RESUMEN
Transcriptomics and phosphoproteomics were carried out in the cerebral cortex of B6.Cg-Mapttm1(EGFP)Klt (tau knockout: tau-KO) and wild-type (WT) 12 month-old mice to learn about the effects of tau ablation. Compared with WT mice, tau-KO mice displayed reduced anxiety-like behavior and lower fear expression induced by aversive conditioning, whereas recognition memory remained unaltered. Cortical transcriptomic analysis revealed 69 downregulated and 105 upregulated genes in tau-KO mice, corresponding to synaptic structures, neuron cytoskeleton and transport, and extracellular matrix components. RT-qPCR validated increased mRNA levels of col6a4, gabrq, gad1, grm5, grip2, map2, rab8a, tubb3, wnt16, and an absence of map1a in tau-KO mice compared with WT mice. A few proteins were assessed with Western blotting to compare mRNA expression with corresponding protein levels. Map1a mRNA and protein levels decreased. However, ß-tubulin III and GAD1 protein levels were reduced in tau-KO mice. Cortical phosphoproteomics revealed 121 hypophosphorylated and 98 hyperphosphorylated proteins in tau-KO mice. Deregulated phosphoproteins were categorized into cytoskeletal (n = 45) and membrane proteins, including proteins of the synapses and vesicles, myelin proteins, and proteins linked to membrane transport and ion channels (n = 84), proteins related to DNA and RNA metabolism (n = 36), proteins connected to the ubiquitin-proteasome system (UPS) (n = 7), proteins with kinase or phosphatase activity (n = 21), and 22 other proteins related to variegated pathways such as metabolic pathways, growth factors, or mitochondrial function or structure. The present observations reveal a complex altered brain transcriptome and phosphoproteome in tau-KO mice with only mild behavioral alterations.
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Proteostasis , Proteínas tau , Ratones , Animales , Ratones Noqueados , Proteínas tau/genética , Proteínas tau/metabolismo , Neuronas/metabolismo , Corteza Cerebral/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
Heterozygous hTau mice were used for the study of tau seeding. These mice express the six human tau isoforms, with a high predominance of 3Rtau over 4Rtau. The following groups were assessed: (i) non-inoculated mice aged 9 months (n = 4); (ii) Alzheimer's Disease (AD)-inoculated mice (n = 4); (iii) Globular Glial Tauopathy (GGT)-inoculated mice (n = 4); (iv) Pick's disease (PiD)-inoculated mice (n = 4); (v) control-inoculated mice (n = 4); and (vi) inoculated with vehicle alone (n = 2). AD-inoculated mice showed AT8-immunoreactive neuronal pre-tangles, granular aggregates, and dots in the CA1 region of the hippocampus, dentate gyrus (DG), and hilus, and threads and dots in the ipsilateral corpus callosum. GGT-inoculated mice showed unique or multiple AT8-immunoreactive globular deposits in neurons, occasionally extended to the proximal dendrites. PiD-inoculated mice showed a few loose pre-tangles in the CA1 region, DG, and cerebral cortex near the injection site. Coiled bodies were formed in the corpus callosum in AD-inoculated mice, but GGT-inoculated mice lacked globular glial inclusions. Tau deposits in inoculated mice co-localized active kinases p38-P and SAPK/JNK-P, thus suggesting active phosphorylation of the host tau. Tau deposits were absent in hTau mice inoculated with control homogenates and vehicle alone. Deposits in AD-inoculated hTau mice contained 3Rtau and 4Rtau; those in GGT-inoculated mice were mainly stained with anti-4Rtau antibodies, but a small number of deposits contained 3Rtau. Deposits in PiD-inoculated mice were stained with anti-3Rtau antibodies, but rare neuronal, thread-like, and dot-like deposits showed 4Rtau immunoreactivity. These findings show that tau strains produce different patterns of active neuronal seeding, which also depend on the host tau. Unexpected 3Rtau and 4Rtau deposits after inoculation of homogenates from 4R and 3R tauopathies, respectively, suggests the regulation of exon 10 splicing of the host tau during the process of seeding, thus modulating the plasticity of the cytoskeleton.
