A New Approach to the Synthesis of Benzo[b]naphtho[2,3-b]furan-6,11-diones and 2-Benzyl-3-hydroxynaphthalene-1,4-diones

Here we describe modified syntheses of o-acetylbenzoic acids and o-acetylphenylacetic acids by Heck palladium-catalysed arylation of n-butyl vinyl ether with o-iodobenzoic acids or with o-iodophenylacetic acids, respectively. General syntheses of benzo[b]naphtho[2,3-b]furan-6,11-diones from o-acetylbenzoic acids and 2-benzyl3-hydroxynaphthalene-1,4-diones from o-acetylphenylacetic acids are also reported.This work has received financial support from the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2016–2019, ED431G/09; and Project GRC2014/040), the European Union (Europe- an Regional Development Fund-ERDF), FONDECYT (Research Grants 1161816 and 1141264) and Galchimia S.A.S

Bridges of biomaterials promote nigrostriatal pathway regeneration

[EN] Repair of central nervous system (CNS) lesions is difficulted by the lack of ability of central axons to regrow, and the blocking by the brain astrocytes to axonal entry. We hypothesized that by using bridges made of porous biomaterial and permissive olfactory ensheathing glia (OEG), we could provide a scaffold to permit restoration of white matter tracts. We implanted porous polycaprolactone (PCL) bridges between the substantia nigra and the striatum in rats, both with and without OEG. We compared the number of tyrosine-hydroxylase positive (TH+) fibers crossing the striatal-graft interface, and the astrocytic and microglial reaction around the grafts, between animals grafted with and without OEG. Although TH+ fibers were found inside the grafts made of PCL alone, there was a greater fiber density inside the graft and at the striatal-graft interface when OEG was cografted. Also, there was less astrocytic and microglial reaction in those animals. These results show that these PCL grafts are able to promote axonal growth along the nigrostriatal pathway, and that cografting of OEG markedly enhances axonal entry inside the grafts, growth within them, and re-entry of axons into the CNS. These results may have implications in the treatment of diseases such as Parkinson's and others associated with lesions of central white matter tracts.Contract grant sponsor: Regional Government Health Department (Conselleria de Sanitat, Generalitat Valenciana) and Carlos III Health Institute of the Ministry of Health and Consumer Affairs (Spain) (Regenerative Medicine Programme) Contract grant sponsor: Spanish ministry of Education and Science; contract grant number: MAT 2006-13554-C02-02 Contract grant sponsor: Red de Terapia Celular TERCEL (RETICS), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion (ISCIII); contract grant number: RD12/0019/0010 (to J.A.) Contract grant sponsor: Spanish Science & Innovation Ministery; contract grant number: MAT2008-06434 (to M.M.P.) Contract grant sponsor: "Convenio de Colaboracion para la Investigacion Basica y Traslacional en Medicina Regenerativa," Instituto Nacional de Salud Carlos III, the Conselleria de Sanidad of the Generalitat Valenciana, and the Foundation Centro de Investigacion Principe FelipeGómez Pinedo, U.; Sanchez-Rojas, L.; Vidueira, S.; Sancho, FJ.; Martínez-Ramos, C.; Lebourg, M.; Monleón Pradas, M.... (2019). Bridges of biomaterials promote nigrostriatal pathway regeneration. Journal of Biomedical Materials Research Part B Applied Biomaterials. 107(1):190-196. https://doi.org/10.1002/jbm.b.34110S1901961071Pekny, M., Wilhelmsson, U., & Pekna, M. (2014). The dual role of astrocyte activation and reactive gliosis. Neuroscience Letters, 565, 30-38. doi:10.1016/j.neulet.2013.12.071Bliss, T. M., Andres, R. H., & Steinberg, G. K. (2010). Optimizing the success of cell transplantation therapy for stroke. Neurobiology of Disease, 37(2), 275-283. doi:10.1016/j.nbd.2009.10.003Tam, R. Y., Fuehrmann, T., Mitrousis, N., & Shoichet, M. S. (2013). Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach. Neuropsychopharmacology, 39(1), 169-188. doi:10.1038/npp.2013.237Skop, N. B., Calderon, F., Cho, C. H., Gandhi, C. D., & Levison, S. W. (2014). Improvements in biomaterial matrices for neural precursor cell transplantation. Molecular and Cellular Therapies, 2(1), 19. doi:10.1186/2052-8426-2-19Yasuhara, T., Kameda, M., Sasaki, T., Tajiri, N., & Date, I. (2017). Cell Therapy for Parkinson’s Disease. Cell Transplantation, 26(9), 1551-1559. doi:10.1177/0963689717735411Orive, G., Anitua, E., Pedraz, J. L., & Emerich, D. F. (2009). Biomaterials for promoting brain protection, repair and regeneration. Nature Reviews Neuroscience, 10(9), 682-692. doi:10.1038/nrn2685Walker, P. A., Aroom, K. R., Jimenez, F., Shah, S. K., Harting, M. T., Gill, B. S., & Cox, C. S. (2009). Advances in Progenitor Cell Therapy Using Scaffolding Constructs for Central Nervous System Injury. Stem Cell Reviews and Reports, 5(3), 283-300. doi:10.1007/s12015-009-9081-1Zhong, Y., & Bellamkonda, R. V. (2008). Biomaterials for the central nervous system. Journal of The Royal Society Interface, 5(26), 957-975. doi:10.1098/rsif.2008.0071Pérez‐GarnezM BarciaJA Gómez‐PinedoU Monleón‐PradasM Vallés‐LluchA.Materials for Central Nervous System Tissue Engineering Cells and Biomaterials in Regenerative Medicine. InTech;2014. Chap 7.Sinha, V. R., Bansal, K., Kaushik, R., Kumria, R., & Trehan, A. (2004). Poly-ϵ-caprolactone microspheres and nanospheres: an overview. International Journal of Pharmaceutics, 278(1), 1-23. doi:10.1016/j.ijpharm.2004.01.044Raisman, G. (2001). Olfactory ensheathing cells — another miracle cure for spinal cord injury? Nature Reviews Neuroscience, 2(5), 369-375. doi:10.1038/35072576Raisman, G., & Li, Y. (2007). Repair of neural pathways by olfactory ensheathing cells. Nature Reviews Neuroscience, 8(4), 312-319. doi:10.1038/nrn2099Fairless, R., & Barnett, S. C. (2005). Olfactory ensheathing cells: their role in central nervous system repair. The International Journal of Biochemistry & Cell Biology, 37(4), 693-699. doi:10.1016/j.biocel.2004.10.010Collins, A., Li, D., Mcmahon, S. B., Raisman, G., & Li, Y. (2017). Transplantation of Cultured Olfactory Bulb Cells Prevents Abnormal Sensory Responses during Recovery from Dorsal Root Avulsion in the Rat. Cell Transplantation, 26(5), 913-924. doi:10.3727/096368917x695353Navarro, X., Valero, A., Gudi�o, G., For�s, J., Rodr�guez, F. J., Verd�, E., … Nieto-Sampedro, M. (1999). Ensheathing glia transplants promote dorsal root regeneration and spinal reflex restitution after multiple lumbar rhizotomy. Annals of Neurology, 45(2), 207-215. doi:10.1002/1531-8249(199902)45:23.0.co;2-kGómez-Pinedo, U., Félez, M. C., Sancho-Bielsa, F. J., Vidueira, S., Cabanes, C., Soriano, M., … Barcia, J. A. (2008). Improved technique for stereotactic placement of nerve grafts between two locations inside the rat brain. Journal of Neuroscience Methods, 174(2), 194-201. doi:10.1016/j.jneumeth.2008.07.008HowardCV ReedMG.Unbiased Stereology: Three‐Dimensional Measurement in Microscopy. Oxford: Bioimaging Group;1998.Collier, T. J., & Springer, J. E. (1991). Co-grafts of embryonic dopamine neurons and adult sciatic nerve into the denervated striatum enhance behavioral and morphological recovery in rats. Experimental Neurology, 114(3), 343-350. doi:10.1016/0014-4886(91)90160-eBourke, J. L., Coleman, H. A., Pham, V., Forsythe, J. S., & Parkington, H. C. (2014). Neuronal Electrophysiological Function and Control of Neurite Outgrowth on Electrospun Polymer Nanofibers Are Cell Type Dependent. Tissue Engineering Part A, 20(5-6), 1089-1095. doi:10.1089/ten.tea.2013.0295Nga, V. D. W., Lim, J., Choy, D. K. S., Nyein, M. A., Lu, J., Chou, N., … Teoh, S.-H. (2015). Effects of Polycaprolactone-Based Scaffolds on the Blood–Brain Barrier and Cerebral Inflammation. Tissue Engineering Part A, 21(3-4), 647-653. doi:10.1089/ten.tea.2013.0779Pérez-Garnés, M., Martínez-Ramos, C., Barcia, J. A., Escobar Ivirico, J. L., Gómez-Pinedo, U., Vallés-Lluch, A., & Monleón Pradas, M. (2012). One-Dimensional Migration of Olfactory Ensheathing Cells on Synthetic Materials: Experimental and Numerical Characterization. Cell Biochemistry and Biophysics, 65(1), 21-36. doi:10.1007/s12013-012-9399-1Diban, N., Ramos-Vivas, J., Remuzgo-Martinez, S., Ortiz, I., & Urtiaga, A. (2015). Poly(ε-caprolactone) Films with Favourable Properties for Neural Cell Growth. Current Topics in Medicinal Chemistry, 14(23), 2743-2749. doi:10.2174/156802661466614121515393

