Collision-Induced Effects on the Dielectric Properties of Liquid Dimethylsulfoxide

We present a molecular dynamics (MD) simulation study of the dielectric properties of liquid dimethyl sulfoxide that includes interaction-induced effects due to molecular polarizability using a perturbative scheme in which the induced dipoles are computed a posteriori from the MD trajectories generated without explicit inductive forces. Static and dynamical quantities of relevance to the dielectric characterization of the liquid are reported for both polarizable and nonpolarizable versions of the system's collective dipolar densities. Our analysis within this scheme indicates that the role of the interaction induced contributions is predominantly to renormalize the magnitude of the permanent dipole fluctuations, with marginal effects upon the system's dielectric relaxation in the rotational-diffusion, microwave region of the spectrum. At higher frequencies, however, where the dielectric absorption is dominated by fast intermolecular librational motions, the dynamical effects of the molecular polarizability are more pronounced. In the presence of interaction induced contributions, the location of the peak in the MD far infrared absorption coefficient is in much better agreement with recent spectroscopic measurements of the intermolecular dynamics of this liquid.É apresentado um estudo por simulação de dinâmica molecular das propriedades dielétricas do dimetil sulfóxido líquido, onde são incluídos efeitos de indução devido à polarizabilidade molecular através de perturbação em primeira ordem. Neste formalismo, os dipolos induzidos são computados a partir de trajetórias geradas pelos potenciais intermoleculares isentos de forças indutivas. Propriedades dielétricas estáticas e dinâmicas são computadas para as versões polarizável e não-polarizável da densidade dipolar. As análises indicam que o principal papel das componentes de indução nesta abordagem é o de renormalizar o valor das flutuações estáticas dos dipolos permanentes, sendo apenas marginal a influência sobre as propriedades de relaxação no regime de difusão rotacional que caracteriza o espectro na região de micro-ondas. Entretanto, para maiores frequências, onde a absorção dielétrica é predominantemente determinada por movimentos intermoleculares libracionais, os efeitos dinâmicos da polarizabilidade molecular são mais aparentes. Na presença de contribuições indutivas, o máximo do espectro infravermelho obtido das simulações está em melhor concordância com recentes medidas espectroscópicas da dinâmica intermolecular deste líquido.583591Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Microrna profiling analysis of differences between the melanoma of young adults and older adults

<p>Abstract</p> <p>Background</p> <p>This study represents the first attempt to perform a profiling analysis of the intergenerational differences in the microRNAs (miRNAs) of primary cutaneous melanocytic neoplasms in young adult and older age groups. The data emphasize the importance of these master regulators in the transcriptional machinery of melanocytic neoplasms and suggest that differential levels of expressions of these miRs may contribute to differences in phenotypic and pathologic presentation of melanocytic neoplasms at different ages.</p> <p>Methods</p> <p>An exploratory miRNA analysis of 666 miRs by low density microRNA arrays was conducted on formalin fixed and paraffin embedded tissues (FFPE) from 10 older adults and 10 young adults including conventional melanoma and melanocytic neoplasms of uncertain biological significance. Age-matched benign melanocytic nevi were used as controls.</p> <p>Results</p> <p>Primary melanoma in patients greater than 60 years old was characterized by the increased expression of miRs regulating TLR-MyD88-NF-kappaB pathway (hsa-miR-199a), RAS/RAB22A pathway (hsa-miR-204); growth differentiation and migration (hsa-miR337), epithelial mesenchymal transition (EMT) (let-7b, hsa-miR-10b/10b*), invasion and metastasis (hsa-miR-10b/10b*), hsa-miR-30a/e*, hsa-miR-29c*; cellular matrix components (hsa-miR-29c*); invasion-cytokinesis (hsa-miR-99b*) compared to melanoma of younger patients. MiR-211 was dramatically downregulated compared to nevi controls, decreased with increasing age and was among the miRs linked to metastatic processes. Melanoma in young adult patients had increased expression of hsa-miR-449a and decreased expression of hsa-miR-146b, hsa-miR-214*. MiR-30a* in clinical stages I-II adult and pediatric melanoma could predict classification of melanoma tissue in the two extremes of age groups. Although the number of cases is small, positive lymph node status in the two age groups was characterized by the statistically significant expression of hsa-miR-30a* and hsa-miR-204 (F-test, p-value < 0.001).</p> <p>Conclusions</p> <p>Our findings, although preliminary, support the notion that the differential biology of melanoma at the extremes of age is driven, in part, by deregulation of microRNA expression and by fine tuning of miRs that are already known to regulate cell cycle, inflammation, Epithelial-Mesenchymal Transition (EMT)/stroma and more specifically genes known to be altered in melanoma. Our analysis reveals that miR expression differences create unique patterns of frequently affected biological processes that clearly distinguish old age from young age melanomas. This is a novel characterization of the miRnomes of melanocytic neoplasms at two extremes of age and identifies potential diagnostic and clinico-pathologic biomarkers that may serve as novel miR-based targeted modalities in melanoma diagnosis and treatment.</p

