Critical postsynaptic density 95/disc large/zonula occludens-1 interactions by glutamate receptor 1 (GluR1) and GluR2 required at different subcellular sites

Interactions between AMPA receptor subunits and proteins containing postsynaptic density 95/disc large/zonula occludens-1 (PDZ) domains have been shown to play critical roles in the proper trafficking of receptors to excitatory synapses. Synaptic accumulation of AMPA receptors containing the glutamate receptor 1 (GluR1) subunit can be driven by calcium/calmodulin-dependent protein kinase II activity or long-term potentiation and requires an interaction between GluR1 and a type I PDZ domain-containing protein. Synaptic incorporation of AMPA receptors with only GluR2 occurs continuously, and this requires an interaction between GluR2 and a type II PDZ domain-containing protein. We used dual-channel, two-photon laser scanning microscopy to provide high-resolution visualization and quantification of green fluorescent protein-tagged AMPA receptors in different subcellular compartments. We showed that mutations on GluR1 or GluR2 AMPA subunit that perturb interactions with PDZ domain proteins lead to the accumulation of these receptors at different subcellular sites. GluR1 mutants accumulate in the dendrite, whereas GluR2 mutants accumulate in dendritic spines. This suggests that the critical PDZ domain interactions are required for entry into spines for GluR1 and for entry into synapses for GluR2

Including dispersion in density functional theory for adsorption on flat oxide surfaces, in metal–organic frameworks and in acidic zeolites

We examine the performance of nine commonly used methods for including dispersion interactions in density functional theory (DFT): three different parametrizations of damped 1/R$^{n}$ terms (n = 6, 8, …) added to the DFT energy (Grimme\u27s D2 and D3 parameterizations as well as that of Tkatchenko and Scheffler), three different implementations of the many-body dispersion approach (MBD, MBD/HI and MBD/FI), the density-dependent energy correction, called dDsC, and two “first generation” van der Waals density functionals, revPBE-vdW and optB86b-vdW. As test set we use eight molecule–surface systems for which agreement has been reached between experiment and hybrid QM:QM calculations within chemical accuracy limits (±4.2 kJ mol$^{-1}$). It includes adsorption of carbon monoxide and dioxide in the Mg$_{2}$(2,5-dioxido-1,4-benzenedicarboxylate) metal–organic framework (Mg-MOF-74, CPO-27-Mg), adsorption of carbon monoxide as well as of monolayers of methane and ethane on the MgO(001) surface, as well as adsorption of methane, ethane and propane in H-chabazite (H-CHA). D2 with Ne parameters for Mg$^{2+}$, D2(Ne), MBD/HI and MBD/FI perform best. With the PBE functional, the mean unsigned errors are 6.1, 5.6 and 5.4 kJ mol$^{-1}$, respectively

A Nightmare or benevolent dream: global violence and the libidinal economy in Latin American literature

This thesis examines three novels by Latin American writers: Roberto Bolaño’s 2666, Horacio Castellanos Moya’s Senselessness, and Evelio Rosero’s The Armies. These novels look at actual instances of violence in Mexico, Guatemala, and Colombia, contributing to a social critique of historical and ongoing inequality and injustice in Latin America and the global South. Using Jacques Lacan’s psychoanalytic theories of subjectivity, this thesis argues that the novels express the human potential in desire for and to create excess. This has the effect of universalising guilt against the tendency to contextualise or localise events of violence in Mexico, Central, and South America

Tautomeric equilibrium in condensed phases

We present an ab initio molecular dynamics (MD) investigation of the tautomeric equilibrium for aqueous solutions of glycine and acetone at realistic experimental conditions. Metadynamics is used to accelerate proton migration among tautomeric centers. Due to the formation of complex water-ion structures involved the proton dynamics in the aqueous environment, standard enhanced sampling approaches may face severe limitations in providing a general description of the phenomenon. Recently, we developed a set of Collective Variables (CVs) designed to study protons transfer reactions in complex condensed systems [Grifoni et al. PNAS, 2019, 116(10), 4054-4057]. In this work we applied this approach to study proton dissociation dynamics leading to tautomeric interconversion of biologically and chemically relevant prototypical systems, namely glycine and acetone in water. Although relatively simple from a chemical point of view, the results show that even for these small systems complex reaction pathways and non-trivial conversion dynamics are observed. The generality of our method allows obtaining these results without providing any prior information on the dissociation dynamics but only the atomic species that can exchange protons in the process. Our results agree with literature estimates and demonstrate the general applicability of this method in the study of tautomeric reactions

