Brainiac Caspases: Beyond the Wall of Apoptosis

For the last two decades, caspases, a family of cysteine-aspartic proteases, have evolved from being considered solely as regulators of apoptosis or inflammation to having a wider range of functions. In this mini review, we focus on the most recent "non-apoptotic" roles of caspases in the CNS, particularly in neurons, astrocytes and oligodendrocytes. Non-apoptotic caspase functions in microglia have already been reviewed extensively elsewhere. Here we discuss the involvement of caspases in the activation of the inflammasome, autophagy, and non-apoptotic forms of cell death such as necroptosis and pyroptosis. Also, we review the involvement of caspases in synapses and the processing of aggregates key to neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. Likewise, we mention the recently described involvement of caspases in mitochondrial biogenesis, which is a function independent of the enzymatic activity. We conclude discussing the relevance that "new" functions of caspases have in the CNS and the future of this field of researchEspaña Ministerio de Economía y Competitividad SAF2015-64171- R (MINECO/FEDER, EU)España Ministerio de Economía y Competitividad (Programa Ramón y Cajal: RYC-2017-21804

Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson’s Disease

The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson’s disease. Brain inflammation, microglia and astroglia activation, disruption of the blood–brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3-positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra. Microglia activation was triggered earlier than other degenerative events, suggesting that over-activation of microglia (including different polarization states) may induce dopaminergic neuron loss by itself, initiating the endless cycle of inflammation/degeneration. Our study revitalizes the importance of peripheral inflammation as a potential risk factor for Parkinson’s disease and raises the possibility of using new anti-inflammatory therapies to improve the course of neurodegenerative diseases, including those directly aimed at modulating the deleterious activity of disease-associated microglia.España MINECO y FEDER SAF2015-64171-

Self-compacting concrete containing coarse recycled precast-concrete aggregate and its durability in marine-environment-related tests

Marine environments are extremely challenging for the long-term durability of concrete. Prior validation of concrete durability is therefore a prerequisite to guarantee its adequate performance under marine environmental conditions. In this study, the performance of Self-Compacting Concrete (SCC) with variable contents of coarse Recycled Precast-Concrete Aggregate (RPCA) and two different cement contents is assessed in terms of capillary water absorption, natural and accelerated carbonation, resistance to SO2 attack, and moist/dry performance in drinking water, marine water, and sulfate water. These tests are intended to simulate the conditions of a marine environment. In general, the results showed that an SCC containing coarse RPCA of adequate durability under marine conditions could be produced. On the one hand, porosity due to the presence of RPCA increased less as the cement content was increased, which in turn reduced water absorption and SCC carbonation. For example, the effective porosity of the SCC was reduced by 25 % between day 28 and day 180, following the addition of 100 % coarse RPCA. On the other hand, both the SO2-attack and the moist/dry tests revealed that the weight of the SCC with RPCA underwent greater variations, due to the reactions of the cementhydration products with chlorides and sulfates, as well as salt deposition. However, SCC compressive strength was never adversely affected, as the concrete strength increased up to 8 MPa after the drinking-water and the sulfate-water moist/dry tests when using RPCA. According to both Fick's and Parrot's models, the projected service life of all the mixes was over 100 years, regardless of the coarse RPCA content, making this sort of SCC a feasible option for construction in marine environments.This research work was supported by the Spanish Ministry of Universities, MICINN, AEI, EU, ERDF and NextGenerationEU/PRTR [grant numbers PID2020-113837RB-I00; 10.13039/501100011033; TED2021- 129715B-I00]; the Junta de Castilla y León (Regional Government) and ERDF [grant number UIC-231]; and, finally, the University of Burgos [grant number SUCONS, Y135.GI]

Cu-Catalyzed Silylation of Alkynes: A Traceless 2-Pyridylsulfonyl Controller Allows Access to either Regioisomer on Demand

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/jacs.5b02667The Cu-catalyzed silylation of terminal and internal alkynes bearing a 2-pyridyl sulfonyl group (SO2Py) at the propar-gylic position affords a breadth of vinyl silanes in good yields and excellent regio- and stereocontrol under mild conditions. The directing SO2Py group is essential in terms of reaction efficiency and chemoselectivity. Importantly, this group also provides the ability to reverse the regiochemical outcome of the reaction, opening the access to either regioisomer without modification of the starting substrate by virtue of an in situ base-promoted alkyne to allene equilibration which takes place prior to the silylcupration process. Furthermore, removal of the directing SO2Py allows for further elaboration of the silylation products. In particular, a one-pot tandem alkyne silylation/allylic substitution sequence, in which both steps are catalyzed by the same Cu species, opens up a new approach for the access to either formal hydrosilylation regioisomer of unsymmetrical aliphatic-substituted internal alkynes from propargyl sulfonesThis work was supported by the Ministerio de Economía y Com-petitividad (MINECO, CTQ2012-35790) and the European Union for a Marie Curie Career Integration Grant (to P.M). J. R. and P.M. thank MINECO for a FPI predoctoral fellowship and a Ramón y Cajal contract, respectivel

Strategic Management of IT Practices in Tourism for Operation and Service Enhancement.

The information technology infrastructure library (ITIL) standard describes processes that should be implemented in Information Technology (IT) departments for proper operations management, which includes human resources management, economic management, and strategic management, among others. This should be especially considered in the business management of industries with no relation to information technologies (IT), such as tourism and hospitality companies. This work aims to present a method to establish the order of adoption of the IT management processes in companies that belong to the tourism industry. We conducted a survey to obtain the necessary data and developed a methodology that is based on an optimization procedure. This procedure generates the optimal sequence of IT tasks to adopt in a generic small company in the tourism industry. The methodology was then applied to a representative tourism company. Through the sequence obtained, it is shown that it is necessary to implement operative processes, and subsequently, strategic processes. A comparative study was developed to find the differences with other authors’ proposals. The most important result we found was the possibility of efficient use of organizations’ information to build an optimized list of IT procedures to improve their administration. The obtained list of processes is specific for each organization, and not dependent on the solutions offered by other authors who proposed a general or underoptimal list of processes.2022-2

Reformulating Pro-Oxidant Microglia in Neurodegeneration

In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state's proinflammatory M1 (classical activation) and immunosuppressive M2 (alternative activation). Molecular signatures of DAM and proinflammatory microglia (highly pro-oxidant) have shown clear differences, yet a partial overlapping gene profile is evident between both phenotypes. The switch activation of homeostatic microglia into reactive microglia relies on the selective activation of key surface receptors involved in the maintenance of brain homeostasis (a.k.a. pattern recognition receptors, PRRs). Two relevant PRRs are toll-like receptors (TLRs) and triggering receptors expressed on myeloid cells-2 (TREM2), whose selective activation is believed to generate either a proinflammatory or a DAM phenotype, respectively. However, the recent identification of endogenous disease-related ligands, which bind to and activate both TLRs and TREM2, anticipates the existence of rather complex microglia responses. Examples of potential endogenous dual ligands include amyloid β, galectin-3, and apolipoprotein E. These pleiotropic ligands induce a microglia polarization that is more complicated than initially expected, suggesting the possibility that different microglia subtypes may coexist. This review highlights the main microglia polarization states under disease conditions and their leading role orchestrating oxidative stress

RepA-WH1 prionoid: Clues from bacteria on factors governing phase transitions in amyloidogenesis

10 p.-1 fig.In bacterial plasmids, Rep proteins initiate DNA replication by undergoing a structural transformation coupled to dimer dissociation. Amyloidogenesis of the ‘winged-helix’ N-terminal domain of RepA (WH1) is triggered in vitro upon binding to plasmid-specific DNA sequences, and occurs at the bacterial nucleoid in vivo. Amyloid fibers are made of distorted RepA-WH1 monomers that assemble as single or double intertwined tubular protofilaments. RepA-WH1 causes in E. coli an amyloid proteinopathy, which is transmissible from mother to daughter cells, but not infectious, and enables conformational imprinting in vitro and in vivo; i.e. RepA-WH1 is a ‘prionoid’. Microfluidics allow the assessment of the intracellular dynamics of RepA-WH1: bacterial lineages maintain two types (strains-like) of RepA-WH1 amyloids, either multiple compact cytotoxic particles or a single aggregate with the appearance of a fluidized hydrogel that it is mildly detrimental to growth. The Hsp70 chaperone DnaK governs the phase transition between both types of RepA-WH1 aggregates in vivo, thus modulating the vertical propagation of the prionoid. Engineering chimeras between the Sup35p/[PSI*] prion and RepA-WH1 generates [REP-PSI*], a synthetic prion exhibiting strong and weak phenotypic variants in yeast. These recent findings on a synthetic, self-contained bacterial prionoid illuminate central issues of protein amyloidogenesis.Research on RepA-WH1 amyloids at CIBCSIC is currently financed by Spanish MINECO grants BIO2012-30852 and CSD2009-00088.Peer reviewe

Protease technology for obtaining a soy pulp extract enriched in bioactive compounds: isoflavones and peptides

This work presents a new bioprocess process for the extraction of bioactive components from soy pulp by-product (okara) using an enzymatic technology that was compared to a conventional water extraction. Okara is rich in fiber, fat, protein, and bioactive compounds such as isoflavones but its low solubility hampers the use in food and fertilizer industry. After the enzymatic attack with endoproteases half of the original insoluble proteins were converted into soluble peptides. Linked to this process occured the solubilization of isoflavones trapped in the insoluble protein matrix. We were able to extract up to 62.5% of the total isoflavones content, specially aglycones, the more bioactive isoflavone forms, whose values rose 9.12 times. This was probably due to the increased solubilization and interconversion from the original isoflavones. In conclusion, our process resulted in the formulation of a new functional product rich in aglycones and bioactive peptides with higher antioxidant potency than the original source. Therefore, we propose that the enzymatic extraction of okara bioactive compounds is an advantageous tool to replace conventional extraction

Relevance of chronic stress and the two faces of microglia in Parkinson’s disease

This review is aimed to highlight the importance of stress and glucocorticoids (GCs) in modulating the inflammatory response of brain microglia and hence its potential involvement in Parkinson’s disease (PD). The role of inflammation in PD has been reviewed extensively in the literature and it is supposed to play a key role in the course of the disease. Historically, GCs have been strongly associated as anti-inflammatory hormones. However, accumulating evidence from the peripheral and central nervous system have clearly revealed that, under specific conditions, GCs may promote brain inflammation including pro-inflammatory activation of microglia. We have summarized relevant data linking PD, neuroinflamamation and chronic stress. The timing and duration of stress response may be critical for delineating an immune response in the brain thus probably explain the dual role of GCs and/or chronic stress in different animal models of P