A ventromedial prefrontal dysrhythmia in obsessive-compulsive disorder is attenuated by nucleus accumbens deep brain stimulation

Background: Obsessive-compulsive disorder (OCD) has consistently been linked to abnormal frontostriatal activity. The electrophysiological disruption in this circuit, however, remains to be characterized. Objective/hypothesis: The primary goal of this study was to investigate the neuronal synchronization in OCD patients. We predicted aberrant oscillatory activity in frontal regions compared to healthy control subjects, which would be alleviated by deep brain stimulation (DBS) of the nucleus accumbens (NAc). Methods: We compared scalp EEG recordings from nine patients with OCD treated with NAc-DBS with recordings from healthy controls, matched for age and gender. Within the patient group, EEG activity was compared with DBS turned off vs. stimulation at typical clinical settings (3.5 V, frequency of stimulation 130 Hz, pulse width 60 ms). In addition, intracranial EEG was recorded directly from depth macro electrodes in the NAc in four OCD patients. Results: Cross-frequency coupling between the phase of alpha/low beta oscillations and amplitude of high gamma was significantly increased over midline frontal and parietal electrodes in patients when stimulation was turned off, compared to controls. Critically, in patients, beta (16-25 Hz)-gamma (110-166 Hz) phase amplitude coupling source localized to the ventromedial prefrontal cortex, and was reduced when NAc-DBS was active. In contrast, intracranial EEG recordings showed no beta-gamma phase amplitude coupling. The contribution of non-sinusoidal beta waveforms to this coupling are reported. Conclusion: We reveal an increased beta-gamma phase amplitude coupling in fronto-central scalp sensors in patients suffering from OCD, compared to healthy controls, which may derive from ventromedial prefrontal regions implicated in OCD and is normalized by DBS of the nucleus accumbens. This aberrant cross-frequency coupling could represent a biomarker of OCD, as well as a target for novel therapeutic approaches. (C) 2021 The Authors. Published by Elsevier Inc.This work was supported by Project grants SAF2015-65982-R from the Spanish Ministry of Economy and Competitiveness to BS and PSI2014-58654-JIN to JGR, an FPI Predoctoral Fellowship (BES-2016-079470) to ST, and BIAL Foundation Grant 119/12 to BS. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC-2018-COG 819814)

One-dimensional migration of olfactory ensheathing cells on synthetic materials: Experimental and numerical characterization