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Enfermedad de Alzheimer , Enfermedad de Pick , Tauopatías , Humanos , Ratones , Animales , Ratones Transgénicos , Proteínas tau/genética , Proteínas tau/metabolismo , Encéfalo/metabolismo , Hipocampo/metabolismoRESUMEN
Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau-WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)-were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula.
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Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Genotipo , Hipocampo/metabolismo , Tauopatías/etiología , Tauopatías/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Enfermedad de Alzheimer/patología , Animales , Biomarcadores , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Ratones , Ratones Noqueados , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Tauopatías/patologíaRESUMEN
Alzheimer's disease (AD) and other tauopathies are common neurodegenerative diseases in older adults; in contrast, abnormal tau deposition in neurons and glial cells occurs only exceptionally in children. Sarkosyl-insoluble fractions from sporadic AD (sAD) containing paired helical filaments (PHFs) were inoculated unilaterally into the thalamus in newborn and three-month-old wild-type C57BL/6 mice, which were killed at different intervals from 24 h to six months after inoculation. Tau-positive cells were scanty and practically disappeared at three months in mice inoculated at the age of a newborn. In contrast, large numbers of tau-positive cells, including neurons and oligodendrocytes, were found in the thalamus of mice inoculated at three months and killed at the ages of six months and nine months. Mice inoculated at the age of newborn and re-inoculated at the age of three months showed similar numbers and distribution of positive cells in the thalamus at six months and nine months. This study shows that (a) differences in tau seeding between newborn and young adults may be related to the ratios between 3Rtau and 4Rtau, and the shift to 4Rtau predominance in adults, together with the immaturity of connections in newborn mice, and (b) intracerebral inoculation of sAD PHFs in newborn mice does not protect from tau seeding following intracerebral inoculation of sAD PHFs in young/adult mice.
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Enfermedad de Alzheimer , Tauopatías , Animales , Encéfalo/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovillos Neurofibrilares/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
In this work, the production of biologically synthesized silica nanoparticles was proposed to prepare a nanosuspension as a thermal fluid in parabolic solar panels at the laboratory level. Silica nanoparticles were produced from construction sand in two stages. Biosynthesis broth was produced by Aspergillus niger aerated fermentation in a 1 L bioreactor for 9 days. Each supernatant was contacted with 18% construction sand in a 500 L reactor with mechanical agitation, at a temperature of 25 °C, and a contact time of 30 min. Subsequently, the separation process was carried out. For day 9, a pH value of 1.71 was obtained as well as acid concentrations of 15.78 g/L for citrus and 4.16 g/L for malic. The metal extraction efficiency of Si nanoparticles was 19%. The vibration peaks in the FTIR were characteristic of the presence of silica nanoparticles in wavenumbers 1020 cm-1 and 1150 cm-1. Finally, a prototype solar radiation test bench for parabolic systems was built and provided with a radiation source that falls on a translucent pipe that transports the nanoparticles, which has a pump and a series of thermocouples. The heat capacity of the biotechnologically produced silica nanoparticle suspension was 0.72 ± 0.05 kJ/kgK, using material and energy balances in the flow circuit.
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Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.
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Tauopatías/genética , Tauopatías/metabolismo , Tauopatías/patología , Proteínas tau/genética , Adulto , Animales , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mutación , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Neuronas/patología , Proteínas tau/metabolismoRESUMEN
Neuroinflammation has been correlated with the progress of neurodegeneration in many neuropathologies. Although glial cells have traditionally been considered to be protective, the concept of them as neurotoxic cells has recently emerged. Thus, a major unsolved question is the exact role of astroglia and microglia in neurodegenerative disorders. On the other hand, it is well known that glucocorticoids are the first choice to regulate inflammation and, consequently, neuroglial inflammatory activity. The objective of this study was to determine how chronic dexamethasone treatment influences the host immune response and to characterize the beneficial or detrimental role of glial cells. To date, this has not been examined using a natural neurodegenerative model of scrapie. With this aim, immunohistochemical expression of glial markers, prion protein accumulation, histopathological lesions and clinical evolution were compared with those in a control group. The results demonstrated how the complex interaction between glial populations failed to compensate for brain damage in natural conditions, emphasizing the need for using natural models. Additionally, the data showed that modulation of neuroinflammation by anti-inflammatory drugs might become a research focus as a potential therapeutic target for prion diseases, similar to that considered previously for other neurodegenerative disorders classified as prion-like diseases.
