- Probing the binding mechanism of capecitabine to human serum albumin using spectrometric methods, molecular modeling, and chemometrics approach. [Journal Article]
- BCBioorg Chem 2019 Jun 08; 90:103037
- Capecitabine as a prodrug of 5-Fluorouracil plays an important role in the treatment of breast and gastrointestinal cancers. Herein, in view of the importance of this drug in chemotherapy, interactio…
Capecitabine as a prodrug of 5-Fluorouracil plays an important role in the treatment of breast and gastrointestinal cancers. Herein, in view of the importance of this drug in chemotherapy, interaction mechanism between Capecitabine (CAP) and human serum albumin (HSA) as a major transport protein in the blood circulatory system has been investigated by using a combination of spectroscopic and molecular modeling methods. The fluorescence spectroscopic results revealed that capecitabine could effectively quench the intrinsic fluorescence of HSA through a static quenching mechanism. Evaluation of the thermodynamic parameters suggested that the binding process was spontaneous while hydrogen bonds and van der Waals forces played a major role in this interaction. The value of the binding constant (Kb = 1.820 × 104) suggested a moderate binding affinity between CAP and HSA which implies its easy diffusion from the circulatory system to the target tissue. The efficiency of energy transfer and the binding distance between the donor (HSA) and acceptor (CAP) were determined according to forster theory of nonradiation energy transfer as 0.410 and 4.135 nm, respectively. Furthermore, UV-Vis spectroscopic results confirmed that the interaction was occurred between HSA and CAP and caused conformational and micro-environmental changes of HSA during the interaction. Multivariate curve resolution-alternating least square (MCR-ALS) methodology as an efficient chemometric tool was used to separate the overlapped spectra of the species. The MCR-ALS result was exploited to estimate the stoichiometry of interaction and to provide concentration and structural information about HSA-CAP interactions. Molecular docking studies suggested that CAP binds mainly to the subdomain IIA of HSA, which were compatible with those obtained by experimental data. Finally, molecular dynamics simulation (MD) was performed on the best docked complex by considering the permanence and flexibility of HSA-CAP complex in the binding site. MD result showed that CAP could steadily bind to HSA in the site I based on the formation of hydrogen bond and π-π stacking interaction in addition to hydrophobic force.
- Hierarchical Bayesian inference for concurrent model fitting and comparison for group studies. [Journal Article]
- PCPLoS Comput Biol 2019; 15(6):e1007043
- Computational modeling plays an important role in modern neuroscience research. Much previous research has relied on statistical methods, separately, to address two problems that are actually interde…
Computational modeling plays an important role in modern neuroscience research. Much previous research has relied on statistical methods, separately, to address two problems that are actually interdependent. First, given a particular computational model, Bayesian hierarchical techniques have been used to estimate individual variation in parameters over a population of subjects, leveraging their population-level distributions. Second, candidate models are themselves compared, and individual variation in the expressed model estimated, according to the fits of the models to each subject. The interdependence between these two problems arises because the relevant population for estimating parameters of a model depends on which other subjects express the model. Here, we propose a hierarchical Bayesian inference (HBI) framework for concurrent model comparison, parameter estimation and inference at the population level, combining previous approaches. We show that this framework has important advantages for both parameter estimation and model comparison theoretically and experimentally. The parameters estimated by the HBI show smaller errors compared to other methods. Model comparison by HBI is robust against outliers and is not biased towards overly simplistic models. Furthermore, the fully Bayesian approach of our theory enables researchers to make inference on group-level parameters by performing HBI t-test.