Effect of Age and Lordotic Angle on the Level of Lumbar Disc Herniation

It has been previously suggested in the literature that with aging, degenerative changes as well as disc herniation start at the lower lumbar segments, with higher disc involvement observed in an ascending fashion in older age groups. We conducted a study to investigate this correlation between age and level of disc herniation, and to associate it with the magnitude of the Lumbar Lordotic Angle (LLA), as measured by Cobb's method. We followed retrospectively lumbosacral spine MRI's of 1419 patients with symptomatic disc herniation. Pearson's correlation was used in order to investigate the relationship between LLA, age, and level of disc herniation. Student's t-test was applied to assess gender differences. Young patients were found to have higher LLA (R = 0.44, P < 0.0001) and lower levels of disc herniation (R = 0.302, P < 0.0001), whereas older patients had higher level herniation in lower LLA group (mean LLA 28.6° and 25.4°) and lower level herniation in high LLA group (mean LLA 33.2°). We concluded that Lumbar lordotic Cobb's angle and age can be predictors of the level of lumbar disc herniation. This did not differ among men and women (R = 0.341, P < 0.0001)

A review on the dynamics of water

We present a review on the intermolecular dynamics of liquid aqueous systems focusing mainly on Molecular Dynamics simulation work that has been carried out at the State University of Campinas in recent years. Emphasis is given on simulation results that are more directly related to modern experimental spectroscopic measurements.316Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Electrical stimulation devices for the prevention of venous thromboembolism: Preliminary studies of physiological efficacy and user satisfaction.

Introduction: Electrical stimulation could provide an alternative method for preventing venous thromboembolism in stroke patients. The purpose of this preliminary study was to explore the effects of electrical stimulation and intermittent pneumatic compression on enhancing lower limb venous return in healthy and chronic stroke patients and also to evaluate patient and nurse satisfaction. Methods: We investigated the effectiveness of two electrical stimulation devices: Geko (Firstkind Ltd, High Wycombe, UK) and Orthopaedic Microstim 2V2 (Odstock Medical Ltd, Salisbury, UK); and one intermittent pneumatic compression device: Huntleigh Flowstron Universal (Huntleigh Healthcare Ltd, Cardiff, UK). We recruited 12 healthy and 5 chronic stroke participants. The devices were fitted sequentially, and Doppler ultrasound measurements were taken. Eight patients and nurses were also recruited for a separate usability evaluation. Results: The electrical stimulation devices emulated the blood flow characteristics of intermittent pneumatic compression in both healthy and stroke participants provided that the intensity of electrical stimulation was sufficient. Patients and nurses also felt that the electrical stimulation devices were acceptable. Conclusions: Electrical stimulation may offer benefit as an alternative method for venous thromboembolism prevention in stroke patients. The apparent benefit is sufficient to warrant further investigation in a full powered randomised controlled trial

Partial integration and local mean-field approach for a vector lattice model of microemulsions