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Astrocitos/efectos de los fármacos , Dexametasona/farmacología , Microglía/efectos de los fármacos , Neuroglía/efectos de los fármacos , Scrapie/fisiopatología , Animales , Antiinflamatorios/farmacología , Astrocitos/citología , Astrocitos/metabolismo , Femenino , Estimación de Kaplan-Meier , Microglía/citología , Microglía/metabolismo , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/fisiopatología , Neuroglía/metabolismo , Proteínas Priónicas/metabolismo , Scrapie/diagnóstico , Scrapie/metabolismo , OvinosRESUMEN
Fatal familial insomnia is a rare disease caused by a D178N mutation in combination with methionine (Met) at codon 129 in the mutated allele of PRNP (D178N-129M haplotype). FFI is manifested by sleep disturbances with insomnia, autonomic disorders and spontaneous and evoked myoclonus, among other symptoms. This study describes new neuropathological and biochemical observations in a series of eight patients with FFI. The mediodorsal and anterior nuclei of the thalamus have severe neuronal loss and marked astrocytic gliosis in every case, whereas the entorhinal cortex is variably affected. Spongiform degeneration only occurs in the entorhinal cortex. Synaptic and fine granular proteinase K digestion (PrPres) immunoreactivity is found in the entorhinal cortex but not in the thalamus. Interleukin 6, interleukin 10 receptor alpha subunit, colony stimulating factor 3 receptor and toll-like receptor 7 mRNA expression increases in the thalamus in FFI. PrPc levels are significantly decreased in the thalamus, entorhinal cortex and cerebellum in FFI. This is accompanied by a particular PrPc and PrPres band profile. Altered PrP solubility consistent with significantly reduced PrP levels in the cytoplasmic fraction and increased PrP levels in the insoluble fraction are identified in FFI cases. Amyloid-like deposits are only seen in the entorhinal cortex. The RT-QuIC assay reveals that all the FFI samples of the entorhinal cortex are positive, whereas the thalamus is positive only in three cases and the cerebellum in two cases. The present findings unveil particular neuropathological and neuroinflammatory profiles in FFI and novel characteristics of natural prion protein in FFI, altered PrPres and Scrapie PrP (abnormal and pathogenic PrP) patterns and region-dependent putative capacity of PrP seeding.
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Insomnio Familiar Fatal/genética , Subunidad alfa del Receptor de Interleucina-10/genética , Interleucina-6/genética , Enfermedades por Prión/genética , Proteínas Priónicas/genética , Receptores del Factor Estimulante de Colonias/genética , Receptor Toll-Like 7/genética , Astrocitos/metabolismo , Astrocitos/patología , Corteza Entorrinal/metabolismo , Corteza Entorrinal/fisiopatología , Femenino , Gliosis/genética , Gliosis/fisiopatología , Humanos , Insomnio Familiar Fatal/fisiopatología , Masculino , Neuronas/metabolismo , Neuronas/patología , Enfermedades por Prión/fisiopatología , Tálamo/metabolismo , Tálamo/fisiopatologíaRESUMEN
AIMS: To explore alterations in the expression of genes encoding enzymes involved in purine metabolism in Parkinson's disease (PD) brains as purines are the core of the DNA, RNA, nucleosides and nucleotides which participate in a wide variety of crucial metabolic pathways. METHODS: Analysis of mRNA using real-time quantitative PCR of 22 genes involved in purine metabolism in the substantia nigra, putamen and cerebral cortex area 8 in PD at different stages of disease progression, and localization of selected purine metabolism-related enzymes with immunohistochemistry. RESULTS: Reduced expression of adenylate kinase 2 (AKA2), AK3, AK4, adenine phosphoribosyltransferase, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), ENTPD3, nonmetastatic cells 3, nucleoside-diphosphatese kinase 3 (NME1), NME7 and purine nucleoside phosphorylase 1 (PNP1) mRNA in the substantia nigra at stages 3-6; up-regulation of ADA mRNA in the frontal cortex area 8 at stages 3-4 and of AK1, AK5, NME4, NME5, NME6, 5'-nucleotidase (NT5E), PNP1 and prune homolog Drosophila at stages 5-6. There is no modification in the expression of these genes in the putamen at stages 3-5. CONCLUSIONS: Gene down-regulation in the substantia nigra may be interpreted as a consequence of dopaminergic cell death as ENTPD3, NME1,â NME7, AK1 and PNP1 are mainly expressed in neurons. Yet ENTPD1 and NT5E, also down-regulated in the substantia nigra, are expressed in astrocytes, probably pericytes and microglia, respectively. In contrast, gene up-regulation in the frontal cortex area 8 at advanced stages of the disease suggests a primary manifestation or a compensation of altered purine metabolism in this region.
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Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica , Enfermedad de Parkinson/genética , Purinas/metabolismo , Putamen/metabolismo , Sustancia Negra/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Astrocitos/metabolismo , Astrocitos/patología , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Microglía/metabolismo , Microglía/patología , Persona de Mediana Edad , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Putamen/patología , Sustancia Negra/patologíaRESUMEN
Inflammatory changes are analyzed in the anterior spinal cord and frontal cortex area 8 in typical spinal-predominant ALS cases. Increased numbers of astrocytes and activated microglia are found in the anterior horn of the spinal cord and pyramidal tracts. Significant increased expression of TLR7, CTSS, and CTSC mRNA and a trend to increased expression of IL10RA, TGFB1, and TGFB2 are found in the anterior lumbar spinal cord in ALS cases compared to control cases, whereas C1QTNF7 and TNFRSF1A mRNA expression levels are significantly decreased. IL6 is significantly upregulated and IL1B shows a nonsignificant increased expression in frontal cortex area 8 in ALS cases. IL-6 immunoreactivity is found in scattered monocyte-derived macrophages/microglia and TNF-α in a few cells of unknown origin in ALS cases. Increased expression and abnormal distribution of IL-1ß occurred in motor neurons of the lumbar spinal cord in ALS. Strong IL-10 immunoreactivity colocalizes with TDP-43-positive inclusions in motor neurons in ALS cases. The present observations show a complex participation of cytokines and mediators of the inflammatory response in ALS consistent with increased proinflammatory cytokines and sequestration of anti-inflammatory IL-10 in affected neurons.
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Esclerosis Amiotrófica Lateral/metabolismo , Encefalitis/metabolismo , ARN Mensajero/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/patología , Química Encefálica , Encefalitis/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neuronas Motoras/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Corteza Prefrontal/metabolismo , Médula Espinal/metabolismoRESUMEN
Tauopathies are neurodegenerative diseases characterized by hyper-phosphorylated tau deposition in neurons and glial cells. Chaperones, such as small heat shock proteins αB-crystallin and HSP27 highly expressed in normal glial cells, have been postulated as putative molecules preventing abnormal deposition and folding in glial cells in tauopathies. The objective of this work was to assess the expression of αB-crystallin, phosphorylated αB-crystallin at Ser59 and HSP27 in glial cells with and without tau deposits in progressive supranuclear palsy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick's disease (PiD), Alzheimer's disease, frontotemporal lobar degeneration associated with mutations in the tau gene (FTLD-tau), globular glial tauopathy (GGT) and tauopathy in the elderly. Immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy have been used for this purpose. Increased expression of αB-crystallin and phosphorylated αB-crystallin at Ser59 occurs in a subpopulation of glial cells with and without hyper-phosphorylated tau deposition in all the analyzed tauopathies, but their expression in neurons is restricted to ballooned neurons in CBD, AGD and PiD. HSP27 barely co-localizes with tau and with phosphorylated αB-crystallin at Ser59, thus making the formation of active dimers operating as chaperones unlikely. Results suggest a limited function of αB-crystallin and HSP27 in preventing abnormal tau protein deposition in glial cells and neurons; in addition, the expression of αB-crystallin phosphorylated at Ser59 may act as a protective factor in glial cells.
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Encéfalo/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Neuroglía/metabolismo , Tauopatías/metabolismo , Cadena B de alfa-Cristalina/metabolismo , Proteínas tau/metabolismo , Proteínas de Choque Térmico , Humanos , Chaperonas Moleculares , Neuronas/metabolismo , FosforilaciónRESUMEN
In this work, the bioremediation of wastewater from the textile industry with indigo dye content was carried out using combined bioaugmentation, bioventilation, and biostimulation techniques. Initially, the inoculum was prepared by isolating the microorganisms from the textile wastewater in a 2 L bioreactor. Then, the respirometry technique was implemented to determine the affinity of the microorganisms and the substrate by measuring CO2 and allowed the formulation of an empirical mathematical model for the growth kinetics of the microorganism. Finally, the bioremediation was carried out in a 3 L bioreactor obtaining an indigo dye removal efficiency of 20.7 ± 1.2%, 24.0 ± 1.5%, and 29.7 ± 1.1% for equivalent wavelengths of 436 nm, 525 nm, and 620 nm. The chemical oxygen demand showed an average reduction of 88.9 ± 2.5%, going from 470.7 ± 15.6 to 52.3 ± 10.7 ppm after 30 days under constant agitation and aeration. A negative generalized exponential model was fitted to assess the affinity of the microorganism with the wastewater as a substrate by evaluating the production of CO2 during the bioremediation. Bioremediation techniques improve water discharge parameters compared to chemical treatments implemented in the industry, reducing the use of substances that can generate secondary pollution. Bioaugmentation, biostimulation, and bioventing of the textile wastewater in this study demonstrate the potential of these combined techniques to serve as an efficient alternative for indigo-contaminated wastewater in the textile industry.
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Carmin de Índigo , Aguas Residuales , Biodegradación Ambiental , Dióxido de Carbono , Textiles , Industria TextilRESUMEN
The hippocampus of cases with neurofibrillary tangles (NFT) pathology classified as stages I-II, III-IV, and V-VI without comorbidities, and middle-aged (MA) individuals with no NFT pathology, were examined to learn about the composition of granulovacuolar degeneration (GVD). Our results confirm the presence of CK1-δ, p38-P Thr180/Tyr182, SAPK/JNK-P Thr183/Thr185, GSK-3α/ß-P Tyr279/Tyr216, and GSK-3ß Ser9 in the cytoplasmic granules in a subset of neurons of the CA1 and CA2 subfields of the hippocampus. Also, we identify the presence of PKA α/ß-P Thr197, SRC-P Tyr416, PAK1-P Ser199/Ser204, CAMK2A-P Tyr197, and PKCG-P Thr655 in cytoplasmic granules in cases with NFT pathology, but not in MA cases. Our results also confirm the presence of ß-catenin-P Ser45/Thr41, IREα-P Ser274, eIF2α-P Ser51, TDP-43-P Ser403-404 (but absent TDP-43), and ubiquitin in cytoplasmic granules. Other components of the cytoplasmic granules are MAP2-P Thr1620/1623, MAP1B-P Thr1265, ADD1-P Ser726, and ADD1/ADD1-P Ser726/Ser713, in addition to several tau species including 3Rtau, 4Rtau, and tau-P Ser262. The analysis of GVD at progressive stages of NFT pathology reveals the early appearance of phosphorylated kinases and proteins in cytoplasmic granules at stages I-II, before the appearance of pre-tangles and NFTs. Most of these granules are not surrounded by LAMP1-positive membranes. Markers of impaired ubiquitin-protesome system, abnormal reticulum stress response, and altered endocytic and autophagic pathways occur in a subpopulation of neurons containing cytoplasmic granules, and they appear later. These observations suggest early phosphorylation of kinases leading to their activation, and resulting in the abnormal phosphorylation of various substrates, including tau, as a main alteration at the first stages of GVD.
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Enfermedad de Alzheimer , Ovillos Neurofibrilares , Humanos , Persona de Mediana Edad , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Enfermedad de Alzheimer/metabolismo , Fosforilación , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas tau/metabolismo , Degeneración Nerviosa/patología , Hipocampo/metabolismo , Proteínas de Unión al ADN/metabolismo , Ubiquitinas/metabolismoRESUMEN
AIMS: (Phospho)proteomics of old-aged subjects without cognitive or behavioral symptoms, and without AD-neuropathological changes and lacking any other neurodegenerative alteration will increase understanding about the physiological state of human brain aging without associate neurological deficits and neuropathological lesions. METHODS: (Phospho)proteomics using conventional label-free- and SWATH-MS (Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) has been assessed in the frontal cortex (FC) of individuals without NFTs, senile plaques (SPs) and age-related co-morbidities classified by age (years) in four groups; group 1 (young, 30-44); group 2 (middle-aged: MA, 45-52); group 3 (early-elderly, 64-70); and group 4 (late-elderly, 75-85). RESULTS: Protein levels and deregulated protein phosphorylation linked to similar biological terms/functions, but involving different individual proteins, are found in FC with age. The modified expression occurs in cytoskeleton proteins, membranes, synapses, vesicles, myelin, membrane transport and ion channels, DNA and RNA metabolism, ubiquitin-proteasome-system (UPS), kinases and phosphatases, fatty acid metabolism, and mitochondria. Dysregulated phosphoproteins are associated with the cytoskeleton, including microfilaments, actin-binding proteins, intermediate filaments of neurons and glial cells, and microtubules; membrane proteins, synapses, and dense core vesicles; kinases and phosphatases; proteins linked to DNA and RNA; members of the UPS; GTPase regulation; inflammation; and lipid metabolism. Noteworthy, protein levels of large clusters of hierarchically-related protein expression levels are stable until 70. However, protein levels of components of cell membranes, vesicles and synapses, RNA modulation, and cellular structures (including tau and tubulin filaments) are markedly altered from the age of 75. Similarly, marked modifications occur in the larger phosphoprotein clusters involving cytoskeleton and neuronal structures, membrane stabilization, and kinase regulation in the late elderly. CONCLUSIONS: Present findings may increase understanding of human brain proteostasis modifications in the elderly in the subpopulation of individuals not having AD neuropathological change and any other neurodegenerative change in any telencephalon region.
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Enfermedad de Alzheimer , Enfermedades del Sistema Nervioso , Anciano , Humanos , Persona de Mediana Edad , Enfermedad de Alzheimer/metabolismo , Citoesqueleto/metabolismo , Encéfalo/metabolismo , Neuronas/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Monoéster Fosfórico Hidrolasas , Proteínas tau/metabolismoRESUMEN
Many studies available in the literature focus mainly on the mechanical characterization of fiber, leaving out other physicochemical and thermogravimetric analyses that allow for establishing its potential as an engineering material. This study characterizes fique fiber for its potential use as an engineering material. The fiber's chemical composition and physical, thermal, mechanical, and textile properties were analyzed. The fiber has a high holocellulose content and low lignin and pectin content, indicating its potential as a natural composite material for various applications. Infrared spectrum analysis revealed characteristic bands associated with multiple functional groups. The fiber had monofilaments with diameters around 10 µm and 200 µm, as determined by AFM and SEM images, respectively. Mechanical testing showed the fiber could resist a maximum stress of 355.07 MPa, with an average maximum strain at which breakage occurs of 8.7%. The textile characterization revealed a linear density range of 16.34 to 38.83 tex, with an average value of 25.54 tex and a regain of 13.67%. Thermal analysis showed that the fiber's weight decreased by around 5% due to moisture removal in the range of 40 °C to 100 °C, followed by weight loss due to thermal degradation of hemicellulose and glycosidic linkages of cellulose ranging from 250 to 320 °C. These characteristics suggest that fique fiber can be used in industries such as packaging, construction, composites, and automotive, among others.
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The exponential growth of electronic waste (e-waste) has raised significant environmental concerns, with projections indicating a surge to 74.7 million metric tons of e-waste generated by 2030. Waste printed circuit boards (WPCBs), constituting approximately 10% of all e-waste, are particularly intriguing due to their high content of valuable metals and rare earth elements. However, the presence of hazardous elements necessitates sustainable recycling strategies. This review explores innovative approaches to sustainable metal nanoparticle synthesis from WPCBs. Efficient metal recovery from WPCBs begins with disassembly and the utilization of advanced equipment for optimal separation. Various pretreatment techniques, including selective leaching and magnetic separation, enhance metal recovery efficiency. Green recovery systems such as biohydrometallurgy offer eco-friendly alternatives, with high selectivity. Converting metal ions into nanoparticles involves concentration and transformation methods like chemical precipitation, electrowinning, and dialysis. These methods are vital for transforming recovered metal ions into valuable nanoparticles, promoting sustainable resource utilization and eco-friendly e-waste recycling. Sustainable green synthesis methods utilizing natural sources, including microorganisms and plants, are discussed, with a focus on their applications in producing well-defined nanoparticles. Nanoparticles derived from WPCBs find valuable applications in drug delivery, microelectronics, antimicrobial materials, environmental remediation, diagnostics, catalysis, agriculture, etc. They contribute to eco-friendly wastewater treatment, photocatalysis, protective coatings, and biomedicine. The important implications of this review lie in its identification of sustainable metal nanoparticle synthesis from WPCBs as a pivotal solution to e-waste environmental concerns, paving the way for eco-friendly recycling practices and the supply of valuable materials for diverse industrial applications.
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OBJECTIVE: Psychological and physical distress commonly affect cancer patients. Acceptance and commitment therapy (ACT) has shown promising results when it comes to ameliorating symptoms that may develop as a result of this. Meanwhile, it has come to light that the impact of psychological interventions may be enhanced by the use of mobile applications. However, to date no mobile applications have been developed to support ACT-based interventions in cancer patients. The aim of the present study is to develop and test the usability of a mobile application designed to complement face-to-face ACT-based therapy in a group of cancer patients undergoing treatment. MATERIALS AND METHODS: A total of thirty-nine patients were recruited to participate in this pilot study. Participants had to be: 18 years of age or over, currently undergoing treatment for breast, lung or colorectal cancer, in stage I-III, a smartphone user with daily internet access. The intervention sessions were administered for a period of eight weeks, one hour per week to groups of four to six participants. Patients had the ACT-ON mobile application at their disposal, which provided them with access to therapy-related activities: mindfulness, metaphors and exercises to clarify values. RESULTS: The application obtained adequate adoption (61.54%) and usage (54.17%) rates. Usability and ease of learning scores were as follows: good usability (M = 79.81, SD = 11.87); high usability (M = 80.53, SD = 14.04); ease of learning (M = 37.5, SD = 23.85). DISCUSSION: This is the first study to develop and evaluate the usability of an application designed to support ACT-based interventions in cancer patients undergoing treatment. The results show that the ACT-ON app is a feasible tool which achieves high levels of usability. However, said results ought to be confirmed by studies that include a larger number of cancer patients.
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Terapia de Aceptación y Compromiso , Aplicaciones Móviles , Neoplasias , Humanos , Estudios de Factibilidad , Proyectos Piloto , Neoplasias/terapiaRESUMEN
Nanoparticle deposition on various substrates has gained significant attention due to the potential applications of nanoparticles in various fields. This review paper comprehensively analyzes different nanoparticle deposition techniques on ceramic, polymeric, and metallic substrates. The deposition techniques covered include electron gun evaporation, physical vapor deposition, plasma enriched chemical vapor deposition (PECVD), electrochemical deposition, chemical vapor deposition, electrophoretic deposition, laser metal deposition, and atomic layer deposition (ALD), thermophoretic deposition, supercritical deposition, spin coating, and dip coating. Additionally, the sustainability aspects of these deposition techniques are discussed, along with their potential applications in anti-icing, antibacterial power, and filtration systems. Finally, the review explores the importance of deposition purities in achieving optimal nanomaterial performance. This comprehensive review aims to provide valuable insights into state-of-the-art techniques and applications in the field of nanomaterial deposition.
