Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems

A dynamical approach to nonequilibrium molecular dynamics (D-NEMD), proposed in the 1970s by Ciccotti et al., is undergoing a renaissance and is having increasing impact in the study of biological macromolecules. This D-NEMD approach, combining MD simulations in stationary (in particular, equilibrium) and nonequilibrium conditions, allows for the determination of the time-dependent structural response of a system using the Kubo–Onsager relation. Besides providing a detailed picture of the system’s dynamic structural response to an external perturbation, this approach also has the advantage that the statistical significance of the response can be assessed. The D-NEMD approach has been used recently to identify a general mechanism of inter-domain signal propagation in nicotinic acetylcholine receptors, and allosteric effects in \upbeta -lactamase enzymes, for example. It complements equilibrium MD and is a very promising approach to identifying and analysing allosteric effects. Here, we review the D-NEMD approach and its application to biomolecular systems, including transporters, receptors, and enzymes

Usefulness of Liver and Spleen Acoustic Radiation Force Impulse (ARFI) for the evaluation of cirrhotic patients

Objective: To evaluate the correlation between ARFI and Child-Pugh classification. Secondary Aims: 1) To compare ARFI values (hepatic, splenic and spleno-hepatic index) from cirrhotic to normal population; 2) To correlate biochemical parameters of liver function and ARFI. Materials and Methods: 58 cirrhotic patients (referenced to US for surveillance or to clarify any hepatic decompensation) were included in this prospective study, as well as 38 healthy subjects who underwent ultrasonography for other reasons than hepatic evaluation. All had ARFI liver and spleen evaluation on ACUSON S2000 ARFI equipment. The best cut-off liver and spleen values for the diagnosis of cirrhosis in comparison to the normal subjects were determined using SPSS® v20. Results: Mean liver ARFI values in controls and cirrhotic patients were respectively 1.18 ± 0.22 m/s and 2.93 ± 0.50 m/s. The ROC curve demonstrated an AUC 0.998 and the best cut-off was 1.89. Mean spleen ARFI values in controls and cirrhotic patients were respectively 2.60 ± 0.42 m/s and 3.03 ± 0.71. The ROC curve demonstrated an AUC 0.766 and the best cut-off was 2.73 m/s. The splenohepatic index showed a worse AUC than ARFI liver. A weak correlation was found between the ARFI liver and Child-Pugh. We found no statistically significant differences for spleen ARFI values and Child-Pugh. We found a statistically significant correlation between liver ARFI and bilirubin, ALKP, GGT, AST and AST/ALT ratio; and with spleen ARFI and ALKP and AST/ALT ratio. Conclusion: We showed that there is a tendency of higher levels of liver ARFI values for higher Child-Pugh classification suggesting a definite trend for higher values with more severe disease

Formulações de hidrogel de dextrino para a regeneração de defeitos ósseos e não-uniões de fraturas

National Patent (INPI)A presente invenção consiste em formulações, à base de hidrogel de dextrino, que servem de matriz de suporte e veículo de substituto ósseos granulares para regeneração óssea. especificamente, esta invenção consiste em hidrogéis injetáveis e biorreabsorvíveis, de preparação in situ, os quais atuam como um suporte tridimensional (scaffold) para a colonização celular. a referida formulação contem granulados bioativos osteogénicos (cerâmicos bioativos) à base de fosfatos de cálcio, hidroxiapatite ou mistura de ambos, que atuam como agentes osteocondutores, permitindo assim o crescimento e regeneração tecidual óssea, funcionando a conjugação hidrogel-cerâmico como um substituto ósseo injetável.info:eu-repo/semantics/publishedVersio

Synchrotron X-ray studies on polyamide composites prepared by reactive injection molding