A vector model on the simple cubic lattice, describing a mixture of water, oil, and amphiphile, is considered. An integration over the amphiphile orientational degrees of freedom is performed exactly in order to obtain an effective Hamiltonian for the system. The resulting model is a three-state (spin-1) system and contains many-site interaction terms. The analysis of the ground state reveals the presence of the water-oil-rich phase as well as the amphiphile-rich and the cubic phases. The temperature phase diagram of the system is analyzed in a local mean-field approach, and a triple line of water-rich, oil-rich, and microemulsion coexistence is obtained. For some values of the model parameters, lamellar phases also appear in the system, but only at finite temperature. The Lifshitz line is determined in a semianalytical way in order to locate the microemulsion region of the disordered phase

Structure, computational and biochemical analysis of PcCel45A endoglucanase from <i>Phanerochaete chrysosporium </i>and catalytic mechanisms of GH45 subfamily C members

Abstract The glycoside hydrolase family 45 (GH45) of carbohydrate modifying enzymes is mostly comprised of β-1,4-endoglucanases. Significant diversity between the GH45 members has prompted the division of this family into three subfamilies: A, B and C, which may differ in terms of the mechanism, general architecture, substrate binding and cleavage. Here, we use a combination of X-ray crystallography, bioinformatics, enzymatic assays, molecular dynamics simulations and site-directed mutagenesis experiments to characterize the structure, substrate binding and enzymatic specificity of the GH45 subfamily C endoglucanase from Phanerochaete chrysosporium (PcCel45A). We investigated the role played by different residues in the binding of the enzyme to cellulose oligomers of different lengths and examined the structural characteristics and dynamics of PcCel45A that make subfamily C so dissimilar to other members of the GH45 family. Due to the structural similarity shared between PcCel45A and domain I of expansins, comparative analysis of their substrate binding was also carried out. Our bioinformatics sequence analyses revealed that the hydrolysis mechanisms in GH45 subfamily C is not restricted to use of the imidic asparagine as a general base in the “Newton’s cradle” catalytic mechanism recently proposed for this subfamily

Structure, computational and biochemical analysis of PcCel45A endoglucanase from phanerochaete chrysosporium and catalytic mechanisms of GH45 subfamily C members

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORThe glycoside hydrolase family 45 (GH45) of carbohydrate modifying enzymes is mostly comprised of β-1,4-endoglucanases. Significant diversity between the GH45 members has prompted the division of this family into three subfamilies: A, B and C, which may d8FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR10/52362-511/20505-411/21608-115/13684-0405191/2015-4303988/2016-9440977/2016-9sem informaçãoThe PcCel45A dataset was collected at the Brookhaven National Laboratory, during the RapiData course. This study was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) via grants 10/52362-5, 11/20505-4, 11/21608-1 and 15/13684

A promiscuous cytochrome P450 aromatic O-demethylase for lignin bioconversion

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOMicrobial aromatic catabolism offers a promising approach to convert lignin, a vast source of renewable carbon, into useful products. Aryl-O-demethylation is an essential biochemical reaction to ultimately catabolize coniferyl and sinapyl lignin-derived a9FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO2013/08293-72014/10448-12016/22956-7We acknowledge funding from NSF grants to J.L.D. (MCB-1715176), K.N.H. (CHE-1361104), and E.L.N. (DEB-1556541 and MCB-1615365) and BBSRC grants to J.E.M. (BB/P011918/1, BB/L001926/1 and a studentship to S.J.B.M.). G.T.B., M.M.M., C.W.J., M.F.C., E.L.N.,

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms

Background: Thyroid receptors, TRα and TRβ, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TRβ isoform activation, TRα activation affects heart rates. Therefore, β-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin (Lipitor©) in studies in rats, mice and monkeys. Results: To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRα Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TRβ. The corresponding Arg282 of TRβ is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TRα, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TRβ, in which it strongly interacts with both GC-1 and the Asn331. Conclusion: Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T3. These results shed light into the β-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity