andreas W; Weare, John; Walker, Ross C; Kowalski, Karol; Valiev, Marat

    2017-07-05

    Combined quantum mechanical molecular mechanics (QM/MM) calculations have become a popular methodology for efficient and accurate description of large molecular systems. In this work we introduce our development of a QM/MM framework based on two well-known codes-NWChem and AMBER. As an initial application area we are focused on excited state properties of small molecules in an aqueous phase using an analogue of the green fluorescent protein (GFP) chromophore as a particular test case. Our approach incorporates high level coupled cluster theory for the analysis of excited states providing a reliable theoretical analysis of effects of an aqueous solvation environment on the photochemical properties of the GFP chromophore. Using a systematic approach, which involves comparison of gas phase and aqueous phase results for different protonation states and conformations, we resolve existing uncertainties regarding the theoretical interpretation of experimental data. We observe that the impact of aqueous environment on charged states generally results in blue shifts of the absorption spectra, but the magnitude of the effect is sensitive to both protonation state and conformation and can be rationalized based on charge movement into the area of higher/lower external electrostatic potentials. At neutral pH levels the experimentally observed absorption signal is most likely coming from the phenol protonated form. Our results also show that the high level electron correlated method is essential for a proper description of excited states of GFP. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. Matrix metalloproteinase 2 inhibition: combined quantum mechanics and molecular mechanics studies of the inhibition mechanism of (4-phenoxyphenylsulfonyl)methylthiirane and its oxirane analogue.

    Science.gov (United States)

    Tao, Peng; Fisher, Jed F; Shi, Qicun; Vreven, Thom; Mobashery, Shahriar; Schlegel, H Bernhard

    2009-10-20

    The inhibition mechanism of matrix metalloproteinase 2 (MMP2) by the selective inhibitor (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT) and its oxirane analogue is investigated computationally. The inhibition mechanism involves C-H deprotonation with concomitant opening of the three-membered heterocycle. SB-3CT was docked into the active site of MMP2, followed by molecular dynamics simulation to prepare the complex for combined quantum mechanics and molecular mechanics (QM/MM) calculations. QM/MM calculations with B3LYP/6-311+G(d,p) for the QM part and the AMBER force field for the MM part were used to examine the reaction of these two inhibitors in the active site of MMP2. The calculations show that the reaction barrier for transformation of SB-3CT is 1.6 kcal/mol lower than its oxirane analogue, and the ring-opening reaction energy of SB-3CT is 8.0 kcal/mol more exothermic than that of its oxirane analogue. Calculations also show that protonation of the ring-opened product by water is thermodynamically much more favorable for the alkoxide obtained from the oxirane than for the thiolate obtained from the thiirane. A six-step partial charge fitting procedure is introduced for the QM/MM calculations to update atomic partial charges of the quantum mechanics region and to ensure consistent electrostatic energies for reactants, transition states, and products.

  13. Molecularly Imprinted Nanomicrospheres as Matrix Solid-Phase Dispersant Combined with Gas Chromatography for Determination of Four Phosphorothioate Pesticides in Carrot and Yacon

    Directory of Open Access Journals (Sweden)

    Mengchun Zhou

    2015-01-01

    Full Text Available An efficient, rapid, and selective method for sample pretreatment, namely, molecularly imprinted matrix solid-phase dispersion (MI-MSPD coupled with gas chromatography (GC, was developed for the rapid isolation of four phosphorothioate organophosphorus pesticides (tolclofos-methyl, phoxim, chlorpyrifos, and parathion-methyl from carrot and yacon samples. New molecularly imprinted polymer nanomicrospheres were synthesized by using typical structural analogue tolclofos-methyl as a dummy template via surface grafting polymerization on nanosilica. Then, these four pesticides in carrot and yacon were extracted and adsorbed using the imprinted nanomicrospheres and further determined by gas chromatography. Under the optimized conditions, a good linearity of four pesticides was obtained in a range of 0.05–17.0 ng·g−1 with R varying from 0.9971 to 0.9996, and the detection limit of the method was 0.012~0.026 ng·g−1 in carrot and yacon samples. The recovery rates at two spiked levels were in the range of 85.4–105.6% with RSD ≤9.6%. The presented MI-MSPD method combined the advantages of MSPD for allowing the extraction, dispersion, and homogenization in two steps and the advantages of MIPs for high affinity and selectivity towards four phosphorothioate pesticides, which could be applied to the determination of pesticide residues in complicated vegetal samples.

  14. Drug-protein binding of Danhong injection and the potential influence of drug combination with aspirin: Insight by ultrafiltration LC-MS and molecular modeling.

    Science.gov (United States)

    Zhu, Junfeng; Yi, Xiaojiao; Huang, Peng; Chen, Shuqing; Wu, Yongjiang

    2017-02-05

    Danhong injection (DHI) is a widely used Chinese medicine injection (CMI) for the clinical treatment of cardiovascular and cerebrovascular diseases. In this study, a simple and efficient in vitro method based on ultrafiltration LC-MS and molecular modeling has been developed to study the human serum albumin (HSA) binding of the compounds in DHI. Seven major components including protocatechuic aldehyde, p-coumaric acid, salvianolic acid D, rosmarinic acid, salvianolic acid E, lithospermic acid and salvianolic acid B were identified as HSA ligands and their binding degrees in the proposed non-saturated model were 26.17, 37.69, 99.77, 91.78, 96.91, 99.42 and 98.10%, respectively. Considering the drug-HSA binding property of the compounds in DHI may change during drug combination therapy, competitive binding assay was carried out to evaluate the influence of aspirin on the DHI-HSA binding. Experimental results revealed that the salvianolic acids in DHI had stronger binding ability to HSA than sodium salicylate. To further verify the results above, molecular modeling and probe displacement assay were conducted to investigate the optimum binding site and binding affinity of the ligands on HSA. Our findings suggested that the established method could be a powerful tool to study the drug-HSA binding property of CMIs. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Recognition and binding of β-lactam antibiotics to bovine serum albumin by frontal affinity chromatography in combination with spectroscopy and molecular docking.

    Science.gov (United States)

    Li, Qian; Zhang, Tianlong; Bian, Liujiao

    2016-03-01

    Serum albumins are the most abundant carrier proteins in blood plasma and participate in the binding and transportation of various exogenous and endogenous compounds in the body. This work was designed to investigate the recognition and binding of three typical β-lactam antibiotics including penicillin G (Pen G), penicillin V (Pen V) and cefalexin (Cef) with bovine serum albumin (BSA) by frontal affinity chromatography in combination with UV-vis absorption spectra, fluorescence emission spectra, binding site marker competitive experiment and molecular docking under simulated physiological conditions. The results showed that a BSA only bound with one antibiotic molecule in the binding process, and the binding constants for Pen G-BSA, Pen V-BSA and Cef-BSA complexes were 4.22×10(1), 4.86×10(2) and 3.32×10(3) (L/mol), respectively. All the three β-lactam antibiotics were mainly inserted into the subdomain IIA (binding site 1) of BSA by hydrogen bonds and Van der Waals forces. The binding capacity between the antibiotics and BSA was closely related to the functional groups and flexibility of side chains in antibiotics. This study provided an important insight into the molecular recognition and binding interaction of BSA with β-lactam antibiotics, which may be a useful guideline for the innovative clinical medications and new antibiotic designs with effective pharmacological properties. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. COMBINATION OF MOLECULAR ADSORBENT RECIRCULATING SYSTEM AND RADIOIODINE FOR THE TREATMENT OF CONCURRENT HYPERTHYROIDISM AND SEVERE LIVER DYSFUNCTION: A RETROSPECTIVE COHORT STUDY.

    Science.gov (United States)

    Zhang, Qing; Guan, Yanxing; Xiang, Tianxin; Liu, Shaozheng; Chen, Qingjie; Zhang, Qing

    2017-02-01

    The treatment of hyperthyroidism associated with severe liver dysfunction (LD) is a clinical challenge, and there has been no unified examination of this problem. The objective of this study was to assess the efficacy and safety of radioiodine (131I) in combination with a molecular adsorbent recirculating system (MARS) for the treatment of hyperthyroidism complicated by severe liver LD. A total of 116 hyperthyroidism patients with concomitant LD who received MARS treatment were studied retrospectively. The patients were grouped according to whether or not they also received 131I treatment: Group 1 (59 patients) received 131I following MARS treatment, while Group 2 (57 cases) received only MARS. Clinical outcomes, including thyroid hormone levels, liver function parameters, and therapeutic efficacy were calculated. The overall response rate was significantly greater in Group 1 than in Group 2 (Phyperthyroidism complicated by severe LD was effective and safe. The use of this system could rapidly improve liver function and metabolism, allowing 131I therapy to be applied as early as possible with a shortened recovery time of liver function. ALSS = artificial liver support system ALT = alanine transaminase AST = aspartate transaminase ATD = antithyroid drugs DBil = direct bilirubin FT3 = free tri-iodothyronine FT4 = free thyroxine 131I = radioiodine INR = international normalized ratio LD = liver dysfunction MARS = molecular adsorbent recirculating system MELD = model for end-stage liver disease PT = prothrombin time TBil = total bilirubin TSH = thyroid-stimulating hormone.

  17. Residue Specific Interaction of an Unfolded Protein with Solvents in Mixed Water-Ethanol Solutions: A Combined Molecular Dynamics and ONIOM Study.

    Science.gov (United States)

    Mohanta, Dayanidhi; Santra, Santanu; Reddy, G Naaresh; Giri, Santanab; Jana, Madhurima

    2017-08-17

    The molecular mechanism of ethanol governed unfolding of an enzymatic protein, chymotrypsin inhibitor 2 (CI2), in water-ethanol mixed solutions has been studied by using combined molecular dynamics simulations and ONIOM study. The residue specific solvation of the unfolded protein and the interactions between the individual amino acid residues of the protein with ethanol as well as water have been investigated. The results are compared with that obtained from the folded state of the protein. Further, emphasis has been given to explore the residue's preferential site of attraction toward the nature of the solvents. The heterogeneous structuring of water and ethanol around the hydrophobic and hydrophilic surfaces of the protein is found to correlate well with their available surface areas to the solvents. Both hydrophobic and hydrophilic interactions are found to have important contributions in rupturing protein's secondary structural segments. Further, residue-water as well as residue-ethanol binding energies show significant involvement of the hydrogen bonding environment in the unfolding process; particularly, residue-water hydrogen bonds are found to play an indispensable role.

  18. Cellular and molecular properties of {sup 90}Y-labeled cetuximab in combination with radiotherapy on human tumor cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Saki, M.; Toulany, M.; Rodemann, H.P. [Tuebingen Univ. (Germany). Div. of Radiobiology and Molecular Environmental Research; Sihver, W.; Zenker, M.; Heldt, J.M.; Mosch, B.; Pietzsch, H.J.; Steinbach, J. [Helmholtz-Zentrum Dresden-Rossendorf (HZDR) e.V., Dresden (Germany). Inst. of Radiopharmacy; Baumann, M. [Technische Univ. Dresden (Germany). Dept. of Radiation Oncology

    2012-09-15

    Purpose: Anti-EGFR antibody cetuximab (C225) is used in combination with radiotherapy of head and neck squamous cell carcinoma (HNSCC) patients. We investigated whether conjugation of cetuximab with trans-cyclohexyl-diethylene-triamine-pentaacetic acid (CHX-A''-DTPA) and radiolabeling with {sup 90}Yttrium affect the molecular and cellular function of cetuximab and improve its combined effect with external-beam irradiation (EBI). Methods: The following cell lines were used: HNSCC UT5, SAS, FaDu, as well as A43, Chinese hamster ovary cells (CHO), and human skin fibroblast HSF7. Binding affinity and kinetics, specificity, retention, and the combination of {sup 90}Y-cetuximab with EBI were evaluated. Results: Control cetuximab and CHX-A''-DTPA-cetuximab blocked the proliferation activity of UT5 cells. In combination with EBI, CHX-A''-DTPA-cetuximab increased the radiosensitivity of UT5 to a similar degree as control cetuximab did. In contrast, in SAS and HSF7 cells neither proliferation nor radiosensitivity was affected by either of the antibodies. Binding [{sup 90}Y]Y-CHX-A''-DTPA-cetuximab ({sup 90}Y-cetuximab) to EGFR in HNSCC cells occurred time dependently with a maximum binding at 24 h. Retention of {sup 90}Y-cetuximab was similar in both HNSCC cell lines; 24 h after treatment, approximately 90% of bound activity remained in the cell layer. Competition assays, using cell membranes in the absence of an internalized fraction of cetuximab, showed that the cetuximab affinity is not lost as a result of conjugation with CHX-A''-DTPA. Cetuximab and CHX-A''-DTPA-cetuximab blocked EGF-induced Y1068 phosphorylation of EGFR. The lack of an effect of cetuximab on EGF-induced Akt and ERK1/2 phosphorylation and the inhibition of irradiation (IR)-induced Akt and ERK1/2 phosphorylation by cetuximab were not affected by DTPA conjugation. {sup 90}Y-cetuximab in combination with EBI resulted in a pronounced inhibition of

  19. A combination of epitope prediction and molecular docking allows for good identification of MHC class I restricted T-cell epitopes.

    Science.gov (United States)

    Zhang, Xue Wu

    2013-08-01

    In silico identification of T-cell epitopes is emerging as a new methodology for the study of epitope-based vaccines against viruses and cancer. In order to improve accuracy of prediction, we designed a novel approach, using epitope prediction methods in combination with molecular docking techniques, to identify MHC class I restricted T-cell epitopes. Analysis of the HIV-1 p24 protein and influenza virus matrix protein revealed that the present approach is effective, yielding prediction accuracy of over 80% with respect to experimental data. Subsequently, we applied such a method for prediction of T-cell epitopes in SARS coronavirus (SARS-CoV) S, N and M proteins. Based on available experimental data, the prediction accuracy is up to 90% for S protein. We suggest the use of epitope prediction methods in combination with 3D structural modelling of peptide-MHC-TCR complex to identify MHC class I restricted T-cell epitopes for use in epitope based vaccines like HIV and human cancers, which should provide a valuable step forward for the design of better vaccines and may provide in depth understanding about activation of T-cell epitopes by MHC binding peptides. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Combining charcoal sediment and molecular markers to infer a Holocene fire history in the Maya Lowlands of Petén, Guatemala

    Science.gov (United States)

    Schüpbach, Simon; Kirchgeorg, Torben; Colombaroli, Daniele; Beffa, Giorgia; Radaelli, Marta; Kehrwald, Natalie M.; Barbante, Carlo

    2015-05-01

    Vegetation changes in the Maya Lowlands during the Holocene are a result of changing climate conditions, solely anthropogenic activities, or interactions of both factors. As a consequence, it is difficult to assess how tropical ecosystems will cope with projected changes in precipitation and land-use intensification over the next decades. We investigated the role of fire during the Holocene by combining macroscopic charcoal and the molecular fire proxies levoglucosan, mannosan and galactosan. Combining these two different fire proxies allows a more robust understanding of the complex history of fire regimes at different spatial scales during the Holocene. In order to infer changes in past biomass burning, we analysed a lake sediment core from Lake Petén Itzá, Guatemala, and compared our results with millennial-scale vegetation and climate change available in the area. We detected three periods of high fire activity during the Holocene: 9500-6000 cal yr BP, 3700 cal yr BP and 2700 cal yr BP. We attribute the first maximum mostly to climate conditions and the last maximum to human activities. The rapid change between burned vegetation types at the 3700 cal yr BP fire maximum may result from human activity.

  1. Effects of atorvastatin combined with low-molecular-weight heparin on plasma inflammatory cytokine level and pulmonary pathophysiology of rats with sepsis.

    Science.gov (United States)

    Jing, Fei; Li, Ming; Ren, Hongsheng; Zhang, Jitian; Yao, Qingchun; Chu, Yufeng; Wang, Chunting

    2016-08-01

    The aim of the present study was to investigate the effect of atorvastatin combined with low-molecular-weight heparin (LMWH) on plasma early inflammatory cytokine levels as well as pulmonary pathophysiology of rats with sepsis. A total of 122 rats were randomly divided into five groups including the sham operation group (n=10), CLP group (n=10), atorvastatin group (n=34, 20 mg/kg/day), LMWH group (n=34, 100 IU/kg/day), and atorvastatin combined with LMWH group (n=34). Blood samples from 6 rats in each group were collected to detect TNF-α, IL-1β and HMGB1 concentration in plasma by linked immunosorbent assay at baseline and postoperatively at 4, 8, 12 and 24 h. Pulmonary pathophysiology was observed postoperatively at 24 h. The remaining 10 rats in each group were used to calculate the 7-day cumulative mortality rate. Compared to the sham operation group, the scores in CLP were greater than those of the sham operation group (Ppathophysiology in CLP was more severe. Compared to the CLP group, the damage of pulmonary pathophysiology in other groups was slight. Compared to the CLP group, the 7-day cumulative mortality rate in other groups decreased significantly (Ppathophysiology, and the 7-day cumulative mortality rate. Atorvastatin, and LMWH may therefore be useful for the treatment of sepsis due to its ability to inhibit the release of TNF-α, IL-1β and HMGB1 in septic rats.

  2. Correlating the Integral Sensing Properties of Zeolites with Molecular Processes by Combining Broadband Impedance and DRIFT Spectroscopy—A New Approach for Bridging the Scales

    Directory of Open Access Journals (Sweden)

    Peirong Chen

    2015-11-01

    Full Text Available Zeolites have been found to be promising sensor materials for a variety of gas molecules such as NH3, NOx, hydrocarbons, etc. The sensing effect results from the interaction of the adsorbed gas molecules with mobile cations, which are non-covalently bound to the zeolite lattice. The mobility of the cations can be accessed by electrical low-frequency (LF; mHz to MHz and high-frequency (HF; GHz impedance measurements. Recent developments allow in situ monitoring of catalytic reactions on proton-conducting zeolites used as catalysts. The combination of such in situ impedance measurements with diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS, which was applied to monitor the selective catalytic reduction of nitrogen oxides (DeNOx-SCR, not only improves our understanding of the sensing properties of zeolite catalysts from integral electric signal to molecular processes, but also bridges the length scales being studied, from centimeters to nanometers. In this work, recent developments of zeolite-based, impedimetric sensors for automotive exhaust gases, in particular NH3, are summarized. The electrical response to NH3 obtained from LF impedance measurements will be compared with that from HF impedance measurements, and correlated with the infrared spectroscopic characteristics obtained from the DRIFTS studies of molecules involved in the catalytic conversion. The future perspectives, which arise from the combination of these methods, will be discussed.

  3. Correlating the Integral Sensing Properties of Zeolites with Molecular Processes by Combining Broadband Impedance and DRIFT Spectroscopy--A New Approach for Bridging the Scales.

    Science.gov (United States)

    Chen, Peirong; Schönebaum, Simon; Simons, Thomas; Rauch, Dieter; Dietrich, Markus; Moos, Ralf; Simon, Ulrich

    2015-11-13

    Zeolites have been found to be promising sensor materials for a variety of gas molecules such as NH₃, NOx, hydrocarbons, etc. The sensing effect results from the interaction of the adsorbed gas molecules with mobile cations, which are non-covalently bound to the zeolite lattice. The mobility of the cations can be accessed by electrical low-frequency (LF; mHz to MHz) and high-frequency (HF; GHz) impedance measurements. Recent developments allow in situ monitoring of catalytic reactions on proton-conducting zeolites used as catalysts. The combination of such in situ impedance measurements with diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), which was applied to monitor the selective catalytic reduction of nitrogen oxides (DeNOx-SCR), not only improves our understanding of the sensing properties of zeolite catalysts from integral electric signal to molecular processes, but also bridges the length scales being studied, from centimeters to nanometers. In this work, recent developments of zeolite-based, impedimetric sensors for automotive exhaust gases, in particular NH₃, are summarized. The electrical response to NH₃ obtained from LF impedance measurements will be compared with that from HF impedance measurements, and correlated with the infrared spectroscopic characteristics obtained from the DRIFTS studies of molecules involved in the catalytic conversion. The future perspectives, which arise from the combination of these methods, will be discussed.

  4. Long term efficacy and safety of a combined low and high molecular weight hyaluronic acid in the treatment of osteoarthritis of the knee

    Directory of Open Access Journals (Sweden)

    Robert J. Petrella

    2011-03-01

    Full Text Available The primary objective was to determine the efficacy of intraarticular combined hyaluronic acid versus placebo in patients with grade 1-3 medial compartment osteoarthritis of the knee as evaluated through the self-paced 40 m walking pain visual analog scale (VAS at week 16, 52 and 104. Secondary objectives included pain at rest: a 10 cm VAS, patient global satisfaction using a 5-point numerical scale, consumption of concomitant medications, patients with <45 mm pain at followup 52 and 104 weeks. Safety was determined through the number of recorded adverse events. The study was designed as a prospective, randomized, double-blind, placebo controlled and comparative study. 200 patients were randomized in a 1:1 ratio to one of four treatment groups, to receive 3 weekly intra-articular injections of either: DMW (combined HA of different molecular weight and concentrations; HMW (high molecular weight HA; LMW (low molecular weight HA; PL (placebo, saline. Patients were assessed baseline and at week 16, 52, 104. Analyses were conducted using sigma stat (SPSS Inc., Chicago, Illinois and Microsoft Excel (Microsoft Corp, Redmond, Washington. Significance was established at P<0.05. Analysis of variance with repeated measures and c2 tests were used to test for differences from baseline characteristics of the group among the primary and secondary outcomes at each injection series interval. At 16, 52 and 104 weeks respectively, walking VAS pain was significantly improved in all treatment groups vs. Placebo: DMW (89.3%, P<0.001; 87.4%, P<0.001; 88.1%, P<0.001; LMW (81.3%, P<0.001; 78.2%, P<0.001; 77.0%, P<0.001 and HMW (79.1%, P<0.001; 81.1%, P<0.001; 79.4%, P<0.001. At 52 weeks, 8 patients in DMW group had resting VAS <45 mm. DMW had lower (62 mm, P <0.001 compared to LMW (76 mm and HMW (88 mm VAS at rest. Similar differences were observed for walking VAS 39, 41 and 43 (DMW, LMW, HMW received repeat injections. At 104 weeks, these differences were similar. DMW

  5. Low-molecular-weight model study of peroxide cross-linking of ethylene-propylene-diene rubber using gas chromatography and mass spectrometry II. Addition and combination reactions.

    Science.gov (United States)

    Peters, R; van Duin, M; Tonoli, D; Kwakkenbos, G; Mengerink, Y; van Benthem, R A T M; de Koster, C G; Schoenmakers, P J; van der Wal, Sj

    2008-08-08

    The dicumyl-peroxide-initiated addition and combination reactions of mixtures of alkanes (n-octane, n-decane) and alkenes [5,6-dihydrodicyclopentadiene (DCPDH), 5-ethylidene-2-norbornane (ENBH) and 5-vinylidene-2-norbornane (VNBH)] were studied to mimic the peroxide cross-linking reactions of terpolymerised ethylene, propylene and a diene monomer (EPDM). The reaction products of the mixtures were separated by both gas chromatography (GC) and comprehensive two-dimensional gas chromatography (GCxGC). The separated compounds were identified from their mass spectra and their GC and GCxGC elution pattern. Quantification of the various alkyl/alkyl, alkyl/allyl and allyl/allyl combination products shows that allylic-radicals comprise approximately 60% of the substrate radicals formed. The total concentration of the products formed by combination is found to be independent of the concentration and the type of alkene. The total concentration of the products formed by addition to the alkene increases with increasing concentration of alkene. In addition, the total concentration of the formed addition products depends strongly on the type of the alkene used, viz. VNBH>ENBH approximately DCPDH, which is a consequence of differences in steric hindrance of the unsaturation. The peroxide curing efficiency, defined as the number of moles of cross-linked products formed per mol of peroxide, is 173% using 9% (w/w) 5-vinylidene-2-norbornane (VNBH). This indicates that the addition reaction is recurrent. All these findings are consistent with experimental studies on peroxide curing of EPDM rubber. In addition, the present results provide more-detailed structural information, increasing the understanding of the mechanism of peroxide curing of EPDM. The described approach to use low-molecular-weight model compounds followed by GC-mass spectrometry (MS) and GCxGC-MS analysis is proven to be a very powerful tool to study the cross-linking of EPDM.

  6. ICT-Isomerization-Induced Turn-On Fluorescence Probe with a Large Emission Shift for Mercury Ion: Application in Combinational Molecular Logic.

    Science.gov (United States)

    Bhatta, Sushil Ranjan; Mondal, Bijan; Vijaykumar, Gonela; Thakur, Arunabha

    2017-10-02

    A unique turn-on fluorescent device based on a ferrocene-aminonaphtholate derivative specific for Hg(2+) cation was developed. Upon binding with Hg(2+) ion, the probe shows a dramatic fluorescence enhancement (the fluorescence quantum yield increases 58-fold) along with a large red shift of 68 nm in the emission spectrum. The fluorescence enhancement with a red shift may be ascribed to the combinational effect of C═N isomerization and an extended intramolecular charge transfer (ICT) mechanism. The response was instantaneous with a detection limit of 2.7 × 10(-9) M. Upon Hg(2+) recognition, the ferrocene/ferrocenium redox peak was anodically shifted by ΔE1/2 = 72 mV along with a "naked eye" color change from faint yellow to pale orange for this metal cation. Further, upon protonation of the imine nitrogen, the present probe displays a high fluorescence output due to suppression of the C═N isomerization process. Upon deprotonation using strong base, the fluorescence steadily decreases, which indicates that H(+) and OH(-) can be used to regulate the off-on-off fluorescence switching of the present probe. Density functional theory studies revealed that the addition of acid leads to protonation of the imine N (according to natural bond orbital analysis), and the resulting iminium proton forms a strong H-bond (2.307 Å) with one of the triazole N atoms to form a five-membered ring, which makes the molecule rigid; hence, enhancement of the ICT process takes place, thereby leading to a fluorescence enhancement with a red shift. The unprecedented combination of H(+), OH(-), and Hg(2+) ions has been used to generate a molecular system exhibiting the INHIBIT-OR combinational logic operation.

  7. An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis.

    Science.gov (United States)

    Wang, Taiyi; Lu, Ming; Du, Qunqun; Yao, Xi; Zhang, Peng; Chen, Xiaonan; Xie, Weiwei; Li, Zheng; Ma, Yuling; Zhu, Yan

    2017-05-02

    Wenxin Keli (WK), a Chinese patent medicine, is known to be effective against cardiac arrhythmias and heart failure. Although a number of electrophysiological findings regarding its therapeutic effect have been reported, the active components and system-level characterizations of the component-target interactions of WK have yet to be elucidated. In the current study, we present the first report of a new protective effect of WK on suppressing anti-arrhythmic-agent-induced arrhythmias. In a model of isolated guinea pig hearts, rapid perfusion of quinidine altered the heart rate and prolonged the Q-T interval. Pretreatment with WK significantly prevented quinidine-induced arrhythmias. To explain the therapeutic and protective effects of WK, we constructed an integrated multi-target pharmacological mechanism prediction workflow in combination with machine learning and molecular pathway analysis. This workflow had the ability to predict and rank the probability of each compound interacting with 1715 target proteins simultaneously. The ROC value statistics showed that 97.786% of the values for target prediction were larger than 0.8. We applied this model to carry out target prediction and network analysis for the identified components of 5 herbs in WK. Using the 124 potential anti-arrhythmic components and the 30 corresponding protein targets obtained, an integrative anti-arrhythmic molecular mechanism of WK was proposed. Emerging drug/target networks suggested ion channel and intracellular calcium and autonomic nervous and hormonal regulation had critical roles in WK-mediated anti-arrhythmic activity. A validation of the proposed mechanisms was achieved by demonstrating that calaxin, one of the WK components from Gansong, dose-dependently blocked its predicted target Ca V 1.2 channel in an electrophysiological assay.

  8. Molecular Determinants Underlying Binding Specificities of the ABL Kinase Inhibitors: Combining Alanine Scanning of Binding Hot Spots with Network Analysis of Residue Interactions and Coevolution.

    Directory of Open Access Journals (Sweden)

    Amanda Tse

    Full Text Available Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown that functionally critical regulatory residues can simultaneously embody strong coevolutionary signal and high network centrality with a propensity to be energetic hot spots for drug binding. We have found that selective (Nilotinib and promiscuous (Bosutinib, Dasatinib kinase inhibitors can use their energetic hot spots to differentially modulate stability of the residue interaction networks, thus inhibiting or promoting conformational equilibrium between inactive and active states. According to our results, Nilotinib binding may induce a significant network-bridging effect and enhance centrality of the hot spot residues that stabilize structural environment favored by the specific kinase form. In contrast, Bosutinib and Dasatinib can incur modest changes in the residue interaction network in which ligand binding is primarily coupled only with the identity of the gate-keeper residue. These factors may promote structural adaptability of the active kinase states in binding with these promiscuous inhibitors. Our results have related ligand-induced changes in the residue interaction networks with drug resistance effects, showing that network robustness may be compromised by targeted mutations

  9. Molecular Determinants Underlying Binding Specificities of the ABL Kinase Inhibitors: Combining Alanine Scanning of Binding Hot Spots with Network Analysis of Residue Interactions and Coevolution

    Science.gov (United States)

    Tse, Amanda; Verkhivker, Gennady M.

    2015-01-01

    Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown that functionally critical regulatory residues can simultaneously embody strong coevolutionary signal and high network centrality with a propensity to be energetic hot spots for drug binding. We have found that selective (Nilotinib) and promiscuous (Bosutinib, Dasatinib) kinase inhibitors can use their energetic hot spots to differentially modulate stability of the residue interaction networks, thus inhibiting or promoting conformational equilibrium between inactive and active states. According to our results, Nilotinib binding may induce a significant network-bridging effect and enhance centrality of the hot spot residues that stabilize structural environment favored by the specific kinase form. In contrast, Bosutinib and Dasatinib can incur modest changes in the residue interaction network in which ligand binding is primarily coupled only with the identity of the gate-keeper residue. These factors may promote structural adaptability of the active kinase states in binding with these promiscuous inhibitors. Our results have related ligand-induced changes in the residue interaction networks with drug resistance effects, showing that network robustness may be compromised by targeted mutations of key mediating

  10. Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures.

    Directory of Open Access Journals (Sweden)

    Alessandro Furlan

    Full Text Available The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in

  11. Molecularly imprinted solid-phase extraction combined with high-performance liquid chromatography for analysis of trace olaquindox residues in chick feeds.

    Science.gov (United States)

    Song, Jiaming; Qiao, Xuguang; Chen, Haihua; Zhao, Dongyan; Zhang, Yue; Xu, Zhixiang

    2011-10-01

    Olaquindox, one of the antimicrobial growth accelerants, is usually used as a feed additive in livestock production to improve feed efficiency. Due to health concerns over possible carcinogenic, mutagenic and photoallergenic effects of olaquindox on animals, the development of a simple, rapid and sensitive analytical method for determination of olaquindox is crucial and necessary. In this paper, a novel and hydrophilic functionalised material of olaquindox-imprinted polymer was synthesised in aqueous solution by a surface molecular imprinting in combination with a sol-gel process. This imprinted material was characterised by Fourier transform infrared, scanning electron microscopy, and static and kinetic adsorption experiments, and results showed that it had good recognition and selective ability, and fast adsorption-desorption dynamics for olaquindox. Applying the prepared material as sorbent, a method of molecularly imprinted solid-phase extraction (MISPE) for separation and analysis of olaquindox residues in feeds coupled with HPLC was presented. Under the selected MISPE condition, the detection limit (S/N = 3) for olaquindox was 68.0 ng L(-1), the RSD for five replicate extractions of 50 µg L(-1) olaquindox was 9.8%. The blank chick feed samples spiked with olaquindox at 0.0025 and 0.010 mg g(-1) levels were extracted and determined by the developed method, with recoveries ranging from 90% to 96%. This method was applied for enrichment and analysis of olaquindox in animal feed samples with good accuracy and repeatability. This study will provide a sensitive and fast method for the monitoring of olaquindox residues in foods. Copyright © 2011 Society of Chemical Industry.

  12. COMBINED CO AND DUST SCALING RELATIONS OF DEPLETION TIME AND MOLECULAR GAS FRACTIONS WITH COSMIC TIME, SPECIFIC STAR-FORMATION RATE, AND STELLAR MASS

    Energy Technology Data Exchange (ETDEWEB)

    Genzel, R.; Tacconi, L. J.; Lutz, D.; Berta, S.; Burkert, A. [Max-Planck-Institut für Extraterrestrische Physik (MPE), Giessenbachstr., D-85748 Garching (Germany); Saintonge, A. [Department of Physics and Astronomy, University College London, Gower Place, London WC1E 6BT (United Kingdom); Magnelli, B. [Argelander-Institut für Astronomie, Universität Bonn, Auf dem Hügel 71, D-53121 Bonn (Germany); Combes, F. [Observatoire de Paris, LERMA, CNRS, 61 Av. de l' Observatoire, F-75014 Paris (France); García-Burillo, S. [Observatorio Astronómico Nacional-OAN, Observatorio de Madrid, Alfonso XII, 3, 28014 Madrid (Spain); Neri, R.; Boissier, J. [IRAM, 300 Rue de la Piscine, F-38406 St. Martin d' Heres, Grenoble (France); Bolatto, A. [Department of Astronomy, University of Maryland, College Park, MD 20742-2421 (United States); Contini, T.; Boone, F.; Bouché, N. [Institut d' Astrophysique et de Planétologie, Universite de Toulouse, 9 Avenue du Colonel Roche BP 44346, F-31028 Toulouse Cedex 4 (France); Lilly, S.; Carollo, M. [Institute of Astronomy, Department of Physics, Eidgenössische Technische Hochschule, CH-8093 ETH Zürich (Switzerland); Bournaud, F. [Service d' Astrophysique, DAPNIA, CEA/Saclay, F-91191 Gif-sur-Yvette Cedex (France); Colina, L. [CSIC Instituto Estructura Materia, C/Serrano 121, E-28006 Madrid (Spain); Cooper, M. C., E-mail: linda@mpe.mpg.de, E-mail: genzel@mpe.mpg.de [Department of Physics and Astronomy, Frederick Reines Hall, University of California, Irvine, CA 92697 (United States); and others

    2015-02-10

    We combine molecular gas masses inferred from CO emission in 500 star-forming galaxies (SFGs) between z = 0 and 3, from the IRAM-COLDGASS, PHIBSS1/2, and other surveys, with gas masses derived from Herschel far-IR dust measurements in 512 galaxy stacks over the same stellar mass/redshift range. We constrain the scaling relations of molecular gas depletion timescale (t {sub depl}) and gas to stellar mass ratio (M {sub mol} {sub gas}/M{sub *} ) of SFGs near the star formation ''main-sequence'' with redshift, specific star-formation rate (sSFR), and stellar mass (M{sub *} ). The CO- and dust-based scaling relations agree remarkably well. This suggests that the CO → H{sub 2} mass conversion factor varies little within ±0.6 dex of the main sequence (sSFR(ms, z, M {sub *})), and less than 0.3 dex throughout this redshift range. This study builds on and strengthens the results of earlier work. We find that t {sub depl} scales as (1 + z){sup –0.3} × (sSFR/sSFR(ms, z, M {sub *})){sup –0.5}, with little dependence on M {sub *}. The resulting steep redshift dependence of M {sub mol} {sub gas}/M {sub *} ≈ (1 + z){sup 3} mirrors that of the sSFR and probably reflects the gas supply rate. The decreasing gas fractions at high M{sub *} are driven by the flattening of the SFR-M {sub *} relation. Throughout the probed redshift range a combination of an increasing gas fraction and a decreasing depletion timescale causes a larger sSFR at constant M {sub *}. As a result, galaxy integrated samples of the M {sub mol} {sub gas}-SFR rate relation exhibit a super-linear slope, which increases with the range of sSFR. With these new relations it is now possible to determine M {sub mol} {sub gas} with an accuracy of ±0.1 dex in relative terms, and ±0.2 dex including systematic uncertainties.

  13. Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

    Directory of Open Access Journals (Sweden)

    Menard Sandie

    2012-04-01

    Full Text Available Abstract Background Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ, previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ monotherapy. Then, artemisinin-based combination therapy (ACT, notably artesunate-amodiaquine (AS-AQ or artemether-lumefantrine (AL, was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city. Methods The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. Results This study showed a high prevalence of parasites with mutant pfcrt 76 (83% and pfmdr1 86 (93% codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. Conclusion The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a

  14. The Effect of Operating Conditions on Drying Characteristics and Quality of Ginger (Zingiber Officinale Roscoe) Using Combination of Solar Energy-Molecular Sieve Drying System

    Science.gov (United States)

    Hasibuan, R.; Zamzami, M. A.

    2017-03-01

    Ginger (Zingiber officinale Roscoe) is an agricultural product that can be used as beverages and snacks, and especially for traditional medicines. One of the important stages in the processing of ginger is drying. The drying process intended to reduce the water content of 85-90% to 8-10%, making it safe from the influence of fungi or insecticide. During the drying takes place, the main ingredient contained in ginger is homologous ketone phenolic known as gingerol are chemically unstable at high temperatures, for the drying technology is an important factor in maintaining the active ingredient (gingerol) which is in ginger. The combination of solar energy and molecular sieve dryer that are used in the research is capable of operating 24 hours. The purpose of this research is to study the effect of operating conditions (in this case the air velocity) toward the drying characteristics and the quality of dried ginger using the combination of solar energy and molecular sieve dryer. Drying system consist of three main parts which is: desiccator, solar collector, and the drying chamber. To record data changes in the mass of the sample, a load cell mounted in the drying chamber, and then connected to the automated data recording system using a USB data cable. All data of temperature and RH inside the dryer box and the change of samples mass recorded during the drying process takes place and the result is stored in the form of Microsoft Excel. The results obtained, shows that the air velocity is influencing the moisture content and ginger drying rate, where the moisture content equilibrium of ginger for the air velocity of 1.3 m/s was obtained on drying time of 360 minutes and moisture content of 2.8%, at 1.0 m/s was obtained on drying time of 300 minutes and moisture content of 1.4%, at 0, 8 m/s was obtained at 420 minutes drying time and the moisture content is 2.0%. The drying characteristics shows that there are two drying periods, which is: the increasing drying rate

  15. Influence of the LOV domain on low-lying excited states of flavin: a combined quantum-mechanics/molecular-mechanics investigation.

    Science.gov (United States)

    Salzmann, Susanne; Silva-Junior, Mario R; Thiel, Walter; Marian, Christel M

    2009-11-26

    The ground and low-lying excited states of flavin mononucleotide (FMN) in the light, oxygen, and voltage sensitive (LOV) domain of the blue-light photosensor YtvA of Bacillus subtilis were studied by means of combined quantum-mechanical/molecular-mechanical (QM/MM) methods. The FMN cofactor (without the side chain) was treated with density functional theory (DFT) for the geometry optimizations and a combination of DFT and multireference configuration interaction (MRCI) for the determination of the excitation energies, while the protein environment was represented by the CHARMM force field. In addition, several important amino acid side chains, including the reactive cysteine residue, were included in the QM region in order to probe their influence on the spectral properties of the cofactor in two protein conformations. Spin-orbit coupling was taken into account employing an efficient, nonempirical spin-orbit mean-field Hamiltonian. Our results reveal that the protein environment of YtvA-LOV induces spectral shifts for the (pi pi*) states that are similar to those in aqueous solution. In contrast, the blue shifts of the (n pi*) states are smaller in the protein environment, enabling a participation of these states in the decay processes of the optically bright S(1) state. Increased spin-orbit coupling between the initially populated S(1) state and the T(1) and T(2) states is found in YtvA-LOV as compared to free lumiflavine in water. The enhanced singlet-triplet coupling is brought about partially by configuration interaction with (n pi*) states at the slightly out-of-plane distorted minimum geometry. In addition, an external heavy-atom effect is observed when the sulfur atom of the nearby cysteine residue is included in the QM region, in line with experimental findings.

  16. Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles

    Science.gov (United States)

    Zhang, Ting; Xiong, Hui; Zohra Dahmani, Fatima; Sun, Li; Li, Yuanke; Yao, Li; Zhou, Jianping; Yao, Jing

    2015-04-01

    Based on the complementary effects of doxorubicin (DOX), all-trans retinoic acid (ATRA) and low molecular weight heparin (LMWH), the combination therapy of DOX, ATRA and LMWH was expected to exert the enhanced anti-tumor effects and reduce the side effects. In this study, amphiphilic LMWH-ATRA conjugate was synthesized for encapsulating the DOX. In this way, DOX, ATRA and LMWH were assembled into a single nano-system by both chemical and physical modes to obtain a novel anti-tumor targeting drug delivery system that can realize the simultaneous delivery of multiple drugs with different properties to the tumor. LMWH-ATRA nanoparticles exhibited good loading capacities for DOX with excellent physico-chemical properties, good biocompatibility, and good differentiation-inducing activity and antiangiogenic activity. The drug-loading capacity was up to 18.7% with an entrapment efficiency of 78.8%. It was also found that DOX-loaded LMWH-ATRA nanoparticles (DHR nanoparticles) could be efficiently taken up by tumor cells via endocytic pathway, and mainly distributed in cytoplasm at first, then transferred into cell nucleus. Cell viability assays suggested that DHR nanoparticles maintained the cytotoxicity effect of DOX on MCF-7 cells. Moreover, the in vivo imaging analysis indicated that DiR-loaded LMWH-ATRA nanoparticles could target the tumor more effectively as compared to free DiR. Furthermore, DHR nanoparticles possessed much higher anticancer activity and reduced side effects compared to free drugs solution. These results suggested that DHR nanoparticles could be considered as a promising targeted delivery system for combination cancer chemotherapy with lower adverse effects.

  17. Computing UV/vis spectra using a combined molecular dynamics and quantum chemistry approach: bis-triazin-pyridine (BTP) ligands studied in solution.

    Science.gov (United States)

    Höfener, Sebastian; Trumm, Michael; Koke, Carsten; Heuser, Johannes; Ekström, Ulf; Skerencak-Frech, Andrej; Schimmelpfennig, Bernd; Panak, Petra J

    2016-03-21

    We report a combined computational and experimental study to investigate the UV/vis spectra of 2,6-bis(5,6-dialkyl-1,2,4-triazin-3-yl)pyridine (BTP) ligands in solution. In order to study molecules in solution using theoretical methods, force-field parameters for the ligand-water interaction are adjusted to ab initio quantum chemical calculations. Based on these parameters, molecular dynamics (MD) simulations are carried out from which snapshots are extracted as input to quantum chemical excitation-energy calculations to obtain UV/vis spectra of BTP ligands in solution using time-dependent density functional theory (TDDFT) employing the Tamm-Dancoff approximation (TDA). The range-separated CAM-B3LYP functional is used to avoid large errors for charge-transfer states occurring in the electronic spectra. In order to study environment effects with theoretical methods, the frozen-density embedding scheme is applied. This computational procedure allows to obtain electronic spectra calculated at the (range-separated) DFT level of theory in solution, revealing solvatochromic shifts upon solvation of up to about 0.6 eV. Comparison to experimental data shows a significantly improved agreement compared to vacuum calculations and enables the analysis of relevant excitations for the line shape in solution.

  18. Combined quantum mechanics/molecular mechanics (QM/MM) simulations for protein-ligand complexes: free energies of binding of water molecules in influenza neuraminidase.

    Science.gov (United States)

    Woods, Christopher J; Shaw, Katherine E; Mulholland, Adrian J

    2015-01-22

    The applicability of combined quantum mechanics/molecular mechanics (QM/MM) methods for the calculation of absolute binding free energies of conserved water molecules in protein/ligand complexes is demonstrated. Here, we apply QM/MM Monte Carlo simulations to investigate binding of water molecules to influenza neuraminidase. We investigate five different complexes, including those with the drugs oseltamivir and peramivir. We investigate water molecules in two different environments, one more hydrophobic and one hydrophilic. We calculate the free-energy change for perturbation of a QM to MM representation of the bound water molecule. The calculations are performed at the BLYP/aVDZ (QM) and TIP4P (MM) levels of theory, which we have previously demonstrated to be consistent with one another for QM/MM modeling. The results show that the QM to MM perturbation is significant in both environments (greater than 1 kcal mol(-1)) and larger in the more hydrophilic site. Comparison with the same perturbation in bulk water shows that this makes a contribution to binding. The results quantify how electronic polarization differences in different environments affect binding affinity and also demonstrate that extensive, converged QM/MM free-energy simulations, with good levels of QM theory, are now practical for protein/ligand complexes.

  19. Metastasis of colon cancer to the thyroid gland: a case diagnosed on fine-needle aspirate by a combined cytological, immunocytochemical, and molecular approach.

    Science.gov (United States)

    Cozzolino, Immacolata; Malapelle, Umberto; Carlomagno, Chiara; Palombini, Lucio; Troncone, Giancarlo

    2010-12-01

    Fine-needle aspiration (FNA) with cytological evaluation reliably diagnoses primary and secondary thyroid neoplasms. However, identifying the primary origin of a metastatic process involving the thyroid gland is challenging. In particular, metastasis of colon cancer to the thyroid gland is very rare. In this case report, a right lobe solid thyroid nodule in a 66-year-old male was aspirated. FNA cytology showed necrosis and atypical tall columnar cells; since, the patient at age 60 had undergone surgery for a sigmoid-rectal cancer metastasizing to the liver and subsequently to the lung, a suspicion of metastasis from colon cancer was raised. This was corroborated by cell-block immunocytochemistry showing a cytokeratin (CK) 7 negative/CK20-positive staining pattern; thyreoglobulin and TTF-1 were both negative. Since KRAS codon 12/13 mutations frequently occur in colon cancer, whereas they are extremely uncommon in primary thyroid tumors, DNA was extracted from the aspirated cells, and KRAS mutational analysis was carried out. The codon 12 G12D mutation was found; the same mutation was evident in the primary cancer of the colon and in its liver and lung metastasis. Thus, a combined cytological, immunocytochemical and molecular approach unquestionably correlated metastatic adenocarcinoma cells aspirated from the thyroid to a colo-rectal origin. © 2010 Wiley-Liss, Inc.

  20. Solid phase microextraction of diclofenac using molecularly imprinted polymer sorbent in hollow fiber combined with fiber optic-linear array spectrophotometry

    Science.gov (United States)

    Pebdani, Arezou Amiri; Shabani, Ali Mohammad Haji; Dadfarnia, Shayessteh; Khodadoust, Saeid

    2015-08-01

    A simple solid phase microextraction method based on molecularly imprinted polymer sorbent in the hollow fiber (MIP-HF-SPME) combined with fiber optic-linear array spectrophotometer has been applied for the extraction and determination of diclofenac in environmental and biological samples. The effects of different parameters such as pH, times of extraction, type and volume of the organic solvent, stirring rate and donor phase volume on the extraction efficiency of the diclofenac were investigated and optimized. Under the optimal conditions, the calibration graph was linear (r2 = 0.998) in the range of 3.0-85.0 μg L-1 with a detection limit of 0.7 μg L-1 for preconcentration of 25.0 mL of the sample and the relative standard deviation (n = 6) less than 5%. This method was applied successfully for the extraction and determination of diclofenac in different matrices (water, urine and plasma) and accuracy was examined through the recovery experiments.

  1. Solid phase microextraction of diclofenac using molecularly imprinted polymer sorbent in hollow fiber combined with fiber optic-linear array spectrophotometry.

    Science.gov (United States)

    Pebdani, Arezou Amiri; Shabani, Ali Mohammad Haji; Dadfarnia, Shayessteh; Khodadoust, Saeid

    2015-08-05

    A simple solid phase microextraction method based on molecularly imprinted polymer sorbent in the hollow fiber (MIP-HF-SPME) combined with fiber optic-linear array spectrophotometer has been applied for the extraction and determination of diclofenac in environmental and biological samples. The effects of different parameters such as pH, times of extraction, type and volume of the organic solvent, stirring rate and donor phase volume on the extraction efficiency of the diclofenac were investigated and optimized. Under the optimal conditions, the calibration graph was linear (r(2)=0.998) in the range of 3.0-85.0 μg L(-1) with a detection limit of 0.7 μg L(-1) for preconcentration of 25.0 mL of the sample and the relative standard deviation (n=6) less than 5%. This method was applied successfully for the extraction and determination of diclofenac in different matrices (water, urine and plasma) and accuracy was examined through the recovery experiments. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. The Carboxy Terminus of the Ligand Peptide Determines the Stability of the MHC Class I Molecule H-2Kb: A Combined Molecular Dynamics and Experimental Study.

    Directory of Open Access Journals (Sweden)

    Esam Tolba Abualrous

    Full Text Available Major histocompatibility complex (MHC class I molecules (proteins bind peptides of eight to ten amino acids to present them at the cell surface to cytotoxic T cells. The class I binding groove binds the peptide via hydrogen bonds with the peptide termini and via diverse interactions with the anchor residue side chains of the peptide. To elucidate which of these interactions is most important for the thermodynamic and kinetic stability of the peptide-bound state, we have combined molecular dynamics simulations and experimental approaches in an investigation of the conformational dynamics and binding parameters of a murine class I molecule (H-2Kb with optimal and truncated natural peptide epitopes. We show that the F pocket region dominates the conformational and thermodynamic properties of the binding groove, and that therefore the binding of the C terminus of the peptide to the F pocket region plays a crucial role in bringing about the peptide-bound state of MHC class I.

  3. Combined quantum-mechanical molecular mechanics calculations with NWChem and AMBER: Excited state properties of green fluorescent protein chromophore analogue in aqueous solution

    Energy Technology Data Exchange (ETDEWEB)

    Pirojsirikul, Teerapong [Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive La Jolla California 92093; Götz, Andreas W. [San Diego Supercomputer Center, University of California San Diego, 9500 Gilman Drive La Jolla California 92093; Weare, John [Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive La Jolla California 92093; Walker, Ross C. [Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive La Jolla California 92093; GlaxoSmithKline, 1250 S. Collegeville Road Collegeville Pennsylvania 19426; Kowalski, Karol [Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, P. O. Box 999 Richland Washington 99352; Valiev, Marat [Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, P. O. Box 999 Richland Washington 99352

    2017-05-03

    Green Fluorescent Protein (GFP) is a widely used fluorescent biomarker for the study of biological systems. Our investigation is focused on providing a reliable theoretical description of the GFP chromophore, the photochemical properties of which can be influenced through both the surrounding protein environment and pH levels. In this work we are specifically addressing the effect of an aqueous solvation environment , where a number of experimental measurements have been performed. Our approach is based on a combined quantum mechanics molecular mechanics (QM/MM) methodology, which incorporates high level coupled cluster theory for the analysis of excited states. It also presents the first application of the newly developed NWChem/AMBER QM/MM interface. Using a systematic approach, which involves comparison of gas phase and aqueous results for different protonation states and conformations, we have resolved existing uncertainties regarding theoretical interpretation of the experimental data. We observe that the impact of aqueous environment on charged states generally results in blue shifts, but the magnitude of the effect is sensitive to charge state and conformation and can be rationalized based on charge movement into the area of higher/lower external electrostatic potentials. At neutral pH levels the experimentally observed absorption signal is most likely coming from the phenol protonated form. Our results also show that the high level coupled description is essential for proper description of excited states of GFP.

  4. Novel virtual screening protocol based on the combined use of molecular modeling and electron-ion interaction potential techniques to design HIV-1 integrase inhibitors.

    Science.gov (United States)

    Tintori, Cristina; Manetti, Fabrizio; Veljkovic, Nevena; Perovic, Vladimir; Vercammen, Jo; Hayes, Sean; Massa, Silvio; Witvrouw, Myriam; Debyser, Zeger; Veljkovic, Veljko; Botta, Maurizio

    2007-01-01

    HIV-1 integrase (IN) is an essential enzyme for viral replication and represents an intriguing target for the development of new drugs. Although a large number of compounds have been reported to inhibit IN in biochemical assays, no drug active against this enzyme has been approved by the FDA so far. In this study, we report, for the first time, the use of the electron-ion interaction potential (EIIP) technique in combination with molecular modeling approaches for the identification of new IN inhibitors. An innovative virtual screening approach, based on the determination of both short- and long-range interactions between interacting molecules, was employed with the aim of identifying molecules able to inhibit the binding of IN to viral DNA. Moreover, results from a database screening on the commercial Asinex Gold Collection led to the selection of several compounds. One of them showed a significant inhibitory potency toward IN in the overall integration assay. Biological investigations also showed, in agreement with modeling studies, that these compounds prevent recognition of DNA by IN in a fluorescence fluctuation assay, probably by interacting with the DNA binding domain of IN.

  5. Protective effect of calcium dobesilate combined with benazepril therapy on renal injury in patients with early diabetic nephropathy and the possible molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Ling Zhang

    2017-06-01

    Full Text Available Objective: To explore the protective effect of calcium dobesilate combined with benazepril therapy on renal injury in patients with early diabetic nephropathy and the possible molecular mechanisms. Methods: A total of 50 patients with early diabetic nephropathy treated in our hospital between May 2012 and January 2016 were collected, and according to the random number table, the patients were divided into observation group (n=25 and control group (n=25. On the basis of conventional treatment, control group of patients received benazepril therapy, observation group of patients received calcium dobesilate combined with benazepril therapy, and the treatment lasted for 3 months. Before and after treatment, automatic biochemical analyzer was used to detect the levels of renal injury indexes in peripheral blood, RIA method was used to detect the levels of renal injury indexes in urine, ELISA method was used to detect the levels of renal fibrosis indexes and Western-blot method was used to detect the protein expression of TGF-β1/BMP-7 and Smad signaling pathway molecules in renal tissue. Results: Before treatment, differences in renal injury index levels, renal fibrosis index levels and signaling pathway molecule protein expression were not statistically significant between two groups of patients. After treatment, BUN, SCr and β-TP levels in the peripheral blood as well as KIM-1 level in urine of observation group were lower than those of control group; renal fibrosis indexes TGF-β1, CTGF, TIMP-1, LN and HA levels in serum of observation group were lower than those of control group; TGF-β1 and Smad2/3 protein expression in renal tissue of observation group were lower than those of control group while Smad7 and BMP-7 protein expression were higher than those of control group. Conclusion: Calcium dobesilate combined with benazepril therapy can reduce the renal injury and inhibit the fibrosis process in patients with early diabetic nephropathy, and it

  6. Combining sedimentological, trace metal (Mn, Mo) and molecular evidence for reconstructing past water-column redox conditions: The example of meromictic Lake Cadagno (Swiss Alps)

    Science.gov (United States)

    Wirth, Stefanie B.; Gilli, Adrian; Niemann, Helge; Dahl, Tais W.; Ravasi, Damiana; Sax, Nadja; Hamann, Yvonne; Peduzzi, Raffaele; Peduzzi, Sandro; Tonolla, Mauro; Lehmann, Moritz F.; Anselmetti, Flavio S.

    2013-11-01

    Here, we present sedimentological, trace metal, and molecular evidence for tracking bottom water redox-state conditions during the past 12,500 years in nowadays sulfidic and meromictic Lake Cadagno (Switzerland). A 10.5 m long sediment core from the lake covering the Holocene period was investigated for concentration variations of the trace metals Mn and Mo (XRF core scanning and ICP-MS measurements), and for the presence of anoxygenic phototrophic sulfur bacteria (carotenoid pigment analysis and 16S rDNA real time PCR). Our trace metal analysis documents an oxic-intermediate-sulfidic redox-transition period beginning shortly after the lake formation ˜12.5 kyr ago. The oxic period is characterized by low sedimentary Mn and Mo concentrations, as well as by the absence of any remnants of anoxygenic phototrophic sulfur bacteria. Enhanced accumulation/preservation of Mn (up to 5.6 wt%) in the sediments indicates an intermediate, Mn-enriched oxygenation state with fluctuating redox conditions during a ˜2300-year long transition interval between ˜12.1 and 9.8 kyr BP. We propose that the high Mn concentrations are the result of enhanced Mn2+ leaching from the sediments during reducing conditions and subsequent rapid precipitation of Mn-(oxyhydr)oxide minerals during episodic and short-term water-column mixing events mainly due to flood-induced underflows. At 9800 ± 130 cal yr BP, a rapid transition to fully sulfidic conditions is indicated by the marked enrichment of Mo in the sediments (up to 490 ppm), accompanied by an abrupt drop in Mn concentrations and the increase of molecular biomarkers that indicate the presence of anoxygenic photosynthetic bacteria in the water column. Persistently high Mo concentrations >80 ppm provide evidence that sulfidic conditions prevailed thereafter until modern times, without any lasting hypolimnetic ventilation and reoxygenation. Hence, Lake Cadagno with its persistently stable chemocline offers a framework to study in great

  7. Identification of the Structural Features of Guanine Derivatives as MGMT Inhibitors Using 3D-QSAR Modeling Combined with Molecular Docking

    Directory of Open Access Journals (Sweden)

    Guohui Sun

    2016-06-01

    Full Text Available DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT, which plays an important role in inducing drug resistance against alkylating agents that modify the O6 position of guanine in DNA, is an attractive target for anti-tumor chemotherapy. A series of MGMT inhibitors have been synthesized over the past decades to improve the chemotherapeutic effects of O6-alkylating agents. In the present study, we performed a three-dimensional quantitative structure activity relationship (3D-QSAR study on 97 guanine derivatives as MGMT inhibitors using comparative molecular field analysis (CoMFA and comparative molecular similarity indices analysis (CoMSIA methods. Three different alignment methods (ligand-based, DFT optimization-based and docking-based alignment were employed to develop reliable 3D-QSAR models. Statistical parameters derived from the models using the above three alignment methods showed that the ligand-based CoMFA (Qcv2 = 0.672 and Rncv2 = 0.997 and CoMSIA (Qcv2 = 0.703 and Rncv2 = 0.946 models were better than the other two alignment methods-based CoMFA and CoMSIA models. The two ligand-based models were further confirmed by an external test-set validation and a Y-randomization examination. The ligand-based CoMFA model (Qext2 = 0.691, Rpred2 = 0.738 and slope k = 0.91 was observed with acceptable external test-set validation values rather than the CoMSIA model (Qext2 = 0.307, Rpred2 = 0.4 and slope k = 0.719. Docking studies were carried out to predict the binding modes of the inhibitors with MGMT. The results indicated that the obtained binding interactions were consistent with the 3D contour maps. Overall, the combined results of the 3D-QSAR and the docking obtained in this study provide an insight into the understanding of the interactions between guanine derivatives and MGMT protein, which will assist in designing novel MGMT inhibitors with desired activity.

  8. Combined Atomistic Molecular Calculations and Experimental Investigations for the Architecture, Screening, Optimization, and Characterization of Pyrazinamide Containing Oral Film Formulations for Tuberculosis Management.

    Science.gov (United States)

    Adeleke, Oluwatoyin A; Monama, Nkwe O; Tsai, Pei-Chin; Sithole, Happy M; Michniak-Kohn, Bozena B

    2016-02-01

    semicrystalline in nature and displayed a dual phased ex vivo mucosal permeation pattern. In silico and in vitro physicomechanical quantities revealed OF 2's flexibility, robustness, and compressibility. OF 2 was most stable under controlled environmental humidity, pressure, and temperature conditions in silico and in vitro. OF 2 was potentially non-cytotoxic and biocompatible. Succinctly, this work demonstrated the applicability of a combination of atomistic molecular mechanics and dynamics calculations as well as experimental analyses to the fabrication, screening, optimization, and characterization of drug formulations. Lastly, the fabricated OF 2 formulation can function as a potential alternative for the effective loading and delivery of PYZ.

  9. Tuned and Balanced Redistributed Charge Scheme for Combined Quantum Mechanical and Molecular Mechanical (QM/MM) Methods and Fragment Methods: Tuning Based on the CM5 Charge Model.

    Science.gov (United States)

    Wang, Bo; Truhlar, Donald G

    2013-02-12

    Tuned and balanced redistributed charge schemes have been developed for modeling the electrostatic fields of bonds that are cut by a quantum mechanical-molecular mechanical boundary in combined quantum mechanical and molecular mechanical (QM/MM) methods. First, the charge is balanced by adjusting the charge on the MM boundary atom to conserve the total charge of the entire QM/MM system. In the balanced smeared redistributed charge (BSRC) scheme, the adjusted MM boundary charge is smeared with a smearing width of 1.0 Å and is distributed in equal portions to the midpoints of the bonds between the MM boundary atom and the MM atoms bonded to it; in the balanced redistributed charge-2 (BRC2) scheme, the adjusted MM boundary charge is distributed as point charges in equal portions to the MM atoms that are bonded to the MM boundary atom. The QM subsystem is capped by a fluorine atom that is tuned to reproduce the sum of partial atomic charges of the uncapped portion of the QM subsystem. The new aspect of the present study is a new way to carry out the tuning process; in particular, the CM5 charge model, rather than the Mulliken population analysis applied in previous studies, is used for tuning the capping atom that terminates the dangling bond of the QM region. The mean unsigned error (MUE) of the QM/MM deprotonation energy for a 15-system test suite of deprotonation reactions is 2.3 kcal/mol for the tuned BSRC scheme (TBSRC) and 2.4 kcal/mol for the tuned BRC2 scheme (TBRC2). As was the case for the original tuning method based on Mulliken charges, the new tuning method performs much better than using conventional hydrogen link atoms, which have an MUE on this test set of about 7 kcal/mol. However, the new scheme eliminates the need to use small basis sets, which can be problematic, and it allows one to be more consistent by tuning the parameters with whatever basis set is appropriate for applications. (Alternatively, since the tuning parameters and partial charges

  10. The first phylogeographic population structure and analysis of transmission dynamics of M. africanum West African 1--combining molecular data from Benin, Nigeria and Sierra Leone.

    Directory of Open Access Journals (Sweden)

    Florian Gehre

    Full Text Available Mycobacterium africanum is an important cause of tuberculosis (TB in West Africa. So far, two lineages called M. africanum West African 1 (MAF1 and M. africanum West African 2 (MAF2 have been defined. Although several molecular studies on MAF2 have been conducted to date, little is known about MAF1. As MAF1 is mainly present in countries around the Gulf of Guinea we aimed to estimate its prevalence in Cotonou, the biggest city in Benin. Between 2005-06 we collected strains in Cotonou/Benin and genotyped them using spoligo- and 12-loci-MIRU-VNTR-typing. Analyzing 194 isolates, we found that 31% and 6% were MAF1 and MAF2, respectively. Therefore Benin is one of the countries with the highest prevalence (37% of M. africanum in general and MAF1 in particular. Moreover, we combined our data from Benin with publicly available genotyping information from Nigeria and Sierra Leone, and determined the phylogeographic population structure and genotypic clustering of MAF1. Within the MAF1 lineage, we identified an unexpected great genetic variability with the presence of at least 10 sub-lineages. Interestingly, 8 out of 10 of the discovered sub-lineages not only clustered genetically but also geographically. Besides showing a remarkable local restriction to certain regions in Benin and Nigeria, the sub-lineages differed dramatically in their capacity to transmit within the human host population. While identifying Benin as one of the countries with the highest overall prevalence of M. africanum, this study also contains the first detailed description of the transmission dynamics and phylogenetic composition of the MAF1 lineage.

  11. Evaluating the potential of thermal read-out techniques combined with molecularly imprinted polymers for the sensing of low-weight organic molecules.

    Science.gov (United States)

    van Grinsven, B; Betlem, K; Cleij, T J; Banks, C E; Peeters, M

    2017-01-01

    In recent years, there has been a tremendous increase in the papers published on synthetic recognition elements. Molecularly imprinted polymers (MIPs), also referred to as "man-made mimics" of antibodies, are able to rebind their template molecules with high affinity. Advantages compared with those of natural receptors include their excellent thermal and chemical stability, low cost, and ease of the production process. However, their use in commercial biosensors is limited owing to the difficulty to incorporate MIPs into suitable sensing platforms and traditional detection techniques, such as chromatography, that require bulky and sophisticated equipment. In this review, we evaluate the potential to use MIPs combined with thermal read-out for the detection of low-weight organic molecules. We discuss thermal methods to study MIP-template complexation and to determine neurotransmitters concentrations. In particular, we highlight the heat-transfer method, a recent technique that is straightforward and low cost and requires minimal instrumentation. Until now, sample preparation involves a 2-step process, making it time-consuming, and measuring biological samples is difficult owing to the noise in the signal. Different sample preparation methods are discussed, and it will be demonstrated how this affects the thermal response. An outlook is given in novel methods that can simplify and speed up sample preparation. Finally, we show a novel thermal technique, which is based on the analysis of transport of thermal waves rather than evaluating the fixed heat-transfer resistance. Through applying the concept of thermal waves, signal-noise ratio is significantly increased, which results in lower detection limits and has potential for the study of biological samples. Copyright © 2016 John Wiley & Sons, Ltd.

  12. Low-Molecular-Weight Heparin-Coated and Montelukast-Filled Inhalable Particles: A Dual-Drug Delivery System for Combination Therapy in Asthma.

    Science.gov (United States)

    Patel, Brijeshkumar; Rashid, Jahidur; Gupta, Nilesh; Ahsan, Fakhrul

    2017-04-01

    Montelukast, a cysteinyl leukotriene type 1 receptor antagonist, exhibits secondary anti-inflammatory properties when used at higher concentrations. Low-molecular-weight heparin (LMWH) evokes pronounced anti-inflammatory effects by interrupting leukocyte adhesion and migration. We hypothesized that inhalable particles containing montelukast plus LMWH release both drugs in a sustained fashion and protect the lungs against allergen-induced inflammation. Large porous particles of montelukast and LMWH were prepared using a double-emulsion-solvent-evaporation method. Montelukast was first encapsulated in copolymer-based particles using polyethylenimine as a porosigen; the resulting particles were then coated with LMWH. The particles were evaluated for physicochemical properties, respirability, and release profiles. The anti-inflammatory effect of the optimized formulation was studied in ovalbumin-sensitized asthmatic Sprague Dawley rats. The optimized large porous particles had a diameter of 10.3 ± 0.7 μm, exhibited numerous surface indentations and pores, showed acceptable drug entrapment efficiency (66.8% ± 0.4% for montelukast; 91.7% ± 0.8% adsorption efficiency for LMWH), demonstrated biphasic release patterns, and escaped the uptake by the rat alveolar macrophages. The number of infiltrating inflammatory cells in asthmatic rat lungs, treated with dual-drug particles, was >74% fewer than in untreated asthmatic rat lungs. Similarly, the airway walls of asthmatic animals treated with dual-drug particles were 3-fold thinner than those of untreated asthmatic animals (p montelukast and LMWH, into an inhalable particulate system and establishes that this novel combination therapy produces sustained drug release and elicits a robust anti-inflammatory response in the lungs. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  13. Incorporation of antimicrobial peptides into membranes: a combined liquid-state NMR and molecular dynamics study of alamethicin in DMPC/DHPC bicelles.

    Science.gov (United States)

    Dittmer, Jens; Thøgersen, Lea; Underhaug, Jarl; Bertelsen, Kresten; Vosegaard, Thomas; Pedersen, Jan M; Schiøtt, Birgit; Tajkhorshid, Emad; Skrydstrup, Troels; Nielsen, Niels Chr

    2009-05-14

    Detailed insight into the interplay between antimicrobial peptides and biological membranes is fundamental to our understanding of the mechanism of bacterial ion channels and the action of these in biological host-defense systems. To explore this interplay, we have studied the incorporation, membrane-bound structure, and conformation of the antimicrobial peptide alamethicin in lipid bilayers using a combination of 1H liquid-state NMR spectroscopy and molecular dynamics (MD) simulations. On the basis of experimental NMR data, we evaluate simple in-plane and transmembrane incorporation models as well as pore formation for alamethicin in DMPC/DHPC (1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine/1,2-dihexanoyl-sn-glycero-3-phosphatidylcholine) bicelles. Peptide-lipid nuclear Overhauser effect (NOE) and paramagnetic relaxation enhancement (PRE) data support a transmembrane configuration of the peptide in the bilayers, but they also reveal that the system cannot be described by a single simple conformational model because there is a very high degree of dynamics and heterogeneity in the three-component system. To explore the origin of this heterogeneity and dynamics, we have compared the NOE and PRE data with MD simulations of an ensemble of alamethicin peptides in a DMPC bilayer. From all-atom MD simulations, the contacts between peptide, lipid, and water protons are quantified over a time interval up to 95 ns. The MD simulations provide a statistical base that reflects our NMR data and even can explain some initially surprising NMR results concerning specific interactions between alamethicin and the lipids.

  14. Folding dynamics of the Trp-cage miniprotein: evidence for a native-like intermediate from combined time-resolved vibrational spectroscopy and molecular dynamics simulations.

    Science.gov (United States)

    Meuzelaar, Heleen; Marino, Kristen A; Huerta-Viga, Adriana; Panman, Matthijs R; Smeenk, Linde E J; Kettelarij, Albert J; van Maarseveen, Jan H; Timmerman, Peter; Bolhuis, Peter G; Woutersen, Sander

    2013-10-03

    Trp-cage is a synthetic 20-residue miniprotein which folds rapidly and spontaneously to a well-defined globular structure more typical of larger proteins. Due to its small size and fast folding, it is an ideal model system for experimental and theoretical investigations of protein folding mechanisms. However, Trp-cage's exact folding mechanism is still a matter of debate. Here we investigate Trp-cage's relaxation dynamics in the amide I' spectral region (1530-1700 cm(-1)) using time-resolved infrared spectroscopy. Residue-specific information was obtained by incorporating an isotopic label ((13)C═(18)O) into the amide carbonyl group of residue Gly11, thereby spectrally isolating an individual 310-helical residue. The folding-unfolding equilibrium is perturbed using a nanosecond temperature-jump (T-jump), and the subsequent re-equilibration is probed by observing the time-dependent vibrational response in the amide I' region. We observe bimodal relaxation kinetics with time constants of 100 ± 10 and 770 ± 40 ns at 322 K, suggesting that the folding involves an intermediate state, the character of which can be determined from the time- and frequency-resolved data. We find that the relaxation dynamics close to the melting temperature involve fast fluctuations in the polyproline II region, whereas the slower process can be attributed to conformational rearrangements due to the global (un)folding transition of the protein. Combined analysis of our T-jump data and molecular dynamics simulations indicates that the formation of a well-defined α-helix precedes the rapid formation of the hydrophobic cage structure, implying a native-like folding intermediate, that mainly differs from the folded conformation in the orientation of the C-terminal polyproline II helix relative to the N-terminal part of the backbone. We find that the main free-energy barrier is positioned between the folding intermediate and the unfolded state ensemble, and that it involves the formation of

  15. Free energy calculation using molecular dynamics simulation combined with the three dimensional reference interaction site model theory. I. Free energy perturbation and thermodynamic integration along a coupling parameter.

    Science.gov (United States)

    Miyata, Tatsuhiko; Ikuta, Yasuhiro; Hirata, Fumio

    2010-07-28

    This article proposes a free energy calculation method based on the molecular dynamics simulation combined with the three dimensional reference interaction site model theory. This study employs the free energy perturbation (FEP) and the thermodynamic integration (TDI) along the coupling parameters to control the interaction potential. To illustrate the method, we applied it to a complex formation process in aqueous solutions between a crown ether molecule 18-Crown-6 (18C6) and a potassium ion as one of the simplest model systems. Two coupling parameters were introduced to switch the Lennard-Jones potential and the Coulomb potential separately. We tested two coupling procedures: one is a "sequential-coupling" to couple the Lennard-Jones interaction followed by the Coulomb coupling, and the other is a "mixed-coupling" to couple both the Lennard-Jones and the Coulomb interactions together as much as possible. The sequential-coupling both for FEP and TDI turned out to be accurate and easily handled since it was numerically well-behaved. Furthermore, it was found that the sequential-coupling had relatively small statistical errors. TDI along the mixed-coupling integral path was to be carried out carefully, paying attention to a numerical behavior of the integrand. The present model system exhibited a nonmonotonic behavior in the integrands for TDI along the mixed-coupling integral path and also showed a relatively large statistical error. A coincidence within a statistical error was obtained among the results of the free energy differences evaluated by FEP, TDI with the sequential-coupling, and TDI with the mixed-coupling. The last one is most attractive in terms of the computer power and is accurate enough if one uses a proper set of windows, taking the numerical behavior of the integrands into account. TDI along the sequential-coupling integral path would be the most convenient among the methods we tested, since it seemed to be well-balanced between the computational

  16. Combined Pharmacological and Genetic Manipulations Unlock Unprecedented Temporal Elasticity and Reveal Phase-Specific Modulation of the Molecular Circadian Clock of the Mouse Suprachiasmatic Nucleus.

    Science.gov (United States)

    Patton, Andrew P; Chesham, Johanna E; Hastings, Michael H

    2016-09-07

    activity of the CK1ε isoform. In conclusion, extreme period manipulation reveals unprecedented elasticity and temporal structure of the SCN circadian oscillation. The master circadian clock of the suprachiasmatic nucleus (SCN) encodes time-of-day information that allows mammals to predict and thereby adapt to daily environmental cycles. Using combined genetic and pharmacological interventions, we assessed the temporal elasticity of the SCN network. Despite having evolved to generate a 24 h circadian period, we show that the molecular clock is surprisingly elastic, able to reversibly sustain coherent periods between ≤17 and >42 h at the levels of individual cells and the overall circuit. Using quantitative techniques to analyze these extreme periodicities, we reveal that the oscillator progresses as a sequence of distinct stages. These findings reveal new properties of how the SCN functions as a network and should inform biological and mathematical analyses of circadian timekeeping. Copyright © 2016 Patton et al.

  17. Combination of statistical methods and Fourier transform ion cyclotron resonance mass spectrometry for more comprehensive, molecular-level interpretations of petroleum samples.

    Science.gov (United States)

    Hur, Manhoi; Yeo, Injoon; Park, Eunsuk; Kim, Young Hwan; Yoo, Jongshin; Kim, Eunkyoung; No, Myoung-han; Koh, Jaesuk; Kim, Sunghwan

    2010-01-01

    Complex petroleum mass spectra obtained by Fourier-transform ion cyclotron resonance mass spectrometry (FTICR MS) were successfully interpreted at the molecular level by applying principle component analysis (PCA) and hierarchical clustering analysis (HCA). A total of 40 mass spectra were obtained from 20 crude oil samples using both positive and negative atmospheric pressure photoionization (APPI). Approximately 400,000 peaks were identified at the molecular level. Conventional data analyses would have been impractical with so much data. However, PCA grouped samples into score plots based on their molecular composition. In this way, the overall compositional difference between samples could be easily displayed and identified by comparing score and loading plots. HCA was also performed to group and compare samples based on selected peaks that had been grouped by PCA. Subsequent heat map analyses revealed detailed compositional differences among grouped samples. This study demonstrates a promising new approach for studying multiple, complex petroleum samples at the molecular level.

  18. Combining quantum wavepacket ab initio molecular dynamics with QM/MM and QM/QM techniques: Implementation blending ONIOM and empirical valence bond theory.

    Science.gov (United States)

    Sumner, Isaiah; Iyengar, Srinivasan S

    2008-08-07

    We discuss hybrid quantum-mechanics/molecular-mechanics (QM/MM) and quantum mechanics/quantum mechanics (QM/QM) generalizations to our recently developed quantum wavepacket ab initio molecular dynamics methodology for simultaneous dynamics of electrons and nuclei. The approach is a synergy between a quantum wavepacket dynamics, ab initio molecular dynamics, and the ONIOM scheme. We utilize this method to include nuclear quantum effects arising from a portion of the system along with a simultaneous description of the electronic structure. The generalizations provided here make the approach a potentially viable alternative for large systems. The quantum wavepacket dynamics is performed on a grid using a banded, sparse, and Toeplitz representation of the discrete free propagator, known as the "distributed approximating functional." Grid-based potential surfaces for wavepacket dynamics are constructed using an empirical valence bond generalization of ONIOM and further computational gains are achieved through the use of our recently introduced time-dependent deterministic sampling technique. The ab initio molecular dynamics is achieved using Born-Oppenheimer dynamics. All components of the methodology, namely, quantum dynamics and ONIOM molecular dynamics, are harnessed together using a time-dependent Hartree-like procedure. We benchmark the approach through the study of structural and vibrational properties of molecular, hydrogen bonded clusters inclusive of electronic, dynamical, temperature, and critical quantum nuclear effects. The vibrational properties are constructed through a velocity/flux correlation function formalism introduced by us in an earlier publication.

  19. Optical coherence tomography with pre-calculated reference spectra

    Science.gov (United States)

    Wang, Yi; Chen, Xiaodong; Liang, Haitao; Yu, Daoyin

    2017-02-01

    The resample of spectra which is essential for high-precision spectral-domain OCT data processing is sophisticated, and its precision is dependent on the method and equipment. In this paper, we proposed an OCT without inverse FFT. A series of reference spectra corresponding to different optical path length difference was used to convolve with spectra gotten by OCT to acquire time-domain tomography instead of inverse FFT, thus eliminating the resample of spectra. The reference spectra were calculated before imaging and corrected with correction spectrum from sample arm to compensate the influence of sample arm. Experiment was done with a mirror as sample and validated our setup.

  20. Molecular recognition and binding of beta-lactamase II from Bacillus cereus with penicillin V and sulbactam by spectroscopic analysis in combination with docking simulation.

    Science.gov (United States)

    Zhang, Yeli; Qiao, Pan; Li, Shuaihua; Feng, Xuan; Bian, Liujiao

    2017-09-01

    The molecular recognition and binding interaction of beta-lactamase II from Bacillus cereus (Bc II) with penicillin V (PV) and sulbactam (Sul) at 277 K were studied by spectroscopic analysis and molecular docking. The results showed that a non-fluorescence static complex was separately formed between Bc II and two ligands, the molecular ratio of Bc II to PV or Sul was both 1:1 in the binding and the binding constants were 2.00 × 10(6) and 3.98 × 10(5) (L/mol), respectively. The negative free energy changes and apparent activation energies indicated that both the binding processes were spontaneous. Molecular docking showed that in the binding process, the whole Sul molecule entered into the binding pocket of Bc II while only part of the whole PV molecule entered into the pocket due to a long side chain, and electrostatic interactions were the major contribution to the binding processes. In addition, a weak conformational change of Bc II was also observed in the molecular recognition and binding process of Bc II with PV or Sul. This study may provide some valuable information for exploring the recognition and binding of proteins with ligands in the binding process and for the design of novel super-antibiotics. Copyright © 2017 John Wiley & Sons, Ltd.

  1. A combined spectroscopic, docking and molecular dynamics simulation approach to probing binding of a Schiff base complex to human serum albumin.

    Science.gov (United States)

    Fani, N; Bordbar, A K; Ghayeb, Y

    2013-02-15

    The molecular mechanism of a Schiff base complex ((E)-((E)-2-(3-((E)-((E)-3(mercapto (methylthio) methylene)cyclopentylidene) amino) propylimino) cyclopentylidene) (methylthio) methanethiol) binding to Human Serum Albumin (HSA) was investigated by fluorescence quenching, absorption spectroscopy, molecular docking and molecular dynamics (MD) simulation procedures. The fluorescence emission of HSA was quenched by this Schiff base complex that has been analyzed for estimation of binding parameters. The titration of Schiff base solution by various amount of HSA was also followed by UV-Vis absorption spectroscopy and the corresponding data were analyzed by suitable models. The results revealed that this Schiff base has an ability to bind strongly to HSA and formed 1:1 complex. Energy transfer mechanism of quenching was discussed and the value of 5.45 ± 0.06 nm was calculated as the mean distance between the bound complex and the Trp residue. This is implying the high possibility of energy transfer from HSA to this Schiff base complex. Molecular docking results indicated that the main active binding site for this Schiff base complex is site III in subdomain IB. Moreover, MD simulation results suggested that this Schiff base complex can interact with HSA, without affecting the secondary structure of HSA but probably with a slight modification of its tertiary structure. MD simulations, molecular docking and experimental data reciprocally supported each other. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Combined 3D-QSAR and molecular docking study on 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f] Quinazoline series compounds to understand the binding mechanism of DHFR inhibitors

    Science.gov (United States)

    Aouidate, Adnane; Ghaleb, Adib; Ghamali, Mounir; Chtita, Samir; Choukrad, M'barek; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

    2017-07-01

    A series of nineteen DHFR inhibitors was studied based on the combination of two computational techniques namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were developed using 19 molecules having pIC50 ranging from 9.244 to 5.839. The best CoMFA and CoMSIA models show conventional determination coefficients R2 of 0.96 and 0.93 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.64 and 0.72, respectively. The predictive ability of those models was evaluated by the external validation using a test set of five compounds with predicted determination coefficients R2test of 0.92 and 0.94, respectively. The binding mode between this kind of compounds and the DHFR enzyme in addition to the key amino acid residues were explored by molecular docking simulation. Contour maps and molecular docking identified that the R1 and R2 natures at the pyrazole moiety are the important features for the optimization of the binding affinity to the DHFR receptor. According to the good concordance between the CoMFA/CoMSIA contour maps and docking results, the obtained information was explored to design novel molecules.

  3. Low-molecular-weight model study of peroxide cross-linking of ethylene-propylene (-diene) rubber using gas chromatography and mass spectrometry: I. Combination reactions of alkanes

    NARCIS (Netherlands)

    Peters, R.; Tonoli, D.; van Duin, M.; Mommers, J.; Mengerink, Y.; Wilbers, A.T.M.; van Benthem, R.; de Koster, C.; Schoenmakers, P.J.; van der Wal, S.

    2008-01-01

    The combination reaction of linear and branched alkanes, initiated by dicumyl peroxide, has been studied as a model for the combination cross-linking reaction of peroxide-cured terpolymerised ethylene, propylene and diene monomer. Both gas chromatography-mass spectrometry (GC-MS) and comprehensive

  4. Combining sedimentological, trace metal (Mn, Mo) and molecular evidence for reconstructing past water-column redox conditions: The example of meromictic Lake Cadagno (Swiss Alps)

    DEFF Research Database (Denmark)

    Wirth, S. B.; Gilli, A.; Niemann, H.

    2013-01-01

    Here, we present sedimentological, trace metal, and molecular evidence for tracking bottom water redox-state conditions during the past 12,500 years in nowadays sulfidic and meromictic Lake Cadagno (Switzerland). A 10.5 m long sediment core from the lake covering the Holocene period was investiga...

  5. Artificial intelligence used for the interpretation of combined spectral data *1 : Part II. PEGASUS: a PROLOG program for the generation of acyclic molecular structures

    NARCIS (Netherlands)

    Kleywegt, G.J.; Luinge, H.J.; Klooster, H.A. van 't

    1987-01-01

    A computer program, PEGASUS (PROLOG-based EXSPEC Generator for Acyclic StrUctureS), has been developed which can be used to generate exhaustively and non-redundantly all possible acyclic isomers that satisfy a given molecular weight or formula PEGASUS was written in PROLOG and implemented on an

  6. Understanding binding affinity : A combined isothermal titration calorimetry/molecular dynamics study of the binding of a series of hydrophobically modified benzamidinium chloride inhibitors to trypsin

    NARCIS (Netherlands)

    Talhout, Reinskje; Villa, Alessandra; Mark, AE; Engberts, JBFN

    2003-01-01

    The binding of a series of p-alkylbenzamidinium chloride inhibitors to the serine proteinase trypsin over a range of temperatures has been studied using isothermal titration (micro)calorimetry and molecular dynamics simulation techniques. The inhibitors have small structural variations at the para

  7. Molecular weight​/branching distribution modeling of low-​density-​polyethylene accounting for topological scission and combination termination in continuous stirred tank reactor

    NARCIS (Netherlands)

    Yaghini, N.; Iedema, P.D.

    2014-01-01

    We present a comprehensive model to predict the molecular weight distribution (MWD),(1) and branching distribution of low-density polyethylene (IdPE),(2) for free radical polymerization system in a continuous stirred tank reactor (CSTR).(3) The model accounts for branching, by branching moment or

  8. Combined theoretical and experimental studies on the molecular structure, spectral and Hirshfeld surface studies of NLO tris(thiourea)zinc(II) sulfate crystals

    Science.gov (United States)

    Muthu, K.; Meenatchi, V.; Rajasekar, M.; Aditya Prasad, A.; Meena, K.; Agilandeshwari, R.; Kanagarajan, V.; Meenakshisundaram, SP.

    2015-07-01

    Transparent single crystals of tris(thiourea)zinc(II) sulfate (ZTS) were grown by slow evaporation technique at room temperature from an aqueous solution containing zinc sulfate and thiourea in the molar ratio 1:3. The experimental and theoretical studies on the molecular structure and vibrational spectra of ZTS were investigated by single crystal X-ray diffraction, FT-IR and density functional theory (DFT). The recorded X-ray diffraction bond parameters are compared with theoretical values calculated at B3LYP/LANL2DZ level. The observed vibrational patterns were compared with the computed wave numbers. The energy and oscillator strength calculated by TD-DFT results complement with the experimental findings. The first-order molecular hyperpolarizability, polarizability, dipole moment and HOMO-LUMO band gap energies were derived. The molecular stability and bond strength were investigated by applying the natural bond orbital analysis (NBO). Information about the size, shape, charge density distribution and site of chemical reactivity of the molecule has been obtained by mapping electron density with molecular electrostatic potential (MEP) using the same level of basis set. Intermolecular hydrogen bonding was investigated by means of the Hirshfeld surfaces, and the role of the Nsbnd H⋯O interactions as driving force for crystal structure formation has been demonstrated. The percentages of hydrogen bonding interactions are analyzed by Fingerprint plots of Hirshfeld surface.

  9. Hydration effects on the molecular structure of silica-supported vanadium oxide catalysts: A combined IR, Raman, UV–vis and EXAFS study

    NARCIS (Netherlands)

    Keller, D.E.; Visser, T.|info:eu-repo/dai/nl/110288327; Soulimani, F.|info:eu-repo/dai/nl/313889449; Koningsberger, D.C.|info:eu-repo/dai/nl/073704342; Weckhuysen, B.M.|info:eu-repo/dai/nl/285484397

    2007-01-01

    The effect of hydration on the molecular structure of silica-supported vanadium oxide catalysts with loadings of 1–16 wt.% V has been systematically investigated by infrared, Raman, UV–vis and EXAFS spectroscopy. IR and Raman spectra recorded during hydration revealed the formation of V–OH groups,

  10. Preparation and selective recognition of a novel solid-phase microextraction fiber combined with molecularly imprinted polymers for the extraction of parabens in soy sample.

    Science.gov (United States)

    He, Juan; Chen, Si; Jiang, Yili; Shen, Yanzheng; Zhu, Jing; Wei, Hongliang; Zhang, Hongxia; Lu, Kui

    2012-01-01

    A prepared molecularly imprinted polymer with ethyl p-hydroxybenzoate as template molecule was applied for the first time to a homemade solid-phase microextraction fiber. The molecularly imprinted polymer-coated solid-phase microextraction fiber was characterized by scanning electron microscopy and thermogravimetric analysis. Various parameters were investigated, including extraction temperature, extraction time, and desorption time. Under the optimum extraction conditions, the molecularly imprinted polymer-coated solid-phase microextraction fiber exhibited higher selectivity with greater extraction capacity toward parabens compared with the nonimprinted polymer-coated solid-phase microextraction fiber and commercial fibers. The molecularly imprinted polymer-coated solid-phase microextraction fiber was tested using gas chromatography to determine parabens, including methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, and propyl p-hydroxybenzoate. The linear ranges were 0.01-10 μg/mL with a correlation coefficient above 0.9943. The detection limits (under signal-to-noise ratio of 3) were below 0.30 μg/L. The fiber was successfully applied to the simultaneous analysis of three parabens in spiked soy samples with satisfactory recoveries of 95.48, 97.86, and 92.17%, respectively. The relative standard deviations (n=6) were within 2.83-3.91%. The proposed molecularly imprinted polymer-coated solid-phase microextraction method is suitable for selective extraction and determination of trace parabens in food samples. Copyright © 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Molecular mechanisms of photosynthesis

    Energy Technology Data Exchange (ETDEWEB)

    Youvan, D.C.; Marrs, B.L.

    1987-06-01

    Knowledge of the molecular interactions, structure and genetic basis of the photosynthetic reaction center makes it possible to ask more detailed questions about its function. Spectroscopy, X-ray crystallography and molecular genetics combine to give a detailed picture of events in photosynthesis and shown how particular molecules contribute to the process. The molecular biology of the photosynthesis center of Rhodopseudomonas is investigated.

  12. An Investigation of G-Quadruplex Structural Polymorphism in the Human Telomere Using a Combined Approach of Hydrodynamic Bead Modeling and Molecular Dynamics Simulation

    Science.gov (United States)

    2015-01-01

    Guanine-rich oligonucleotides can adopt noncanonical tertiary structures known as G-quadruplexes, which can exist in different forms depending on experimental conditions. High-resolution structural methods, such as X-ray crystallography and NMR spectroscopy, have been of limited usefulness in resolving the inherent structural polymorphism associated with G-quadruplex formation. The lack of, or the ambiguous nature of, currently available high-resolution structural data, in turn, has severely hindered investigations into the nature of these structures and their interactions with small-molecule inhibitors. We have used molecular dynamics in conjunction with hydrodynamic bead modeling to study the structures of the human telomeric G-quadruplex-forming sequences at the atomic level. We demonstrated that molecular dynamics can reproduce experimental hydrodynamic measurements and thus can be a powerful tool in the structural study of existing G-quadruplex sequences or in the prediction of new G-quadruplex structures. PMID:24779348

  13. Hydration effects on the molecular structure of silica-supported vanadium oxide catalysts: A combined IR, Raman, UV–vis and EXAFS study

    OpenAIRE

    Keller, D.E.; Visser, T; Soulimani, F.; Koningsberger, D. C.; Weckhuysen, B.M.

    2007-01-01

    The effect of hydration on the molecular structure of silica-supported vanadium oxide catalysts with loadings of 1–16 wt.% V has been systematically investigated by infrared, Raman, UV–vis and EXAFS spectroscopy. IR and Raman spectra recorded during hydration revealed the formation of V–OH groups, characterized by a band at 3660 cm−1. Hydroxylation was found to start instantaneously upon exposure to traces of water, reflecting a very high sensitivity of the supported vanadium oxide catalysts ...

  14. Effect of Molecular Guest Binding on the d-d Transitions of Ni(2+) of CPO-27-Ni: A Combined UV-Vis, Resonant-Valence-to-Core X-ray Emission Spectroscopy, and Theoretical Study.

    Science.gov (United States)

    Gallo, Erik; Gorelov, Evgeny; Guda, Alexander A; Bugaev, Aram L; Bonino, Francesca; Borfecchia, Elisa; Ricchiardi, Gabriele; Gianolio, Diego; Chavan, Sachin; Lamberti, Carlo

    2017-10-04

    We used Ni K-edge resonant-valence-to-core X-ray emission spectroscopy (RVtC-XES, also referred to as direct RIXS), an element-selective bulk-sensitive synchrotron-based technique, to investigate the electronic structure of the CPO-27-Ni metal-organic framework (MOF) upon molecular adsorption of significant molecular probes: H2O, CO, H2S, and NO. We compare RVtC-XES with UV-vis spectroscopy, and we show that the element selectivity of RVtC-XES is of strategic significance to observe the full set of d-d excitations in Ni(2+), which are partially overshadowed by the low-energy π-π* transitions of the Ni ligands in standard diffuse-reflectance UV-vis experiments. Our combined RVtC-XES/UV-vis approach provides access to the whole set of d-d excitations, allowing us a complete discussion of the changes undergone by the electronic configuration of the Ni(2+) sites hosted within the MOF upon molecular adsorption. The experimental data have been interpreted by multiplet ligand-field theory calculations based on Wannier orbitals. This study represents a step further in understanding the ability of the CPO-27-Ni MOFs in molecular sorption and separation applications.

  15. Molecular mechanism of inhibitory effects of C-phycocyanin combined with all-trans-retinoic acid on the growth of HeLa cells in vitro.

    Science.gov (United States)

    Yang, Fan; Li, Bing; Chu, Xian-Ming; Lv, Cong-Yi; Xu, Ying-Jie; Yang, Peng

    2014-06-01

    We studied the effects of all-trans-retinoic acid (ATRA), C-phycocyanin (C-PC), or ATRA+C-PC on the growth of cervical cells (HeLa cells), cell cycle distribution, and apoptosis. The anticancer mechanism of the drug combination was revealed. MTT assay was adopted to determine the effects of C-PC and ATRA on the growth of HeLa cells. The expression quantities of cyclin-dependent kinase (CDK) 4, cyclin D1, Bcl-2, caspase-3, and CD59 were determined by in situ hybridization, immunofluorescence, immunohistochemistry staining, Western blot, and RT-PCR. TUNEL assay was adopted to determine the cellular apoptosis levels. Both C-PC and ATRA could inhibit the growth of HeLa cells, and the combination of ATRA+C-PC functioned cooperatively to induce apoptosis in HeLa cells. The dosage of ATRA was reduced when it cooperated with C-PC to reduce the toxicity. ATRA treated with C-PC could induce more cell cycle arrests than the single drug used by decrease in cyclin D1 and CDK4 expression. The combination of the two drugs could upregulate caspase-3 and downregulate the Bcl-2 gene and induce cell apoptosis. Moreover, the combination therapy has an important immunological significance in decreased expression of the CD59 protein. Singly, C-PC or ATRA could inhibit the growth of HeLa cells, and the effects of treatment were further enhanced in the combination group. In combination with C-PC, the dosage of ATRA was effectively reduced. The C-PC + ATRA combination might take effect by inhibiting the progress of the cell cycle, inducing cell apoptosis and promoting complement-mediated cytolysis.

  16. A combined in silico/in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems.

    Science.gov (United States)

    Carta, A; Briguglio, I; Piras, S; Corona, P; Ibba, R; Laurini, E; Fermeglia, M; Pricl, S; Desideri, N; Atzori, E M; La Colla, P; Collu, G; Delogu, I; Loddo, R

    2016-07-19

    In this work, we present and discuss a comprehensive set of both newly and previously synthesized compounds belonging to 5 distinct molecular classes of linear aromatic N-polycyclic systems that efficiently inhibits bovine viral diarrhea virus (BVDV) infection. A coupled in silico/in vitro investigation was employed to formulate a molecular rationale explaining the notable affinity of all molecules to BVDV RNA dependent RNA polymerase (RdRp) NS5B. We initially developed a three-dimensional common-feature pharmacophore model according to which two hydrogen bond acceptors and one hydrophobic aromatic feature are shared by all molecular series in binding the viral polymerase. The pharmacophoric information was used to retrieve a putative binding site on the surface of the BVDV RdRp and to guide compound docking within the protein binding site. The affinity of all compounds towards the enzyme was scored via molecular dynamics-based simulations, showing high correlation with in vitro EC50 data. The determination of the interaction spectra of the protein residues involved in inhibitor binding highlighted amino acids R295 and Y674 as the two fundamental H-bond donors, while two hydrophobic cavities HC1 (residues A221, I261, I287, and Y289) and HC2 (residues V216, Y303, V306, K307, P408, and A412) fulfill the third pharmacophoric requirement. Three RdRp (K263, R295 and Y674) residues critical for drug binding were selected and mutagenized, both in silico and in vitro, into alanine, and the affinity of a set of selected compounds towards the mutant RdRp isoforms was determined accordingly. The agreement between predicted and experimental data confirmed the proposed common molecular rationale shared by molecules characterized by different chemical scaffolds in binding to the BVDV RdRp, ultimately yielding compound 6b (EC50 = 0.3 μM; IC50 = 0.48 μM) as a new, potent inhibitor of this Pestivirus. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Analysis of diffusion limitation in the alkylation of benzene over H-ZSM-5 by combining quantum chemical calculations, molecular simulations, and a continuum approach

    NARCIS (Netherlands)

    Hansen, N.; Krishna, R.; van Baten, J.M.; Bell, A.T.; Keil, F.J.

    2009-01-01

    A continuum model based on the Maxwell−Stefan (M-S) equations in combination with the ideal adsorbed solution theory has been used to analyze the influence of adsorption thermodynamics and intraparticle diffusional transport on the overall kinetics of benzene alkylation with ethene over H-ZSM-5. The

  18. Low-molecular-weight model study of peroxide cross-linking of ethylene-propylene-diene rubber using gas chromatography and mass spectrometry: II. Addition and combination reactions

    NARCIS (Netherlands)

    Peters, R.; van Duin, M.; Tonoli, D.; Kwakkenbos, G.; Mengerink, Y.; van Benthem, R.A.T.M.; de Koster, C.G.; Schoenmakers, P.J.; van der Wal, S.

    2008-01-01

    The dicumyl-peroxide-initiated addition and combination reactions of mixtures of alkanes (n-octane, n-decane) and alkenes [5,6-dihydrodicyclopentadiene (DCPDH), 5-ethylidene-2-norbornane (ENBH) and 5-vinylidene-2-norbornane (VNBH)] were studied to mimic the peroxide cross-linking reactions of

  19. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission...

  20. Identification of potential Gly/NMDA receptor antagonists by cheminformatics approach: a combination of pharmacophore modelling, virtual screening and molecular docking studies.

    Science.gov (United States)

    Ugale, V G; Bari, S B

    2016-01-01

    The Gly/NMDA receptor has become known as potential target for the management of neurodegenerative diseases. Discovery of Gly/NMDA antagonists has thus attracted much attention in recent years. In the present research, a cheminformatics approach has been used to determine structural requirements for Gly/NMDA antagonism and to identify potential antagonists. Here, 37 quinoxaline derivatives were selected to develop a significant pharmacophore model with good certainty. The selected model was validated by leave-one-out cross-validation, an external test set, decoy set and Y-randomization test. Applicability domain was verified by the standardization approach. The validated 3D-QSAR model was used to screen virtual hits from the ZINC database by pharmacophore mapping. Molecular docking was used for assessment of receptor-ligand binding modes and binding affinities. The GlideScore and molecular interactions with critical amino acids were considered as crucial features to identify final hits. Furthermore, hits were analysed for in silico pharmacokinetic parameters and Lipinski's rule of five, demonstrating their potential as drug-like candidates. The PubChem and SciFinder search tools were used to authenticate the novelty of leads retrieved. Finally, five different leads have been suggested as putative novel candidates for the exploration of potent Gly/NMDA receptor antagonists.

  1. Molecular structure and vibrational spectroscopic analysis of an antiplatelet drug; clopidogrel hydrogen sulphate (form 2) - A combined experimental and quantum chemical approach

    Science.gov (United States)

    Srivastava, Anubha; Mishra, Soni; Tandon, Poonam; Patel, Sarasvatkumar; Ayala, A. P.; Bansal, A. K.; Siesler, H. W.

    2010-02-01

    Clopidogrel hydrogen sulphate which belongs to a class of medicine called antiplatelet drugs. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno [3,2- c] pyridine-5-acetate hydrogen sulphate having the empirical formula C 16H 17ClNO 2S.HSO 4 and molecular mass 321.82 g/mol. The present study is confined to vibrational spectroscopy of the polymorph identified as form 2 of the clopidogrel hydrogen sulphate. The vibrational analysis of clopidogrel hydrogen sulphate salt (form 2) considering separately the two counterions has been performed. We also report a theoretical and experimental study of the molecular conformation and vibrational dynamics of the independent moieties of the clopidogrel hydrogen sulphate salt. The equilibrium geometry, harmonic vibrational frequencies, infrared intensities and activities of Raman scattering were calculated by ab initio Hartree-Fock and density functional theory employing B3LYP with complete relaxation in the potential energy surface using 6-311++G(d,p) basis set. The calculated wavenumbers after a proper scaling show a very good agreement with the observed values. A complete vibrational assignment is provided for the observed Raman and infrared spectra of clopidogrel hydrogen sulphate form 2.

  2. Identification of intact high molecular weight glutenin subunits from the wheat proteome using combined liquid chromatography-electrospray ionization mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Bert Lagrain

    Full Text Available The present paper describes a method for the identification of intact high molecular weight glutenin subunits (HMW-GS, the quality determining proteins from the wheat storage proteome. The method includes isolation of HMW-GS from wheat flour, further separation of HMW-GS by reversed-phase high-performance liquid chromatography (RP-HPLC, and their subsequent molecular identification with electrospray ionization mass spectrometry using a quadrupole-time-of-flight mass analyzer. For HMW-GS isolation, wheat proteins were reduced and extracted from flour with 50% 1-propanol containing 1% dithiothreitol. HMW-GS were then selectively precipitated from the protein mixture by adjusting the 1-propanol concentration to 60%. The composition of the precipitated proteins was first evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Coomassie staining and RP-HPLC with ultraviolet detection. Besides HMW-GS (≥65%, the isolated proteins mainly contained ω5-gliadins. Secondly, the isolated protein fraction was analyzed by liquid chromatography-mass spectrometry. Optimal chromatographic separation of HMW-GS from the other proteins in the isolated fraction was obtained when the mobile phase contained 0.1% trifluoroacetic acid as ion-pairing agent. Individual HMW-GS were then identified by determining their molecular masses from the high-resolution mass spectra and comparing these with theoretical masses calculated from amino acid sequences. Using formic acid instead of trifluoroacetic acid in the mobile phase increased protein peak intensities in the base peak mass chromatogram. This allowed the detection of even traces of other wheat proteins than HMW-GS in the isolated fraction, but the chromatographic separation was inferior with a major overlap between the elution ranges of HMW-GS and ω-gliadins. Overall, the described method allows a rapid assessment of wheat quality through the direct determination of the HMW-GS composition and

  3. Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies.

    Science.gov (United States)

    Mirza, Shaher Bano; Lee, Regina Ching Hua; Chu, Justin Jang Hann; Salmas, Ramin Ekhteiari; Mavromoustakos, Thomas; Durdagi, Serdar

    2017-10-24

    Dengue virus is a major issue of tropical and sub-tropical regions. The proliferation of virus results in immense number of deaths each year because of unavailability of on-shelf drugs. This issue necessitates the design of novel anti-Dengue drugs. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of Dengue virus. Keeping in mind the worsening situation regarding Dengue virus, approximately eighteen million drug-like compounds from the ZINC small molecule database have been screened against Nonstructural Protein 3 (NS3) previously by our group. In this study, in order to investigate the effect of extended time of molecular dynamics (MD) simulations on structural and dynamical profiles of used complexes, simulation run time is increased from 50-ns to 100-ns for the each system. In addition, a well-known Dengue virus inhibitor (MB21) from literature is used as reference structure (positive control) to compare the proposed molecules. Post-processing MD analyses including Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations were conducted to predict binding free energies of inhibitors from derived trajectory frames of MD simulations. Identified compounds are further directed to Quantum-Polarized Ligand Docking (QPLD), molecular fingerprint-based virtual screening of another small molecule database (Otava Drug Like small molecule database), and Structure-based Pharmacophore Modeling (E-Pharmacophore). Finally, cell proliferation and cytotoxicity tests as well as pre- and post-treatment on HUH7 cells infected with DENV2 NGC strain are applied for four identified hit molecules (ZINC36681949, ZINC44921800, ZINC95518765 and ZINC39500661) to check whether these drugs inhibit DENV2 from entry and/or exit pathways. Based on cell-based Dengue quantification assays, there is no effect seen on pre-treatment of cells with these compounds indicating that the early

  4. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-a may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission...... of therapy. Lower doses of Peg-IFN-a2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent....

  5. Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases

    OpenAIRE

    Bulaj, Grzegorz; Ahern, Margaret M.; Kuhn, Alexis; Judkins, Zachary S.; Bowen, Randy C.; Chen, Yizhe

    2016-01-01

    Merging pharmaceutical and digital (mobile health, mHealth) ingredients to create new therapies for chronic diseases offers unique opportunities for natural products such as omega-3 polyunsaturated fatty acids (n-3 PUFA), curcumin, resveratrol, theanine, or ?-lipoic acid. These compounds, when combined with pharmaceutical drugs, show improved efficacy and safety in preclinical and clinical studies of epilepsy, neuropathic pain, osteoarthritis, depression, schizophrenia, diabetes and cancer. T...

  6. Combined main-chain/side-chain ionic liquid crystalline polymer based on ‘jacketing’ effect: Design, synthesis, supra-molecular self-assembly and photophysical properties

    Directory of Open Access Journals (Sweden)

    L. Weng

    2015-06-01

    Full Text Available Reasonably fabricating ordered structures of ionic polymers is very important for the development of novel functional materials. By combining the ions and liquid cry stalline polymer, we successfully designed and synthesized a series of novel combined main-chain/side-chain ionic liquid crystalline polymer (MCSC-ILCPs containing imidazolium groups and different counter-anions, poly (2,5-bis{[6-(4-butoxy-4'-imidazolium biphenylhexyl]oxycarbonyl}styrene salts poly(BImBHCS-X with the following types of counter-anions (Br¯, BF4¯, PF6¯ and TFSI¯. Combined technologies confirmed the chemical structures of the monomers and polymers with imidazolium cation and different counter-anions. Differential scanning calorimetry (DSC, polarized light microscopy (PLM and one- and two-dimensional wide-angle X-ray diffraction (1D and 2D WAXD results illustrated that the LC structures and the transitions of ordered structures depended on the nature of the counter-anion employed. The polymers with Br¯ and BF4¯ counter-anions exhibited smectic A (SmA LC behavior below the isotropic temperature. The another one, poly(BImBHCS–TFSI with the large volume of the TFSI¯ anion destroyed the packing of the LC ordered structure resulting in an amorphous structure. The photophysical properties of the polymers prepared can be adjusted by tuning the ionic interaction of the polymers by switching the counter-anion.

  7. Relative contribution of combined kinetic and exchange energy terms vs the electronic component of molecular electrostatic potential in hardness potential derivatives.

    Science.gov (United States)

    Bhattacharjee, Rituparna; Roy, Ram Kinkar

    2013-11-14

    The relative contribution of the sum of kinetic [(10/9)CFρ(r)2/3] and exchange energy [(4/9)CXρ(r)1/3] terms to that of the electronic part of the molecular electrostatic potential [Vel(r)] in the variants of hardness potential is investigated to assess the proposed definition of Δ+h(k) = −[VelN+1(k) – VelN(k)] and Δ–h(k) = −[VelN(k) – VelN–1(k)] (Saha; et al. J. Comput. Chem. 2013, 34, 662). Some substituted benzenes and polycyclic aromatic hydrocarbons (PAHs) (undergoing electrophilic aromatic substitution), carboxylic acids, and their derivatives are chosen to carry out the theoretical investigation as stated above. Intra- and intermolecular reactivity trends generated by Δ+h(k) and Δ–h(k) are found to be satisfactory and are correlated reasonably well with experimental results.

  8. Pressure-induced phase transitions in organic molecular crystals: a combination of x-ray single-crystal and powder diffraction, raman and IR-spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Boldyreva, E V; Goryainov, S V; Seryotkin, Y V; Kolesnik, E N; Shakhtshneider, T P; Ivashevskaya, S N; Drebushchak, T N [Research and Education Center ' Molecular Design and Ecologically Safe Technologies' , REC-008, Novosibirsk State University (Russian Federation); Sowa, H [Goettingen University (Germany); Ahsbahs, H; Chernyshev, V V [Marburg University (Germany); Dmitriev, V P [Swiss-Norwegian Beamline ESRF, Grenoble (France)], E-mail: boldyrev@nsu.ru

    2008-07-15

    The contribution summarizes the results of recent studies of phase transitions induced by high pressure in a number of molecular organic crystals, such as polymorphs of paracetamol, chlorpropamide, polymorphs of glycine, L- and DL-serine, {beta}-alanine. The main attention is paid to the following topics: (1) Reversible / irreversible transformations; (2) Different behavior of single crystals / powders; (3) The role of pressure-transmitting liquid; (4) The role of the kinetic factors: phase transitions on decompression, or after a long storage at a selected pressure; (5) Isosymmetric phase transitions; (6) The role of the changes in the hydrogen bond networks / intramolecular conformational changes in the phase transitions; (7) Superstructures / nanostructures formed as a result of pressure-induced phase transitions.

  9. Molecular structure and vibrational analysis of Trifluoperazine by FT-IR, FT-Raman and UV-Vis spectroscopies combined with DFT calculations.

    Science.gov (United States)

    Rajesh, P; Gunasekaran, S; Gnanasambandan, T; Seshadri, S

    2015-02-25

    The complete vibrational assignment and analysis of the fundamental vibrational modes of Trifluoperazine (TFZ) was carried out using the experimental FT-IR, FT-Raman and UV-Vis data and quantum chemical studies. The observed vibrational data were compared with the wavenumbers derived theoretically for the optimized geometry of the compound from the DFT-B3LYP gradient calculations employing 6-31G (d,p) basis set. Thermodynamic properties like entropy, heat capacity and enthalpy have been calculated for the molecule. The HOMO-LUMO energy gap has been calculated. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Important non-linear properties such as first hyperpolarizability of TFZ have been computed using B3LYP quantum chemical calculation. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. 15-prostaglandin dehydrogenase expression alone or in combination with ACSM1 defines a subgroup of the apocrine molecular subtype of breast carcinoma

    DEFF Research Database (Denmark)

    Celis, J.E.; Gromov, P.; Cabezon, T.

    2008-01-01

    Established histopathological criteria divide invasive breast carcinomas into defined groups. Ductal of no specific type and lobular are the two major subtypes accounting for around 75 and 15% of all cases, respectively. The remaining 10% include rarer types such as tubular, cribriform, mucinous......, papillary, medullary, metaplastic, and apocrine breast carcinomas. Molecular profiling technologies, on the other hand, subdivide breast tumors into five subtypes, basal-like, luminal A, luminal B, normal breast tissue-like, and ERBB2-positive, that have different prognostic characteristics. An additional...... proteins that are specifically expressed by benign apocrine lesions as well as by the few IACs that were available to us at the time. Here we reiterate our strategy to reveal apocrine cell markers and present novel data, based on the analysis of a considerably larger number of samples, establishing...

  11. Two emissive-magnetic composite platforms for Hg(II) sensing and removal: The combination of magnetic core, silica molecular sieve and rhodamine chemosensors.

    Science.gov (United States)

    Mao, Hanping; Liu, Zhongshou

    2018-01-15

    In this paper, a composite sensing platform for Hg(II) optical sensing and removal was designed and reported. A core-shell structure was adopted, using magnetic Fe3O4 nanoparticles as the core, silica molecular sieve MCM-41 as the shell, respectively. Two rhodamine derivatives were synthesized as chemosensor and covalently immobilized into MCM-41 tunnels. Corresponding composite samples were characterized with SEM/TEM images, XRD analysis, IR spectra, thermogravimetry and N2 adsorption/desorption analysis, which confirmed their core-shell structure. Their emission was increased by Hg(II), showing emission turn on effect. High selectivity, linear working curves and recyclability were obtained from these composite samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Combined Molecular Dynamics, Atoms in Molecules, and IR Studies of the Bulk Monofluoroethanol and Bulk Ethanol To Understand the Role of Organic Fluorine in the Hydrogen Bond Network.

    Science.gov (United States)

    Biswas, Biswajit; Mondal, Saptarsi; Singh, Prashant Chandra

    2017-02-16

    The presence of the fluorocarbon group in fluorinated alcohols makes them an important class of molecules that have diverse applications in the field of separation techniques, synthetic chemistry, polymer industry, and biology. In this paper, we have performed the density function theory calculation along with atom in molecule analysis, molecular dynamics simulation, and IR measurements of bulk monofluoroethanol (MFE) and compared them with the data for bulk ethanol (ETH) to understand the effect of the fluorocarbon group in the structure and the hydrogen bond network of bulk MFE. It has been found that the intramolecular O-H···F hydrogen bond is almost absent in bulk MFE. Molecular dynamics simulation and density function theory calculation along with atom in molecule analysis clearly depict that in the case of bulk MFE, a significant amount of intermolecular O-H···F and C-H···F hydrogen bonds are present along with the intermolecular O-H···O hydrogen bond. The presence of intermolecular O-H···F and C-H···F hydrogen bonds causes the difference in the IR spectrum of bulk MFE as compared to bulk ETH. This study clearly depicts that the organic fluorine (fluorocarbon) of MFE acts as a hydrogen bond acceptor and plays a significant role in the structure and hydrogen bond network of bulk MFE through the formation of weak O-H···F as well C-H···F hydrogen bonds, which may be one of the important reasons behind the unique behavior of the fluoroethanols.

  13. A combined molecular dynamics simulation and quantum mechanics study on mercaptopurine interaction with the cucurbit [6,7] urils: Analysis of electronic structure

    Science.gov (United States)

    Zaboli, Maryam; Raissi, Heidar

    2018-01-01

    In the current study, the probability of complex formation between mercaptopurine drug with cucurbit[6]urils and cucurbit[7]urils has been investigated. The calculations for geometry optimization of complexes have been carried out by means of DFT (B3LYP), DFT-D (B3LYP-D) and M06-2X methods. The Atoms In Molecules (AIM), Natural Bond Orbital (NBO), NMR, the density of states (DOSs) and frontier molecular orbital (MO) analyses have been done on the inclusion complexes. In addition, the UV-Vis spectra of the first eight states have been obtained by CAM-B3LYP/TD-DFT calculation. The obtained results of the complexation process reveal that CB[7]-DRG complexes are more favorable than that of CB[6]-DRG interactions. Furthermore, our theoretical results show that configurations III and I are the most stable configurations related to the CB[6]/DRG and CB[7]/DRG interactions, respectively. The positive ∇2ρ(r) and HC values at the bond critical points indicate that exist the weak H-bonds between CB[6] and CB[7] with H atoms of the drug molecule. The obtained negative binding energy values of CB[7]-DRG interaction in solution phase show the stability of these complexes in the aqueous medium. Also, all of the observed parameters of molecular dynamics simulation such as the number of contacts, hydrogen bonding, center-of-mass distance and van der Waals energy values confirm the encapsulation of mercaptopurine molecule inside the cucurbit[7]urils cavity at about 3.2 ns.

  14. A combined molecular dynamics simulation and quantum mechanics study on mercaptopurine interaction with the cucurbit [6,7] urils: Analysis of electronic structure.

    Science.gov (United States)

    Zaboli, Maryam; Raissi, Heidar

    2018-01-05

    In the current study, the probability of complex formation between mercaptopurine drug with cucurbit[6]urils and cucurbit[7]urils has been investigated. The calculations for geometry optimization of complexes have been carried out by means of DFT (B3LYP), DFT-D (B3LYP-D) and M06-2X methods. The Atoms In Molecules (AIM), Natural Bond Orbital (NBO), NMR, the density of states (DOSs) and frontier molecular orbital (MO) analyses have been done on the inclusion complexes. In addition, the UV-Vis spectra of the first eight states have been obtained by CAM-B3LYP/TD-DFT calculation. The obtained results of the complexation process reveal that CB[7]-DRG complexes are more favorable than that of CB[6]-DRG interactions. Furthermore, our theoretical results show that configurations III and I are the most stable configurations related to the CB[6]/DRG and CB[7]/DRG interactions, respectively. The positive ∇ 2 ρ (r) and HC values at the bond critical points indicate that exist the weak H-bonds between CB[6] and CB[7] with H atoms of the drug molecule. The obtained negative binding energy values of CB[7]-DRG interaction in solution phase show the stability of these complexes in the aqueous medium. Also, all of the observed parameters of molecular dynamics simulation such as the number of contacts, hydrogen bonding, center-of-mass distance and van der Waals energy values confirm the encapsulation of mercaptopurine molecule inside the cucurbit[7]urils cavity at about 3.2ns. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Combining molecular dynamics simulation and ligand-receptor contacts analysis as a new approach for pharmacophore modeling: beta-secretase 1 and check point kinase 1 as case studies.

    Science.gov (United States)

    Hatmal, Ma'mon M; Jaber, Shadi; Taha, Mutasem O

    2016-12-01

    Ligand-based pharmacophore modeling require relatively long lists of active compounds, while a pharmacophore based on a single ligand-receptor crystallographic structure is often promiscuous. These problems prompted us to combine molecular dynamics (MD) simulation with ligand-receptor contacts analysis as means to develop valid pharmacophore model(s). The particular ligand-receptor complex is allowed to perturb over a few nano-seconds using MD simulation. Subsequently, ligand-receptor contact points (≤2.5 Å) are identified. Ligand-receptor contacts maintained above certain threshold during molecular dynamics simulation are considered critical and used to guide pharmacophore development. We termed this method as Molecular-Dynamics Based Ligand-Receptor Contact Analysis. We implemented this new methodology to develop valid pharmacophore models for check point kinase 1 (Chk1) and beta-secretase 1 (BACE1) inhibitors as case studies. The resulting pharmacophore models were validated by receiver operating characteristic curved analysis against inhibitors obtained from CHEMBL database.

  16. Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases.

    Science.gov (United States)

    Bulaj, Grzegorz; Ahern, Margaret M; Kuhn, Alexis; Judkins, Zachary S; Bowen, Randy C; Chen, Yizhe

    2016-01-01

    Merging pharmaceutical and digital (mobile health, mHealth) ingredients to create new therapies for chronic diseases offers unique opportunities for natural products such as omega-3 polyunsaturated fatty acids (n-3 PUFA), curcumin, resveratrol, theanine, or α-lipoic acid. These compounds, when combined with pharmaceutical drugs, show improved efficacy and safety in preclinical and clinical studies of epilepsy, neuropathic pain, osteoarthritis, depression, schizophrenia, diabetes and cancer. Their additional clinical benefits include reducing levels of TNFα and other inflammatory cytokines. We describe how pleiotropic natural products can be developed as bioactive incentives within the network pharmacology together with pharmaceutical drugs and self-care interventions. Since approximately 50% of chronically-ill patients do not take pharmaceutical drugs as prescribed, psychobehavioral incentives may appeal to patients at risk for medication non-adherence. For epilepsy, the incentive-based network therapy comprises anticonvulsant drugs, antiseizure natural products (n-3 PUFA, curcumin or/and resveratrol) coupled with disease-specific behavioral interventions delivered by mobile medical apps. The add-on combination of antiseizure natural products and mHealth supports patient empowerment and intrinsic motivation by having a choice in self-care behaviors. The incentivized therapies offer opportunities: (1) to improve clinical efficacy and safety of existing drugs, (2) to catalyze patient-centered, disease self-management and behavior-changing habits, also improving health-related quality-of-life after reaching remission, and (3) merging copyrighted mHealth software with natural products, thus establishing an intellectual property protection of medical treatments comprising the natural products existing in public domain and currently promoted as dietary supplements. Taken together, clinical research on synergies between existing drugs and pleiotropic natural products

  17. Selective molecularly imprinted polymer combined with restricted access material for in-tube SPME/UHPLC-MS/MS of parabens in breast milk samples

    Energy Technology Data Exchange (ETDEWEB)

    Souza, Israel D.; Melo, Lidervan P. [Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Jardim, Isabel C.S.F. [Instituto de Química, Universidade Estadual de Campinas, Campinas, SP (Brazil); Monteiro, Juliana C.S.; Nakano, Ana Marcia S. [Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Queiroz, Maria Eugênia C., E-mail: mariaeqn@ffclrp.usp.br [Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2016-08-17

    A new molecularly imprinted polymer modified with restricted access material (a hydrophilic external layer), (MIP-RAM) was synthesized via polymerization in situ in an open fused silica capillary. This stationary phase was used as sorbent for in-tube solid phase microextraction (in-tube SPME) to determine parabens in breast milk samples by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Scanning electron micrographs (SEM) illustrate MIP surface modification after glycerol dimethacrylate (hydrophilic monomer) incorporation. The interaction between parabens and MIP-RAM was investigated by Fourier-transform infrared (FTIR) spectroscopy. The Scatchard plot for MIP-RAM presented two linear parts with different slopes, illustrating binding sites with high- and low-affinity. Endogenous compounds exclusion from the MIP-RAM capillary was demonstrated by in-tube SPME/LC-UV assays carried out with blank milk samples. The in-tube SPME/UHPLC-MS/MS method presented linear range from 10 ng mL{sup −1} (LLOQ) to 400 ng mL{sup −1} with coefficients of determination higher than 0.99, inter-assay precision with coefficient of variation (CV) values ranging from 2 to 15%, and inter-assay accuracy with relative standard deviation (RSD) values ranging from −1% to 19%. Analytical validation parameters attested that in-tube SPME/UHPLC-MS/MS is an appropriate method to determine parabens in human milk samples to assess human exposure to these compounds. Analysis of breast milk samples from lactating women demonstrated that the proposed method is effective. - Highlights: • Molecularly imprinted polymer modified with a hydrophilic external layer (RAM-MIP) was synthesized in a silica capillary. • RAM-MIP capillary, used as sorbent for in-tube SPME, established specific interaction with parabens present in milk samples. • The matrix components that interacted only with the hydrophilic external layer (non-adsorptive network) were excluded.

  18. Principal Component Analysis Coupled with Artificial Neural Networks—A Combined Technique Classifying Small Molecular Structures Using a Concatenated Spectral Database

    Directory of Open Access Journals (Sweden)

    Mihail Lucian Birsa

    2011-10-01

    Full Text Available In this paper we present several expert systems that predict the class identity of the modeled compounds, based on a preprocessed spectral database. The expert systems were built using Artificial Neural Networks (ANN and are designed to predict if an unknown compound has the toxicological activity of amphetamines (stimulant and hallucinogen, or whether it is a nonamphetamine. In attempts to circumvent the laws controlling drugs of abuse, new chemical structures are very frequently introduced on the black market. They are obtained by slightly modifying the controlled molecular structures by adding or changing substituents at various positions on the banned molecules. As a result, no substance similar to those forming a prohibited class may be used nowadays, even if it has not been specifically listed. Therefore, reliable, fast and accessible systems capable of modeling and then identifying similarities at molecular level, are highly needed for epidemiological, clinical, and forensic purposes. In order to obtain the expert systems, we have preprocessed a concatenated spectral database, representing the GC-FTIR (gas chromatography-Fourier transform infrared spectrometry and GC-MS (gas chromatography-mass spectrometry spectra of 103 forensic compounds. The database was used as input for a Principal Component Analysis (PCA. The scores of the forensic compounds on the main principal components (PCs were then used as inputs for the ANN systems. We have built eight PC-ANN systems (principal component analysis coupled with artificial neural network with a different number of input variables: 15 PCs, 16 PCs, 17 PCs, 18 PCs, 19 PCs, 20 PCs, 21 PCs and 22 PCs. The best expert system was found to be the ANN network built with 18 PCs, which accounts for an explained variance of 77%. This expert system has the best sensitivity (a rate of classification C = 100% and a rate of true positives TP = 100%, as well as a good selectivity (a rate of true negatives TN

  19. Combination of culture-independent and culture-dependent molecular methods for the determination of bacterial community of iru, a fermented Parkia biglobosa seeds.

    Directory of Open Access Journals (Sweden)

    Gbenga Adedeji Adewumi

    2013-01-01

    Full Text Available In this study, bacterial composition of iru produced by natural, uncontrolled fermentation of Parkia biglobosa seeds was assessed using culture-independent method in combination with culture-based genotypic typing techniques. PCR-denaturing gradient gel electrophoresis (DGGE revealed similarity in DNA fragments with the two DNA extraction methods used and confirmed bacterial diversity in the sixteen iru samples from different production regions. DNA sequencing of the highly variable V3 region of the 16S rRNA genes obtained from PCR-DGGE identified species related to Bacillus subtilis as consistent bacterial species in the fermented samples, while other major bands were identified as close relatives of Staphylococcus vitulinus, Morganella morganii, B. thuringiensis, Staphylococcus saprophyticus, Tetragenococcus halophilus, Ureibacillus thermosphaericus, Brevibacillus parabrevis, Salinicoccus jeotgali, Brevibacterium sp. and Uncultured bacteria clones. Bacillus species were cultured as potential starter cultures and clonal relationship of different isolates determined using amplified ribosomal DNA restriction analysis (ARDRA combined with 16S-23S rRNA gene internal transcribed spacer (ITS PCR amplification, restriction analysis (ITS-PCR-RFLP and randomly amplified polymorphic DNA (RAPD-PCR. This further discriminated Bacillus subtilis and its variants from food-borne pathogens such as Bacillus cereus and suggested the need for development of controlled fermentation processes and good manufacturing practices (GMP for iru production to achieve product consistency, safety quality and improved shelf life.

  20. Synthesis, molecular structure and spectral analysis of ethyl 4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylate thiosemicarbazone: A combined DFT and AIM approach

    Science.gov (United States)

    Singh, R. N.; Kumar, Amit; Tiwari, R. K.; Rawat, Poonam; Verma, Divya; Baboo, Vikas

    2012-05-01

    A new ethyl 4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylate thiosemicarbazone (EFDMPCT) has been synthesized and characterized by elemental analysis and FT-IR, 1H NMR, UV-Visible, DART-mass spectroscopy. Quantum chemical calculations have been performed by DFT level of theory using B3LYP functional and 6-31G (d,p) as basis set. The calculated 1H NMR chemical shifts using gauge including atomic orbitals (GIAO) approach are in good agreement with the observed chemical shifts. The electronic transitions within molecule have been interpreted using the time dependent density functional theory (TD-DFT). The calculated and experimental wavenumbers analyses confirm the existence of dimer. Topological parameters electron density, Laplacian of electron density, kinetic electron energy density, potential electron density and the total electron energy density at the bond critical points (BCP) analyzed using 'Atoms in Molecules' AIM theory reveals intra and inter molecular hydrogen bonding other weaker interactions in detail. The calculated intermolecular hydrogen bond energy of dimer is -12.2176 kcal/mol using AIM calculation. The results of AIM ellipticity confirm the existence of resonance assisted hydrogen bonds in dimer. The calculated thermodynamic parameters show that reaction is exothermic and non-spontaneous at room temperature. The local reactivity descriptors find the reactive sites within molecules have been calculated.

  1. Combining MOSCED with molecular simulation free energy calculations or electronic structure calculations to develop an efficient tool for solvent formulation and selection.

    Science.gov (United States)

    Cox, Courtney E; Phifer, Jeremy R; Ferreira da Silva, Larissa; Gonçalves Nogueira, Gabriel; Ley, Ryan T; O'Loughlin, Elizabeth J; Pereira Barbosa, Ana Karolyne; Rygelski, Brett T; Paluch, Andrew S

    2017-02-01

    Solubility parameter based methods have long been a valuable tool for solvent formulation and selection. Of these methods, the MOdified Separation of Cohesive Energy Density (MOSCED) has recently been shown to correlate well the equilibrium solubility of multifunctional non-electrolyte solids. However, before it can be applied to a novel solute, a limited amount of reference solubility data is required to regress the necessary MOSCED parameters. Here we demonstrate for the solutes methylparaben, ethylparaben, propylparaben, butylparaben, lidocaine and ephedrine how conventional molecular simulation free energy calculations or electronic structure calculations in a continuum solvent, here the SMD or SM8 solvation model, can instead be used to generate the necessary reference data, resulting in a predictive flavor of MOSCED. Adopting the melting point temperature and enthalpy of fusion of these compounds from experiment, we are able to predict equilibrium solubilities. We find the method is able to well correlate the (mole fraction) equilibrium solubility in non-aqueous solvents over four orders of magnitude with good quantitative agreement.

  2. How to boost marine fungal research: A first step towards a multidisciplinary approach by combining molecular fungal ecology and natural products chemistry.

    Science.gov (United States)

    Reich, Marlis; Labes, Antje

    2017-12-01

    Marine fungi have attracted attention in recent years due to increased appreciation of their functional role in ecosystems and as important sources of new natural products. The concomitant development of various "omic" technologies has boosted fungal research in the fields of biodiversity, physiological ecology and natural product biosynthesis. Each of these research areas has its own research agenda, scientific language and quality standards, which have so far hindered an interdisciplinary exchange. Inter- and transdisciplinary interactions are, however, vital for: (i) a detailed understanding of the ecological role of marine fungi, (ii) unlocking their hidden potential for natural product discovery, and (iii) designing access routes for biotechnological production. In this review and opinion paper, we describe the two different "worlds" of marine fungal natural product chemists and marine fungal molecular ecologists. The individual scientific approaches and tools employed are summarised and explained, and enriched with a first common glossary. We propose a strategy to find a multidisciplinary approach towards a comprehensive view on marine fungi and their chemical potential. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Combination of first-principles molecular dynamics and XANES simulations for LiCoO2-electrolyte interfacial reactions in a lithium-ion battery

    Science.gov (United States)

    Tamura, Tomoyuki; Kohyama, Masanori; Ogata, Shuji

    2017-07-01

    We performed a first-principles molecular dynamics (FPMD) simulation of the interfacial reactions between a LiCoO2 electrode and a liquid ethylene carbonate (EC) electrolyte. For configurations during the FPMD simulation, we also performed first-principles Co K-edge x-ray absorption near-edge structure (XANES) simulations, which can properly reproduce the bulk and surface spectra of LiCoO2. We observed strong absorption of an EC molecule on the LiCoO2 {110} surface, involving ring opening of the molecule, bond formation between oxygen atoms in the molecule and surface Co ions, and emission of one surface Li ion, while all the surface Co ions remain Co3 +. The surface Co ions having the bond with an oxygen atom in the molecule showed remarkable changes in simulated K-edge spectra which are similar to those of the in situ observation under electrolyte soaking [D. Takamatsu et al., Angew. Chem., Int. Ed. 51, 11597 (2012), 10.1002/anie.201203910]. Thus, the local environmental changes of surface Co ions due to the reactions with an EC molecule can explain the experimental spectrum changes.

  4. Combining gas-phase electrophoretic mobility molecular analysis (GEMMA), light scattering, field flow fractionation and cryo electron microscopy in a multidimensional approach to characterize liposomal carrier vesicles.

    Science.gov (United States)

    Urey, Carlos; Weiss, Victor U; Gondikas, Andreas; von der Kammer, Frank; Hofmann, Thilo; Marchetti-Deschmann, Martina; Allmaier, Günter; Marko-Varga, György; Andersson, Roland

    2016-11-20

    For drug delivery, characterization of liposomes regarding size, particle number concentrations, occurrence of low-sized liposome artefacts and drug encapsulation are of importance to understand their pharmacodynamic properties. In our study, we aimed to demonstrate the applicability of nano Electrospray Gas-Phase Electrophoretic Mobility Molecular Analyser (nES GEMMA) as a suitable technique for analyzing these parameters. We measured number-based particle concentrations, identified differences in size between nominally identical liposomal samples, and detected the presence of low-diameter material which yielded bimodal particle size distributions. Subsequently, we compared these findings to dynamic light scattering (DLS) data and results from light scattering experiments coupled to Asymmetric Flow-Field Flow Fractionation (AF4), the latter improving the detectability of smaller particles in polydisperse samples due to a size separation step prior detection. However, the bimodal size distribution could not be detected due to method inherent limitations. In contrast, cryo transmission electron microscopy corroborated nES GEMMA results. Hence, gas-phase electrophoresis proved to be a versatile tool for liposome characterization as it could analyze both vesicle size and size distribution. Finally, a correlation of nES GEMMA results with cell viability experiments was carried out to demonstrate the importance of liposome batch-to-batch control as low-sized sample components possibly impact cell viability. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  5. Free-energy analysis of the electron-density fluctuation in the quantum-mechanical/molecular-mechanical simulation combined with the theory of energy representation.

    Science.gov (United States)

    Matubayasi, Nobuyuki; Takahashi, Hideaki

    2012-01-28

    The relationship is investigated for QM/MM (quantum-mechanical/molecular-mechanical) systems between the fluctuations of the electronic state of the QM subsystem and of the solvation effect due to the QM-MM interaction. The free-energy change due to the electron-density fluctuation around its average is highlighted, and is evaluated through an approximate functional formulated in terms of distribution functions of the many-body coupling (pairwise non-additive) part of the QM-MM interaction energy. A set of QM/MM simulations are conducted in MM water solvent for QM water solute in ambient and supercritical conditions and for QM glycine solute in the neutral and zwitterionic forms. The variation of the electronic distortion energy of the QM solute in the course of QM/MM simulation is then shown to be compensated by the corresponding variation of the free energy of solvation. The solvation free energy conditioned by the electronic distortion energy is further analyzed with its components. It is found that the many-body contribution is essentially equal between the free energy and the average sum of solute-solvent interaction energy. © 2012 American Institute of Physics

  6. Combining animal personalities with transcriptomics resolves individual variation within a wild-type zebrafish population and identifies underpinning molecular differences in brain function.

    Science.gov (United States)

    Rey, S; Boltana, S; Vargas, R; Roher, N; Mackenzie, S

    2013-12-01

    Resolving phenotype variation within a population in response to environmental perturbation is central to understanding biological adaptation. Relating meaningful adaptive changes at the level of the transcriptome requires the identification of processes that have a functional significance for the individual. This remains a major objective towards understanding the complex interactions between environmental demand and an individual's capacity to respond to such demands. The interpretation of such interactions and the significance of biological variation between individuals from the same or different populations remain a difficult and under-addressed question. Here, we provide evidence that variation in gene expression between individuals in a zebrafish population can be partially resolved by a priori screening for animal personality and accounts for >9% of observed variation in the brain transcriptome. Proactive and reactive individuals within a wild-type population exhibit consistent behavioural responses over time and context that relates to underlying differences in regulated gene networks and predicted protein-protein interactions. These differences can be mapped to distinct regions of the brain and provide a foundation towards understanding the coordination of underpinning adaptive molecular events within populations. © 2013 John Wiley & Sons Ltd.

  7. Combining MOSCED with molecular simulation free energy calculations or electronic structure calculations to develop an efficient tool for solvent formulation and selection

    Science.gov (United States)

    Cox, Courtney E.; Phifer, Jeremy R.; Ferreira da Silva, Larissa; Gonçalves Nogueira, Gabriel; Ley, Ryan T.; O'Loughlin, Elizabeth J.; Pereira Barbosa, Ana Karolyne; Rygelski, Brett T.; Paluch, Andrew S.

    2017-02-01

    Solubility parameter based methods have long been a valuable tool for solvent formulation and selection. Of these methods, the MOdified Separation of Cohesive Energy Density (MOSCED) has recently been shown to correlate well the equilibrium solubility of multifunctional non-electrolyte solids. However, before it can be applied to a novel solute, a limited amount of reference solubility data is required to regress the necessary MOSCED parameters. Here we demonstrate for the solutes methylparaben, ethylparaben, propylparaben, butylparaben, lidocaine and ephedrine how conventional molecular simulation free energy calculations or electronic structure calculations in a continuum solvent, here the SMD or SM8 solvation model, can instead be used to generate the necessary reference data, resulting in a predictive flavor of MOSCED. Adopting the melting point temperature and enthalpy of fusion of these compounds from experiment, we are able to predict equilibrium solubilities. We find the method is able to well correlate the (mole fraction) equilibrium solubility in non-aqueous solvents over four orders of magnitude with good quantitative agreement.

  8. Physiological and molecular analysis on root growth associated with the tolerance to aluminum and drought individual and combined in Tibetan wild and cultivated barley.

    Science.gov (United States)

    Ahmed, Imrul Mosaddek; Nadira, Umme Aktari; Cao, Fangbin; He, Xiaoyan; Zhang, Guoping; Wu, Feibo

    2016-04-01

    The drought-stimulated gene expression of NCED, SUS, and KS - DHN and ABA signal cross-talk with other phytohormones maintains barley root growth under drought stress at pH 4.0 plus polyethylene glycol plus aluminum. Aluminum (Al) toxicity and drought are two major factors that limit barley production. In this work, the individual and combined effects of Al/acid and polyethylene glycol (PEG 6000) induced drought stress that suppressed root growth and caused oxidative damage as characterized by increased H2O2 and O2(.-) accumulation. The wild-barley genotypes, XZ5 and XZ29, exhibited a higher tolerance than the two cultivars Dayton (Al tolerant) and Tadmor (drought tolerant) under combined stress (pH 4.0 + PEG + Al). The oxidative damage induced by PEG was more severe at pH 4.0 than at pH 6.0. In XZ29, the highest root secretion of malate and citrate was recorded, and the least Al uptake in the four genotypes. In XZ5, a peak accumulation of ABA and minor synthesis of zeatin riboside and ethylene were found being essential in maintaining primary root elongation and root hair development. PEG-induced drought stress repressed Al uptake in root tips, with a lower increase in callose formation and HvMATE (Hordeum vulgare multidrug and toxic compound exudation) expression compared to Al-induced callose production. Stress by pH 4.0 + PEG + Al up-regulated 9-cis-epoxycarotenoid dioxygenase (NCED) which is involved in ABA biosynthesis. Such treatment stimulated the regulation of ABA-dependent genes sucrose synthase (SUS) and KS-type dehydrin (KS-DHN) in root tips. Our results suggest that the tolerance ranking to pH 4.0 + PEG + Al stress in Tibetan wild barley by gene expression is closely correlated to physiological indices. The results show that acclimatisation to pH 4.0 + PEG + Al stress involves specific responses in XZ5 and XZ29. The present study provides insights into the effects of Al/acid and drought combined stress on the abundance of physiological indices in the

  9. Use of a combined cryo-EM and X-ray crystallography approach to reveal molecular details of bacterial pilus assembly by the chaperone/usher pathway

    Energy Technology Data Exchange (ETDEWEB)

    Li, H.; Thanassi, D. G.

    2009-06-01

    Many bacteria assemble hair-like fibers termed pili or fimbriae on their cell surface. These fibers mediate adhesion to various surfaces, including host cells, and play crucial roles in pathogenesis. Pili are polymers composed of thousands of individual subunit proteins. Understanding how these subunit proteins cross the bacterial envelope and correctly assemble at the cell surface is important not only for basic biology but also for the development of novel antimicrobial agents. The chaperone/usher pilus biogenesis pathway is one of the best-understood protein secretion systems, thanks largely to innovative efforts in biophysical techniques such as X-ray crystallography and cryo-electron microscopy. Such a combined approach holds promise for further elucidating remaining questions regarding the multi-step and highly dynamic pilus assembly process, as well as for studying other protein secretion and organelle biogenesis systems.

  10. Relationship of Parental Genetic Distance with Heterosis and Specific Combining Ability in Sesame (Sesamum indicum L.) Based on Phenotypic and Molecular Marker Analysis.

    Science.gov (United States)

    Pandey, Sarita K; Dasgupta, Tapash; Rathore, Abhishek; Vemula, Anilkumar

    2018-01-10

    The genetic distance analysis for selection of suitable parents has been established and effectively used in many crops; however, there is dearth of conclusive report of relationship of genetic distance analysis with heterosis in sesame. In the present study, an attempt was made to estimate the associations of genetic distances using SSR (GDSSR), seed-storage protein profiling (GDSDS) and agro-morphological traits (GDMOR) with hybrid performance. Seven parents were selected from 60 exotic and Indian genotypes based on genetic distance from clustering pattern based on SSR, seed-storage protein, morphological traits and per se performance. For combining ability analysis, 7 parents and 21 crosses generated from 7 × 7 half diallel evaluated at two environments in a replicated field trial during pre-kharif season of 2013. Compared with the average parents yield (12.57 g plant -1 ), eight hybrids had a significant (P sesame.

  11. Low-molecular-weight model study of peroxide cross-linking of ethylene-propylene (-diene) rubber using gas chromatography and mass spectrometry I. Combination reactions of alkanes.

    Science.gov (United States)

    Peters, R; Tonoli, D; van Duin, M; Mommers, J; Mengerink, Y; Wilbers, A T M; van Benthem, R; de Koster, Ch; Schoenmakers, P J; van der Wal, Sj

    2008-08-08

    The combination reaction of linear and branched alkanes, initiated by dicumylperoxide, has been studied as a model for the combination cross-linking reaction of peroxide-cured terpolymerised ethylene, propylene and diene monomer. Both gas chromatography-mass spectrometry (GC-MS) and comprehensive two-dimensional GC-MS (GCxGC-MS) analyses have been employed to analyse the isomeric reaction products. The identification of these products based on their MS fragmentation patterns is quite complex, due to the high tendency of random rearrangements. Careful elucidation of the high-mass ions at optimised ionisation energy (55eV) has resulted in proposed structures for the different isomeric reaction products. The structure assignment by MS is in agreement with the GCxGC elution pattern and with the result of a theoretical model to predict the boiling points and, thus, the GC retention times. In addition, a model that provided a direct correlation between chemical structure and retention times was developed and this was found to provide a useful fit. Quantification of the identified reaction products by GC separation and flame ionization detection allows classification according to the hydrogen abstraction sites for the alkanes by dicumylperoxide. The selectivity for hydrogen abstraction generally follows the expected order, but a higher reactivity was observed for the methylene group next to a primary methyl group, while a reduced reactivity of the methylene group next to ethyl and to methyl groups was observed. The used approach proved to be a very powerful tool to enhance our understanding of the mechanism of peroxide cross-linking of (branched) alkanes.

  12. Ultrasound assisted combined molecularly imprinted polymer for selective extraction of nicotinamide in human urine and milk samples: Spectrophotometric determination and optimization study.

    Science.gov (United States)

    Asfaram, Arash; Ghaedi, Mehrorang; Dashtian, Kheibar

    2017-01-01

    Ultrasound-assisted dispersive solid phase microextraction followed by UV-vis spectrophotometer (UA-DSPME-UV-vis) was designed for extraction and preconcentration of nicotinamide (vitamin B3) by HKUST-1 metal organic framework (MOF) based molecularly imprinted polymer (MIP). This new material was characterized by FTIR and FE-SEM techniques. The preliminary Plackett-Burman design was used for screening and subsequently the central composite design justifies significant terms and possible construction of mathematical equation which give the individual and cooperative contribution of variables like HKUST-1-MOF-NA-MIP mass, sonication time, temperature, eluent volume, pH and vortex time. Accordingly the optimum condition was set as: 2.0mg HKUST-1-MOF-NA-MIP, 200μL eluent and 5.0min sonication time in center points other variables were determined as the best conditions to reach the maximum recovery of the analyte. The UA-DSPME-UV-vis method performances like excellent linearity (LR), limits of detection (LOD), limits of quantification of 10-5000μgL(-1) with R(2) of 0.99, LOD (1.96ngmL(-1)), LOQ (6.53μgL(-1)), respectively show successful and accurate applicability of the present method for monitoring analytes with within- and between-day precision of 0.96-3.38%. The average absolute recoveries of the nicotinamide extracted from the urine, milk and water samples were 95.85-101.27%. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Insight into the intermolecular recognition mechanism between Keap1 and IKKβ combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation.

    Directory of Open Access Journals (Sweden)

    Zheng-Yu Jiang

    Full Text Available Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1, a substrate adaptor component of the Cullin3 (Cul3-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2 and IκB kinase β (IKKβ, which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI, the intermolecular recognition mechanism of Keap1 and IKKβ has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKβ, the PPI model of Keap1 and IKKβ was investigated. The structure of human IKKβ was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKβ as the template. A protein-protein docking method was applied to develop the Keap1-IKKβ complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot-spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKβ and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKβ or Nrf2 will be helpful to further know the crosstalk between NF-κB and Nrf2 signaling.

  14. Selective molecularly imprinted polymer combined with restricted access material for in-tube SPME/UHPLC-MS/MS of parabens in breast milk samples.

    Science.gov (United States)

    Souza, Israel D; Melo, Lidervan P; Jardim, Isabel C S F; Monteiro, Juliana C S; Nakano, Ana Marcia S; Queiroz, Maria Eugênia C

    2016-08-17

    A new molecularly imprinted polymer modified with restricted access material (a hydrophilic external layer), (MIP-RAM) was synthesized via polymerization in situ in an open fused silica capillary. This stationary phase was used as sorbent for in-tube solid phase microextraction (in-tube SPME) to determine parabens in breast milk samples by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Scanning electron micrographs (SEM) illustrate MIP surface modification after glycerol dimethacrylate (hydrophilic monomer) incorporation. The interaction between parabens and MIP-RAM was investigated by Fourier-transform infrared (FTIR) spectroscopy. The Scatchard plot for MIP-RAM presented two linear parts with different slopes, illustrating binding sites with high- and low-affinity. Endogenous compounds exclusion from the MIP-RAM capillary was demonstrated by in-tube SPME/LC-UV assays carried out with blank milk samples. The in-tube SPME/UHPLC-MS/MS method presented linear range from 10 ng mL(-1) (LLOQ) to 400 ng mL(-1) with coefficients of determination higher than 0.99, inter-assay precision with coefficient of variation (CV) values ranging from 2 to 15%, and inter-assay accuracy with relative standard deviation (RSD) values ranging from -1% to 19%. Analytical validation parameters attested that in-tube SPME/UHPLC-MS/MS is an appropriate method to determine parabens in human milk samples to assess human exposure to these compounds. Analysis of breast milk samples from lactating women demonstrated that the proposed method is effective. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Combined parasitological and molecular-based diagnostic tools improve the detection of Trypanosoma cruzi in single peripheral blood samples from patients with Chagas disease

    Directory of Open Access Journals (Sweden)

    Fabiana Caroline Zempulski Volpato

    Full Text Available Abstract INTRODUCTION In order to detect Trypanosoma cruzi and determine the genetic profiles of the parasite during the chronic phase of Chagas disease (ChD, parasitological and molecular diagnostic methods were used to assess the blood of 91 patients without specific prior treatment. METHODS Blood samples were collected from 68 patients with cardiac ChD and 23 patients with an indeterminate form of ChD, followed by evaluation using blood culture and polymerase chain reaction. T . cruzi isolates were genotyped using three different genetic markers. RESULTS: Blood culture was positive in 54.9% of all patients, among which 60.3% had the cardiac form of ChD, and 39.1% the indeterminate form of ChD. There were no significant differences in blood culture positivity among patients with cardiac and indeterminate forms. Additionally, patient age and clinical forms did not influence blood culture results. Polymerase chain reaction (PCR was positive in 98.9% of patients, although comparisons between blood culture and PCR results showed that the two techniques did not agree. Forty-two T . cruzi stocks were isolated, and TcII was detected in 95.2% of isolates. Additionally, one isolate corresponded to TcIII or TcIV, and another corresponded to TcV or TcVI. CONCLUSIONS Blood culture and PCR were both effective for identifying T. cruzi using a single blood sample, and their association did not improve parasite detection. However, we were not able to establish an association between the clinical form of ChD and the genetic profile of the parasite.

  16. Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development.

    Science.gov (United States)

    Kayık, Gülru; Tüzün, Nurcan Ş; Durdagi, Serdar

    2017-12-01

    The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3',5'-cyclic guanosine monophosphate (cGMP) and/or 3',5'-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i.e. sildenafil and vardenafil) are also competitive inhibitors of PDE6 and PDE11. Since the major challenge of designing novel PDE5 inhibitors is to decrease their cross-reactivity with PDE6 and PDE11, in this study, we attempt to identify potent tadalafil-like PDE5 inhibitors that have PDE5/PDE6 and PDE5/PDE11 selectivity. For this aim, the similarity-based virtual screening protocol is applied for the "clean drug-like subset of ZINC database" that contains more than 20 million small compounds. Moreover, molecular dynamics (MD) simulations of selected hits complexed with PDE5 and off-targets were performed in order to get insights for structural and dynamical behaviors of the selected molecules as selective PDE5 inhibitors. Since tadalafil blocks hERG1 K channels in concentration dependent manner, the cardiotoxicity prediction of the hit molecules was also tested. Results of this study can be useful for designing of novel, safe and selective PDE5 inhibitors.

  17. A rapid molecular diagnosis of cutaneous leishmaniasis by colorimetric malachite green-loop-mediated isothermal amplification (LAMP) combined with an FTA card as a direct sampling tool.

    Science.gov (United States)

    Nzelu, Chukwunonso O; Cáceres, Abraham G; Guerrero-Quincho, Silvia; Tineo-Villafuerte, Edwin; Rodriquez-Delfin, Luis; Mimori, Tatsuyuki; Uezato, Hiroshi; Katakura, Ken; Gomez, Eduardo A; Guevara, Angel G; Hashiguchi, Yoshihisa; Kato, Hirotomo

    2016-01-01

    Leishmaniasis remains one of the world's most neglected diseases, and early detection of the infectious agent, especially in developing countries, will require a simple and rapid test. In this study, we established a quick, one-step, single-tube, highly sensitive loop-mediated isothermal amplification (LAMP) assay for rapid detection of Leishmania DNA from tissue materials spotted on an FTA card. An FTA-LAMP with pre-added malachite green was performed at 64°C for 60min using a heating block and/or water bath and DNA amplification was detected immediately after incubation. The LAMP assay had high detection sensitivity down to a level of 0.01 parasites per μl. The field- and clinic-applicability of the colorimetric FTA-LAMP assay was demonstrated with 122 clinical samples collected from patients suspected of having cutaneous leishmaniasis in Peru, from which 71 positives were detected. The LAMP assay in combination with an FTA card described here is rapid and sensitive, as well as simple to perform, and has great potential usefulness for diagnosis and surveillance of leishmaniasis in endemic areas. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. The use of a novel combination of diagnostic molecular and cytogenetic approaches in horses with sexual karyotype abnormalities: a rare case with an abnormal cellular chimerism.

    Science.gov (United States)

    Demyda-Peyrás, S; Anaya, G; Bugno-Poniewierska, M; Pawlina, K; Membrillo, A; Valera, M; Moreno-Millán, M

    2014-05-01

    Sex chromosome aberrations are known to cause congenital abnormalities and unexplained infertility in horses. Most of these anomalies remain undiagnosed because of the complexity of the horse karyotype and the lack of specialized laboratories that can perform such diagnoses. On the other hand, the utilization of microsatellite markers is a technique widely spread in horse breeding, mostly because of their usage in parentage tests. We studied the usage of a novel combination of diagnostic approaches in the evaluation of a very uncommon case of chromosomal abnormalities in a Spanish purebred colt, primarily detected using a commercial panel of short tandem repeat (STR) makers. Based on these results, we performed a full cytogenetic analysis using conventional and fluorescent in situ hybridization techniques with individual Equus caballus chromosome X and Equus caballus chromosome Y painting probes. We also tested the presence of two genes associated with the sexual development in horses and an extra novel panel of eight microsatellite markers specifically located in the sex chromosome pair. This is the first case report of a leukocyte chimerism between chromosomally normal (64,XY) and abnormal (63,X0) cell lines in horses. Our results indicate that the use of the short tandem repeat markers as a screening technique and as a confirmation utilizing cytogenetic techniques can be used as a very interesting, easy, and nonexpensive diagnostic approach to detect chromosomal abnormalities in the domestic horse. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Combining molecular and bioprocess techniques to produce poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) with controlled monomer composition by Burkholderia sacchari.

    Science.gov (United States)

    Mendonça, Thatiane T; Tavares, Rafaela R; Cespedes, Lucas G; Sánchez-Rodriguez, Ruben J; Schripsema, Jan; Taciro, Marilda K; Gomez, José G C; Silva, Luiziana F

    2017-05-01

    Biopolymers as polyhydroxyalkanoates (PHA) composed by different co-monomers 3-hydroxybutyrate and 3-hydroxyhexanoate [P(3HB-co-3HHx)] has attracted interest since its properties are similar to low density polyethylene. Burkholderia sacchari produces this copolymer with a very low 3HHx molar fraction, about 2 mol%. B. sacchari mutant (unable to produce polymer) was engineered to host PHA biosynthesis genes (phaPCJ) from Aeromonas sp. In addition, a two-step bioprocess to increase biopolymer production was developed. The combination of these techniques resulted in the production of P(3HB-co-3HHx) with 3HHx content up to 20 mol%. The PHA content was about 78% of dry biomass, resulting in PHA volumetric productivities around 0.45gl-1h-1. The P(3HB-co-3HHx) containing 20 mol% of 3HHx presented an elongation at brake of 945%, higher than reported before for this PHA composition. Here we have described an approach to increase 3HHx content into the copolymer, allowing the precise control of the 3HHx molar fractions. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Gas-surface interactions using accommodation coefficients for a dilute and a dense gas in a micro- or nanochannel: heat flux predictions using combined molecular dynamics and Monte Carlo techniques.

    Science.gov (United States)

    Nedea, S V; van Steenhoven, A A; Markvoort, A J; Spijker, P; Giordano, D

    2014-05-01

    The influence of gas-surface interactions of a dilute gas confined between two parallel walls on the heat flux predictions is investigated using a combined Monte Carlo (MC) and molecular dynamics (MD) approach. The accommodation coefficients are computed from the temperature of incident and reflected molecules in molecular dynamics and used as effective coefficients in Maxwell-like boundary conditions in Monte Carlo simulations. Hydrophobic and hydrophilic wall interactions are studied, and the effect of the gas-surface interaction potential on the heat flux and other characteristic parameters like density and temperature is shown. The heat flux dependence on the accommodation coefficient is shown for different fluid-wall mass ratios. We find that the accommodation coefficient is increasing considerably when the mass ratio is decreased. An effective map of the heat flux depending on the accommodation coefficient is given and we show that MC heat flux predictions using Maxwell boundary conditions based on the accommodation coefficient give good results when compared to pure molecular dynamics heat predictions. The accommodation coefficients computed for a dilute gas for different gas-wall interaction parameters and mass ratios are transferred to compute the heat flux predictions for a dense gas. Comparison of the heat fluxes derived using explicit MD, MC with Maxwell-like boundary conditions based on the accommodation coefficients, and pure Maxwell boundary conditions are discussed. A map of the heat flux dependence on the accommodation coefficients for a dense gas, and the effective accommodation coefficients for different gas-wall interactions are given. In the end, this approach is applied to study the gas-surface interactions of argon and xenon molecules on a platinum surface. The derived accommodation coefficients are compared with values of experimental results.

  1. Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial.

    Science.gov (United States)

    Chen, Guo; McQuade, Jennifer L; Panka, David J; Hudgens, Courtney W; Amin-Mansour, Ali; Mu, Xinmeng Jasmine; Bahl, Samira; Jané-Valbuena, Judit; Wani, Khalida M; Reuben, Alexandre; Creasy, Caitlyn A; Jiang, Hong; Cooper, Zachary A; Roszik, Jason; Bassett, Roland L; Joon, Aron Y; Simpson, Lauren M; Mouton, Rosalind D; Glitza, Isabella C; Patel, Sapna P; Hwu, Wen-Jen; Amaria, Rodabe N; Diab, Adi; Hwu, Patrick; Lazar, Alexander J; Wargo, Jennifer A; Garraway, Levi A; Tetzlaff, Michael T; Sullivan, Ryan J; Kim, Kevin B; Davies, Michael A

    2016-08-01

    Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma. Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy. Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600. The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points. A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75

  2. Fundamental relation between molecular geometry and real-space topology. Combined AIM, ELI-D, and ASF analysis of hapticities and intramolecular hydrogen-hydrogen bonds in zincocene-related compounds.

    Science.gov (United States)

    Mebs, Stefan; Chilleck, Maren Annika; Meindl, Kathrin; Hübschle, Christian Bertram

    2014-06-19

    Despite numerous advanced and widely distributed bonding theories such as MO, VB, NBO, AIM, and ELF/ELI-D, complex modes of bonding such as M-Cp*((R)) interactions (hapticities) in asymmetrical metallocenes or weak intramolecular interactions (e.g., hydrogen-hydrogen (H···H) bonds) still remain a challenge for these theories in terms of defining whether or not an atom-atom interaction line (a "chemical bond") should be drawn. In this work the intramolecular Zn-C(Cp*(R)) (R = Me, -(CH2)2NMe2, and -(CH2)3NMe2) and H···H connectivity of a systematic set of 12 zincocene-related compounds is analyzed in terms of AIM and ELI-D topology combined with the recently introduced aspherical stockholder fragment (ASF) surfaces. This computational analysis unravels a distinct dependency of the AIM and ELI-D topology against the molecular geometry for both types of interactions, which confirms and extends earlier findings on smaller sets of compounds. According to these results the complete real-space topology including strong, medium, and weak interactions of very large compounds such as proteins may be reliably predicted by sole inspection of accurately determined molecular geometries, which would on the one hand afford new applications (e.g., accurate estimation of numbers, types, and strengths of intra- and intermolecular interactions) and on the other hand have deep implications on the significance of the method.

  3. Development and optimisation of a novel three-way extraction technique based on a combination of Soxhlet extraction, membrane assisted solvent extraction and a molecularly imprinted polymer using sludge polycyclic aromatic hydrocarbons as model compounds.

    Science.gov (United States)

    Ncube, Somandla; Lekoto, Goitsemang; Cukrowska, Ewa; Chimuka, Luke

    2017-11-28

    A novel technique that integrates extraction and clean-up into a single step format is reported as part of the search for new sample preparation techniques in the analysis of persistent organic pollutants from complex samples. This was achieved by combining the extraction efficiency of the Soxhlet extractor, the selectivity of a size exclusion membrane and the specificity of a molecularly imprinted polymer for the extraction of polycyclic aromatic hydrocarbons from wastewater sludge followed by quantitation using gas chromatography with time-of-flight mass spectrometry. The approach is described as the Soxhlet extraction membrane-assisted solvent extraction molecularly imprinted polymer technique. This technique was optimised for various parameters such as extraction solvent, reflux time and membrane acceptor phase. The applicability of the developed technique was optimised using a wastewater sludge certified reference material and then tested on real wastewater sludge samples. The method detection limits ranged from 0.14 to 12.86 ng/g with relative standard deviation values for the extraction of the 16 US-EPA priority polycyclic aromatic hydrocarbons from wastewater sludge samples ranging from 0.78 to 18%. The extraction process was therefore reproducible and showed remarkable selectivity. The developed technique is a promising prospect that can be applied in the analysis of organic pollutants from complex solid samples. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Ionic and Molecular Liquids

    DEFF Research Database (Denmark)

    Chaban, Vitaly V.; Prezhdo, Oleg

    2013-01-01

    applications of RTILs in combination with molecular liquids, concentrating on three significant areas: (1) the use of molecular liquids to decrease the viscosity of RTILs; (2) the role of RTIL micelle formation in water and organic solvents; and (3) the ability of RTILs to adsorb pollutant gases. Current...

  5. Molecular Imprinting

    Science.gov (United States)

    Dufaud, V.; Bonneviot, L.

    Our senses of smell and taste are able to recognise molecules selectively, to the point where they can even discriminate between different chiral states. This property, called molecular recognition, is essential to all forms of life [1]. It is based on the principle of a specific interaction between a receptor or host and a target molecule, which will be identified among a multitude of others, then selectively adsorbed. If the host is endowed with reactive functions, the attached molecule may be transported or transformed. Enzymes are the archetypal host molecules exploiting the idea of molecular recognition. Their complexation sites comprise a hydrophobic pocket with definite shape within which amino acid residues are located in a precisely defined way. The combined effect of these different characteristics underlies not only the affinity for some specific substrate, but also the transformation of this substrate into the desired product [2]. In fact, the phenomena actually brought into play are much more involved, being made up of an ensemble of physicochemical events that act together in a cooperative way, either simultaneously or sequentially, and in which the molecular processes are difficult to follow in detail.

  6. An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin and Fulvestrant (Falsodex, as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts.

    Directory of Open Access Journals (Sweden)

    Qing Chen

    Full Text Available To investigate the effects of trastuzumab (herceptin and fulvestrant (falsodex either in combination or alone, on downstream cell signaling pathways in lab-cultured human HR+/HER2+ breast cancer cell lines ZR-75-1 and BT-474, as well as on protein expression levels in mouse xenograft tissue.Cells were cultivated in the presence of trastuzumab or fulvestrant or both. Molecular events that resulted in an inhibition of cell proliferation and cell cycle progression or in an increased rate of apoptosis were studied. The distribution and abundance of the proteins p-Akt and p-Erk expressed in these cells in response to single agents or combinatorial treatment were also investigated. In addition, the effects of trastuzumab and fulvestrant, either as single agents or in combination on tumor growth as well as on expression of the protein p-MED1 expressed in in vivo mouse xenograft models was also examined.Cell proliferation was increasingly inhibited by trastuzumab or fulvestrant or both, with a CI1 in both human cell lines. The rate of apoptosis increased only in the BT-474 cell line and not in the ZR-75-1 cell line upon treatment with fulvestrant and not trastuzumab as a single agent (P0.05. Cell accumulation in the G1 phase of cell cycle was investigated in all treatment groups (P<0.05, and the combination of trastuzumab and fulvestrant reversed the effects of fulvestrant alone on p-Akt and p-Erk protein expression levels. Using ZR-75-1 or BT-474 to generate in vivo tumor xenografts in BALB/c athymic mouse models, we showed that a combination of both drugs resulted in a stronger inhibition of tumor growth (P<0.05 and a greater decrease in the levels of activated MED1 (p-MED1 expressed in tumor issues compared with the use of either drug as a single agent.We demonstrate that the administration of trastuzumab and fulvestrant in combination results in positive synergistic effects on both, ZR-75-1 and BT-474 cell lines. This combinatorial approach is

  7. An Experimental Analysis of the Molecular Effects of Trastuzumab (Herceptin) and Fulvestrant (Falsodex), as Single Agents or in Combination, on Human HR+/HER2+ Breast Cancer Cell Lines and Mouse Tumor Xenografts.

    Science.gov (United States)

    Chen, Qing; Weng, Ziyi; Lu, Yunshu; Jia, Yijun; Ding, Longlong; Bai, Fang; Ge, Meixin; Lin, Qing; Wu, Kejin

    2017-01-01

    To investigate the effects of trastuzumab (herceptin) and fulvestrant (falsodex) either in combination or alone, on downstream cell signaling pathways in lab-cultured human HR+/HER2+ breast cancer cell lines ZR-75-1 and BT-474, as well as on protein expression levels in mouse xenograft tissue. Cells were cultivated in the presence of trastuzumab or fulvestrant or both. Molecular events that resulted in an inhibition of cell proliferation and cell cycle progression or in an increased rate of apoptosis were studied. The distribution and abundance of the proteins p-Akt and p-Erk expressed in these cells in response to single agents or combinatorial treatment were also investigated. In addition, the effects of trastuzumab and fulvestrant, either as single agents or in combination on tumor growth as well as on expression of the protein p-MED1 expressed in in vivo mouse xenograft models was also examined. Cell proliferation was increasingly inhibited by trastuzumab or fulvestrant or both, with a CI1 in both human cell lines. The rate of apoptosis increased only in the BT-474 cell line and not in the ZR-75-1 cell line upon treatment with fulvestrant and not trastuzumab as a single agent (P0.05). Cell accumulation in the G1 phase of cell cycle was investigated in all treatment groups (P<0.05), and the combination of trastuzumab and fulvestrant reversed the effects of fulvestrant alone on p-Akt and p-Erk protein expression levels. Using ZR-75-1 or BT-474 to generate in vivo tumor xenografts in BALB/c athymic mouse models, we showed that a combination of both drugs resulted in a stronger inhibition of tumor growth (P<0.05) and a greater decrease in the levels of activated MED1 (p-MED1) expressed in tumor issues compared with the use of either drug as a single agent. We demonstrate that the administration of trastuzumab and fulvestrant in combination results in positive synergistic effects on both, ZR-75-1 and BT-474 cell lines. This combinatorial approach is likely to reduce

  8. Feasibility of continuous, catheter-directed thrombolysis using low-dose urokinase in combination with low molecular-weight heparin for acute iliofemoral venous thrombosis in patients at risk of bleeding.

    Science.gov (United States)

    Chen, Guoping; Shi, Wangyin; He, Xu; Lou, Wensheng; Chen, Liang; Gu, Jianping

    2017-02-01

    The present study aimed to examine the feasibility of catheter-directed thrombolysis (CDT) using continuous infusion of low-dose urokinase in combination with low molecular weight heparin (LMWH) for acute iliofemoral venous thrombosis. This retrospective analysis included patients with symptomatic acute iliofemoral venous thrombosis who received CDT using continuous infusion of low-dose urokinase in combination with LMWH within the past four years. Urokinase was administered at 1×104 U/h and 2×104 U/h in patients at high-risk and low-risk of bleeding, respectively. Measurements included urokinase dosage, duration, clinical outcomes and CDT-related complications. A total of 46 patients were included (high-risk, n=17; low-risk, n=29). In the high-risk patients, 64.7% experienced dissolution of ≥50% thrombi after a median CDT duration of 8 days (range, 6-10 days) and median total urokinase dose of 1.92×106 units (range, 1.44-2.4×106 units). In the low-risk patients, 82.8% achieved dissolution of ≥50% thrombi after a median CDT duration of 7 days (range, 4-10 days) and a median total urokinase dose of 3.36×106 units (range, 1.92-4.80×106 units). Remission of clinical symptoms after CDT was achieved in 15 (88.2%) and 28 (96.6%) cases in high-risk and low-risk patients, respectively. No treatment-associated pulmonary embolism or major bleeding was observed. Three (6.5%) subjects (high-risk, n=1; low-risk, n=2) experienced minor bleeding. In conclusion, continuous infusion of low-dose urokinase via CDT in combination with LMWH is effective and safe for acute iliofemoral venous thrombosis in patients with one or more risk factor for bleeding.

  9. Efficacy of antimalarial treatment in Guinea: in vivo study of two artemisinin combination therapies in Dabola and molecular markers of resistance to sulphadoxine-pyrimethamine in N'Zérékoré

    Directory of Open Access Journals (Sweden)

    Coulibaly Léonie

    2007-05-01

    Full Text Available Abstract Background In the last five years, countries have been faced with changing their malaria treatment policy to an artemisinin-based combination therapy (ACT, many with no national data on which to base their decision. This is particularly true for a number of West African countries, including Guinea, where these studies were performed. Two studies were conducted in 2004/2005 in programmes supported by Medecins Sans Frontieres, when chloroquine was still national policy, but artesunate (AS/sulphadoxine-pyrimethamine (SP had been used in refugee camps for two years. Methods In Dabola (central Guinea, 220 children aged 6–59 months with falciparum malaria were randomized to receive either AS/amodiaquine (AQ or AS/SP. In vivo efficacy was assessed following the 2003 World Health Organization guidelines. In a refugee camp in Laine (south of Guinea, where an in vivo study was not feasible due to the unstable context, a molecular genotyping study in 160 patients assessed the prevalence of mutations in the dihydrofolate reductase (dhfr (codons 108, 51, 59 and dihydropteroate synthase (dhps (codons 436, 437, 540 genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulphadoxine, respectively. Results In Dabola, after 28 days of follow-up, Polymerase Chain Reaction (PCR-adjusted failure rates were 1.0% (95%CI 0–5.3 for AS/AQ and 1.0% (95%CI 0–5.5 for AS/SP. In the refugee camp in Laine, the molecular genotyping study found three dhfr mutations in 85.6% (95%CI 79.2–90.7 patients and quintuple dhfr/dhps mutations in 9.6% (95%CI 5.2–15.9. Conclusion Both AS/AQ and AS/SP are highly efficacious in Dabola, whereas there is molecular evidence of established SP resistance in Laine. This supports the choice of the national programme of Guinea to adopt AS/AQ as first line antimalarial treatment. The results highlight the difficulties faced by control programmes, which have gone through the upheaval of

  10. Molecular Modeling

    Science.gov (United States)

    Holmes, Jon L.

    1999-06-01

    Molecular modeling has trickled down from the realm of pharmaceutical and research laboratories into the realm of undergraduate chemistry instruction. It has opened avenues for the visualization of chemical concepts that previously were difficult or impossible to convey. I am sure that many of you have developed exercises using the various molecular modeling tools. It is the desire of this Journal to become an avenue for you to share these exercises among your colleagues. It is to this end that Ron Starkey has agreed to edit such a column and to publish not only the description of such exercises, but also the software documents they use. The WWW is the obvious medium to distribute this combination and so accepted submissions will appear online as a feature of JCE Internet. Typical molecular modeling exercise: finding conformation energies. Molecular Modeling Exercises and Experiments is the latest feature column of JCE Internet, joining Conceptual Questions and Challenge Problems, Hal's Picks, and Mathcad in the Chemistry Curriculum. JCE Internet continues to seek submissions in these areas of interest and submissions of general interest. If you have developed materials and would like to submit them, please see our Guide to Submissions for more information. The Chemical Education Resource Shelf, Equipment Buyers Guide, and WWW Site Review would also like to hear about chemistry textbooks and software, equipment, and WWW sites, respectively. Please consult JCE Internet Features to learn more about these resources at JCE Online. Email Announcements Would you like to be informed by email when the latest issue of the Journal is available online? when a new JCE Software title is shipping? when a new JCE Internet article has been published or is available for Open Review? when your subscription is about to expire? A new feature of JCE Online makes this possible. Visit our Guestbook to learn how. When you submit the form on this page, which includes your email address

  11. Dummy-surface molecularly imprinted polymers as a sorbent of micro-solid-phase extraction combined with dispersive liquid-liquid microextraction for determination of five 2-phenylpropionic acid NSAIDs in aquatic environmental samples.

    Science.gov (United States)

    Guo, Ping; Yuan, Xucan; Zhang, Jingjing; Wang, Binjie; Sun, Xiaoyang; Chen, Xiaohui; Zhao, Longshan

    2018-01-01

    environmental fate and risk to ecological health. Graphical abstract Dummy-surface molecularly imprinted polymers as a sorbent of micro-solid-phase extraction combined with dispersive liquid-liquid microextraction for determination of five 2-phenylpropionic acid NSAIDs in aquatic environmental samples.

  12. Magnetismo Molecular (Molecular Magentism)

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Mario S [Universidade Federal Fluminense, Brasil; Moreira Dos Santos, Antonio F [ORNL

    2010-07-01

    The new synthesis processes in chemistry open a new world of research, new and surprising materials never before found in nature can now be synthesized and, as a wonderful result, observed a series of physical phenomena never before imagined. Among these are many new materials the molecular magnets, the subject of this book and magnetic properties that are often reflections of the quantum behavior of these materials. Aside from the wonderful experience of exploring something new, the theoretical models that describe the behavior these magnetic materials are, in most cases, soluble analytically, which allows us to know in detail the physical mechanisms governing these materials. Still, the academic interest in parallel this subject, these materials have a number of properties that are promising to be used in technological devices, such as in computers quantum magnetic recording, magnetocaloric effect, spintronics and many other devices. This volume will journey through the world of molecular magnets, from the structural description of these materials to state of the art research.

  13. Combining research in physical chemistry and chemical education: Part A. The femtosecond molecular dynamics of small gas-phase anion clusters. Part B. Surveying student beliefs about chemistry and the development of physical chemistry learning tutorials

    Science.gov (United States)

    Barbera, Jack

    2007-12-01

    This dissertation combines work in the areas of experimental physical chemistry and chemical education. In the area of physical chemistry, femtosecond pump-probe spectroscopy is used to interrogate the time-dependence for energy redistribution, solvent reorientation, and dissociation dynamics in small gas-phase anion clusters. The chemical education research addressed in this manuscript include the development and validation of a survey to measure students' beliefs about chemistry and the learning of chemistry and the development and testing of learning tutorials for use in undergraduate physical chemistry courses in thermodynamics and kinetics. In the first part of this dissertation, the Cu(CD3OD) dynamics are investigated using a combination of femtosecond pump-probe experiments and ab initio calculations. Dissociation of this complex into Cu and CD3OD occurs on two distinct time scales: 3 and 30 ps, which arise, respectively, from the coupling of intermolecular solvent rotations and excited methyl rotor rotation into the Cu-O dissociation component upon electron photodetachment of the precursor anion. In the second part of this dissertation, the time-resolved recombination of photodissociated IBr-(CO2)n (n = 5 - 10) cluster anions is investigated. Upon excitation to the A' 2pi 1/2 state of the chromophore, the bare anion results in I- and Br products, upon solvation with CO2, the IBr- chromophore regains near-IR absorption after recombination and vibrational relaxation on the ground electronic state. The recombination times vary with the number of solvent molecules from 12 ps for n = 5 to 900 ps for n = 10. Extensive electronic structure and non-adiabatic molecular dynamic simulations provide a framework to understand this behavior. In the third part of this dissertation, the modification and validation of the Colorado Learning Attitudes about Science Survey (CLASS) for use in chemistry is presented in detail. The CLASS survey is designed to measure student

  14. Molecular evidence of increased resistance to anti-folate drugs in Plasmodium falciparum in North-East India: a signal for potential failure of artemisinin plus sulphadoxine-pyrimethamine combination therapy.

    Science.gov (United States)

    Mohapatra, Pradyumna Kishore; Sarma, Devojit Kumar; Prakash, Anil; Bora, Khukumoni; Ahmed, Md Atique; Sarma, Bibhas; Goswami, Basanta Kumar; Bhattacharyya, Dibya Ranjan; Mahanta, Jagadish

    2014-01-01

    North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant Plasmodium falciparum malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both in vivo therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating P. falciparum strains. A total of 220 P. falciparum positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0%) the isolates had mutant pfcrt genotype (76 T), while 68% had mutant pfmdr-1 genotype (86 Y). Mutation in dhps 437 codon was the most prevalent one while dhfr codon 108 showed 100% mutation. A total of 23 unique haplotypes at the dhps locus and 7 at dhfr locus were found while dhps-dhfr combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (F/AGEGS/T) at dhps locus. Detection of quadruple mutants (51 I/59 R/108 N/164 L) in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in sulphadoxine

  15. Molecular evidence of increased resistance to anti-folate drugs in Plasmodium falciparum in North-East India: a signal for potential failure of artemisinin plus sulphadoxine-pyrimethamine combination therapy.

    Directory of Open Access Journals (Sweden)

    Pradyumna Kishore Mohapatra

    Full Text Available North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant Plasmodium falciparum malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both in vivo therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating P. falciparum strains. A total of 220 P. falciparum positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0% the isolates had mutant pfcrt genotype (76 T, while 68% had mutant pfmdr-1 genotype (86 Y. Mutation in dhps 437 codon was the most prevalent one while dhfr codon 108 showed 100% mutation. A total of 23 unique haplotypes at the dhps locus and 7 at dhfr locus were found while dhps-dhfr combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (F/AGEGS/T at dhps locus. Detection of quadruple mutants (51 I/59 R/108 N/164 L in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in

  16. Novel quantum mechanical/molecular mechanical method combined with the theory of energy representation: Free energy calculation for the Beckmann rearrangement promoted by proton transfers in the supercritical water

    Science.gov (United States)

    Takahashi, Hideaki; Tanabe, Kohsuke; Aketa, Masataka; Kishi, Ryohei; Furukawa, Shin-ichi; Nakano, Masayoshi

    2007-02-01

    The Beckmann rearrangement of acetone oxime promoted by proton transfers in the supercritical water has been investigated by means of the hybrid quantum mechanical/molecular mechanical approach combined with the theory of energy representation (QM/MM-ER) recently developed. The transition state (TS) structures have been explored by ab initio calculations for the reaction of hydrated acetone oxime on the assumption that the reaction is catalyzed by proton transfers along the hydrogen bonds connecting the solute and the solvent water molecules. Up to two water molecules have been considered as reactants that take part in the proton transfers. As a result of the density functional theory calculations with B3LYP functional and aug-cc-pVDZ basis set, it has been found that participation of two water molecules in the reaction reduces the activation free energy by -12.3kcal/mol. Furthermore, the QM/MM-ER simulations have revealed that the TS is more stabilized than the reactant state in the supercritical water by 2.7kcal/mol when two water molecules are involved in the reaction. Solvation free energies of the reactant and the TS have been decomposed into terms due to the electronic polarization of the solute, electron density fluctuation, and others to elucidate the origin of the stabilization of the TS as compared with the reactant. It has been revealed that the promotion of the chemical reaction due to the hydration mainly originates from the interaction between the nonpolarized solute and the solvent water molecules at the supercritical state.

