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Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson’s disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson’s disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders., 血液脳関門開放術による遺伝子治療法の開発 --身体を傷つけない脳疾患の治療を目指して--. 京都大学プレスリリース. 2023-04-20.

Producción Científica, A set of linear polymers were synthesized utilizing an electrophilic aromatic substitution reaction (SEAr) between biphenyl and ketone containing electron-withdrawing groups (isatin, IS; N-methylisatin, MeIS; and 4,5-diazafluoren-9-one, DF). Optimization of the polycondensation reaction was made to obtain high molecular weight products when using DF, which has not previously been used for linear polymer synthesis. Due to the absence of chemically labile units, these polymers exhibited excellent chemical and thermal stability. Linear SEAr polymers were blended with porous polymer networks derived from IS and MeIS, and both neat/mixed materials were tested as membranes for gas separation. The gas separation properties of both pristine polymers and mixed matrix membranes were good, showing some polymer membrane CO2 permeability values higher than 200 barrer.

A key pathological event occurring in Parkinson's disease (PD) is the transneuronal spreading of alpha-synuclein (α-syn). Other hallmarks of PD include neurodegeneration, glial activation, and immune cell infiltration in susceptible brain regions. Although preclinical models can mimic most of the key characteristics of PD, it is crucial to know the biological bases of individual differences between them when choosing one over another, to ensure proper interpretation of the results and to positively influence the outcome of the experiments.This review provides an overview of current preclinical models actively used to study the interplay between α-syn pathology, neuroinflammation and immune response in PD but also to explore new potential preclinical models or emerging therapeutic strategies intended to fulfill the unmet medical needs in this disease. Lastly, this review also considers the current state of the ongoing clinical trials of new drugs designed to target these processes and delay the initiation or progression of the disease.Anti-inflammatory and immunomodulatory agents have been demonstrated to be very promising candidates for reducing disease progression; however, more efforts are needed to reduce the enormous gap between these and dopaminergic drugs, which have dominated the therapeutic market for the last sixty years.

A set of aromatic copolyimides was obtained by reaction of 4,4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA), and mixtures of the diamines 1,4-bis(4-amino-2-trifluoromethylphenoxy)-2,5-di-tert-butylbenzene (CF3TBAPB) and 3,5-diamino benzoic acid (DABA). These polymers were characterized and compared with the homopolymer derived from 6FDA and CF3TBAPB. All copolyimides showed high molecular weight values and good mechanical properties. The presence of carboxylic groups in these copolymers allowed their cross-linking by reaction with 1,4-butanediol. The crosslinked polymer films were extensively characterized and it was observed that the degree of crosslinking was low in the copolyimides possessing a small number of carboxyl groups. The degradation temperature of these crosslinked copolyimides was lower than their corresponding non-crosslinked ones. Glass transition temperatures were higher than 260 oC, showing the non-crosslinked copolyimides the highest values. Young moduli of these crosslinked showed values higher than 1.9 GPa, and slightly lower elongation at break when compared with the precursor copolyimides. All copolyimides (precursor, and crosslinked ones) films could be tested as gas separation membranes. It was seen that CO2 permeability values were around 100 barrer, having better selectivity than that of the homopolymer. Moreover, the plasticization resistance of the crosslinked material having a large number of carboxylic groups was excellent.

A set of aromatic copolyimides was obtained by reaction of 4,4'-(hexafluoroisopropylidene) diphthalic anhydride (6FDA), and mixtures of the diamines 1,4-bis(4-amino-2-trifluoromethylphenoxy)-2,5-di

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve, remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone, however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.

