Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy.

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

Conformational inhibitors of protein aggregation.

Amyloidoses are fatal conditions associated with the aggregation of proteins into amyloid fibrils that deposit systemically and/or locally. Possibly because the causal mechanism of protein aggregation and deposition is not fully understood, this group of diseases remains uncurable. Advances in structural biology, such as the use of nuclear magnetic resonance and cryo-electron microscopy, have enabled the study of the structures and the conformational nature of the proteins whose aggregation is associated with the underlying pathogenesis of amyloidosis. As a result, the last years of research have translated into the development of directed therapeutic strategies that target the specific conformations of precursors, fibrils, and intermediary species. Current efforts include the use of small molecules, peptides, and antibodies. This review summarizes the recent progress in developing strategies that target specific protein conformations for the treatment of amyloidoses.

Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis.

Understanding early amyloidogenesis is key to rationally develop therapeutic strategies. Tau protein forms well-characterized pathological deposits but its aggregation mechanism is still poorly understood. Using single-molecule force spectroscopy based on a mechanical protection strategy, we studied the conformational landscape of the monomeric tau repeat domain (tau-RD244-368 ). We found two sets of conformational states, whose frequency is influenced by mutations and the chemical context. While pathological mutations Δ280K and P301L and a pro-amyloidogenic milieu favored expanded conformations and destabilized local structures, an anti-amyloidogenic environment promoted a compact ensemble, including a conformer whose topology might mask two amyloidogenic segments. Our results reveal that to initiate aggregation, monomeric tau-RD244-368 decreases its polymorphism adopting expanded conformations. This could account for the distinct structures found in vitro and across tauopathies.

Changes in the nutritional composition and antioxidant capacity of chia seeds (Salvia hispanica L.) during germination process.

This study aimed to evaluate the influence of germination on the content of protein, lipids, fiber, ashes, tryptophan, vitamin C, total phenolic and total flavonoid compounds, as well as on the protein digestibility and antioxidant activity of chia seeds germinated for 1, 2, 3, and 4 days. The results showed that germination for 2 days augmented the protein content of chia seeds by 13% while fiber, tryptophan, total phenolic and flavonoid contents increased by 46%, 93%, 300%, and 197%, respectively, after 4 days of germination. Vitamin C was not detected in dry seeds but increased up to 2.33 mg/100 g at fourth day of germination. The antioxidant capacity increased approximately 100% but protein digestibility decreased by 14% at day 4 of germination. Germination can be a good method to increase the nutritional and nutraceutical potential of chia seed for its use in the design of functional foods.

Personalidad situacional y síndrome de burnout en trabajadores de una institución especializada en rehabilitación / Situational personality and burnout syndrome in workers of a rehabilitation center

RESUMEN Objetivo Demostrar el nivel de correlación entre las dimensiones del síndrome de burnout y los factores de personalidad situacional en los trabajadores de una institución especializada en rehabilitación. Materiales y métodos Estudio de tipo no experimental, transversal y correlacional. Fueron 194 participantes entre personal asistencial y administrativo, nombrados y contratados, del Instituto Nacional de Rehabilitación, a quienes se les instruyó de manera individual para la aplicación personalizada del Maslach Burnout Inventory (MBI) y del Cuestionario de Personalidad Situacional (CPS). Resultados Existe un nivel mayor de agotamiento emocional en el personal asistencial en comparación con el personal administrativo. El agotamiento emocional se asocia, principalmente, a los factores de ansiedad, estabilidad emocional, agresividad y confianza y seguridad en sí mismo; mientras que la dimensión realización personal (RP) se relaciona más a las escalas de control cognitivo, eficacia, agresividad y confianza y seguridad en sí mismo. Conclusiones En este estudio, el síndrome de burnout demostró estar relacionado con algunas características de la personalidad situacional.