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Parkinson disease (PD) is no longer considered a complex motor disorder characterized by parkinsonism but rather a systemic disease with variegated non-motor deficits and neurological symptoms, including impaired olfaction, sleep disorders, gastrointestinal and urinary abnormalities and cardiovascular dysfunction, in addition to other symptoms and signs such as pain, depression and mood disorders. Many of these alterations appear before or in parallel with motor deficits and then worsen with disease progression. Although there is a close relation between motor symptoms and the presence of Lewy bodies (LBs) and neurites filled with abnormal α-synuclein, other neurological alterations are independent of LBs, thereby indicating that different mechanisms probably converge in the degenerative process. This review presents cardinal observations at very early stages of PD and provides personal experience based on the study of a consecutive series of brains with PD-related pathology and without parkinsonism, mainly cases categorized as stages 2-3 of Braak. Alterations in the substantia nigra, striatum and frontal cortex in pPD are here revised in detail. Early modifications in the substantia nigra at pre-motor stages of PD (preclinical PD: pPD) include abnormal small aggregates of α-synuclein which is phosphorylated, nitrated and oxidized, and which exhibits abnormal solubility and truncation. This occurs in association with a plethora of altered molecular events including increased oxidative stress, altered oxidative stress responses, altered balance of L-ferritin and H-ferritin, reduced expression of neuronal globin α and ß chains in neurons with α-synuclein deposits, increased expression of endoplasmic reticulum stress markers, increased p62 and ubiquitin immunoreactivity in relation to α-synuclein deposits, and altered distribution of LC3 and other autophagosome/lysosome markers. In spite of the relatively small decrease in the number of dopaminergic neurons in the substantia nigra, which does not reach thresholds causative of parkinsonism, levels of tyrosine hydroxylase and cannabinoid 1 receptor are reduced, whereas levels of adenosine receptor 2A are increased in the caudate in pPD. Moreover, biochemical alterations are also present in the cerebral cortex (at least in the frontal cortex) in pPD including increased oxidative stress and oxidative damage to proteins α-synuclein, ß-synuclein, superoxide dismutase 2, aldolase A, enolase 1, and glyceraldehyde dehydrogenase, among others, indicating post-translational modifications of PD-related proteins, and suggesting altered function of pathways involved in glycolysis and energy metabolism in the cerebral cortex in pPD. Current evidence suggests convergence of several altered metabolic pathways leading to chronic neuronal dysfunction, mainly manifested as sub-optimal energy metabolism, altered synaptic function, oxidative and endoplasmic reticulum stress damage and corresponding altered responses, among others. By understanding that these alterations occur at very early stages of PD and that neuronal fatigue and exhaustion may precede, for years, cell death and neuronal loss, we may direct therapeutic strategies towards the prevention and delay of disease progression starting at pre-parkinsonian stages of PD.
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Neuronas/metabolismo , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Quinasa de la Caseína II/metabolismo , Progresión de la Enfermedad , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Hierro/metabolismo , Enfermedades Mitocondriales/etiología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Neuronas/ultraestructura , Estrés Oxidativo , Enfermedad de Parkinson/complicaciones , Sustancia Negra/metabolismo , Superóxido Dismutasa/metabolismo , Ubiquitinación/fisiología , alfa-Sinucleína/metabolismoRESUMEN
Sporadic amyotrophic lateral sclerosis (sALS) and FTLD-TDP are neurodegenerative diseases within the spectrum of TDP-43 proteinopathies. Since abnormal blood vessels and altered blood-brain barrier have been described in sALS, we wanted to know whether TDP-43 pathology also occurs in blood vessels in sALS/FTLD-TDP. TDP-43 deposits were identified in association with small blood vessels of the spinal cord in 7 of 14 cases of sALS and in small blood vessels of frontal cortex area 8 in 6 of 11 FTLD-TDP and sALS cases, one of them carrying a GRN mutation. This was achieved using single and double-labeling immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy. In the sALS spinal cord, P-TDP43 Ser403-404 deposits were elongated and parallel to the lumen, whereas others were granular, seldom forming clusters. In the frontal cortex, the inclusions were granular, or elongated and parallel to the lumen, or forming small globules within or in the external surface of the blood vessel wall. Other deposits were localized in the perivascular space. The present findings are in line with previous observations of TDP-43 vasculopathy in a subset of FTLD-TDP cases and identify this pathology in the spinal cord and frontal cortex in a subset of cases within the sALS/FTLD-TDP spectrum.