Dynamin-2 R465W mutation induces long range perturbation in highly ordered oligomeric structures

High order oligomers are crucial for normal cell physiology, and protein function perturbed by missense mutations underlies several autosomal dominant diseases. Dynamin-2 is one of such protein forming helical oligomers that catalyze membrane fission. Mutations in this protein, where R465W is the most frequent, cause dominant centronuclear myopathy, but the molecular mechanisms underpinning the functional modifications remain to be investigated. To unveil the structural impact of this mutation in dynamin-2, we used full-atom molecular dynamics simulations and coarse-grained models and built dimers and helices of wild-type (WT) monomers, mutant monomers, or both WT and mutant monomers combined. Our results show that the mutation R465W causes changes in the interactions with neighbor amino acids that propagate through the oligomer. These new interactions perturb the contact between monomers and favor an extended conformation of the bundle signaling element (BSE), a dynamin region that transmits the conformational changes from the GTPase domain to the rest of the protein. This extended configuration of the BSE that is only relevant in the helices illustrates how a small change in the microenvironment surrounding a single residue can propagate through the oligomer structures of dynamin explaining how dominance emerges in large protein complexes. © 2020, The Author(s).Indexación Scopushttps://www-nature-com.recursosbiblioteca.unab.cl/articles/s41598-020-75216-

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Arsenic Exposure Assessment Of Children Living In A Lead Mining Area In Southeastern Brazil [avaliação Da Exposição De Crianças Ao Arsênio Em área De Mineração De Chumbo Na Região Sudeste Do Brasil]

Environmental contamination by arsenic compounds in the Ribeira River Valley, São Paulo, Brazil has already been observed. Lead mining and refining activities had been carried on since late colonial times and finished recently, at the end of 1995. The source of As in the region is known to be mainly from arsenopirite geological presence in the lead ore. Chronic exposure to arsenic compounds may cause peripheral vascular disorders, hyperpigmentation, hiperkeratosis and cancer of the skin, bladder, lung, liver and other internal organs. The purpose of this study was to assess children exposure to arsenic from environmental sources in the region. Urine samples from children between 7 to 14 years old were collected at the following localities: Cerro Azul (Paraná); urban areas of Ribeira (São Paulo) and Adrianópolis (Paraná); Vila Mota neighborhood (rural area of Adrianópolis) and Serra neighborhood (Iporanga, São Paulo), identified as groups 1, 2, 3 and 4, respectively. Group 1 was considered as non-exposed control group. Toxicologically relevant forms of As were determined by atomic absorption spectrometry with hydride generation system. The median values of urine arsenic levels obtained in groups 1, 2, 3 and 4 were respectively: 3.60, 6.30, 6.41 e 8.94μg/L.262391398Navarro, M., Sánchez, M., López, H., López, M.C., Arsenic contamination levels in waters, soils and sludges in Southeast Spain (1993) Bull Environ Contam Toxicol, 50, pp. 356-362Das, D., Chatterjee, A., Mandal, B.K., Samanta, G., Chakraborti, D., Chanda, B., Arsenic in ground water in six districts of West Bengal, India: The biggest arsenic calamity in the world. Part 2. 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(2002) Environ Res, 88, pp. 219-224Hwang, Y.H., Bornschein, R.L., Grote, J., Menrath, W., Roda, S., Urinary arsenic excretion as a biomarker of arsenic exposure in children (1997) Arch Environ Health, 52, pp. 139-147Gong, Z., Lu, X., Cullen, W.R., Le, X.C., Unstable trivalent arsenic metabolites, monomethylarsonous acid and dimethylarsinous acid (2001) J Anal At Spectrom, 16, pp. 1409-1413Santos, E.C.O., Jesus, I.M., Brabo, E.S., Fayal, K.F., Sá Filho, G.C., Lima, M.O., Exposição ao mercúrio e ao arsênio em Estados da Amazônia: Síntese dos estudos do Instituto Evandro Chagas/FUNASA (2003) Rev Bras Epidemiol, 6, pp. 171-185Silva, R.H.P., (1997) Geoquímica E Impacto Ambiental Do Arsênio No Vale Do Ribeira (SP-PR) [Dissertação De Mestrado], , Campinas: Instituto de Geociências, Universidade Estadual de CampinasMatschullat, J., Borba, R.P., Deschamps, E., Figueiredo, B.R., Gabrio, T.E., Schwenk, M., Human and environmental contamination in the iron quadrangle, Brazil (2000) Applied Geochem, 15, pp. 181-190Rosa, R.T., (1999) Arsênio E Metais Associados Na Região Aurífera Do Piririca, Vale Do Ribeira, São Paulo, Brasil [Dissertação De Mestrado], , Campinas: Instituto de Geociências, Universidade Estadual de CampinasToujague, R., (1999) Arsênio E Metais Associados Na Região Aurífera Do Piririca, Vale Do Ribeira, São Paulo, Brasil [Dissertação De Mestrado], , Campinas: Instituto de Geociências, Universidade Estadual de CampinasBraga, P.S., Figueiredo, B.R., (2002) Comportamento De Metais Pesados Em Solos Na Região Do Vale Do Ribeira (SP), p. 231. , In: Anais do 41o Congresso Brasileiro de Geologia. 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Supramolecular complexes of quantum dots and a polyamidoamine (PAMAM)-folate derivative for molecular imaging of cancer cells

Geraldo, DA (Geraldo, Daniela A.)1,2;Duran-Lara, EF (Duran-Lara, Esteban F.)1;Tapia, J (Tapia, Jaime)1; Gonzalez-Nilo, FD (Gonzalez-Nilo, Fernando Danilo)2; Santos, LS (Santos, Leonardo S.)1.........../1. Univ Talca, Lab Asymmetr Synth, Chem Inst Nat Resources, Talca, Chile 2. Univ Talca, Ctr Bioinformat & Mol Simulat, Talca, Chileolyamidoamine (PAMAM) dendrimers and water-soluble 3-mercaptopropionic acid (MPA)-capped CdSe quantum dots (QDs) were combined to produce a new gel containing supramolecular complexes of QDs/PAMAM dendrimers. The formation of the QDs/PAMAM supramolecular complexes was confirmed by high resolution electron microscopy and Fourier transform infrared (FTIR) analyses. Molecular dynamics simulations corroborated the structure of the new QDs/PAMAM-based supramolecular compound. Finally, on the basis of the prominent fluorescent properties of the supramolecular complexes, PAMAM dendrimer was functionalized with folic acid to produce a new QDs/PAMAM-folate derivative that showed an efficient and selective performance as a marker for gastric cancer cells

Effect of several HIV antigens simultaneously loaded with G2-NN16 carbosilane dendrimer in the cell uptake and functionality of human dendritic cells

Dendrimers are highly branched, star-shaped, and nanosized polymers that have been proposed as new carriers for specific HIV-1 peptides. Dendritic cells (DCs) are the most-potent antigen-presenting cells that play a major role in the development of cell-mediated immunotherapy due to the generation and regulation of adaptive immune responses against HIV-1. This article reports on the associated behavior of two or three HIV-derived peptides simultaneously (p24/gp160 or p24/gp160/NEF) with cationic carbosilane dendrimer G2-NN16. We have found that (i) immature DCs (iDCs) and mature (mDCs) did not capture efficiently HIV peptides regarding the uptake level when cells were treated with G2-NN16-peptide complex alone; (ii) the ability of DCs to migrate was not depending on the peptides presence; and (iii) with the use of molecular dynamic simulation, a mixture of peptides decreased the cell uptake of the other peptides (in particular, NEF hinders the binding of more peptides a nd is especially obstructing of the binding of gp160 to G2-NN16). The results suggest that G2-NN16 cannot be considered as an alternative carrier for delivering two or more HIV-derived peptides to DCs

Molecular determinants for cyclooligosaccharide-based nanoparticle-mediated effective siRNA transfection

Aim: To study the structural requirements that a cyclooligosaccharide-based nanoparticle must fulfill to be an efficient siRNA transfection vector. Materials & methods: siRNA protection from degradation by RNAses, transfection efficiency and the thermodynamic parameters of the nanoparticle/siRNA interactions were studied on pairs of amphiphilic molecules using biochemical techniques and molecular dynamics. Results: The lower the siRNA solvent accessible surface area in the presence of the nanoparticle, higher the protection from RNAse-mediated degradation in the corresponding nanocomplex; a moderate nanoparticle/siRNA binding energy value further facilitates reversible complexation and binding to the target cellular mRNA. Conclusion: The use, in advance, of these parameters will provide a useful indication of the potential of a molecular nanoparticle as siRNA transfecting vector

Chemoinformatics and artificial intelligence colloquium: progress and challenges in developing bioactive compounds

We report the main conclusions of the first Chemoinformatics and Artificial Intelligence Colloquium, Mexico City, June 15–17, 2022. Fifteen lectures were presented during a virtual public event with speakers from industry, academia, and non-for-profit organizations. Twelve hundred and ninety students and academics from more than 60 countries. During the meeting, applications, challenges, and opportunities in drug discovery, de novo drug design, ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) property predictions, organic chemistry, peptides, and antibiotic resistance were discussed. The program along with the recordings of all sessions are freely available at https://www.difacquim.com/english/events/2022-colloquium/. © 2022, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]