Semicrystalline polyamide 6 (PA6) and composites on its basis are among the most frequently used polymer materials for highly demanding applications. The performance of these composites depends on the crystalline structure of the PA6 matrix in which two crystalline forms most frequently coexist: α- and γ-polymorphs. This work reports on the crystalline structure of a variety of composite materials produced by in-mold reactive polymerization of caprolactam in specially designed semi-automatic equipment for reactive processing of nylons (NYRIM), carried out in the presence of particulate mineral reinforcements (natural or-ganically treated aluminum silicates and synthetic titanosilicates), PA6 oriented monofilaments and textile structures of glass fibers. The morphology and the crystalline structure of all composites were studied by syn-chrotron X-ray diffraction. Transcrystalline PA6 layer was observed in all fibrous PA6 laminates whose struc-ture fine crystalline structure was accessed.Fundação para a Ciência e Tecnologia; German Synchrotorn Radiation Source - DESY, Hambur

Potential association of HCF164, a chloroplast nuclear-encoded thioredoxin-like protein, with Coffea SH9 resistance factor against Hemileia vastatrix

29th Conference of Association for the Science and Information on Coffee, 11 Sept. - 14 Sept. 2023 Hanoi, Vietnaminfo:eu-repo/semantics/publishedVersio

An integrated in vitro approach unveils the biocompetence and glutathiolomic profile of a human hepatocyte-like cell 3d model

Funding: This work was supported by FCT (Portugal) through the research grant PTDC/MED-TOX/29183/2017. Acknowledgments: The authors thank ECBio S.A. for providing the hnMSCs and F.A. Beland (NCTR, Jefferson, AR, USA) for the kind donation of nevirapine. FCT (UID/DTP/04138/2019, UID/QUI/00100/2019, RECI/QEQ-MED/0330/2012, SFRH/BD/144130/2019 to J.S.R., SFRH/BD/110945/2015 to P.F.P. and CEECIND/02001/2017 to A.M.M.A) are also acknowledged.The need for competent in vitro liver models for toxicological assessment persists. The differentiation of stem cells into hepatocyte-like cells (HLC) has been adopted due to its human origin and availability. Our aim was to study the usefulness of an in vitro 3D model of mesenchymal stem cell-derived HLCs. 3D spheroids (3D-HLC) or monolayer (2D-HLC) cultures of HLCs were treated with the hepatotoxic drug nevirapine (NVP) for 3 and 10 days followed by analyses of Phase I and II metabolites, biotransformation enzymes and drug transporters involved in NVP disposition. To ascertain the toxic effects of NVP and its major metabolites, the changes in the glutathione net flux were also investigated. Phase I enzymes were induced in both systems yielding all known correspondent NVP metabolites. However, 3D-HLCs showed higher biocompetence in producing Phase II NVP metabolites and upregulating Phase II enzymes and MRP7. Accordingly, NVP-exposure led to decreased glutathione availability and alterations in the intracellular dynamics disfavoring free reduced glutathione and glutathionylated protein pools. Overall, these results demonstrate the adequacy of the 3D-HLC model for studying the bioactivation/metabolism of NVP representing a further step to unveil toxicity mechanisms associated with glutathione net flux changes.publishersversionpublishe

Structural and Functional insights into the catalytic mechanism of the Type II NADH:quinone oxidoreductase family

Type II NADH:quinone oxidoreductases (NDH-2s) are membrane proteins involved in respiratory chains. These proteins contribute indirectly to the establishment of the transmembrane difference of electrochemical potential by catalyzing the reduction of quinone by oxidation of NAD(P)H. NDH-2s are widespread enzymes being present in the three domains of life. In this work, we explored the catalytic mechanism of NDH-2 by investigating the common elements of all NDH-2s, based on the rationale that conservation of such elements reflects their structural/functional importance. We observed conserved sequence motifs and structural elements among 1762 NDH-2s. We identified two proton pathways possibly involved in the protonation of the quinone. Our results led us to propose the first catalytic mechanism for NDH-2 family, in which a conserved glutamate residue, E(172) (in NDH-2 from Staphylococcus aureus) plays a key role in proton transfer to the quinone pocket. This catalytic mechanism may also be extended to the other members of the two-Dinucleotide Binding Domains Flavoprotein (tDBDF) superfamily, such as sulfide:quinone oxidoreductases