  17. Computation of the free energy change associated with one-electron reduction of coenzyme immersed in water: a novel approach within the framework of the quantum mechanical/molecular mechanical method combined with the theory of energy representation.

    Science.gov (United States)

    Takahashi, Hideaki; Ohno, Hajime; Kishi, Ryohei; Nakano, Masayoshi; Matubayasi, Nobuyuki

    2008-11-28

    The isoalloxazine ring (flavin ring) is a part of the coenzyme flavin adenine dinucleotide and acts as an active site in the oxidation of a substrate. We have computed the free energy change Deltamicro(red) associated with one-electron reduction of the flavin ring immersed in water by utilizing the quantum mechanical/molecular mechanical method combined with the theory of energy representation (QM/MM-ER method) recently developed. As a novel treatment in implementing the QM/MM-ER method, we have identified the excess charge to be attached on the flavin ring as a solute while the remaining molecules, i.e., flavin ring and surrounding water molecules, are treated as solvent species. Then, the reduction free energy can be decomposed into the contribution Deltamicro(red)(QM) due to the oxidant described quantum chemically and the free energy Deltamicro(red)(MM) due to the water molecules represented by a classical model. By the sum of these contributions, the total reduction free energy Deltamicro(red) has been given as -80.1 kcal/mol. To examine the accuracy and efficiency of this approach, we have also conducted the Deltamicro(red) calculation using the conventional scheme that Deltamicro(red) is constructed from the solvation free energies of the flavin rings at the oxidized and reduced states. The conventional scheme has been implemented with the QM/MM-ER method and the calculated Deltamicro(red) has been estimated as -81.0 kcal/mol, showing excellent agreement with the value given by the new approach. The present approach is efficient, in particular, to compute free energy change for the reaction occurring in a protein since it enables ones to circumvent the numerical problem brought about by subtracting the huge solvation free energies of the proteins in two states before and after the reduction.

  18. Novel quantum mechanical/molecular mechanical method combined with the theory of energy representation: free energy calculation for the Beckmann rearrangement promoted by proton transfers in the supercritical water.

    Science.gov (United States)

    Takahashi, Hideaki; Tanabe, Kohsuke; Aketa, Masataka; Kishi, Ryohei; Furukawa, Shin-ichi; Nakano, Masayoshi

    2007-02-28

    The Beckmann rearrangement of acetone oxime promoted by proton transfers in the supercritical water has been investigated by means of the hybrid quantum mechanical/molecular mechanical approach combined with the theory of energy representation (QM/MM-ER) recently developed. The transition state (TS) structures have been explored by ab initio calculations for the reaction of hydrated acetone oxime on the assumption that the reaction is catalyzed by proton transfers along the hydrogen bonds connecting the solute and the solvent water molecules. Up to two water molecules have been considered as reactants that take part in the proton transfers. As a result of the density functional theory calculations with B3LYP functional and aug-cc-pVDZ basis set, it has been found that participation of two water molecules in the reaction reduces the activation free energy by -12.3 kcal/mol. Furthermore, the QM/MM-ER simulations have revealed that the TS is more stabilized than the reactant state in the supercritical water by 2.7 kcal/mol when two water molecules are involved in the reaction. Solvation free energies of the reactant and the TS have been decomposed into terms due to the electronic polarization of the solute, electron density fluctuation, and others to elucidate the origin of the stabilization of the TS as compared with the reactant. It has been revealed that the promotion of the chemical reaction due to the hydration mainly originates from the interaction between the nonpolarized solute and the solvent water molecules at the supercritical state.

  19. Combination vaccines

    Directory of Open Access Journals (Sweden)

    David AG Skibinski

    2011-01-01

    Full Text Available The combination of diphtheria, tetanus, and pertussis vaccines into a single product has been central to the protection of the pediatric population over the past 50 years. The addition of inactivated polio, Haemophilus influenzae, and hepatitis B vaccines into the combination has facilitated the introduction of these vaccines into recommended immunization schedules by reducing the number of injections required and has therefore increased immunization compliance. However, the development of these combinations encountered numerous challenges, including the reduced response to Haemophilus influenzae vaccine when given in combination; the need to consolidate the differences in the immunization schedule (hepatitis B; and the need to improve the safety profile of the diphtheria, tetanus, and pertussis combination. Here, we review these challenges and also discuss future prospects for combination vaccines.

  20. [Molecular mechanisms of macroevolution].

    Science.gov (United States)

    Tikhodeev, O N

    2005-01-01

    The present paper is devoted to the evolutionary role of genetic modules shuffing. The mechanisms capable to produce new molecular functions and significant complications of ontogenesis are reviewed. Two-step model of macroevolution is proposed. This model comprises: (1) Arising of a new combination of genetic modules. This step does not result in formation of a new taxon but makes necessary ground for that process. (2) Precise structure completing of the new combination of modules and corresponding genome optimization by use of various mechanisms including point mutations. This step concerns many genes and finally leads to formation of a new taxon. It is shown that arising of new combinations of genetic modules might work out as molecular basis for progressive evolution, while alternative structural completing of the same combination might result in adaptive radiation.

  1. Molecular hematology

    National Research Council Canada - National Science Library

    Provan, Drew; Gribben, John

    2010-01-01

    ... The molecular basis of hemophilia, 219 Paul LF Giangrande 4 The genetics of acute myeloid leukemias, 42 Carolyn J Owen & Jude Fitzgibbon 19 The molecular basis of von Willebrand disease, 233 Luciano Baronc...

  2. Combined TLR2 and TLR4 ligation in the context of bacterial or helminth extracts in human monocyte derived dendritic cells: Molecular correlates for Th1/Th2 polarization

    NARCIS (Netherlands)

    Riet, E. van; Everts, B.; Retra, K.; Phylipsen, M.; Hellemond, J.J. van; Tielens, A.G.M.; Kleij, D. van der; Hartgers, F.C.; Yazdanbakhsh, M.

    2009-01-01

    Background: Recognition of pathogens by dendritic cells (DCs) through interaction with pattern recognition receptors, including Toll like receptors (TLR), is crucial for the initiation of appropriate polarized T helper (Th) cell responses. Yet, the characteristics and differences in molecular

  3. combination Dictionary

    African Journals Online (AJOL)

    rbr

    advanced-level Spanish-speaking EFL learners. 2. Word combinations ... a certain process of segregation as a separate branch of linguistics. While lexi- ... As substantiated by Ilson's investigation of lexicographic practices, most dictionaries ...

  4. Molecular pharmacognosy.

    Science.gov (United States)

    Huang, LuQi; Xiao, PeiGen; Guo, LanPing; Gao, WenYuan

    2010-06-01

    This article analyzes the background and significance of molecular pharmacognosy, including the molecular identification of medicinal raw materials, phylogenetic evolution of medicinal plants and animals, evaluation and preservation of germplasm resources for medicinal plants and animals, etiology of endangerment and protection of endangered medicinal plants and animals, biosynthesis and bioregulation of active components in medicinal plants, and characteristics and the molecular bases of top-geoherbs.

  5. Molecular Gastronomy

    OpenAIRE

    Burke, Roisin; This, Herve; Kelly, Alan

    2016-01-01

    Molecular gastronomy may be defined as the scientific discipline that explores the phenomena occurring during culinary transformations. In contrast with traditional approaches of food science and technology, which considered mostly the chemistry, physics, or biology of food ingredients and industrial transformations, the focus is on phenomena occurring during the preparation of dishes. Applications building on the principles of molecular gastronomy, such as ‘Molecular Cooking’ and ‘Note-by-No...

  6. Molecular dynamics

    NARCIS (Netherlands)

    Bergstra, J.A.; Bethke, I.

    2002-01-01

    Molecular dynamics is a model for the structure and meaning of object based programming systems. In molecular dynamics the memory state of a system is modeled as a fluid consisting of a collection of molecules. Each molecule is a collection of atoms with bindings between them. A computation is

  7. Winning Combinations

    DEFF Research Database (Denmark)

    Criscuolo, Paola; Laursen, Keld; Reichstein, Toke

    2017-01-01

    Searching for the most rewarding sources of innovative ideas remains a key challenge in management of technological innovation. Yet, little is known about which combinations of internal and external knowledge sources are triggers for innovation. Extending theories about searching for innovation, ...

  8. Molecular motors

    Science.gov (United States)

    Allemand, Jean François Desbiolles, Pierre

    2015-10-01

    How do we move? More precisely, what are the molecular mechanisms that can explain that our muscles, made of very small components can move at a osopic scale? To answer these questions we must introduce molecular motors. Those motors are proteins, or small protein assemblies that, in our cells, transform chemical energy into mechanical work. Then, like we could do for a oscopic motor, used in a car or in a fan, we are going to study the basic behavior of these molecular machines, present what are their energy sources, calculate their power, their yield. If molecular motors are crucial for our oscopic movements, we are going to see that they are also essential to cellular transport and that considering the activity of some enzymes as molecular motors bring some interesting new insights on their activity.

  9. Combined normal-phase and reversed-phase liquid chromatography/ESI-MS as a tool to determine the molecular diversity of A-type procyanidins in peanut skins

    NARCIS (Netherlands)

    Appeldoorn, M.M.; Vincken, J.P.; Sanders, M.B.; Hollman, P.C.H.; Gruppen, H.

    2009-01-01

    Peanut skins, a byproduct of the peanut butter industry, are a rich source of proanthocyanidins, which might be used in food supplements. Data on the molecular diversity of proanthocyanidins in peanut skins is limited and conflicting with respect to the ratio of double- (A-type) versus single-linked

  10. Combined homicide

    Directory of Open Access Journals (Sweden)

    Slović Živana

    2017-01-01

    Full Text Available Introduction: Combined homicide is a combination of two or more different modes of killing. These homicides occur when multiple perpetrators have different mode of killing, to hide the true manner of death, or when an initially unsuccessful attack with one weapon is abandoned and changed by another mode which is more successful, or due to availability of weapons at the scene of homicide, or unexpected appearance of possible eyewitness, or else. Case report: This case report is about 65-year old woman who was found in her residence on the floor next to the bed lying on her back with two kitchen knives in her neck. Autopsy revealed an abrasion on the frontal part of the neck and a bruise of the soft tissues of the neck with a double fracture of both greater horns of the hyoid bone and a fracture of both superior horns of the thyroid cartilage. The cause of death was exsanguination into right half of the thoracic cavity from the left subclavian artery which was cut, on the spot of stab wound in the neck. Conclusion: Hemorrhage in the soft tissue near broken hyoid bone and thyroid cartilage indicate that the victim was first strangulated and then stabbed with kitchen knives. Combined homicides are caused by one or more killers in order to accelerate the killing, or to be sure to provide the fatal outcome. This case is also interesting because the killer left weapon in the victim's neck.

  11. Molecular imaging in oncology

    Energy Technology Data Exchange (ETDEWEB)

    Schober, Otmar; Riemann, Burkhard (eds.) [Universitaetsklinikum Muenster (Germany). Klinik fuer Nuklearmedizin

    2013-02-01

    Considers in detail all aspects of molecular imaging in oncology, ranging from basic research to clinical applications in the era of evidence-based medicine. Examines technological issues and probe design. Discusses preclinical studies in detail, with particular attention to multimodality imaging. Presents current clinical use of PET/CT, SPECT/CT, and optical imagingWritten by acknowledged experts. The impact of molecular imaging on diagnostics, therapy, and follow-up in oncology is increasing significantly. The process of molecular imaging includes key biotarget identification, design of specific molecular imaging probes, and their preclinical evaluation, e.g., in vivo using small animal studies. A multitude of such innovative molecular imaging probes have already entered clinical diagnostics in oncology. There is no doubt that in future the emphasis will be on multimodality imaging in which morphological, functional, and molecular imaging techniques are combined in a single clinical investigation that will optimize diagnostic processes. This handbook addresses all aspects of molecular imaging in oncology, ranging from basic research to clinical applications in the era of evidence-based medicine. The first section is devoted to technology and probe design, and examines a variety of PET and SPECT tracers as well as multimodality probes. Preclinical studies are then discussed in detail, with particular attention to multimodality imaging. In the third section, diverse clinical applications are presented, and the book closes by looking at future challenges. This handbook will be of value to all who are interested in the revolution in diagnostic oncology that is being brought about by molecular imaging.

  12. Molecular geometry

    CERN Document Server

    Rodger, Alison

    1995-01-01

    Molecular Geometry discusses topics relevant to the arrangement of atoms. The book is comprised of seven chapters that tackle several areas of molecular geometry. Chapter 1 reviews the definition and determination of molecular geometry, while Chapter 2 discusses the unified view of stereochemistry and stereochemical changes. Chapter 3 covers the geometry of molecules of second row atoms, and Chapter 4 deals with the main group elements beyond the second row. The book also talks about the complexes of transition metals and f-block elements, and then covers the organometallic compounds and trans

  13. Molecular Haeckel.

    Science.gov (United States)

    Elinson, Richard P; Kezmoh, Lorren

    2010-07-01

    More than a century ago, Ernst Haeckel created embryo drawings to illustrate the morphological similarity of vertebrate early embryos. These drawings have been both widely presented and frequently criticized. At the same time that the idea of morphological similarity was recently attacked, there has been a growing realization of molecular similarities in the development of tissues and organs. We have surveyed genes expressed in vertebrate embryos, and we have used them to construct drawings that we call Molecular Haeckels. The Molecular Haeckels emphasize that, based on gene expression, there is a greater similarity among vertebrate embryos than even Haeckel might have imagined. (c) 2010 Wiley-Liss, Inc.

  14. Molecular Origami

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 5; Issue 9. Molecular Origami - Modular Construction of Platonic Solids as Models for Reversible Assemblies. Subramania Ranganathan. General Article Volume 5 Issue 9 September 2000 pp 82-91 ...

  15. Combination of polarized TIRF and ATR spectroscopies for determination of the second and fourth order parameters of molecular orientation in thin films and construction of an orientation distribution based on the maximum entropy method.

    Science.gov (United States)

    Runge, Anne F; Saavedra, S Scott; Mendes, Sergio B

    2006-04-06

    This article describes two mathematical formalisms for the determination of the second and fourth order parameters of molecular films using optical spectroscopy. Method A uses polarized total internal reflection fluorescence (TIRF) to calculate the second and fourth order parameters, {P2(cos theta)} and {P4(cos theta)}, using an independently determined value for the angle between the absorption and emission dipoles, gamma. Method B uses {P2(cos theta)} obtained from attenuated total reflectance (ATR) data, along with polarized TIRF measurements to calculate {P4(cos theta)} and {cos2 gamma}. The choice of a specific method should rely on experimental considerations. We also present a method to separate the contributions of substrate surface roughness and dipole orientation with respect to the molecular axis from the spectroscopically determined second and fourth order parameters. Finally, a maximum entropy approach for construction of an orientation distribution from order parameters is compared with the commonly used delta and Gaussian distributions.

  16. Molecular opacities for exoplanets.

    Science.gov (United States)

    Bernath, Peter F

    2014-04-28

    Spectroscopic observations of exoplanets are now possible by transit methods and direct emission. Spectroscopic requirements for exoplanets are reviewed based on existing measurements and model predictions for hot Jupiters and super-Earths. Molecular opacities needed to simulate astronomical observations can be obtained from laboratory measurements, ab initio calculations or a combination of the two approaches. This discussion article focuses mainly on laboratory measurements of hot molecules as needed for exoplanet spectroscopy.

  17. Three-phase molecularly imprinted sol-gel based hollow fiber liquid-phase microextraction combined with liquid chromatography-tandem mass spectrometry for enrichment and selective determination of a tentative lung cancer biomarker.

    Science.gov (United States)

    Moein, Mohammad Mahdi; Javanbakht, Mehran; Karimi, Mohammad; Akbari-Adergani, Behrouz; Abdel-Rehim, Mohamed

    2015-07-15

    In the present study, the modification of a polysulfone hollow fiber membrane with in situ molecularly imprinted sol-gel process (as a novel and one-step method) was prepared and investigated. 3-(propylmethacrylate)trimethoxysilane (3PMTMOS) as an inorganic precursor was used for preparation of molecularly imprinted sol-gel. The modified molecularly imprinted sol-gel hollow fiber membrane (MSHM) was used for the liquid-phase microextraction (LPME) of hippuric acid (HA) in human plasma and urine samples. MSHM as a selective, robust, and durable tool was used for at least 50 extractions without significant decrease in the extraction efficiency. The non-molecularly imprinted sol-gel hollow fiber membrane (NSHM) as blank hollow fiber membrane was prepared by the same process, only without HA. To achieve the best condition, influential parameters on the extraction efficiency were thoroughly investigated. The capability of this robust, green, and simple method for extraction of HA was successfully accomplished with LC/MS/MS. The limits of detection (LOD) and quantification (LOQ) in human plasma and urine samples were 0.3 and 1.0nmolL(-1), respectively. The standard calibration curves were obtained within the concentration range 1-2000nmolL(-1) for HA in human plasma and urine. The coefficients of determination (r(2)) were ≥0.998. The obtained data exhibited recoveries were higher than 89% for the extraction of HA in human plasma and urine samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Molecular fountain.

    Energy Technology Data Exchange (ETDEWEB)

    Strecker, Kevin E.; Chandler, David W.

    2009-09-01

    A molecular fountain directs slowly moving molecules against gravity to further slow them to translational energies that they can be trapped and studied. If the molecules are initially slow enough they will return some time later to the position from which they were launched. Because this round trip time can be on the order of a second a single molecule can be observed for times sufficient to perform Hz level spectroscopy. The goal of this LDRD proposal was to construct a novel Molecular Fountain apparatus capable of producing dilute samples of molecules at near zero temperatures in well-defined user-selectable, quantum states. The slowly moving molecules used in this research are produced by the previously developed Kinematic Cooling technique, which uses a crossed atomic and molecular beam apparatus to generate single rotational level molecular samples moving slowly in the laboratory reference frame. The Kinematic Cooling technique produces cold molecules from a supersonic molecular beam via single collisions with a supersonic atomic beam. A single collision of an atom with a molecule occurring at the correct energy and relative velocity can cause a small fraction of the molecules to move very slowly vertically against gravity in the laboratory. These slowly moving molecules are captured by an electrostatic hexapole guiding field that both orients and focuses the molecules. The molecules are focused into the ionization region of a time-of-flight mass spectrometer and are ionized by laser radiation. The new molecular fountain apparatus was built utilizing a new design for molecular beam apparatus that has allowed us to miniaturize the apparatus. This new design minimizes the volumes and surface area of the machine allowing smaller pumps to maintain the necessary background pressures needed for these experiments.

  19. Molecular Electronics

    DEFF Research Database (Denmark)

    Jennum, Karsten Stein

    This thesis includes the synthesis and characterisation of organic compounds designed for molecular electronics. The synthesised organic molecules are mainly based on two motifs, the obigo(phenyleneethynylenes) (OPE)s and tetrathiafulvalene (TTF) as shown below. These two scaffolds (OPE and TTF...... transistors (Part 2). The synthetic protocols rely on stepwise Sonogashira coupling reactions. Conductivity studies on various OPE-based molecular wires reveal that mere OPE compounds have a higher electrical resistance compared to the cruciform based wires (up to 9 times higher). The most spectacular result...... be potential candidates for future molecular electronics Synthesis of a new donor-acceptor chromophore based on a benzoquinone- TTF motif (QuinoneDTF) is also described herein (Part 2). Reaction of this molecule with acid induces a colour change from purple to orange. The purple colour can be restored...

  20. Determination of clenbuterol in bovine liver by combining matrix solid phase dispersion and molecularly imprinted solid phase extraction followed by liquid chromatography/electrospray ion trap multiple stage mass spectrometry

    NARCIS (Netherlands)

    Crescenzi, C; Bayoudh, S; Cormack, P.A G; Klein, T; Ensing, K

    2001-01-01

    Matrix solid-phase dispersion(MSPD) is a new sample pretreatment for solid samples. This technique greatly simplifies sample pretreatment but, nonetheless, the extracts often still require an extra cleanup step that is both laborious and time-consuming. The potential;of combining MSPD with

  1. COMPLEMENTARY MOLECULAR AND ELEMENTAL DETECTION OF SPECIATED THIOARSENICALS USING ESI-MS IN COMBINATION WITH A XENON-BASED COLLISION-CELL ICP-MS WITH APPLICATION TO FORTIFIED NIST FREEZE-DRIED URINE

    Science.gov (United States)

    The simultaneous detection of arsenic and sulfur in thio-arsenicals was achieved using xenonbased collision cell ICP-MS in combination with HPLC. In an attempt to minimize the 16O16O+ interference at m/z 32, both sample introduction and collision cell experimental parameters were...

  2. Molecular pathways

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine Terra

    2014-01-01

    that 45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection...... of fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res; 20(14); 3637-43. ©2014 AACR....

  3. Molecular modeling

    Directory of Open Access Journals (Sweden)

    Aarti Sharma

    2009-01-01

    Full Text Available The use of computational chemistry in the development of novel pharmaceuticals is becoming an increasingly important tool. In the past, drugs were simply screened for effectiveness. The recent advances in computing power and the exponential growth of the knowledge of protein structures have made it possible for organic compounds to be tailored to decrease the harmful side effects and increase the potency. This article provides a detailed description of the techniques employed in molecular modeling. Molecular modeling is a rapidly developing discipline, and has been supported by the dramatic improvements in computer hardware and software in recent years.

  4. Molecular epidemiology of malaria in Cameroon. XXX. sequence analysis of Plasmodium falciparum ATPase 6, dihydrofolate reductase, and dihydropteroate synthase resistance markers in clinical isolates from children treated with an artesunate-sulfadoxine-pyrimethamine combination.

    Science.gov (United States)

    Menemedengue, Virginie; Sahnouni, Khalifa; Basco, Leonardo; Tahar, Rachida

    2011-07-01

    Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes are reliable molecular markers for antifolate resistance. The P. falciparum ATPase 6 (pfatp6) gene has been proposed to be a potential marker for artemisinin resistance. In our previous clinical study, we showed that artesunate-sulfadoxine-pyrimethamine is highly effective against uncomplicated malaria in Yaoundé, Cameroon. In the present study, dhfr, dhps, and pfatp6 mutations in P. falciparum isolates obtained from children treated with artesunate-sulfadoxine-pyrimethamine were determined. All 61 isolates had wild-type Pfatp6 263, 623, and 769 alleles, and 11 (18%) had a single E431K substitution. Three additional mutations, E643Q, E432K, and E641Q, were detected. The results did not indicate any warning signal of serious concern (i.e., no parasites were seen with quintuple dhfr-dhps, DHFR Ile164Leu, or pfatp6 mutations), as confirmed by the high clinical efficacy of artesunate-sulfadoxine-pyrimethamine. Further studies are required to identify a molecular marker that reliably predicts artemisinin resistance.

  5. Data warehousing in molecular biology.

    Science.gov (United States)

    Schönbach, C; Kowalski-Saunders, P; Brusic, V

    2000-05-01

    In the business and healthcare sectors data warehousing has provided effective solutions for information usage and knowledge discovery from databases. However, data warehousing applications in the biological research and development (R&D) sector are lagging far behind. The fuzziness and complexity of biological data represent a major challenge in data warehousing for molecular biology. By combining experiences in other domains with our findings from building a model database, we have defined the requirements for data warehousing in molecular biology.

  6. Molecular gastronomy

    Science.gov (United States)

    This, Hervé

    2005-01-01

    For centuries, cooks have been applying recipes without looking for the mechanisms of the culinary transformations. A scientific discipline that explores these changes from raw ingredients to eating the final dish, is developing into its own field, termed molecular gastronomy. Here, one of the founders of the discipline discusses its aims and importance.

  7. Molecular farming

    NARCIS (Netherlands)

    Merck, K.B.; Vereijken, J.M.

    2006-01-01

    Molecular Farming is a new and emerging technology that promises relatively cheap and flexible production of large quantities of pharmaceuticals in genetically modified plants. Many stakeholders are involved in the production of pharmaceuticals in plants, which complicates the discussion on the

  8. Gualou Guizhi decoction reverses brain damage with cerebral ischemic stroke, multi-component directed multi-target to screen calcium-overload inhibitors using combination of molecular docking and protein-protein docking.

    Science.gov (United States)

    Hu, Juan; Pang, Wen-Sheng; Han, Jing; Zhang, Kuan; Zhang, Ji-Zhou; Chen, Li-Dian

    2018-12-01

    Stroke is a disease of the leading causes of mortality and disability across the world, but the benefits of drugs curative effects look less compelling, intracellular calcium overload is considered to be a key pathologic factor for ischemic stroke. Gualou Guizhi decoction (GLGZD), a classical Chinese medicine compound prescription, it has been used to human clinical therapy of sequela of cerebral ischemia stroke for 10 years. This work investigated the GLGZD improved prescription against intracellular calcium overload could decreased the concentration of [Ca2+]i in cortex and striatum neurone of MCAO rats. GLGZD contains Trichosanthin and various small molecular that they are the potential active ingredients directed against NR2A, NR2B, FKBP12 and Calnodulin target proteins/enzyme have been screened by computer simulation. "Multicomponent systems" is capable to create pharmacological superposition effects. The Chinese medicine compound prescriptions could be considered as promising sources of candidates for discovery new agents.

  9. Molecularly imprinted-solid phase extraction combined with simultaneous derivatization and dispersive liquid-liquid microextraction for selective extraction and preconcentration of methamphetamine and ecstasy from urine samples followed by gas chromatography.

    Science.gov (United States)

    Djozan, Djavanshir; Farajzadeh, Mir Ali; Sorouraddin, Saeed Mohammad; Baheri, Tahmineh

    2012-07-27

    In this study, a developed technique was reported for extraction and pre-concentration of methamphetamine (MAMP) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) from urine samples using molecularly imprinted-solid phase extraction (MISPE) along with simultaneous derivatization and dispersive liquid-liquid microextraction (DLLME). Molecularly imprinted microspheres as sorbent in solid phase extraction (SPE) procedure were synthesized using precipitation polymerization with MAMP as the template. Aqueous solution of the target analytes was passed through MAMP-MIP cartridge and the adsorbed analytes were then eluted with methanol. The collected eluate was mixed with butylchloroformate which served as the derivatization reagent as well as the extraction solvent. The mixture was immediately injected into deionized water. After centrifugation, 1 μL of the settled organic phase was injected into gas chromatography-flame ionization detection (GC-FID) or gas chromatography-mass spectrometry (GC-MS). Various experimental parameters affecting the performance of both of the steps (MISPE and DLLME) were thoroughly investigated. The calibration graphs were linear in the ranges of 10-1500 ng mL(-1) (MAMP) and 50-1500 ng mL(-1) (MDMA), and the detection limits (LODs) were 2 and 18 ng mL(-1), respectively. The relative standard deviations (%RSDs) obtained for six repeated experiments (100 ng mL(-1) of each drug) were 5.1% and 6.8% for MAMP and MDMA, respectively. The relative recoveries obtained for the analytes in human urine samples, spiked with different levels of each drug, were within the range of 80-88%. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Molecular ion photofragment spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Bustamente, S.W.

    1983-11-01

    A new molecular ion photofragment spectrometer is described which features a supersonic molecular beam ion source and a radio frequency octapole ion trap interaction region. This unique combination allows several techniques to be applied to the problem of detecting a photon absorption event of a molecular ion. In particular, it may be possible to obtain low resolution survey spectra of exotic molecular ions by using a direct vibrational predissociation process, or by using other more indirect detection methods. The use of the spectrometer is demonstrated by measuring the lifetime of the O/sub 2//sup +/(/sup 4/..pi../sub u/) metastable state which is found to consist of two main components: the /sup 4/..pi../sub 5/2/ and /sup 4/..pi../sub -1/2/ spin components having a long lifetime (approx. 129 ms) and the /sup 4/..pi../sub 3/2/ and /sup 4/..pi../sub 1/2/ spin components having a short lifetime (approx. 6 ms).

  11. A combined metabolomic and phylogenetic study reveals putatively prebiotic effects of high molecular weight arabino-oligosaccharides when assessed by in vitro fermentation in bacterial communities derived from humans

    DEFF Research Database (Denmark)

    Sulek, Karolina; Vigsnæs, Louise Kristine; Schmidt, Line Rieck

    2014-01-01

    Prebiotic oligosaccharides are defined by their selective stimulation of growth and/or activity of bacteria in the digestive system in ways claimed to be beneficial for health. However, apart from the short chain fatty acids, little is known about bacterial metabolites created by fermentation...... plant structures. Additionally, the combination of qPCR and LC–MS revealed a number of other putative interactions between intestinal microbes and the oligosaccharides, which contributes to the understanding of the mechanisms behind prebiotic impact on human health....

  12. Molecular cytogenetics.

    Science.gov (United States)

    Carpenter, N J

    2001-09-01

    In the past decade, clinical cytogenetics has undergone remarkable advancement as molecular biology techniques have been applied to conventional chromosome analysis. The limitations of conventional banding analysis in the accurate diagnosis and interpretation of certain chromosome abnormalities have largely been overcome by these new technologies, which include fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), and multicolor FISH (M-FISH, SKY, and Rx-FISH). Clinical applications include diagnosis of microdeletion and microduplication syndromes, detection of subtelomeric rearrangements in idiopathic mental retardation, identification of marker and derivative chromosomes, prenatal diagnosis of trisomy syndromes, and gene rearrangements and gene amplification in tumors. Molecular cytogenetic methods have expanded the possibilities for precise genetic diagnoses, which are extremely important for clinical management of patients and appropriate counseling of their families.

  13. Molecular Modelling

    Directory of Open Access Journals (Sweden)

    Aarti Sharma

    2009-12-01

    Full Text Available

    The use of computational chemistry in the development of novel pharmaceuticals is becoming an increasingly important
    tool. In the past, drugs were simply screened for effectiveness. The recent advances in computing power and
    the exponential growth of the knowledge of protein structures have made it possible for organic compounds to tailored to
    decrease harmful side effects and increase the potency. This article provides a detailed description of the techniques
    employed in molecular modeling. Molecular modelling is a rapidly developing discipline, and has been supported from
    the dramatic improvements in computer hardware and software in recent years.

  14. Molecular belts.

    Science.gov (United States)

    Evans, Paul J; Jasti, Ramesh

    2014-01-01

    Rigid hydrocarbon macrocycles with radially-oriented π-systems and continuous conjugation have attracted great interest in recent years. These molecular belts have novel optoelectronic properties and host-guest behavior. Certain belts may also ultimately lead to a rational synthesis of carbon nanotubes. The high strain associated with the nonplanar, conjugated backbones requires the development of new synthetic methods, and clever synthetic design. Herein we describe the synthetic history and properties of these structurally simple but synthetically challenging molecules.

  15. Metabolic Rate Calibrates the Molecular Clock: Reconciling Molecular and Fossil Estimates of Evolutionary Divergence

    OpenAIRE

    Gillooly, James F.; Andrew P. Allen; West, Geoffrey B.; Brown, James H.

    2004-01-01

    Observations that rates of molecular evolution vary widely within and among lineages have cast doubts upon the existence of a single molecular clock. Differences in the timing of evolutionary events estimated from genetic and fossil evidence have raised further questions about the existence of molecular clocks and their use. Here we present a model of nucleotide substitution that combines new theory on metabolic rate with the now classic neutral theory of molecular evolution. The model quanti...

  16. Optically controllable molecular logic circuits

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, Takahiro, E-mail: t-nishimura@ist.osaka-u.ac.jp; Fujii, Ryo; Ogura, Yusuke; Tanida, Jun [Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2015-07-06

    Molecular logic circuits represent a promising technology for observation and manipulation of biological systems at the molecular level. However, the implementation of molecular logic circuits for temporal and programmable operation remains challenging. In this paper, we demonstrate an optically controllable logic circuit that uses fluorescence resonance energy transfer (FRET) for signaling. The FRET-based signaling process is modulated by both molecular and optical inputs. Based on the distance dependence of FRET, the FRET pathways required to execute molecular logic operations are formed on a DNA nanostructure as a circuit based on its molecular inputs. In addition, the FRET pathways on the DNA nanostructure are controlled optically, using photoswitching fluorescent molecules to instruct the execution of the desired operation and the related timings. The behavior of the circuit can thus be controlled using external optical signals. As an example, a molecular logic circuit capable of executing two different logic operations was studied. The circuit contains functional DNAs and a DNA scaffold to construct two FRET routes for executing Input 1 AND Input 2 and Input 1 AND NOT Input 3 operations on molecular inputs. The circuit produced the correct outputs with all possible combinations of the inputs by following the light signals. Moreover, the operation execution timings were controlled based on light irradiation and the circuit responded to time-dependent inputs. The experimental results demonstrate that the circuit changes the output for the required operations following the input of temporal light signals.

  17. Molecular cytogenetics of lymphoma : where do we stand in 2010?

    NARCIS (Netherlands)

    Kluin, Philip; Schuuring, Ed

    For the past 20 years most malignant lymphomas have been classified as clinicopathological entities, each with its own combination of clinical, morphological, immunophenotypic and molecular genetic characteristics. Molecular and cytogenetic abnormalities can be detected by a wide range of

  18. Development of a coupled diffusion denuder system combined with gas chromatography/mass spectrometry for the separation and quantification of molecular iodine and the activated iodine compounds iodine monochloride and hypoiodous acid in the marine atmosphere.

    Science.gov (United States)

    Huang, Ru-Jin; Hoffmann, Thorsten

    2009-03-01

    This study concerns the development of a coupled diffusion denuder system capable of separating and quantifying gaseous molecular iodine (I(2)) and two other highly reactive iodine species, ICl and HOI, which are collectively named activated iodine compounds (AIC). Both I(2) and AIC are key species in the atmospheric chemistry of iodine. 1,3,5-Trimethoxybenzene (1,3,5-TMB)- and alpha-cyclodextrin/(129)I(-) (alpha-CD/(129)I(-))-coated denuders proved to be suitable for the collection of gaseous AIC and I(2), respectively. The experimental collection efficiencies for AIC (tested as ICl) and I(2) agreed well with the theoretical values for gas flow rates in the range between 300 and 1800 mL min(-1). The coupled denuder system (1,3,5-TMB-coated denuder as front-denuder coupled upstream of an alpha-CD/(129)I(-)-coated denuder) was applied successfully to separate test gas mixtures of ICl and I(2) at various mixing ratios in the laboratory. The operation of both denuder systems was demonstrated to be independent of relative humidity (0-100%) and storage period (at least 2 weeks prior to and after sampling). Detection limits were achieved at sub-parts-per-trillion-by-volume (sub-pptv) level. The presented method provides a reliable and practical approach for the speciation of gaseous iodine compounds. In addition, we report for the first time ambient air measurements of AIC mixing ratios, carried out at the atmospheric research station in Mace Head, Ireland. A maximum concentration of AIC of 30.2 pptv was observed for nighttime measurements and 6.0 pptv for daytime measurements. A similar diurnal pattern was found for I(2) with an average concentration level of 23.2 pptv during daytime and 85.1 pptv during nighttime, indicating a strong correlation with AIC.

  19. Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering, protein-protein docking, peptide docking and molecular dynamics simulations.

    Science.gov (United States)

    Mirza, Shaher Bano; Ekhteiari Salmas, Ramin; Fatmi, M Qaiser; Durdagi, Serdar

    2017-12-01

    The Klotho is known as lifespan enhancing protein involved in antagonizing the effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted exposure of Wnt proteins to the cell can cause stem and progenitor cell senescence, which may lead to aging. Keeping in mind the importance of Klotho in Wnt signaling, in silico approaches have been applied to study the important interactions between Klotho and Wnt3 and Wnt3a (wingless-type mouse mammary tumor virus (MMTV) integration site family members 3 and 3a). The main aim of the study is to identify important residues of the Klotho that help in designing peptides which can act as Wnt antagonists. For this aim, a protein engineering study is performed for Klotho, Wnt3 and Wnt3a. During the theoretical analysis of homology models, unexpected role of number of disulfide bonds and secondary structure elements has been witnessed in case of Wnt3 and Wnt3a proteins. Different in silico experiments were carried out to observe the effect of correct number of disulfide bonds on 3D protein models. For this aim, total of 10 molecular dynamics (MD) simulations were carried out for each system. Based on the protein-protein docking simulations of selected protein models of Klotho with Wnt3 and Wnt3a, different peptides derived from Klotho have been designed. Wnt3 and Wnt3a proteins have three important domains: Index finger, N-terminal domain and a patch of ∼10 residues on the solvent exposed surface of palm domain. Protein-peptide docking of designed peptides of Klotho against three important domains of palmitoylated Wnt3 and Wnt3a yields encouraging results and leads better understanding of the Wnt protein inhibition by proposed Klotho peptides. Further in vitro studies can be carried out to verify effects of novel designed peptides as Wnt antagonists.

  20. Molecular optoelectronics: the interaction of molecular conduction junctions with light.

    Science.gov (United States)

    Galperin, Michael; Nitzan, Abraham

    2012-07-14

    The interaction of light with molecular conduction junctions is attracting growing interest as a challenging experimental and theoretical problem on one hand, and because of its potential application as a characterization and control tool on the other. It stands at the interface between two important fields, molecular electronics and molecular plasmonics and has attracted attention as a challenging scientific problem with potentially important technological consequences. Here we review the present state of the art of this field, focusing on several key phenomena and applications: using light as a switching device, using light to control junction transport in the adiabatic and non-adiabatic regimes, light generation in biased junctions and Raman scattering from such systems. This field has seen remarkable progress in the past decade, and the growing availability of scanning tip configurations that can combine optical and electrical probes suggests that further progress towards the goal of realizing molecular optoelectronics on the nanoscale is imminent.

  1. Molecular nanomagnets

    CERN Document Server

    Gatteschi, Dante; Villain, Jacques

    2006-01-01

    Nanomagnetism is a rapidly expanding area of research which appears to be able to provide novel applications. Magnetic molecules are at the very bottom of the possible size of nanomagnets and they provide a unique opportunity to observe the coexistence of classical and quantum properties. The discovery in the early 90's that a cluster comprising twelve manganese ions shows hysteresis of molecular origin, and later proved evidence of quantum effects, opened a new research area whichis still flourishing through the collaboration of chemists and physicists. This book is the first attempt to cover

  2. Molecular plasmonics

    CERN Document Server

    Fritzsche, Wolfgang

    2014-01-01

    Adopting a novel approach, this book provides a unique ""molecular perspective"" on plasmonics, concisely presenting the fundamentals and applications in a way suitable for beginners entering this hot field as well as for experienced researchers and practitioners. It begins by introducing readers to the optical effects that occur at the nanoscale and particularly their modification in the presence of biomolecules, followed by a concise yet thorough overview of the different methods for the actual fabrication of nanooptical materials. Further chapters address the relevant nanooptics, as well as

  3. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

    Directory of Open Access Journals (Sweden)

    Rogers William O

    2010-04-01

    Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study

  4. Emerging molecular phenotypes of asthma

    Science.gov (United States)

    Ray, Anuradha; Oriss, Timothy B.

    2014-01-01

    Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

  5. Molecular and clinical analyses with neuropsychological assessment of a case of del(10)(q26.2qter) without intellectual disability: Genomic and transcriptomic combined approach and review of the literature.

    Science.gov (United States)

    Laudier, Béatrice; Epiais, Tiphanie; Pâris, Arnaud; Menuet, Arnaud; Briault, Sylvain; Ozsancak, Canan; Perche, Olivier

    2016-07-01

    Terminal deletion of the long arm of the chromosome 10 is a rare but well known abnormality, with a large phenotypic variability. Very few data are available about subtelomeric deletion 10q26 patients without intellectual disability. Herein, we report the case of a young adult with a classical 10q26.2qter deletion. She exhibited mainly short stature at birth and in childhood/adulthood without intellectual disability or behavioral problems. After clinical and neuropsychological assessments, we performed genomic array and transcriptomic analysis and compared our results to the data available in the literature. The patient presents a 6.525 Mb heterozygous 10q26.2qter deletion, encompassed 48 genes. Among those genes, DOCK1, C10orf90, and CALY previously described as potential candidate genes for intellectual disability, were partially or completed deleted. Interestingly, they were not deregulated as demonstrated by transcriptomic analysis. This allowed us to suggest that the mechanism involved in the deletion 10qter phenotype is much more complex that only the haploinsufficiency of DOCK1 or other genes encompassed in the deletion. Genomic and transcriptomic combined approach has to be considered to understand this pathogenesis. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Advances in multimodal molecular imaging.

    Science.gov (United States)

    Auletta, Luigi; Gramanzini, Matteo; Gargiulo, Sara; Albanese, Sandra; Salvatore, Marco; Greco, Adelaide

    2017-03-01

    Preclinical molecular imaging is an emerging field. Improving the ability of scientists to study the molecular basis of human pathology in animals is of the utmost importance for future advances in all fields of human medicine. Moreover, the possibility of developing new imaging techniques or of implementing old ones adapted to the clinic is a significant area. Cardiology, neurology, immunology and oncology have all been studied with preclinical molecular imaging. The functional techniques of photoacoustic imaging (PAI), fluorescence molecular tomography (FMT), positron emission tomography (PET), and single photon emission computed tomography (SPECT) in association with each other or with the anatomic reference provided by computed tomography (CT) as well as with anatomic and functional information provided by magnetic resonance (MR) have all been proficiently applied to animal models of human disease. All the above-mentioned imaging techniques have shown their ability to explore the molecular mechanisms involved in animal models of disease. The clinical translatability of most of the techniques motivates the ongoing study of their possible fields of application. The ability to combine two or more techniques allows obtaining as much information as possible on the molecular processes involved in pathologies, reducing the number of animals necessary in each experiment. Merging molecular probes compatible with various imaging technique will further expand the capability to achieve the best results.

  7. a Molecular Fountain

    Science.gov (United States)

    Cheng, Cunfeng; van der Poel, Aernout P. P.; Ubachs, Wim; Bethlem, Hendrick

    2017-06-01

    The resolution of any spectroscopic experiment is limited by the coherent interaction time between the probe radiation and the particle that is being studied. The introduction of cooling techniques for atoms and ions has resulted in a dramatic increase of interaction times and accuracy, it is hoped that molecular cooling techniques will lead to a similar increase. Here we demonstrate the first molecular fountain, a development which permits hitherto unattainably long interrogation times with molecules. In our experiment, beams of ammonia molecules are decelerated, trapped and cooled using inhomogeneous electric fields and subsequently launched. Using a combination of quadrupole lenses and buncher elements, the beam is shaped such that it has a large position spread and a small velocity spread (corresponding to a transverse temperature of less than 10μK and a longitudinal temperature of less than 1μK) while the molecules are in free fall, but strongly focused at the detection region. The molecules are in free fall for up to 266 milliseconds, making it possible, in principle, to perform sub-Hz measurements in molecular systems and paving the way for stringent tests of fundamental physics theories.

  8. Molecularly Imprinted Biodegradable Nanoparticles

    Science.gov (United States)

    Gagliardi, Mariacristina; Bertero, Alice; Bifone, Angelo

    2017-01-01

    Biodegradable polymer nanoparticles are promising carriers for targeted drug delivery in nanomedicine applications. Molecu- lar imprinting is a potential strategy to target polymer nanoparticles through binding of endogenous ligands that may promote recognition and active transport into specific cells and tissues. However, the lock-and-key mechanism of molecular imprinting requires relatively rigid cross-linked structures, unlike those of many biodegradable polymers. To date, no fully biodegradable molecularly imprinted particles have been reported in the literature. This paper reports the synthesis of a novel molecularly- imprinted nanocarrier, based on poly(lactide-co-glycolide) (PLGA) and acrylic acid, that combines biodegradability and molec- ular recognition properties. A novel three-arm biodegradable cross-linker was synthesized by ring-opening polymerization of glycolide and lactide initiated by glycerol. The resulting macromer was functionalized by introduction of end-functions through reaction with acryloyl chloride. Macromer and acrylic acid were used for the synthesis of narrowly-dispersed nanoparticles by radical polymerization in diluted conditions in the presence of biotin as template molecule. The binding capacity of the imprinted nanoparticles towards biotin and biotinylated bovine serum albumin was twentyfold that of non-imprinted nanoparti- cles. Degradation rates and functional performances were assessed in in vitro tests and cell cultures, demonstrating effective biotin-mediated cell internalization.

  9. The Molecular Atlas Project

    Science.gov (United States)

    Silverberg, Jesse; Yin, Peng

    The promise of super-resolution microscopy is a technology to discover new biological mechanisms that occur at smaller length scales then previously observable. However, with higher-resolution, we generally lose the larger spatial context of the image itself. The Molecular Atlas Project (MAP) directly asks how these competing interests between super-resolution imaging and broader spatially contextualized information can be reconciled. MAP enables us to acquire, visualize, explore, and annotate proteomic image data representing 7 orders of magnitude in length ranging from molecular (nm) to tissue (cm) scales. This multi-scale understanding is made possible by combining multiplexed DNA-PAINT, a DNA nanotechnology approach to super-resolution imaging, with ``big-data'' strategies for information management and image visualization. With these innovations combined, MAP enables us to explore cell-specific heterogeneity in ductal carcinoma for every cellin a cm-sized tissue section, analyze organoid growth for advances in high-throughput tissue-on-a-chip technology, and examine individual synapses for connectome mapping over extremely wide areas. Ultimately, MAP is a fundamentally new way to interact with multiscale biophysical data.

  10. [Magnetic resonance tomography: potentials of molecular imaging].

    Science.gov (United States)

    Hiller, Karl-Heinz; Faber, Cornelius; Neuberger, Thomas; Köhler, Sascha; Stroh, Albrecht; Zimmer, Claus; Jakob, Peter

    2005-01-01

    Molecular imaging is "the in-vivo characterization and measurement of biological processes at the cellular and molecular level" and allows the imaging of molecular abnormalities associated with diseases long before morphological changes can be detected. At present, the use of magnetic resonance imaging (MRI) for molecular and cellular imaging is rapidly increasing. MRI is a very attractive candidate, since current MRI protocols already provide anatomic, functional, and biochemical information of excellent image quality and with high spatial resolution. Combining this high spatial resolution/high contrast imaging modality with specific MRI contrast imaging agents for molecular imaging is currently the focus of research in many laboratories worldwide. This paper summarizes the rationale for molecular MRI imaging and describes the basic features of modern molecular imaging strategies with MRI. Finally, a special focus is given to the growing field of applications, e.g., stem cell imaging, imaging of apoptosis, plaques, and other biological targets of interest.

  11. Molecular Rheology of Complex Fluids

    DEFF Research Database (Denmark)

    Huang, Qian; Rasmussen, Henrik Koblitz

    fluids as a function of molecular chemistry has attracted a long history of collaboration between industry and academia. In industrial polymer processes, there is usually a combination of both shear and extensional flows. In some processing operations such as blow molding and fiber spinning, extensional......–state viscosity between melts and solutions is still an open question. Branched polymer melts have more complex molecular structures. A stress maximum during the start–up of uniaxial extensional flow was reported in 1979 for a low–density polyethylene (LDPE) melt. Subsequently observations of a steady stress...

  12. Communication: Understanding molecular representations in machine learning: The role of uniqueness and target similarity

    Science.gov (United States)

    Huang, Bing; von Lilienfeld, O. Anatole

    2016-10-01

    The predictive accuracy of Machine Learning (ML) models of molecular properties depends on the choice of the molecular representation. Inspired by the postulates of quantum mechanics, we introduce a hierarchy of representations which meet uniqueness and target similarity criteria. To systematically control target similarity, we simply rely on interatomic many body expansions, as implemented in universal force-fields, including Bonding, Angular (BA), and higher order terms. Addition of higher order contributions systematically increases similarity to the true potential energy and predictive accuracy of the resulting ML models. We report numerical evidence for the performance of BAML models trained on molecular properties pre-calculated at electron-correlated and density functional theory level of theory for thousands of small organic molecules. Properties studied include enthalpies and free energies of atomization, heat capacity, zero-point vibrational energies, dipole-moment, polarizability, HOMO/LUMO energies and gap, ionization potential, electron affinity, and electronic excitations. After training, BAML predicts energies or electronic properties of out-of-sample molecules with unprecedented accuracy and speed.

  13. Communication: Understanding molecular representations in machine learning: The role of uniqueness and target similarity.

    Science.gov (United States)

    Huang, Bing; von Lilienfeld, O Anatole

    2016-10-28

    The predictive accuracy of Machine Learning (ML) models of molecular properties depends on the choice of the molecular representation. Inspired by the postulates of quantum mechanics, we introduce a hierarchy of representations which meet uniqueness and target similarity criteria. To systematically control target similarity, we simply rely on interatomic many body expansions, as implemented in universal force-fields, including Bonding, Angular (BA), and higher order terms. Addition of higher order contributions systematically increases similarity to the true potential energy and predictive accuracy of the resulting ML models. We report numerical evidence for the performance of BAML models trained on molecular properties pre-calculated at electron-correlated and density functional theory level of theory for thousands of small organic molecules. Properties studied include enthalpies and free energies of atomization, heat capacity, zero-point vibrational energies, dipole-moment, polarizability, HOMO/LUMO energies and gap, ionization potential, electron affinity, and electronic excitations. After training, BAML predicts energies or electronic properties of out-of-sample molecules with unprecedented accuracy and speed.

  14. Clinical effects of low-molecular-weight heparin combined with ...

    African Journals Online (AJOL)

    The treatment lasted for 2 weeks. Clinical parameters, laboratory test indices, Acute Physiology and Chronic Health Evaluation (APACHE II) score, and computed tomography score of pancreatic necrosis (CTSPN) were assessed in both groups. Results: On admission, no significant differences were noted in clinical features, ...

  15. Engineering nanomaterials with a combined electrochemical and molecular biomimetic approach

    Science.gov (United States)

    Dai, Haixia

    Biocomposite materials, such as bones, teeth, and shells, are created using mild aqueous solution-based processes near room temperature. Proteins add flexibility to these processes by facilitating the nucleation, growth, and ordering of specific inorganic materials into hierarchical structures. We aim to develop a biomimetic strategy for engineering technologically relevant inorganic materials with controlled compositions and structures, as Nature does, using proteins to orchestrate material formation and assembly. This approach involves three basic steps: (i) preparation of inorganic substrates compatible with combinatorial polypeptide screening; (ii) identification of inorganic-binding polypeptides and their engineering into inorganic-binding proteins; and (iii) protein-mediated inorganic nucleation and organization. Cuprous oxide (Cu2O), a p-type semiconductor, has been used to demonstrate all three steps. Zinc oxide (ZnO), an n-type semiconductor, has been used to show the generality of selected steps. Step (i), preparation of high quality inorganic substrates to select inorganic-binding polypeptides, was accomplished using electrochemical microfabrication to grow and pattern Cu2O and ZnO. Raman spectroscopy and x-ray photoelectron spectroscopy were used to verify phase purity and compositional stability of these surfaces during polypeptide screening. Step (ii), accomplished in collaboration with personnel in Prof Baneyx' lab at the University of Washington, involved incubating the inorganic substrates with the FliTrx(TM) random peptide library to identify cysteine-constrained dodecapeptides that bind the targeted inorganic. Insertion of a Cu2O-binding dodecapeptide into the DNA-binding protein TraI endowed the engineered TraI with strong affinity for Cu2O (Kd ≈ 10 -8 M). Finally, step (iii) involved nonequilibrium synthesis and organization of Cu2O nanoparticles, taking advantage of the inorganic and DNA recognition properties of the engineered TraI. The high affinity of the engineered TraI for Cu2O over other related copper compounds led to the formation of Cu2O nanoparticles from a cuprous chloride complex (Cu2Cln1-n, n = 2 or 3) electrolyte under conditions where the mineral atacamite (CuCl(OH) 3) is thermodynamically preferred. The nonequilibrium Cu 2O nanoparticles consisted of 2--3 nm Cu2O cores and functional protein shells that enabled predictable meso-scale assembly on DNA templates. In short, we have rationally designed a protein-based scheme for forming and organizing inorganic materials that Nature has not previous worked with.

  16. Curcumin in combined cancer therapy.

    Science.gov (United States)

    Troselj, Koraljka Gall; Kujundzic, Renata Novak

    2014-01-01

    The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-κB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-κB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-κB activity and its inhibitory effect on NF-κB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-κB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-κB by selectively combining curcumin and various anticancer drugs.

  17. Analysis of molecular interactions in solid dosage forms; challenge to molecular pharmaceutics.

    Science.gov (United States)

    Yamamoto, Keiji; Limwikrant, Waree; Moribe, Kunikazu

    2011-01-01

    The molecular states of active pharmaceutical ingredients (APIs) in pharmaceutical dosage forms strongly affect the properties and quality of a drug. Various important fundamental physicochemical studies were reviewed from the standpoint of molecular pharmaceutics. Mechanochemical effects were evaluated in mixtures of APIs and pharmaceutical additives. Amorphization, complex formation and nanoparticle formation are observed after grinding process depending on the combination of APIs and pharmaceutical additives. Sealed-heating method and mesoporous materials have been used to investigate drug molecular interactions in dosage forms. Molecular states have been investigated using powder X-ray diffraction, thermal analysis, IR, solid state fluorometry, and NMR. © 2011 Pharmaceutical Society of Japan

  18. Understanding molecular structure from molecular mechanics.

    Science.gov (United States)

    Allinger, Norman L

    2011-04-01

    Molecular mechanics gives us a well known model of molecular structure. It is less widely recognized that valence bond theory gives us structures which offer a direct interpretation of molecular mechanics formulations and parameters. The electronic effects well-known in physical organic chemistry can be directly interpreted in terms of valence bond structures, and hence quantitatively calculated and understood. The basic theory is outlined in this paper, and examples of the effects, and their interpretation in illustrative examples is presented.

  19. Internal motions in proteins: A combined neutron scattering and ...

    Indian Academy of Sciences (India)

    phycocyanin, that can be obtained in protonated and deuterated forms. Diffusive motions have been studied using the protonated C-phycocyanin, protein. Molecular dynamics simulation and analytical theory have been combined to analyse the data ...

  20. Charge Transport Along Phenylenevinylene Molecular Wires

    OpenAIRE

    Siebbeles, Laurens; Prins, Paulette; Grozema, Ferdinand

    2006-01-01

    Abstract A model to calculate the mobility of charges along molecular wires is presented. The model is based on the tight-binding approximation and combines a quantum mechanical description of the charge with a classical description of the structural degrees of freedom. It is demonstrated that the average mobility of charge carriers along molecular wires can be obtained by time-propagation of states which are initially localised. The model is used to calculate the mobility of charg...

  1. Quantum Transport Through Tunable Molecular Diodes

    KAUST Repository

    Obodo, Tobechukwu Joshua

    2017-07-31

    Employing self-interaction corrected density functional theory combined with the non-equilibrium Green\\'s function method, we study the quantum transport through molecules with different numbers of phenyl (donor) and pyrimidinyl (acceptor) rings in order to evaluate the effects of the molecular composition on the transport properties. Excellent agreement with the results of recent experiments addressing the rectification behavior of molecular junctions is obtained, which demonstrates the potential of quantum transport simulations for designing high performance junctions by tuning the molecular specifications.

  2. Molecular replacement: tricks and treats

    Energy Technology Data Exchange (ETDEWEB)

    Abergel, Chantal, E-mail: chantal.abergel@igs.cnrs-mrs.fr [IGS UMR 7256, CNRS, Aix-Marseille Université, IMM, FR3479, 163 Avenue de Luminy – case 934, 13288 Marseille CEDEX 09 (France)

    2013-11-01

    To be successful, molecular replacement relies on the quality of the model and of the crystallographic data. Some tricks that could be applied to the models or to the crystal to increase the success rate of MR are discussed here. Molecular replacement is the method of choice for X-ray crystallographic structure determination provided that suitable structural homologues are available in the PDB. Presently, there are ∼80 000 structures in the PDB (8074 were deposited in the year 2012 alone), of which ∼70% have been solved by molecular replacement. For successful molecular replacement the model must cover at least 50% of the total structure and the C{sub α} r.m.s.d. between the core model and the structure to be solved must be less than 2 Å. Here, an approach originally implemented in the CaspR server (http://www.igs.cnrs-mrs.fr/Caspr2/index.cgi) based on homology modelling to search for a molecular-replacement solution is discussed. How the use of as much information as possible from different sources can improve the model(s) is briefly described. The combination of structural information with distantly related sequences is crucial to optimize the multiple alignment that will define the boundaries of the core domains. PDB clusters (sequences with ≥30% identical residues) can also provide information on the eventual changes in conformation and will help to explore the relative orientations assumed by protein subdomains. Normal-mode analysis can also help in generating series of conformational models in the search for a molecular-replacement solution. Of course, finding a correct solution is only the first step and the accuracy of the identified solution is as important as the data quality to proceed through refinement. Here, some possible reasons for failure are discussed and solutions are proposed using a set of successful examples.

  3. Advances in molecular vibrations and collision dynamics molecular clusters

    CERN Document Server

    Bacic, Zatko

    1998-01-01

    This volume focuses on molecular clusters, bound by van der Waals interactions and hydrogen bonds. Twelve chapters review a wide range of recent theoretical and experimental advances in the areas of cluster vibrations, spectroscopy, and reaction dynamics. The authors are leading experts, who have made significant contributions to these topics.The first chapter describes exciting results and new insights in the solvent effects on the short-time photo fragmentation dynamics of small molecules, obtained by combining heteroclusters with femtosecond laser excitation. The second is on theoretical work on effects of single solvent (argon) atom on the photodissociation dynamics of the solute H2O molecule. The next two chapters cover experimental and theoretical aspects of the energetics and vibrations of small clusters. Chapter 5 describes diffusion quantum Monte Carlo calculations and non additive three-body potential terms in molecular clusters. The next six chapters deal with hydrogen-bonded clusters, refle...

  4. Birth control pills - combination

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/patientinstructions/000655.htm Birth control pills - combination To use the sharing features on ... both progestin and estrogen. What Are Combination Birth Control Pills? Birth control pills help keep you from ...

  5. COMBINE 2 seminar

    DEFF Research Database (Denmark)

    Sørensen, Lars Schiøtt; Jacobsen, Kim

    1995-01-01

    A seminar about the COMBINE project was described. Further, the project was described in generel, i.e. the COMBINE´s data model (IDM), the data exchange system (DES) and the different I/O-systems included in COMBINE 2......A seminar about the COMBINE project was described. Further, the project was described in generel, i.e. the COMBINE´s data model (IDM), the data exchange system (DES) and the different I/O-systems included in COMBINE 2...

  6. Basic molecular spectroscopy

    CERN Document Server

    Gorry, PA

    1985-01-01

    BASIC Molecular Spectroscopy discusses the utilization of the Beginner's All-purpose Symbolic Instruction Code (BASIC) programming language in molecular spectroscopy. The book is comprised of five chapters that provide an introduction to molecular spectroscopy through programs written in BASIC. The coverage of the text includes rotational spectra, vibrational spectra, and Raman and electronic spectra. The book will be of great use to students who are currently taking a course in molecular spectroscopy.

  7. Artificial molecular motors

    NARCIS (Netherlands)

    Kassem, Salma; van Leeuwen, Thomas; Lubbe, Anouk S.; Wilson, Miriam R.; Feringa, Ben L.; Leigh, David A.

    2017-01-01

    Motor proteins are nature's solution for directing movement at the molecular level. The field of artificial molecular motors takes inspiration from these tiny but powerful machines. Although directional motion on the nanoscale performed by synthetic molecular machines is a relatively new

  8. Electronic transport in molecular junctions

    Science.gov (United States)

    Liu, Rui

    2006-01-01

    A combined density functional theory and Green function method is used to study some basics and applications in the field of molecular electronics. We have investigated the effects of lateral interactions on the conductance of two molecules connected in parallel to semi-infinite leads. The system, modeled after a self-assembled monolayer, consists of benzylmercaptane molecules sandwiched between gold electrodes. We find that the conductance increases when intermolecular interaction comes into play. The source of this increase is the indirect interaction through the gold substrate rather than direct molecule-molecule interaction. As for applications, single-molecule spintronic switch and spin valve, rectifier and negative differential resistive (NDR) diode are proposed. Spintronic switch is constructed by a di-cobaltocene containing molecule. The anti-parallel (singlet) configuration blocks electron transport near the Fermi energy, while the spin parallel (triplet) configuration enables a much higher current. The energy difference between the anti-parallel and parallel states depends on the insulating spacer separating the two cobaltocenes, allowing switching through the application of a moderate magnetic field. In addition, single cobaltocene containing molecule can be used as a spin valve. Rectification of current through a single molecule with an intrinsic spatial asymmetry is studied. The molecule contains a cobaltocene moiety in order to take advantage of its relatively localized and high energy d states. A rectifier with large voltage range, high current density, and low threshold voltage can be realized. The evolution of molecular orbitals under both forward and reverse bias reveals the source of rectification being asymmetric potential drop. Our calculations demonstrate the plausibility of making excellent molecular diodes by using metallocenes, pointing to a fruitful class of molecules. Analogous to a quantum double dot system, we found that diblock

  9. Molecular computing origins and promises

    CERN Document Server

    Rambidi, Nicholas G

    2014-01-01

    Molecular Computing explores whether molecular primitives can prove to be real alternatives to contemporary semiconductor means. The text discusses molecular primitives and circuitry for information processing devices.

  10. Concurrent triple-scale simulation of molecular liquids

    Science.gov (United States)

    Delgado-Buscalioni, Rafael; Kremer, Kurt; Praprotnik, Matej

    2008-03-01

    We present a triple-scale simulation of a molecular liquid, in which the atomistic, coarse-grained, and continuum descriptions of the liquid are concurrently coupled. The presented multiscale approach, which covers the length scales ranging from the micro- to macroscale, is a combination of two dual-scale models: a particle-based adaptive resolution scheme (AdResS), which couples the atomic and mesoscopic scales, and a hybrid continuum-molecular dynamics scheme (HybridMD). The combined AdResS-HybridMD scheme successfully sorts out the problem of large molecule insertion in the hybrid particle-continuum simulations of molecular liquids. The combined model is shown to correctly describe the hydrodynamics within a hybrid particle-continuum framework. The presented approach opens up the possibility to perform efficient grand-canonical molecular dynamics simulations of truly open molecular liquid systems.

  11. Molecular Taxonomy of the Trichophyton rubrum Complex

    OpenAIRE

    Gräser, Y.; Kuijpers, A.F.A.; Presber, W; de Hoog, G.S.

    2000-01-01

    The validity of taxa around Trichophyton rubrum was evaluated by a combination of phenetic and molecular methods. Morphological and physiological features were compared to results of sequencing of the internal transcribed spacer region of the ribosomal operon, PCR fingerprinting, and amplified fragment length polymorphism analysis. The 15 species and varieties investigated (Trichophyton circonvolutum, Trichophyton fischeri, Trichophyton fluviomuniense, Trichophyton glabrum, Trichophyton gourv...

  12. A simple and rapid molecular method for Leptospira species identification

    NARCIS (Netherlands)

    Ahmed, Ahmed; Anthony, Richard M.; Hartskeerl, Rudy A.

    2010-01-01

    Serological and DNA-based classification systems only have little correlation. Currently serological and molecular methods for characterizing Leptospira are complex and costly restricting their world-wide distribution and use. Ligation mediated amplification combined with microarray analysis

  13. Use of remote sensing and molecular markers to detect toxic ...

    African Journals Online (AJOL)

    Jane

    2010-12-20

    2) to correlate remote sensing imagery with ground level monitoring for the detection and characterization of the development of cyanobacterial hyperscum crust over a period of 6 months; (3) to use a combination of molecular ...

  14. Recent development of nanoparticles for molecular imaging

    Science.gov (United States)

    Kim, Jonghoon; Lee, Nohyun; Hyeon, Taeghwan

    2017-10-01

    Molecular imaging enables us to non-invasively visualize cellular functions and biological processes in living subjects, allowing accurate diagnosis of diseases at early stages. For successful molecular imaging, a suitable contrast agent with high sensitivity is required. To date, various nanoparticles have been developed as contrast agents for medical imaging modalities. In comparison with conventional probes, nanoparticles offer several advantages, including controllable physical properties, facile surface modification and long circulation time. In addition, they can be integrated with various combinations for multimodal imaging and therapy. In this opinion piece, we highlight recent advances and future perspectives of nanomaterials for molecular imaging. This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

  15. MOLECULAR CYTOGENETICS OF LYMPHOMA. WHERE DO WE STAND IN 2010?

    OpenAIRE

    Kluin, Philip M.; Schuuring, Ed

    2011-01-01

    Abstract Since approximately 20 years most malignant lymphomas are classified by the recognition of clinico-pathologic entities, each with its own combination of clinical, morphologic, immunophenotypic and molecular genetic characteristics. Obviously, in many instances molecular cytogenetics is of great help for classification and in some lymphomas it is even a prerequisite. Molecular cytogenetic alterations can be detected by a large variety of techniques, ranging from conventiona...

  16. Linear dichroism in molecular resonant inelastic x-ray scattering

    Energy Technology Data Exchange (ETDEWEB)

    Lindle, D W; Stolte, W C [Department of Chemistry, University of Nevada, Las Vegas, NV 89154-4003 (United States); Guillemint, R; Carniato, S; Journel, L; Taieb, R; Simon, M, E-mail: lindle@unlv.nevada.ed [UPMC, CNRS U Paris 06, UMR 7614, Laboratoire de Chimie Physique Matiere et Rayonnement, F-75005 Paris (France)

    2009-11-01

    Polarization-dependent resonant inelastic x-ray scattering (RIXS) is shown to be a new probe of molecular-field effects on molecular electronic structure. Combining experiment and theory, linear dichroism in Cl 2p RIXS following Cl 1s excitation in HCl, Cl{sub 2}, and CF{sub 3}Cl is ascribed to molecular-field effects, indicating polarized-RIXS provides a direct probe of spin-orbit-state populations generally applicable to all molecules.

  17. Sampling Molecular Conformers in Solution with Quantum Mechanical Accuracy at a Nearly Molecular-Mechanics Cost.

    Science.gov (United States)

    Rosa, Marta; Micciarelli, Marco; Laio, Alessandro; Baroni, Stefano

    2016-09-13

    We introduce a method to evaluate the relative populations of different conformers of molecular species in solution, aiming at quantum mechanical accuracy, while keeping the computational cost at a nearly molecular-mechanics level. This goal is achieved by combining long classical molecular-dynamics simulations to sample the free-energy landscape of the system, advanced clustering techniques to identify the most relevant conformers, and thermodynamic perturbation theory to correct the resulting populations, using quantum-mechanical energies from density functional theory. A quantitative criterion for assessing the accuracy thus achieved is proposed. The resulting methodology is demonstrated in the specific case of cyanin (cyanidin-3-glucoside) in water solution.

  18. Practical, general parser combinators

    NARCIS (Netherlands)

    A. Izmaylova (Anastasia); A. Afroozeh (Ali); T. van der Storm (Tijs)

    2016-01-01

    textabstractParser combinators are a popular approach to parsing where contextfree grammars are represented as executable code. However, conventional parser combinators do not support left recursion, and can have worst-case exponential runtime. These limitations hinder the expressivity and

  19. Combinators for Paraconsistent Attitudes

    DEFF Research Database (Denmark)

    Villadsen, Jørgen

    2001-01-01

    In order to analyse the semantics of natural language sentences a translation into a partial type logic using lexical and logical combinators is presented. The sentences cover a fragment of English with propositional attitudes like knowledge, belief and assertion. A combinator is a closed term of...

  20. Molecular probe technology detects bacteria without culture

    Directory of Open Access Journals (Sweden)

    Hyman Richard W

    2012-03-01

    Full Text Available Abstract Background Our ultimate goal is to detect the entire human microbiome, in health and in disease, in a single reaction tube, and employing only commercially available reagents. To that end, we adapted molecular inversion probes to detect bacteria using solely a massively multiplex molecular technology. This molecular probe technology does not require growth of the bacteria in culture. Rather, the molecular probe technology requires only a sequence of forty sequential bases unique to the genome of the bacterium of interest. In this communication, we report the first results of employing our molecular probes to detect bacteria in clinical samples. Results While the assay on Affymetrix GenFlex Tag16K arrays allows the multiplexing of the detection of the bacteria in each clinical sample, one Affymetrix GenFlex Tag16K array must be used for each clinical sample. To multiplex the clinical samples, we introduce a second, independent assay for the molecular probes employing Sequencing by Oligonucleotide Ligation and Detection. By adding one unique oligonucleotide barcode for each clinical sample, we combine the samples after processing, but before sequencing, and sequence them together. Conclusions Overall, we have employed 192 molecular probes representing 40 bacteria to detect the bacteria in twenty-one vaginal swabs as assessed by the Affymetrix GenFlex Tag16K assay and fourteen of those by the Sequencing by Oligonucleotide Ligation and Detection assay. The correlations among the assays were excellent.

  1. Effective Nutritional Supplement Combinations

    Science.gov (United States)

    Cooke, Matt; Cribb, Paul J.

    Few supplement combinations that are marketed to athletes are supported by scientific evidence of their effectiveness. Quite often, under the rigor of scientific investigation, the patented combination fails to provide any greater benefit than a group given the active (generic) ingredient. The focus of this chapter is supplement combinations and dosing strategies that are effective at promoting an acute physiological response that may improve/enhance exercise performance or influence chronic adaptations desired from training. In recent years, there has been a particular focus on two nutritional ergogenic aids—creatine monohydrate and protein/amino acids—in combination with specific nutrients in an effort to augment or add to their already established independent ergogenic effects. These combinations and others are discussed in this chapter.

  2. Photoionization studies with molecular beams

    Energy Technology Data Exchange (ETDEWEB)

    Ng, C.Y.