- Further psychometric analysis of the 20-item Partner Interaction Questionnaire in an adult sample of smokers. [Journal Article]
- PAPsychol Addict Behav 2019 Jun 13
- The 20-item Partner Interaction Questionnaire (PIQ-20) is frequently used to assess social support for adults wanting to stop smoking. Given that social support may play a significant role in quittin…
The 20-item Partner Interaction Questionnaire (PIQ-20) is frequently used to assess social support for adults wanting to stop smoking. Given that social support may play a significant role in quitting success, there is a need to understand the structure and psychometric properties of assessment instruments designed to measure the construct of partner support. The current study examined the psychometric properties of the PIQ-20 when used to assess the frequency of partner behaviors. The study participants included 380 adult volunteers (M age = 41 years, SD = 12; 58% male). To assess internal consistency, we used both the traditional coefficient-alpha and the latent variable modeling composite reliability (coefficient-ρ) procedures. We conducted independent factor analytic methods to address issues of dimensionality and scoring of responses to the PIQ-20 items. Also, we used an item response theory modeling procedure to examine the specificity of scores on the items. Reliability estimates for the PIQ-20 subscale scores were adequate (values ≥.70). The bifactor analysis supported deriving a total score for each subscale. Item response theory modeling demonstrated that the discrimination (a-slope) parameter for each subscale item was significantly different from zero. The majority of items were associated strongly with their respective subscales. Twelve items were identified that could be adopted as a potential short form of the PIQ-20. The PIQ-20 or short form provides an opportunity for assessing positive and negative partner support simultaneously. There is empirical support for the dimensional structures and scoring of responses for both versions of the instrument. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
- Theory and practice of modeling van der Waals interactions in electronic-structure calculations. [Review]
- CSChem Soc Rev 2019 Jun 13
- The accurate description of long-range electron correlation, most prominently including van der Waals (vdW) dispersion interactions, represents a particularly challenging task in the modeling of mole…
The accurate description of long-range electron correlation, most prominently including van der Waals (vdW) dispersion interactions, represents a particularly challenging task in the modeling of molecules and materials. vdW forces arise from the interaction of quantum-mechanical fluctuations in the electronic charge density. Within (semi-)local density functional approximations or Hartree-Fock theory such interactions are neglected altogether. Non-covalent vdW interactions, however, are ubiquitous in nature and play a key role for the understanding and accurate description of the stability, dynamics, structure, and response properties in a plethora of systems. During the last decade, many promising methods have been developed for modeling vdW interactions in electronic-structure calculations. These methods include vdW-inclusive Density Functional Theory and correlated post-Hartree-Fock approaches. Here, we focus on the methods within the framework of Density Functional Theory, including non-local van der Waals density functionals, interatomic dispersion models within many-body and pairwise formulation, and random phase approximation-based approaches. This review aims to guide the reader through the theoretical foundations of these methods in a tutorial-style manner and, in particular, highlight practical aspects such as the applicability and the advantages and shortcomings of current vdW-inclusive approaches. In addition, we give an overview of complementary experimental approaches, and discuss tools for the qualitative understanding of non-covalent interactions as well as energy decomposition techniques. Besides representing a reference for the current state-of-the-art, this work is thus also designed as a concise and detailed introduction to vdW-inclusive electronic structure calculations for a general and broad audience.
- Pediatric Perceived Cognitive Functioning: Psychometric Properties and Normative Data of the Dutch Item Bank and Short Form. [Journal Article]
- JIJ Int Neuropsychol Soc 2019 Jun 10; :1-12
- CONCLUSIONS: In this first study of the PedsPCF outside the United States, studied psychometric properties of the translated PedsPCF were satisfactory, and allowed for IRT modeling. Based on the IRT analyses and the content of items, we proposed a new 10-item short form. Further research should determine the relation of PedsPCF outcomes with neurocognitive measures and its ability to facilitate neuropsychological screening in clinical practice.
- Adsorption and insertion of polyarginine peptides into membrane pores: The trade-off between electrostatics, acid-base chemistry and pore formation energy. [Journal Article]
- JCJ Colloid Interface Sci 2019 May 30; 552:701-711
- The mechanism that arginine-rich cell penetrating peptides (ARCPPs) use to translocate lipid membranes is not entirely understood. In the present work, we develop a molecular theory that allows to in…
The mechanism that arginine-rich cell penetrating peptides (ARCPPs) use to translocate lipid membranes is not entirely understood. In the present work, we develop a molecular theory that allows to investigate the adsorption and insertion of ARCPPs on membranes bearing hydrophilic pores. This method accounts for size, shape, conformation, protonation state and charge distribution of the peptides; it also describes the state of protonation of acidic membrane lipids. We present a systematic investigation of the effect of pore size, peptide concentration and sequence length on the extent of peptide adsorption and insertion into the pores. We show that adsorption on the intact (non-porated) lipid membrane plays a key role on peptide translocation. For peptides shorter than nona-arginine, adsorption on the intact membrane increases significantly with chain length, but it saturates for longer peptides. However, this adsorption behavior only occurs at relatively low peptide concentrations; increasing peptide concentration favors adsorption of the shorter molecules. Adsorption of longer peptides increases the intact membrane negative charge as a result of further deprotonation of acidic lipids. Peptide insertion into the pores depends non-monotonically on pore radius, which reflects the short range nature of the effective membrane-peptide interactions. The size of the pore that promotes maximum adsorption depends on the peptide chain length. Peptide translocation is a thermally activated process, so we complement our thermodynamic approach with a simple kinetic model that allows to rationalize the ARCPPs translocation rate in terms of the free energy gain of adsorption, and the energy cost of creating a transmembrane pore with peptides in it. Our results indicate that strategies to improve translocation efficiency should focus on enhancing peptide adsorption.