Precision tests of the Standard Model with leptonic and semileptonic kaon decays

We present a global analysis of leptonic and semileptonic kaon decays data, including all recent results by BNL-E865, KLOE, KTeV, ISTRA+, and NA48. Experimental results are critically reviewed and combined, taking into account theoretical (both analytical and numerical) constraints on the semileptonic kaon form factors. This analysis leads to a very accurate determination of Vus and allows us to perform several stringent tests of the Standard Model

Confinement effects and acid strength in zeolites

Chemical reactivity and sorption in zeolites are coupled to confinement and—to a lesser extent—to the acid strength of Brønsted acid sites (BAS). In presence of water the zeolite Brønsted acid sites eventually convert into hydronium ions. The gradual transition from zeolite Brønsted acid sites to hydronium ions in zeolites of varying pore size is examined by ab initio molecular dynamics combined with enhanced sampling based on Well-Tempered Metadynamics and a recently developed set of collective variables. While at low water content (1–2 water/BAS) the acidic protons prefer to be shared between zeolites and water, higher water contents (n > 2) invariably lead to solvation of the protons within a localized water cluster adjacent to the BAS. At low water loadings the standard free energy of the formed complexes is dominated by enthalpy and is associated with the acid strength of the BAS and the space around the site. Conversely, the entropy increases linearly with the concentration of waters in the pores, favors proton solvation and is independent of the pore size/shape

Three-Dimensional Self-Navigated T2 Mapping for the Detection of Acute Cellular Rejection After Orthotopic Heart Transplantation.

T2 mapping is a magnetic resonance imaging technique measuring T2 relaxation time, which increases with the myocardial tissue water content. Myocardial edema is a component of acute cellular rejection (ACR) after heart transplantation. This pilot study compares in heart transplantation recipients a novel high resolution 3-dimensional (3D) T2-mapping technique with standard 2-dimensional (2D) T2-mapping for ACR detection. Consecutive asymptomatic patients (n = 26) underwent both 3D T2 mapping and reference 2D T2 mapping magnetic resonance imaging on the day of endomyocardial biopsy (EMB). 3D T2 maps were obtained at an isotropic spatial resolution of 1.72 mm (voxel volume 5.1 mm(3)). 2D and 3D maps were matched anatomically, and maximum segmental T2 values were compared blinded to EMB results. In addition, all 3D T2 maps were rendered as 3D images and inspected for foci of T2 elevation. T2 values of segments from 2D and reformatted 3D T2 maps agreed (p > 0.5). The highest 2D segmental T2 values were 49.9 ± 4.0 ms (no ACR = 0R, n = 18), 48.9 ± 0.8 ms (mild ACR = 1R, n = 3), and 65.0 ms (moderate ACR = 2R). Rendered 3D T2 maps of cases with 1R showed foci with significantly elevated T2 signal (T2 = 58.2 ± 3.6 ms); 5 cases (28%) in the 0R group showed foci with increased T2 values (>2 SD above adjacent tissue) that were not visible on the 2D T2 maps. This pilot study in a small cohort suggests equivalency of standard segmental analysis between 3D and 2D T2-mapping. 3D T2 mapping provides a spatial resolution that permits detection of foci with elevated T2 in patients with mild ACR

Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF.

IntroductionPatient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.MethodsROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).ResultsA total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.ConclusionsStudy drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.FundingThe ROCKET AF trial was funded by Johnson & Johnson and Bayer

Brain Computer Interfaces for inclusion

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