Olfactory ensheathing cells (OECs) are of great interest for regenerative purposes since they are believed to aid axonal growth. With the view set on the strategies to achieve reconnection between neuronal structures, it is of great importance to characterize the behaviour of these cells on long thread-like structures that may efficiently guide cell spread in a targeted way. Here, rat OECs were studied on polycaprolactone (PCL) long monofilaments, on long bars and on discs. PCL turns out to be an excellent substrate for OECs. The cells cover long distances along the monofilaments and colonize completely these struc- tures. With the help of a one-dimensional (1D) analytical model, a migration coefficient, a net proliferation rate constant and the fraction of all cells which undergo migration were obtained. The separate effect of the three phenomena summarized by these parameters on the colo- nization patterns of the 1D path was qualitatively dis- cussed. Other features of interest were also determined, such as the speed of the advance front of colonization and the order of the kinetics of net cell proliferation. Charac- terizing migration by means of these quantities may be useful for comparing and predicting features of the colo- nization process (such as times, patterns, advance fronts and proportion of motile cells) of different cell substrate combinations.Support of the Spanish Science & Innovation Ministery through project MAT2008-06434 is acknowledged. MMP and CMR acknowledge partial funding through the "Convenio de Colaboracion para la Investigacion Basica y Traslacional en Medicina Regenerativa" between the Instituto Nacional de Salud Carlos III, the Conselleria de Sanidad of the Generalitat Valenciana and the Foundation Centro de Investigacion Principe Felipe.Perez Garnes, M.; Martínez Ramos, C.; Barcia, JA.; Escobar Ivirico, JL.; Gomez Pinedo, UA.; Vallés Lluch, A.; Monleón Pradas, M. (2013). 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Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke.

[EN] Endogenous neurogenesis in stroke is insufficient to replace the lost brain tissue, largely due to the lack of a proper biological structure to let new cells dwell in the damaged area. We hypothesized that scaffolds made of hyaluronic acid (HA) biomaterials (BM) could provide a suitable environment to home not only new neurons, but also vessels, glia and neurofilaments. Further, the addition of exogenous cells, such as adipose stem cells (ASC) could increase this effect. Athymic mice were randomly assigned to a one of four group: stroke alone, stroke and implantation of BM, stroke and implantation of BM with ASC, and sham operated animals. Stroke model consisted of middle cerebral artery thrombosis with FeCl3. After 30 days, animals underwent magnetic resonance imaging (MRI) and were sacrificed. Proliferation and neurogenesis increased at the subventricular zone ipsilateral to the ventricle and neuroblasts, glial, and endothelial cells forming capillaries were seen inside the BM. Those effects increased when ASC were added, while there was less inflammatory reaction. Three-dimensional scaffolds made of HA are able to home newly formed neurons, glia, and endothelial cells permitting the growth neurofilaments inside them. The addition of ASC increase these effects and decrease the inflammatory reaction to the implant.Contract grant sponsor: CIBER BBN Contract grant sponsor: ERANET NEURON CALL; contract grant number: PRI-PIMNEU-2011-1372 Contract grant sponsor: Spanish Science & Innovation Ministery; contract grant number: MAT 2011-28791-C03-01, MAT 2011-28791-C03-02 an Contract grant sponsor: TERCEL; contract grant number: RD12/0019/0010 Contract grant sponsor: Spanish Ministry of Economy and Competitiveness through grants MAT2015-66666-C3, and DPI2015-72863-EXPSanchez-Rojas, L.; Gómez-Pinedo, U.; Benito-Martin, MS.; León-Espinosa, G.; Rascón-Ramirez, F.; Lendinez, C.; Martínez-Ramos, C.... (2019). 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Human Mesenchymal Stem Cells Prevent Neurological Complications of Radiotherapy

Radiotherapy is a highly effective tool for the treatment of brain cancer. However, radiation also causes detrimental effects in the healthy tissue, leading to neurocognitive sequelae that compromise the quality of life of brain cancer patients. Despite the recognition of this serious complication, no satisfactory solutions exist at present. Here we investigated the effects of intranasal administration of human mesenchymal stem cells (hMSCs) as a neuroprotective strategy for cranial radiation in mice. Our results demonstrated that intranasally delivered hMSCs promote radiation-induced brain injury repair, improving neurological function. This intervention confers protection against inflammation, oxidative stress, and neuronal loss. hMSC administration reduces persistent activation of damage-induced c-AMP response element-binding signaling in irradiated brains. Furthermore, hMSC treatment did not compromise the survival of glioma-bearing mice. Our findings encourage the therapeutic use of hMSCs as a non-invasive approach to prevent neurological complications of radiotherapy, improving the quality of life of brain tumor patients