- Quantum thermodynamics and open-systems modeling. [Journal Article]
- JCJ Chem Phys 2019 May 28; 150(20):204105
- A comprehensive approach to modeling open quantum systems consistent with thermodynamics is presented. The theory of open quantum systems is employed to define system bath partitions. The Markovian m…
A comprehensive approach to modeling open quantum systems consistent with thermodynamics is presented. The theory of open quantum systems is employed to define system bath partitions. The Markovian master equation defines an isothermal partition between the system and bath. Two methods to derive the quantum master equation are described: the weak coupling limit and the repeated collision model. The role of the eigenoperators of the free system dynamics is highlighted, in particular, for driven systems. The thermodynamical relations are pointed out. Models that lead to loss of coherence, i.e., dephasing are described. The implication of the laws of thermodynamics to simulating transport and spectroscopy is described. The indications for self-averaging in large quantum systems and thus its importance in modeling are described. Basic modeling by the surrogate Hamiltonian is described, as well as thermal boundary conditions using the repeated collision model and their use in the stochastic surrogate Hamiltonian. The problem of modeling with explicitly time dependent driving is analyzed. Finally, the use of the stochastic surrogate Hamiltonian for modeling ultrafast spectroscopy and quantum control is reviewed.
- Far Red Fluorescent Proteins: Where is the Limit of the Acylimine Chromophore? [Journal Article]
- JCJ Chem Theory Comput 2019 May 30
- The search for new near-infrared probes for fluorescence imaging applications is a rapidly growing field of research. Monomeric fluorescent proteins that autocatalyse their chromophore are the most v…
The search for new near-infrared probes for fluorescence imaging applications is a rapidly growing field of research. Monomeric fluorescent proteins that autocatalyse their chromophore are the most versatile markers for in-vivo applications, but the development of bright far-red fluorescent proteins (RFPs) has proven difficult. In this contribution, we search for the theoretical limit of the red shift and how it can be reached without sacrificing the fluorescence quantum yield. Through extensive excited-state pathway calculations, molecular dynamics sampling and statistical modeling using QM/MM schemes, we provide a new understanding of the chromophore's photophysics including the role of its acylimine extension, which is the main difference from other families of fluorescent proteins. The excited-state dynamics of the mPlum RFP and its mutants provide an ideal basis due to mPlum's flexible binding pocket and extended dynamic Stokes shift. We found a large number of structural species with red-shifted emission that differ in rotamer states and H-bonds between key amino acid residues in the binding pocket. By analysing their spectral and structural features, we derive guidelines for future rational genetic design strategies.
- Incorporating content related to value and cost-considerations in clinical decision-making: enhancements to medical education. [Journal Article]
- AHAdv Health Sci Educ Theory Pract 2019 May 29
- Although incorporating cost-considerations during healthcare decision-making is increasingly important to American patients and physicians, content related to these constructs is not routinely includ…
Although incorporating cost-considerations during healthcare decision-making is increasingly important to American patients and physicians, content related to these constructs is not routinely included in medical education. As a result, physicians are ill-equipped to consider costs. This study sought input from practicing physicians on perceived deficiencies in current teaching and recommendations for necessary content to include in medical teaching. We conducted a qualitative descriptive study using semi-structured interviews utilizing a purposeful maximum variation sample of cardiologists and neonatologists practicing in diverse settings. We analyzed interviews using conventional content analysis. 18 cardiologists and 17 neonatologists participated in this study. Respondents perceived that current teaching does not impart sufficient knowledge of value and cost considerations to achieve patient-centered, high-value decision-making. They identified the following priority areas for education related to healthcare costs: the business of medicine and information about out-of-pocket patient costs, training in health research interpretation skills to critically appraise evidence, and communication skills to engage patients as partners in shared decision-making. Participants recommended a variety of teaching methods, including didactic sessions on core topics, role modeling and case studies. American physicians perceive learning needs related to the incorporation of costs into clinical decision-making that can inform curriculum development initiatives in this field. Physicians perceive knowledge of these topics and skills to be crucial to achieving patient-centered high-value care. Concomitant health system reforms supporting the needs of the patient at its center are essential to enable physicians to focus on a patient-centered approach to healthcare delivery.
New Search Next
- What Drives the Trickle-Down Effect of Calling Orientation From Supervisors to Subordinates? The Perspective of Social Learning Theory. [Journal Article]
- FPFront Psychol 2019; 10:905
- Despite an increase in research on calling orientation, few studies have investigated its antecedents. Drawing on social learning theory, we hypothesized that subordinates' perceptions of their super…
Despite an increase in research on calling orientation, few studies have investigated its antecedents. Drawing on social learning theory, we hypothesized that subordinates' perceptions of their supervisor's role modeling mediate the relationship between supervisor's and subordinates' calling orientations. Supervisor's organizational status is supposed to augment the trickle-down process for calling orientation. We used multilevel modeling to test these hypotheses in a sample of 738 subordinates nested in 77 work teams in Chinese firm. We found that supervisor's calling orientation was positively related to subordinate's calling orientation and that the relationship was fully mediated by subordinates' perceptions of role modeling. Additionally, the relationship between supervisor's calling orientation and subordinates' calling orientation via role modeling was moderated by supervisor's organizational status at the second stage.