Producción Científica, A new generation of confined palladium(II) catalysts covalently attached inside of porous organic polymers (POPs) has been attained. The synthetic approach employed was straightforward, and there was no prerequisite for making any modification of the precursor polymer. First, POP-based catalytic supports were obtained by reacting one symmetric trifunctional aromatic monomer (1,3,5-triphenylbenzene) with two ketones having electron-withdrawing groups (4,5-diazafluoren-9-one, DAFO, and isatin) in superacidic media. The homopolymers and copolymers were made using stoichiometric ratios between the functional groups, and they were obtained with quantitative yields after the optimization of reaction conditions. Moreover, the number of chelating groups (bipyridine moieties) available to bind Pd(II) ions to the catalyst supports was modified using different DAFO/isatin ratios. The resulting amorphous polymers and copolymers showed high thermal stability, above 500 °C, and moderate–high specific surface areas (from 760 to 935 m2 g–1), with high microporosity contribution (from 64 to 77%). Next, POP-supported Pd(II) catalysts were obtained by simple immersion of the catalyst supports in a palladium(II) acetate solution, observing that the metal content was similar to that theoretically expected according to the amount of bipyridine groups present. The catalytic activity of these heterogeneous catalysts was explored for the synthesis of biphenyl and terphenyl compounds, via the Suzuki–Miyaura cross-coupling reaction using a green solvent (ethanol/water), low palladium loads, and aerobic conditions. The findings showed excellent catalytic activity with quantitative product yields. Additionally, the recyclability of the catalysts, by simply washing it with ethanol, was excellent, with a sp2–sp2 coupling yield higher than 95% after five cycles of use. Finally, the feasibility of these catalysts to be employed in tangible organic reactions was assessed. Thus, the synthesis of a bulky compound, 4,4′-dimethoxy-5′-tert-butyl-m-terphenylene, which is a precursor of a thermal rearrangement monomer, was scaled-up to 2 g, with high conversion and 96% yield of the pure product., Agencia Estatal de Investigación (projects PID2019-109403RB-C22, MAT2016-76413-C2-R2, CTQ2017-89217- P and MAT2016-76413-C2-R1), Junta de Castilla y León (project VA038G18)

Introduction Several experimental studies have suggested the potential remyelinating effects of vitamin D (VitD) supplements regardless of the presence of VitD deficiency. This study aims to analyze neurogenesis in a model of toxic demyelination in order to evaluate the effects of VitD on demyelination and remyelination. Material and methods We used 24 male Wistar rats that had received surgical lesions to the corpus callosum and were injected with lysolecithin. Rats were divided into three groups: Group 1 included eight rats with lesions to the corpus callosum but not lysolecithin injections (sham group), group 2 included eight rats with lesions to the corpus callosum that were injected with lysolecithin (lysolecithin group), and group 3 included eight rats with lesions that were injected with lysolecithin and received VitD (VitD group). We analyzed neurogenesis both in the subventricular zone and at the lesion site. Results Administration of VitD promotes the proliferation and differentiation of neural stem cells in the subventricular zone and the migration of these cells to the lesion site in the corpus callosum; these cells subsequently differentiate into oligodendrocyte lineage cells and produce myelin basic protein. This phenomenon was not caused by microglial activation, which was less marked in rats receiving VitD. Megalin expression did not increase at the lesion site, which suggests that VitD is internalized by other mechanisms. Conclusion Our results support the hypothesis that regardless of the presence of VitD deficiency, treatment with VitD may contribute to remyelination by promoting the proliferation of oligodendrocyte precursor cells., Vitamin D promotes remyelination in rats with lysolecithin‐induced demyelination. Vitamin D promotes differentiation into oligodendrocyte lineage cells. Vitamin D promotes proliferation and differentiation of neural stem cells.

The estimation of the deformation modulus of a rock mass is a fundamental factor in the design of civil works such as tunnels and dams. However, it is one of the parameters that entails highest difficulty when evaluating the rock mass. In this paper, a new analytical model is presented to assess rock mass deformability, with the aim of improving the estimation of the properties and their implementation in numerical models. The model presented is analytical, anisotropic and based on the equivalent continuum approach, and considers: the geometry of the rock mass for orientation, spacing and thickness of the discontinuities, the presence of fill; and, finally, the deformational properties of the intact rock and the discontinuities. The resultant model was adapted for the specific case of filled discontinuities using both the linear elastic model and the Hertz-Mindlin law. The assessment presented includes: the implementation of the model, the analysis of various theoretical scenarios, the estimation of deformabilities for multiple cases, a numerical validation using the Distinct Element Method, and a discussion of the scale effect. The results are compared with some empirical formulations for the deformability assessment of rock masses. This comparison underlines the importance of separately considering all the factors that define the rock mass, as well as the necessity of heeding the anisotropy caused by the orientation of the discontinuity sets.