Dissemination of Cephalosporin Resistance Genes between Escherichia coli Strains from Farm Animals and Humans by Specific Plasmid Lineages

Third-generation cephalosporins are a class of β-lactam antibiotics that are often used for the treatment of human infections caused by Gram-negative bacteria, especially Escherichia coli. Worryingly, the incidence of human infections caused by third-generation cephalosporin-resistant E. coli is increasing worldwide. Recent studies have suggested that these E. coli strains, and their antibiotic resistance genes, can spread from food-producing animals, via the food-chain, to humans. However, these studies used traditional typing methods, which may not have provided sufficient resolution to reliably assess the relatedness of these strains. We therefore used whole-genome sequencing (WGS) to study the relatedness of cephalosporin-resistant E. coli from humans, chicken meat, poultry and pigs. One strain collection included pairs of human and poultry-associated strains that had previously been considered to be identical based on Multi-Locus Sequence Typing, plasmid typing and antibiotic resistance gene sequencing. The second collection included isolates from farmers and their pigs. WGS analysis revealed considerable heterogeneity between human and poultry-associated isolates. The most closely related pairs of strains from both sources carried 1263 Single-Nucleotide Polymorphisms (SNPs) per Mbp core genome. In contrast, epidemiologically linked strains from humans and pigs differed by only 1.8 SNPs per Mbp core genome. WGS-based plasmid reconstructions revealed three distinct plasmid lineages (IncI1- and IncK-type) that carried cephalosporin resistance genes of the Extended-Spectrum Beta-Lactamase (ESBL)- and AmpC-types. The plasmid backbones within each lineage were virtually identical and were shared by genetically unrelated human and animal isolates. Plasmid reconstructions from short-read sequencing data were validated by long-read DNA sequencing for two strains. Our findings failed to demonstrate evidence for recent clonal transmission of cephalosporin-resistant E. coli strains from poultry to humans, as has been suggested based on traditional, low-resolution typing methods. Instead, our data suggest that cephalosporin resistance genes are mainly disseminated in animals and humans via distinct plasmids

Comparative Modeling of a Parabolic Trough Collectors Solar Power Plant with MARS Models

Power plants producing energy through solar fields use a heat transfer fluid that lends itself to be influenced and changed by different variables. In solar power plants, a heat transfer fluid (HTF) is used to transfer the thermal energy of solar radiation through parabolic collectors to a water vapor Rankine cycle. In this way, a turbine is driven that produces electricity when coupled to an electric generator. These plants have a heat transfer system that converts the solar radiation into heat through a HTF, and transfers that thermal energy to the water vapor heat exchangers. The best possible performance in the Rankine cycle, and therefore in the thermal plant, is obtained when the HTF reaches its maximum temperature when leaving the solar field (SF). In addition, it is necessary that the HTF does not exceed its own maximum operating temperature, above which it degrades. The optimum temperature of the HTF is difficult to obtain, since the working conditions of the plant can change abruptly from moment to moment. Guaranteeing that this HTF operates at its optimal temperature to produce electricity through a Rankine cycle is a priority. The oil flowing through the solar field has the disadvantage of having a thermal limit. Therefore, this research focuses on trying to make sure that this fluid comes out of the solar field with the highest possible temperature. Modeling using data mining is revealed as an important tool for forecasting the performance of this kind of power plant. The purpose of this document is to provide a model that can be used to optimize the temperature control of the fluid without interfering with the normal operation of the plant. The results obtained with this model should be necessarily contrasted with those obtained in a real plant. Initially, we compare the PID (proportional–integral–derivative) models used in previous studies for the optimization of this type of plant with modeling using the multivariate adaptive regression splines (MARS) model