    1976-09-01

    A molecular beam photoionization apparatus which combines the advantages of both the molecular beam method with photoionization mass spectrometry has been designed and constructed for carrying out some unique photoionization experiments. Rotational cooling during the supersonic expansion has resulted in high resolution photoionization efficiency curves for NO, ICl, C/sub 2/H/sub 2/ and CH/sub 3/I. The analysis of these spectra has yielded ionization potentials for these molecules to an accuracy of +- 3 MeV. Detailed autoionization structures were also resolved. This allows the investigation of the selection rules for autoionization, and the identification of the Rydberg series which converge to the excited states of the molecular ions. The degree of relaxation for thermally populated excited states has been examined using NO and ICl as examples. As a result of adiabatic cooling, a small percentage of dimers is also formed during the expansion. The photoionization efficiency curves for (NO)/sub 2/, ArICl, Ar/sub 2/, Kr/sub 2/ and Xe/sub 2/ have been obtained near the thresholds. Using the known dissociation energies of the (NO)/sub 2/, Ar/sub 2/, Kr/sub 2/ and Xe/sub 2/ van der Waals molecules, the corresponding dissociation energies for NO-NO/sup +/, Ar/sub 2//sup +/, Kr/sub 2//sup +/, and Xe/sub 2//sup +/ have been determined. The ionization mechanisms for this class of molecules are examined and discussed.

  3. Combination of antiarrhythmic drugs.

    Science.gov (United States)

    Lüderitz, B; Mletzko, R; Jung, W; Manz, M

    1991-01-01

    Antiarrhythmic treatment with single agents is often ineffective and can be limited by dose-dependent side effects. Therefore, combinations of antiarrhythmic drugs in smaller and well-tolerated doses are advocated in cases refractory to single antiarrhythmic drugs. Basically, substances belonging to the same electrophysiologic class should not be combined. However, drugs of different subsets of class I may be combined. Agents that have pharmacokinetic interactions, such as quinidine and amiodarone, should not be given together because this combination may be associated with a considerable proarrhythmic effect. A combination of beta-adrenoreceptor blockers with class I antiarrhythmic drugs may be effective, mainly in cases in which the arrhythmia is dependent on adrenergic stimulation. The combination of class III and IB substances can be useful in some cases, from the electrophysiological and clinical point of view. Among the successful combinations of this type are amiodarone and mexiletine, sotalol and mexiletine, or sotalol and tocainide. In 34 patients, the reduction of ventricular premature beats by sotalol alone was 28%, and by sotalol plus mexiletine or tocainide was 79%. Complex ventricular arrhythmias were suppressed by sotalol alone by less than 40% and by sotalol plus mexiletine or tocainide by more than 80%. There was no difference in the effectiveness of mexiletine and tocainide (both of them being class IB drugs) in this combination. However, mexiletine was associated with fewer adverse effects than was tocainide. In patients refractory to amiodarone alone or to a combination with mexiletine, the combined treatment with amiodarone and class IC drugs such as flecainide and encainide prolongs the cycle length of ventricular tachycardia, but does not suppress induction of ventricular tachycardia during programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Molecular Population Genetics

    OpenAIRE

    Casillas, S?nia; Barbadilla, Antonio

    2017-01-01

    Molecular population genetics aims to explain genetic variation and molecular evolution from population genetics principles. The field was born 50 years ago with the first measures of genetic variation in allozyme loci, continued with the nucleotide sequencing era, and is currently in the era of population genomics. During this period, molecular population genetics has been revolutionized by progress in data acquisition and theoretical developments. The conceptual elegance of the neutral theo...

  5. [Molecular diagnostics in melanoma].

    Science.gov (United States)

    Lang, R; Bauer, J W; Laimer, M

    2015-04-01

    The molecular landscape of melanoma is changing more rapidly than ever since new molecular technology approaches have made it possible to examine human melanoma for genetic alterations underlying the disease. In recent years, these approaches have identified new familial melanoma susceptibility genes, most of them also conferring risk to other cancers. This has implications for clinical testing and surveillance. Furthermore, molecular testing of melanoma to determine therapeutic eligibility for targeted therapies is now standard of care and should be familiar to the dermatologist.

  6. Molecular heat pump

    OpenAIRE

    Segal, Dvira; Nitzan, Abraham

    2005-01-01

    We propose a novel molecular device that pumps heat against a thermal gradient. The system consists of a molecular element connecting two thermal reservoirs that are characterized by different spectral properties. The pumping action is achieved by applying an external force that periodically modulates molecular levels. This modulation affects periodic oscillations of the internal temperature of the molecule and the strength of its coupling to each reservoir resulting in a net heat flow in the...

  7. Translational Molecular Nuclear Cardiology.

    Science.gov (United States)

    Thackeray, James T; Bengel, Frank M

    2016-02-01

    Increased rollout and availability of preclinical imaging provides a foundation for development of novel molecular nuclear imaging agents. The current armamentarium of radiotracers available for nuclear cardiology allows for the interrogation of critical molecular processes involved in a myriad of cardiovascular disorders, including altered metabolism, ventricular remodeling, sympathetic neuronal activation, and systemic inflammation. Effective translational molecular imaging requires coordination of clinical need with tracer development and molecular biology, leading to the identification of ideal translational imaging compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. The modern molecular clock.

    Science.gov (United States)

    Bromham, Lindell; Penny, David

    2003-03-01

    The discovery of the molecular clock--a relatively constant rate of molecular evolution--provided an insight into the mechanisms of molecular evolution, and created one of the most useful new tools in biology. The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral. Theory predicts several sources of variation in the rate of molecular evolution. However, even an approximate clock allows time estimates of events in evolutionary history, which provides a method for testing a wide range of biological hypotheses ranging from the origins of the animal kingdom to the emergence of new viral epidemics.

  9. Polymer friction Molecular Dynamics

    DEFF Research Database (Denmark)

    Sivebæk, Ion Marius; Samoilov, Vladimir N.; Persson, Bo N. J.

    We present molecular dynamics friction calculations for confined hydrocarbon solids with molecular lengths from 20 to 1400 carbon atoms. Two cases are considered: a) polymer sliding against a hard substrate, and b) polymer sliding on polymer. In the first setup the shear stresses are relatively...... independent of molecular length. For polymer sliding on polymer the friction is significantly larger, and dependent on the molecular chain length. In both cases, the shear stresses are proportional to the squeezing pressure and finite at zero load, indicating an adhesional contribution to the friction force....

  10. Subacute combined degeneration

    Science.gov (United States)

    ... the term "combined." At first, the nerve covering (myelin sheath) is damaged. Later, the entire nerve cell is affected. Doctors do not know exactly how a lack of vitamin B12 damages the nerves. It is possible that the lack ...

  11. Resonant High Power Combiners

    CERN Document Server

    Langlois, Michel; Peillex-Delphe, Guy

    2005-01-01

    Particle accelerators need radio frequency sources. Above 300 MHz, the amplifiers mostly used high power klystrons developed for this sole purpose. As for military equipment, users are drawn to buy "off the shelf" components rather than dedicated devices. IOTs have replaced most klystrons in TV transmitters and find their way in particle accelerators. They are less bulky, easier to replace, more efficient at reduced power. They are also far less powerful. What is the benefit of very compact sources if huge 3 dB couplers are needed to combine the power? To alleviate this drawback, we investigated a resonant combiner, operating in TM010 mode, able to combine 3 to 5 IOTs. Our IOTs being able to deliver 80 kW C.W. apiece, combined power would reach 400 kW minus the minor insertion loss. Values for matching and insertion loss are given. The behavior of the system in case of IOT failure is analyzed.

  12. Molecular Stirrers in Action

    NARCIS (Netherlands)

    Chen, Jiawen; Kistemaker, Jos C. M.; Robertus, Jort; Feringa, Ben L.

    2014-01-01

    A series of first-generation light-driven molecular motors with rigid substituents of varying length was synthesized to act as "molecular stirrers". Their rotary motion was studied by H-1 NMR and UV-vis absorption spectroscopy in a variety of solvents with different polarity and viscosity.

  13. Molecular microbial ecology manual

    NARCIS (Netherlands)

    Kowalchuk, G.A.; Bruijn, de F.J.; Head, I.M.; Akkermans, A.D.L.

    2004-01-01

    The field of microbial ecology has been revolutionized in the past two decades by the introduction of molecular methods into the toolbox of the microbial ecologist. This molecular arsenal has helped to unveil the enormity of microbial diversity across the breadth of the earth's ecosystems, and has

  14. Molecular phosphates and siloxanes

    Indian Academy of Sciences (India)

    Administrator

    There has been immense interest and enthusiasm recently among chemists to develop materials at low temperatures through molecular routes. Especially interesting are the studies carried out on molecular phosphonates 1 and siloxanes 2,3 by Roesky, Tilley,. Mason, Feher and others. This presentation focuses on the ...

  15. Principles of molecular oncology

    National Research Council Canada - National Science Library

    Bronchud, Miguel H

    2008-01-01

    ...-threatening diseases. Many new molecularly targeted diagnostics and therapeutics described in this text, developed based on the rapid growth in our understanding of the molecular basis of cancer, already substantially improve survival of patients with previously lethal malignancies, and also improve quality of life because of fewer toxicities. Clearly re...

  16. Making molecular machines work

    NARCIS (Netherlands)

    Browne, Wesley R.; Feringa, Ben L.

    2006-01-01

    In this review we chart recent advances in what is at once an old and very new field of endeavour the achievement of control of motion at the molecular level including solid-state and surface-mounted rotors, and its natural progression to the development of synthetic molecular machines. Besides a

  17. A molecular view of heterogeneous catalysis

    DEFF Research Database (Denmark)

    Christensen, Claus H.; Nørskov, Jens Kehlet

    2008-01-01

    The establishment of a molecular view of heterogeneous catalysis has been hampered for a number of reasons. There are, however, recent developments, which show that we are now on the way towards reaching a molecular-scale picture of the way solids work as catalysts. By a combination of new...... by enabling a rational design of new catalysts. We illustrate this important development in heterogeneous catalysis by highlighting recent examples of catalyst systems for which it has been possible to achieve such a detailed understanding. In particular, we emphasize examples where this progress has made...

  18. A Similarity Search Using Molecular Topological Graphs

    Directory of Open Access Journals (Sweden)

    Yoshifumi Fukunishi

    2009-01-01

    Full Text Available A molecular similarity measure has been developed using molecular topological graphs and atomic partial charges. Two kinds of topological graphs were used. One is the ordinary adjacency matrix and the other is a matrix which represents the minimum path length between two atoms of the molecule. The ordinary adjacency matrix is suitable to compare the local structures of molecules such as functional groups, and the other matrix is suitable to compare the global structures of molecules. The combination of these two matrices gave a similarity measure. This method was applied to in silico drug screening, and the results showed that it was effective as a similarity measure.

  19. Artificial intelligence in drug combination therapy.

    Science.gov (United States)

    Tsigelny, Igor F

    2018-02-09

    Currently, the development of medicines for complex diseases requires the development of combination drug therapies. It is necessary because in many cases, one drug cannot target all necessary points of intervention. For example, in cancer therapy, a physician often meets a patient having a genomic profile including more than five molecular aberrations. Drug combination therapy has been an area of interest for a while, for example the classical work of Loewe devoted to the synergism of drugs was published in 1928-and it is still used in calculations for optimal drug combinations. More recently, over the past several years, there has been an explosion in the available information related to the properties of drugs and the biomedical parameters of patients. For the drugs, hundreds of 2D and 3D molecular descriptors for medicines are now available, while for patients, large data sets related to genetic/proteomic and metabolomics profiles of the patients are now available, as well as the more traditional data relating to the histology, history of treatments, pretreatment state of the organism, etc. Moreover, during disease progression, the genetic profile can change. Thus, the ability to optimize drug combinations for each patient is rapidly moving beyond the comprehension and capabilities of an individual physician. This is the reason, that biomedical informatics methods have been developed and one of the more promising directions in this field is the application of artificial intelligence (AI). In this review, we discuss several AI methods that have been successfully implemented in several instances of combination drug therapy from HIV, hypertension, infectious diseases to cancer. The data clearly show that the combination of rule-based expert systems with machine learning algorithms may be promising direction in this field. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Theoretical molecular biophysics

    CERN Document Server

    Scherer, Philipp O J

    2017-01-01

    This book gives an introduction to molecular biophysics. It starts from material properties at equilibrium related to polymers, dielectrics and membranes. Electronic spectra are developed for the understanding of elementary dynamic processes in photosynthesis including proton transfer and dynamics of molecular motors. Since the molecular structures of functional groups of bio-systems were resolved, it has become feasible to develop a theory based on the quantum theory and statistical physics with emphasis on the specifics of the high complexity of bio-systems. This introduction to molecular aspects of the field focuses on solvable models. Elementary biological processes provide as special challenge the presence of partial disorder in the structure which does not destroy the basic reproducibility of the processes. Apparently the elementary molecular processes are organized in a way to optimize the efficiency. Learning from nature by means exploring the relation between structure and function may even help to b...

  1. Knowledge environments representing molecular entities for the virtual physiological human.

    Science.gov (United States)

    Hofmann-Apitius, Martin; Fluck, Juliane; Furlong, Laura; Fornes, Oriol; Kolárik, Corinna; Hanser, Susanne; Boeker, Martin; Schulz, Stefan; Sanz, Ferran; Klinger, Roman; Mevissen, Theo; Gattermayer, Tobias; Oliva, Baldo; Friedrich, Christoph M

    2008-09-13

    In essence, the virtual physiological human (VPH) is a multiscale representation of human physiology spanning from the molecular level via cellular processes and multicellular organization of tissues to complex organ function. The different scales of the VPH deal with different entities, relationships and processes, and in consequence the models used to describe and simulate biological functions vary significantly. Here, we describe methods and strategies to generate knowledge environments representing molecular entities that can be used for modelling the molecular scale of the VPH. Our strategy to generate knowledge environments representing molecular entities is based on the combination of information extraction from scientific text and the integration of information from biomolecular databases. We introduce @neuLink, a first prototype of an automatically generated, disease-specific knowledge environment combining biomolecular, chemical, genetic and medical information. Finally, we provide a perspective for the future implementation and use of knowledge environments representing molecular entities for the VPH.

  2. Molecularly Imprinted Filtering Adsorbents for Odor Sensing

    Directory of Open Access Journals (Sweden)

    Sho Shinohara

    2016-11-01

    Full Text Available Versatile odor sensors that can discriminate among huge numbers of environmental odorants are desired in many fields, including robotics, environmental monitoring, and food production. However, odor sensors comparable to an animal’s nose have not yet been developed. An animal’s olfactory system recognizes odor clusters with specific molecular properties and uses this combinatorial information in odor discrimination. This suggests that measurement and clustering of odor molecular properties (e.g., polarity, size using an artificial sensor is a promising approach to odor sensing. Here, adsorbents composed of composite materials with molecular recognition properties were developed for odor sensing. The selectivity of the sensor depends on the adsorbent materials, so specific polymeric materials with particular solubility parameters were chosen to adsorb odorants with various properties. The adsorption properties of the adsorbents could be modified by mixing adsorbent materials. Moreover, a novel molecularly imprinted filtering adsorbent (MIFA, composed of an adsorbent substrate covered with a molecularly imprinted polymer (MIP layer, was developed to improve the odor molecular recognition ability. The combination of the adsorbent and MIP layer provided a higher specificity toward target molecules. The MIFA thus provides a useful technique for the design and control of adsorbents with adsorption properties specific to particular odor molecules.

  3. Towards Rectifying Performance at the Molecular Scale.

    Science.gov (United States)

    Zhang, Guang-Ping; Xie, Zhen; Song, Yang; Hu, Gui-Chao; Wang, Chuan-Kui

    2017-10-24

    Molecular diode, proposed by Mark Ratner and Arieh Aviram in 1974, is the first single-molecule device investigated in molecular electronics. As a fundamental device in an electric circuit, molecular diode has attracted an enduring and extensive focus during the past decades. In this review, the theoretical and experimental progresses of both charge-based and spin-based molecular diodes are summarized. For the charge-based molecular diodes, the rectifying properties originated from asymmetric molecules including D-σ-A, D-π-A, D-A, and σ-π type compounds, asymmetric electrodes, asymmetric nanoribbons, and their combination are analyzed. Correspondingly, the rectification mechanisms are discussed in detail. Furthermore, a series of strategies for modulating rectification performance is figured out. Discussion on concept of molecular spin diode is also involved based on a magnetic co-oligomer. At the same time, the intrinsic mechanism as well as the modulation of the spin-current rectification performance is introduced. Finally, several crucial issues that need to be addressed in the future are given.

  4. EDITORIAL: Focus on Molecular Electronics FOCUS ON MOLECULAR ELECTRONICS

    Science.gov (United States)

    Scheer, Elke; Reineker, Peter

    2008-06-01

    exciton model applies in which the excitation is distributed over several molecules or whether a good description is given by the Frenkel exciton model with the electron and the whole being localized at the same molecular unit. In organic semiconductors the charge transport usually occurs on the basis of holes because of the presence of many defects giving rise to a localization of the electrons. It is therefore a challenge to produce materials with both positive and negative mobile charge carriers. In the 1990s V M Agranovich introduced the idea of hybrid excitons, i.e. of nanostructured materials consisting of both organic and inorganic semiconductors. At the interface between the organic and inorganic parts new excitons can appear, being a superposition of both Frenkel and Wannier excitons and having both the high oscillator strength of the Frenkel and the large optical nonlinearity of the Wannier exciton. The problem is to find optimum combinations of the organic and inorganic parts to enable the hybrid structure concept to work. Micro-cavities also play an important role in the investigation of organic materials resulting in a new state (polariton) as the superposition of a photon and an exciton because of the large exciton-photon interaction. A similar excitation arises because of the interaction between plasmons and photons. A special geometrical shape of a nano-cavity increases the interaction between the electromagnetic radiation and a dipole sitting in the cavity. The interaction between vibronic degrees of freedom and electronic excitations plays an important role for various phenomena such as nonlinear processes, the question of coherence, information on the shape of a potential hypersurface, etc. With the help of femtosecond laser pulses, detailed information on such vibrations can be obtained. Also of great importance is the investigation of the energy transfer in artificial light-harvesting systems, e.g. in dendrimers. Finally the combination of

  5. Molecular Programming with DNA

    Science.gov (United States)

    Winfree, Erik

    2009-05-01

    Information can be stored in molecules and processed by molecular reactions. Molecular information processing is at the heart of all biological systems; might it soon also be at the heart of non-biological synthetic chemical systems? Perhaps yes. One technological approach comes from DNA nanotechnology and DNA computing, where DNA is used as a non-biological informational polymer that can be rationally designed to create a rich class of molecular systems -- for example, DNA molecules that self-assemble precisely, that fold into complex nanoscale objects, that act as mechanical actuators and molecular motors, and that make decisions based on digital and analog logic. I will argue that to fully exploit their design potential, we will need to invent programming languages for specifying the behavior of information-based molecular systems, to create theoretical tools for understanding and analyzing the behavior of molecular programs, to develop compilers that automate the design of molecules with the desired behaviors, and to expand experimental techniques so that the implementation and debugging of complex molecular systems becomes as commonplace and practical as computer programming.

  6. Molecular markers in melanoma.

    Science.gov (United States)

    Kashani-Sabet, M

    2014-01-01

    The last few years have witnessed the dawn of the molecular era in melanoma treatment. With the advent of successful therapy targeting mutant BRAF, melanoma is leading the field of cancer research in the molecular approach to therapy of advanced disease. Attempting to keep pace with advances in therapy are advances in the molecular assessment of melanoma progression, facilitated by the availability of genome-wide approaches to interrogate the malignant phenotype. At the DNA level, this has included approaches such as comparative genomic hybridization. At the RNA level, this has consisted of gene expression profiling using various assay methodologies. In certain instances, markers identified using these platforms have been further examined and developed using fluorescence in situ hybridization and immunohistochemical analysis. In this article, we will review recent progress in the development of novel molecular markers for melanoma that are nearing clinical application. We will review developments in the molecular classification of melanoma, in the molecular diagnosis of melanoma, and in the molecular assessment of melanoma prognosis. © 2013 British Association of Dermatologists.

  7. Molecular Population Genetics.

    Science.gov (United States)

    Casillas, Sònia; Barbadilla, Antonio

    2017-03-01

    Molecular population genetics aims to explain genetic variation and molecular evolution from population genetics principles. The field was born 50 years ago with the first measures of genetic variation in allozyme loci, continued with the nucleotide sequencing era, and is currently in the era of population genomics. During this period, molecular population genetics has been revolutionized by progress in data acquisition and theoretical developments. The conceptual elegance of the neutral theory of molecular evolution or the footprint carved by natural selection on the patterns of genetic variation are two examples of the vast number of inspiring findings of population genetics research. Since the inception of the field, Drosophila has been the prominent model species: molecular variation in populations was first described in Drosophila and most of the population genetics hypotheses were tested in Drosophila species. In this review, we describe the main concepts, methods, and landmarks of molecular population genetics, using the Drosophila model as a reference. We describe the different genetic data sets made available by advances in molecular technologies, and the theoretical developments fostered by these data. Finally, we review the results and new insights provided by the population genomics approach, and conclude by enumerating challenges and new lines of inquiry posed by increasingly large population scale sequence data. Copyright © 2017 Casillas and Barbadilla.

  8. Molecular heat pump.

    Science.gov (United States)

    Segal, Dvira; Nitzan, Abraham

    2006-02-01

    We propose a molecular device that pumps heat against a thermal gradient. The system consists of a molecular element connecting two thermal reservoirs that are characterized by different spectral properties. The pumping action is achieved by applying an external force that periodically modulates molecular levels. This modulation affects periodic oscillations of the internal temperature of the molecule and the strength of its coupling to each reservoir resulting in a net heat flow in the desired direction. The heat flow is examined in the slow and fast modulation limits and for different modulation wave forms, thus making it possible to optimize the device performance.

  9. Molecularly Imprinted Membranes

    Science.gov (United States)

    Trotta, Francesco; Biasizzo, Miriam; Caldera, Fabrizio

    2012-01-01

    Although the roots of molecularly imprinted polymers lie in the beginning of 1930s in the past century, they have had an exponential growth only 40–50 years later by the works of Wulff and especially by Mosbach. More recently, it was also proved that molecular imprinted membranes (i.e., polymer thin films) that show recognition properties at molecular level of the template molecule are used in their formation. Different procedures and potential application in separation processes and catalysis are reported. The influences of different parameters on the discrimination abilities are also discussed. PMID:24958291

  10. Emerging trends in molecular systematics and molecular phylogeny of mayflies (Insecta: Ephemeroptera

    Directory of Open Access Journals (Sweden)

    K.G. Sivaramakrishnan

    2011-08-01

    Full Text Available Current trends are reviewed in the molecular systematics and phylogeny of the Ephemeroptera (mayflies, an ancient monophyletic lineage of pterygote insects. Theories of mayfly origins are analyzed, followed by a discussion of higher classification schemes in light of recent developments in molecular systematics. Ephemeroptera evolution is a classic example of ancient rapid radiation, presenting challenges for phylogenetic analysis. The utility of combined studies of morphological and molecular data is substantiated with examples and the role of molecular systematics in unraveling the taxonomy of cryptic species complexes is highlighted. The importance of DNA barcoding in mayfly taxonomy is discussed in the light of recent progress, and future contributions of genetics to the study of taxonomy, ecology and evolution in mayflies are discussed.

  11. Tamices moleculares que combinan micro y meso porosidad: una revisión

    Directory of Open Access Journals (Sweden)

    Carmen M. López*

    2009-12-01

    Full Text Available Molecular sieves combining micro and mesoporosity: a review. A review of molecular sieves combining micro and mesoporosity is presented. A summary of different routes employed for the preparation of these solids, is showed by citing recent works reported in this subject. In order to evaluate the catalytic potential of these new solids, several catalytic studies are presented.

  12. Combine Harvester Simulator

    DEFF Research Database (Denmark)

    Vilmann, Ole; Sørlie, James Arnold

    1999-01-01

    A simulator for training pilots in the operation of a modern high-tech combine harvester is presented. The new simulator application is based on DMI´s well-known DMS maritime simulator architecture. Two major challenges have been encountered in the development of the simulator: 1) interfacing the...

  13. Liouville-von Neumann molecular dynamics.

    Science.gov (United States)

    Jakowski, Jacek; Morokuma, Keiji

    2009-06-14

    We present a novel first principles molecular dynamics scheme, called Liouville-von Neumann molecular dynamics, based on Liouville-von Neumann equation for density matrices propagation and Magnus expansion of the time-evolution operator. The scheme combines formally accurate quantum propagation of electrons represented via density matrices and a classical propagation of nuclei. The method requires a few iterations per each time step where the Fock operator is formed and von Neumann equation is integrated. The algorithm (a) is free of constraint and fictitious parameters, (b) avoids diagonalization of the Fock operator, and (c) can be used in the case of fractional occupation as in metallic systems. The algorithm is very stable, and has a very good conservation of energy even in cases when a good quality conventional Born-Oppenheimer molecular dynamics trajectories is difficult to obtain. Test simulations include initial phase of fullerene formation from gaseous C(2) and retinal system.

  14. Molecular Motors: A Theorist's Perspective

    Science.gov (United States)

    Kolomeisky, Anatoly B.; Fisher, Michael E.

    Individual molecular motors, or motor proteins, are enzymatic molecules that convert chemical energy, typically obtained from the hydrolysis of ATP (adenosine triphosphate), into mechanical work and motion. Processive motor proteins, such as kinesin, dynein, and certain myosins, step unidirectionally along linear tracks, specifically microtubules and actin filaments, and play a crucial role in cellular transport processes, organization, and function. In this review some theoretical aspects of motor-protein dynamics are presented in the light of current experimental methods that enable the measurement of the biochemical and biomechanical properties on a single-molecule basis. After a brief discussion of continuum ratchet concepts, we focus on discrete kinetic and stochastic models that yield predictions for the mean velocity, V(F, [ATP],…), and other observables as a function of an imposed load force F, the ATP concentration, and other variables. The combination of appropriate theory with single-molecule observations should help uncover the mechanisms underlying motor-protein function.

  15. Atomic & Molecular Interactions

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-07-12

    The Gordon Research Conference (GRC) on Atomic & Molecular Interactions was held at Roger Williams University, Bristol, RI. Emphasis was placed on current unpublished research and discussion of the future target areas in this field.

  16. Appendix II. Molecular Analysis

    Science.gov (United States)

    The study of crop evolution, origins, and conservation entails the assessment of genetic variability with and between populations and species at different genetic, evolutionary, and taxonomic hierarchical levels. Molecular biology has greatly increased the amount of data and computational intensity...

  17. Natural Product Molecular Fossils.

    Science.gov (United States)

    Falk, Heinz; Wolkenstein, Klaus

    The natural products synthesized by organisms that were living a long time ago gave rise to their molecular fossils. These can consist of either the original unchanged compounds or they may undergo peripheral transformations in which their skeletons remain intact. In cases when molecular fossils can be traced to their organismic source, they are termed "geological biomarkers".This contribution describes apolar and polar molecular fossils and, in particular biomarkers, along the lines usually followed in organic chemistry textbooks, and points to their bioprecursors when available. Thus, the apolar compounds are divided in linear and branched alkanes followed by alicyclic compounds and aromatic and heterocyclic molecules, and, in particular, the geoporphyrins. The polar molecular fossils contain as functional groups or constituent units ethers, alcohols, phenols, carbonyl groups, flavonoids, quinones, and acids, or are polymers like kerogen, amber, melanin, proteins, or nucleic acids. The final sections discuss the methodology used and the fundamental processes encountered by the biomolecules described, including diagenesis, catagenesis, and metagenesis.

  18. Molecular Machines: Nanoscale gadgets

    Science.gov (United States)

    Garcia-Garibay, Miguel A.

    2008-06-01

    Meeting their biological counterparts halfway, artificial molecular machines embedded in liquid crystals, crystalline solids and mesoporous materials are poised to meet the demands of the next generation of functional materials.

  19. Are there molecular signatures?

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, W.P.

    1995-10-01

    This report describes molecular signatures and mutational spectrum analysis. The mutation spectrum is defined as the type and location of DNA base change. There are currently about five well documented cases. Mutations and radon-associated tumors are discussed.

  20. The Molecular Foundry (TMF)

    Data.gov (United States)

    Federal Laboratory Consortium — Founded in 2006 by the Department of Energy (DOE), the Molecular Foundry is a critical part of the DOE's National Nanotechnology Initiative, a multi-agency framework...

  1. Open quantum system parameters from molecular dynamics

    CERN Document Server

    Wang, Xiaoqing; Wüster, Sebastian; Eisfeld, Alexander

    2015-01-01

    We extract the site energies and spectral densities of the Fenna-Matthews-Olson (FMO) pigment protein complex of green sulphur bacteria from simulations of molecular dynamics combined with energy gap calculations. Comparing four different combinations of methods, we investigate the origin of quantitative differences regarding site energies and spectral densities obtained previously in the literature. We find that different forcefields for molecular dynamics and varying local energy minima found by the structure relaxation yield significantly different results. Nevertheless, a picture averaged over these variations is in good agreement with experiments and some other theory results. Throughout, we discuss how vibrations external- or internal to the pigment molecules enter the extracted quantities differently and can be distinguished. Our results offer some guidance to set up more computationally intensive calculations for a precise determination of spectral densities in the future. These are required to determ...

  2. Alcohol dependence: molecular and behavioral evidence

    Science.gov (United States)

    Trudell, James R.; Messing, Robert O.; Mayfield, Jody; Harris, R. Adron

    2014-01-01

    Alcohol dependence is a complex condition with clear genetic factors. Some of the leading candidate genes code for subunits of the inhibitory GABAA and glycine receptors. These and related ion channels are also targets for the acute actions of alcohol, and there is considerable progress in understanding interactions of alcohol with these proteins at the molecular and even atomic levels. X-ray structures of open and closed states of ion channels combined with structural modeling and site-directed mutagenesis have elucidated direct actions of alcohol. Alcohol also alters channel function by translational and post-translational mechanisms, including phosphorylation and protein trafficking. Construction of mutant mice with either deletion of key proteins or introduction of alcohol-resistant channels has further linked specific proteins with discrete behavioral effects of alcohol. A combination of approaches, including genome wide association studies in humans, continues to advance the molecular basis of alcohol action on receptor structure and function. PMID:24865944

  3. Molecular Typing of Borrelia burgdorferi

    Science.gov (United States)

    Wang, Guiqing; Liveris, Dionysios; Mukherjee, Priyanka; Jungnick, Sabrina; Margos, Gabriele; Schwartz, Ira

    2015-01-01

    Borrelia burgdorferi sensu lato is a group of spirochetes belonging to the genus Borrelia in the family of Spirochaetaceae. The spirochete is transmitted between reservoirs and hosts by ticks of the family Ixodidae. Infection with B. burgdorferi in humans causes Lyme disease or Lyme borreliosis. Currently, 20 Lyme disease-associated Borrelia species and more than 20 relapsing fever-associated Borrelia species have been described. Identification and differentiation of different Borrelia species and strains is largely dependent on analyses of their genetic characteristics. A variety of molecular techniques have been described for Borrelia isolate speciation, molecular epidemiology, and pathogenicity studies. In this unit, we focus on three basic protocols, PCR-RFLP-based typing of the rrs-rrlA and rrfA-rrlB ribosomal spacer, ospC typing, and MLST. These protocols can be employed alone or in combination for characterization of B. burgdorferi isolates or directly on uncultivated organisms in ticks, mammalian host reservoirs, and human clinical specimens. PMID:25082003

  4. Human papillomavirus molecular biology.

    Science.gov (United States)

    Harden, Mallory E; Munger, Karl

    Human papillomaviruses are small DNA viruses with a tropism for squamous epithelia. A unique aspect of human papillomavirus molecular biology involves dependence on the differentiation status of the host epithelial cell to complete the viral lifecycle. A small group of these viruses are the etiologic agents of several types of human cancers, including oral and anogenital tract carcinomas. This review focuses on the basic molecular biology of human papillomaviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Molecular electronic junction transport

    DEFF Research Database (Denmark)

    Solomon, Gemma C.; Herrmann, Carmen; Ratner, Mark

    2012-01-01

    Whenasinglemolecule,oracollectionofmolecules,isplacedbetween two electrodes and voltage is applied, one has a molecular transport junction. We discuss such junctions, their properties, their description, and some of their applications. The discussion is qualitative rather than quantitative......, and focuses on mechanism, structure/function relations, regimes and mechanisms of transport, some molecular regularities, and some substantial challenges facing the field. Because there are many regimes and mechanisms in transport junctions, we will discuss time scales, geometries, and inelastic scattering...

  6. Charge Transport Processes in Molecular Junctions

    Science.gov (United States)

    Smith, Christopher Eugene

    Molecular electronics (ME) has evolved into a rich area of exploration that combines the fields of chemistry, materials, electronic engineering and computational modeling to explore the physics behind electronic conduction at the molecular level. Through studying charge transport properties of single molecules and nanoscale molecular materials the field has gained the potential to bring about new avenues for the miniaturization of electrical components where quantum phenomena are utilized to achieve solid state molecular device functionality. Molecular junctions are platforms that enable these studies and consist of a single molecule or a small group of molecules directly connected to electrodes. The work presented in this thesis has built upon the current understanding of the mechanisms of charge transport in ordered junctions using self-assembled monolayer (SAM) molecular thin films. Donor and acceptor compounds were synthesized and incorporated into SAMs grown on metal substrates then the transport properties were measured with conducting probe atomic force microscopy (CP-AFM). In addition to experimentally measured current-voltage (I-V) curves, the transport properties were addressed computationally and modeled theoretically. The key objectives of this project were to 1) investigate the impact of molecular structure on hole and electron charge transport, 2) understand the nature of the charge carriers and their structure-transport properties through long (electronic coupling from experimental I-V curves. Here, we lay ground work for creating a more complete picture of charge transport in macroscopically ordered molecular junctions of controlled architecture, length and charge carrier. The polaronic nature of hopping transport has been predicted in long, conjugated molecular wires. Using quantum-based calculations, we modeled 'p-type' polaron transport through oligophenylenethiophene (OPTI) wires and assigned transport activation energies to specific modes of

  7. Molecular toxicity of nanomaterials.

    Science.gov (United States)

    Chang, Xue-Ling; Yang, Sheng-Tao; Xing, Gengmei

    2014-10-01

    With the rapid developments in the fields of nanoscience and nanotechnlogy, more and more nanomaterials and their based consumer products have been used into our daily life. The safety concerns of nanomaterials have been well recognized by the scientific community and the public. Molecular mechanism of interactions between nanomaterials and biosystems is the most essential topic and final core of the biosafety. In the last two decades, nanotoxicology developed very fast and toxicity phenomena of nanomaterials have been reported. To achieve better understanding and detoxication of nanomaterials, thorough studies of nanotoxicity at molecular level are important. The interactions between nanomaterials and biomolecules have been widely investigated as the first step toward the molecular nanotoxicology. The consequences of such interactions have been discussed in the literature. Besides this, the chemical mechanism of nanotoxicology is gaining more attention, which would lead to a better design of nontoxic nanomaterials. In this review, we focus on the molecular nanotoxicology and explore the toxicity of nanomaterials at molecular level. The molecular level studies of nanotoxicology are summarized and the published nanotoxicological data are revisited.