Immunobiology of Prion Diseases

Prion diseases are invariably lethal neurodegenerative diseases, associated with the structural conversion of the cellular isoform of the prion protein to its pathological, disease-associated isoform. The cellular isoform of the prion protein is highly conserved and virtually ubiquitously expressed; nevertheless, its physiological role remains unclear. Mounting evidence suggests its involvement in the regulation and function of the immune system. At the same time, the immune system is heavily involved in the pathogenesis of the diseases, playing a major role in the peripheral replication of the infectious agent and spread toward the central nervous system. On the other hand, immunotherapies are among the most promising means of intervention. This chapter deals with these fascinating and sometimes contrasting aspects of prion biology, with an emphasis on the immunization protocols developed for prophylaxis and treatment of prion diseases

New multifunctional sulfonato-containing metal phosphonates proton conductors

Anchoring of acidic functional groups to organic linkers acting as ligands in metal phosphonates has been demonstrate to be a valid strategy to develop new proton conductor materials, which exhibit tunable properties and are potentially applicable to proton exchange membranes, such as those used in PEMFCs [1,2]. In this work, the structural and proton conductivity properties of several families of divalent and trivalent metal amino-sulfophosphonates are presented. The chosen ligand, (H2O3PCH2)2-N-(CH2)2-SO3H, was reacted with the appropriate metal salt using highthrough-put screening and/or microwave-assisted synthesis. Different crystal structures haven been solved displaying a variety of metal ligand coordination modes, in whose frameworks acidic groups contribute to create strong H-bond networks; together with lattice and bound water molecules. Proton conductivity values oscillate between 10-4 and 10-2 S.cm-1, at 80 ºC and 95 % relative humidity, most of them showing activation energies characteristic of a Grotthuss-type proton transport mechanism.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. MINECO: MAT2016-77648-R Junta de Andalucía: P-12-FQM-1656 y FQM-11

Species and Strain Glycosylation Patterns of PrPSc

). Both PrP isoforms bear two potential glycosylation sites and thus in a typical western blot with an anti-PrP antibody three distinct bands appear, corresponding to the di-, mono- or unglycosylated forms of the protein. The relative intensity and electrophoretic mobility of the three bands are characteristic of each TSE strain and have been used to discriminate between them. protein. and could play an accessory role in the appearance of some of the characteristic features of TSE strains. The differences in sugar composition could also be used as an additional tool for discrimination between the various TSEs

Layered Lanthanide Sulfophosphonates and Their Proton Conduction Properties in Membrane Electrode Assemblies

Metal phosphonates containing acidic groups exhibit a wide range of proton conduction properties, which may enhance the performance of membrane electrode assemblies (MEAs). In this work, focus is placed on proton conduction properties of coordination polymers derived from the combination of lanthanide ions with a phosphonate derivative of taurine (2-[bis(phosphonomethyl)amino]-ethanesulfonic acid, H5SP). High-throughput hydrothermal screening (140 °C) was used to reach optimal synthesis conditions and access pure crystalline phases. Seven compounds with the composition Ln[H(O3PCH2)2−NH−(CH2)2−SO3]·2H2O were isolated and characterized, which crystallize in two different structures, monoclinic m-LaH2SP and orthorhombic o-LnH2SP (Ln = Pr, Nd, Sm, Eu, Gd, and Tb), with unit cell volumes of ∼1200 and ∼2500 Å3, respectively. Their crystal structures, solved ab initio from X-ray powder diffraction data, correspond to different layered frameworks depending on the Ln3+ cation size. In the orthorhombic series, o-LnH2SP, the sulfonate group is noncoordinated and points toward the interlayer space, while for m-LaH2SP, both phosphonate and sulfonate groups coordinate to the Ln3+ centers. As a consequence, different H-bonding networks and proton transfer pathways are generated. Proton conductivity measurements have been carried out between 25 and 80 °C at 70−95% relative humidity. The Sm3+ derivative exhibits a conductivity of ∼1 × 10−3 S·cm−1 and activation energy characteristic of a Grotthuss-type mechanism for proton transfer. Preliminary MEA assays indicate that these layered lanthanide sulfophosphonates assist in maintaining the proton conductivity of Nafion membranes at least up to 90 °C and perform satisfactorily in single proton-exchange membrane fuel cells.Proyectos MAT2016-77648-R del MINECO y P12-FQM-1656 de la Junta de Andalucía Proyectos PROTONCELL ENE2017-86711-C3-1-R y REPICOMES ENE2017-90932-REDT y MAT2016-81001-P

Phase Transformation Dynamics in Sulfate-Loaded Lanthanide Triphosphonates. Proton Conductivity and Application as Fillers in PEMFCs

Phase transformation dynamics and proton conduction properties are reported for cationic layer-featured coordination polymers derived from the combination of lanthanide ions (Ln3+) with nitrilo-tris(methylenephosphonic acid) (H6NMP) in the presence of sulfate ions. Two families of materials are isolated and structurally characterized, i.e., [Ln2(H4NMP)2(H2O)4](HSO4)2·nH2O (Ln = Pr, Nd, Sm, Eu, Gd, Tb, Er, Yb; n = 4−5, Series I) and [Ln(H5NMP)]SO4· 2H2O (Ln = Pr, Nd, Eu, Gd, Tb; Series II). Eu/Tb bimetallic solid solutions are also prepared for photoluminescence studies. Members of families I and II display high proton conductivity (10−3 and 10−2 S·cm−1 at 80 °C and 95% relative humidity) and are studied as fillers for Nafion-based composite membranes in PEMFCs, under operating conditions. Composite membranes exhibit higher power and current densities than the pristine Nafion membrane working in the range of 70−90 °C and 100% relative humidity and with similar proton conductivity.Proyectos de Ministero de Ciencia e Innovación MAT2016-77648-R (MICINN/FEDER); PID2019-110249RB-I00 (MICINN/FEDER) y la Junta de Andalucía (FQM113). Funding for open access change: Universidad de Málaga/ CBU

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGF�)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGF� pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers

From Pillars to AI Technology-Based Forest Fire Protection Systems

The importance of forest environment in the perspective of the biodiversity as well as from the economic resources which forests enclose, is more than evident. Any threat posed to this critical component of the environment should be identified and attacked through the use of the most efficient available technological means. Early warning and immediate response to a fire event are critical in avoiding great environmental damages. Fire risk assessment, reliable detection and localization of fire as well as motion planning, constitute the most vital ingredients of a fire protection system. In this chapter, we review the evolution of the forest fire protection systems and emphasize on open issues and the improvements that can be achieved using artificial intelligence technology. We start our tour from the pillars which were for a long time period, the only possible method to oversee the forest fires. Then, we will proceed to the exploration of early AI systems and will end-up with nowadays systems that might receive multimodal data from satellites, optical and thermal sensors, smart phones and UAVs and use techniques that cover the spectrum from early signal processing algorithms to latest deep learning-based ones to achieving the ultimate goal

MicroRNA alterations in the brain and body fluids of human and animal príon disease models: current status and perspectives

Prion diseases are transmissible progressive neurodegenerative conditions characterized by rapid neuronal loss accompanied by a heterogeneous neuropathology, including spongiform degeneration, gliosis and protein aggregation. The pathogenic mechanisms and the origins of prion diseases remain unclear on the molecular level. Even though neurodegenerative diseases, including prion diseases, represent distinct entities, their pathogenesis shares a number of features including disturbed protein homeostasis, an overload of protein clearance pathways, the aggregation of pathological altered proteins, and the dysfunction and/or loss of specific neuronal populations. Recently, direct links have been established between neurodegenerative diseases and miRNA dysregulated patterns. miRNAs are a class of small non-coding RNAs involved in the fundamental post-transcriptional regulation of gene expression. Studies of miRNA alterations in the brain and body fluids in human prion diseases provide important insights into potential miRNA-associated disease mechanisms and biomarker candidates. miRNA alterations in prion disease models represent a unique tool to investigate the cause-consequence relationships of miRNA dysregulation in prion disease pathology, and to evaluate the use of miRNAs in diagnosis as biomarkers. Here, we provide an overview of studies on miRNA alterations in human prion diseases and relevant disease models, in relation to pertinent studies on other neurodegenerative diseases. KEYWORDS: CSF; blood; brain; microRNAs; neurodegenerative disorders; prion diseases; prion diseases animal models; sCJ

Cerebrospinal fluid neurofilament light in suspected sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human prion disease. It is invariably fatal and displays a short clinical disease stage. The key event in sCJD is the propagation of a beta-sheet rich conformer of the physiological PrPC protein, known as PrPSc. Neuropathological disease characteristics include gliosis, neuronal loss and spongiform degeneration; disease clinical manifestations refer to mental and visual disabilities, cognitive impairment, gait or limb ataxia, myoclonus and mutism. Definite sCJD diagnosis requires post-mortem brain material histopathological examination. However, highly certain pre-mortem differential diagnosis is desired to exclude other treatable disorders and to reduce disease transmission risks. Detection and/or quantification of cerebrospinal fluid (CSF) biomarkers reflecting neuronal damage and PrPC misfolding in the diseased brain significantly enhance pre-mortem diagnosis. Previously established and newly identified biomarkers are used towards this direction. Increased CSF Neurofilament light chain (NFL) concentrations have been reported in several neurological disorders, including prion diseases. In the present study, we analyzed CSF NFL levels in two independent patient cohorts, consisting of highly suspected sCJD cases that were further classified as sCJD or non-CJD according to established diagnostic criteria. CSF NFL concentrations were increased in sCJD compared to non-CJD cases in both cohorts (area under the curve (with 95% confidence interval) equal to 0.89 (0.82 to 0.97) and 0.86 (0.77 to 0.96), respectively. CSF NFL was associated neither to age nor to sex but correlated with total-tau concentrations in both cohorts. Overall, our data provide independent validation of CSF NFL utility in sCJD differential diagnosis

MicroRNA Alterations in the Brain and Body Fluids of Humans and Animal Prion Disease Models: Current Status and Perspectives

Prion diseases are transmissible progressive neurodegenerative conditions characterized by rapid neuronal loss accompanied by a heterogeneous neuropathology, including spongiform degeneration, gliosis and protein aggregation. The pathogenic mechanisms and the origins of prion diseases remain unclear on the molecular level. Even though neurodegenerative diseases, including prion diseases, represent distinct entities, their pathogenesis shares a number of features including disturbed protein homeostasis, an overload of protein clearance pathways, the aggregation of pathological altered proteins, and the dysfunction and/or loss of specific neuronal populations. Recently, direct links have been established between neurodegenerative diseases and miRNA dysregulated patterns. miRNAs are a class of small non-coding RNAs involved in the fundamental post-transcriptional regulation of gene expression. Studies of miRNA alterations in the brain and body fluids in human prion diseases provide important insights into potential miRNA-associated disease mechanisms and biomarker candidates. miRNA alterations in prion disease models represent a unique tool to investigate the cause-consequence relationships of miRNA dysregulation in prion disease pathology, and to evaluate the use of miRNAs in diagnosis as biomarkers. Here, we provide an overview of studies on miRNA alterations in human prion diseases and relevant disease models, in relation to pertinent studies on other neurodegenerative diseases