Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder.

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

Reaction mechanism of the dengue virus serine protease: a QM/MM study.

The dengue virus (DENV) is the causative agent of the viral infection dengue fever. In spite of all the efforts made to prevent the spread of the disease, once it is contracted, there is no specific treatment for dengue and the WHO guidelines are limited to rest and symptomatic treatment. In its reproductive cycle, DENV utilizes the NS2B-NS3pro, a serine protease, to cleave the viral polyprotein into its constituents. This enzyme is essential for the virus lifecycle, and presents an attractive target for the development of specific dengue treatments. Here we used a hybrid Quantum Mechanics and Molecular Mechanics (QM/MM) Molecular Dynamics approach and Umbrella Sampling to study the first step (acylation) of the reaction catalyzed by NS2B-NS3pro, using the Pairwise Distance Directed Gaussian PM3 (PDDG/PM3) semi-empirical Hamiltonian for the QM subsystem, and Amber ff99SB for the MM subsystem. Our results indicate that the nucleophilic attack on the substrate by Ser135 occurs in a stepwise manner, in which a proton transfer to His51 first activates Ser135, which only later attacks the substrate. The rate-determining step is the Ser135 activation, with a barrier of 24.1 kcal mol-1. Water molecules completing the oxyanion hole stabilize the negative charge formed on the carbonyl oxygen of the substrate. The final step in the process is a proton transfer from His51 to the substrate's nitrogen, which happens with a lower barrier of 5.1 kcal mol-1, and leads directly to the breakage of the peptide bond.

QM/MM simulations of amyloid-ß 42 degradation by IDE in the presence and absence of ATP.

The ability of the insulin-degrading enzyme (IDE) to degrade amyloid-ß 42 (Aß42), a process regulated by ATP, has been studied as an alternative path in the development of drugs against Alzheimer's disease. In this study, we calculated the potential of mean force for the degradation of Aß42 by IDE in the presence and absence of ATP by umbrella sampling with hybrid quantum mechanics and molecular mechanics (QM/MM) calculations, using the SCC-DFTB QM Hamiltonian and Amber ff99SB force field. Results indicate that the reaction occurs in two steps: The first step is characterized by the formation of the intermediate. The second step is characterized by breaking the peptide bond of the substrate, the latter being the rate-determining step. In our simulations, the activation energy barrier in the absence of ATP is 15 ± 2 kcal mol(-1), which is 7 kcal mol(-1) lower than in the presence of ATP, indicating that the presence of the nucleotide decreases the reaction rate by about 10(5) times.

Molecular photoionization cross sections in electron propagator theory: angular distributions beyond the dipole approximation.

Corrections to dipole approximation results for angular distributions in photoionization of first-row hydrides have determined by using Dyson orbitals calculated with ab initio electron propagator theory and by considering the full multipole expansion for the incident photon representation. The relative importance of first-order corrections which consist of electric quadrupole and magnetic dipole terms and of higher-order terms has been estimated as a function of photon energy. Multipole corrections to the dipole approximation depend on photon energy and on the characteristics of the Dyson orbitals.

Electron propagator theory calculations of molecular photoionization cross sections: the first-row hydrides.

Together with ionization potentials, cross sections provide valuable information for the interpretation of photoelectron spectra. We have developed a program to perform ab initio calculations of photoionization cross sections within the electric dipole approximation using electron propagator theory. Applications to the first-row hydrides CH(4), NH(3), H(2)O, and HF, using several approximations for the propagator self-energy and the plane-wave and orthogonalized-plane-wave approximations to represent the photoelectron, as well as comparison to experimental data, are presented. This program is implemented within the quantum chemistry package GAUSSIAN.

Effects of a chlorhexidine varnish on the gingival status of adolescents.

The purpose of this blind study was to determine the effect of a two-stage chlorhexidine varnish, after three months, on the gingival status of 11- to 15-year-old children attending a school in Rio de Janeiro, Brazil. Subjects participating in the study were randomly allocated to control (C) and treatment (T) groups, n = 53 and n = 57, respectively. All subjects were matched at baseline on age, salivary levels of mutans streptococci, and caries scores. After elimination of carious lesions, a prophylaxis was given to both groups. The chlorhexidine varnish was then painted on the entire dentition of Group T subjects only. Prior to caries elimination, and again after three months, the gingival index was used to assess the gingival status of study subjects. An average of 106.6 +/- 8.9 and 107.7 +/- 6.2 gingival sites per subject (four sites per tooth) in Groups C and T, respectively, were examined by the same calibrated examiner on two occasions. For statistical purposes, data were dichotomized [(0,1) (2,3)] for the gingival index. Independent t-tests and paired t-tests were used to analyze the data. The percentage of sites per subject with scores of two or three at the baseline were balanced between study groups (3.7 +/- 7.1 for T; 1.8 +/- 3.2 for C; p = 0.08). After three months, a statistically significant decrease in the average percentage of sites with scores of two or three was demonstrated in the T group (0.7 +/- 2.4, T, p < 0.0001; 1.3 +/- 3.0, C, p < 0.25). The authors concluded that the application of a chlorhexidine varnish significantly improved the gingival health of T subjects for up to three months. A significant improvement in the gingival health could not be demonstrated in the C group.