ABSTRACT Objective To demonstrate the correlation between the dimensions of burnout syndrome and the factors of situational personality in workers of a rehabilitation center. Materials and methods A non-experimental, cross-sectional and correlational study conducted with 194 participants belonging to the health and administrative personnel, as permanent or temporary employees, of the Instituto Nacional de Rehabilitación, who were individually instructed to answer the Maslach Burnout Inventory (MBI) and the Situational Personality Questionnaire (SPQ). Results The health personnel showed higher levels of psychological burnout than the administrative personnel. Psychological burnout was mainly associated with factors such as anxiety, emotional stability, aggressiveness, self- confidence and self-assurance, whereas the personal realization (PR) dimension was related, to a greater extent, to scales of cognitive control, efficacy, aggressiveness, self-confidence and self-assurance. Conclusions The study showed that the burnout syndrome is related to some characteristics of situational personality.

Molecular mechanism of the inhibition of TDP-43 amyloidogenesis by QBP1.

Transactive Response DNA-Binding Protein of 43 kDa (TDP-43) is an essential human protein implicated in Amyotrophic Lateral Sclerosis (ALS) and common dementias. Its C-terminal disordered region, composed of residues 264-414 includes a hydrophobic segment (residues 320-340), which drives physiological liquid/liquid phase separation and a Q/N-rich segment (residues 341-357), which is essential for pathological amyloid formation. Due to TDP-43's relevance for pathology, identifying inhibitors and characterizing their mechanism of action are important pharmacological goals. The Polyglutamine Binding Peptide 1 (QBP1), whose minimal active core is the octapeptide WGWWPGIF, strongly inhibits the aggregation of polyQ-containing amyloidogenic proteins such as Huntingtin. Rather promiscuous, this inhibitor also blocks the aggregation of other glutamine containing amyloidogenic proteins, but not Aß, and its mechanism of action remains unknown. Using a series of spectroscopic assays and biochemical tests, we establish that QBP1 binds and inhibits amyloid formation by TDP-43's Q/N-rich region. NMR spectroscopic data evince that the aromatic rings of QBP1 accept hydrogen bonds from the HN groups of the Asn and Gln to block amyloidogenesis. This mechanism of blockage may be general to polyphenol amyloid inhibitors.

Efficient and simplified nanomechanical analysis of intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) lack a tertiary structure. Amyloidogenic IDPs (aIDPs) in particular have attracted great interest due to their implication in several devastating diseases as well as in critical biological functions. However, the conformational changes that trigger amyloid formation in aIDPs are largely unknown. aIDPs' conformational polymorphism at the monomer level encumbers their study using bulk techniques. Single-molecule techniques like atomic force microscopy-based single-molecule force spectroscopy represent a promising approach and a "carrier-guest" strategy, in which the protein of interest is mechanically protected, was developed to overcome the spurious signals from the noisy proximal region. However, since the carrier and single-molecule markers have similar mechanostabilities, their signals can intermingle in the force-extension recordings, making peak selection and analysis very laborious, cumbersome and prone to error for the non-expert. Here we have developed a new carrier, the c8C module from the CipC scaffoldin, with a higher mechanostability so that the signals from the protected protein will appear at the end of the recordings. This assures an accurate, more efficient and expert-independent analysis, simplifying both the selection and analysis of the single-molecule data. Furthermore, this modular design can be integrated into any SMFS polyprotein-based vector, thus constituting a useful utensil in the growing toolbox of protein nanomechanics.

Ciencia y moral en la prevención de las enfermedades venéreas. La Sociedad Mexicana de Profilaxis Sanitaria y Moral, 1908-1923 / Science and morality in the prevention of venereal diseases. The Mexican Society for Sanitary and Moral Prophylaxis, 1908-1923

La Sociedad Mexicana de Profilaxis Sanitaria y Moral fue fundada en 1908 con el propósito de luchar contra las enfermedades venéreas. A diferencia de iniciativas anteriores de prevención que se centraban en el control sanitario de la prostitución, la Sociedad promovió la creación de dispensarios para la atención médica de los enfermos, así como la difusión de conocimientos por medio de conferencias y de propaganda impresa. Este artículo analiza las ideas que dieron lugar a la fundación de la Sociedad, los principales mensajes que buscaba difundir, los obstáculos y las críticas que enfrentó, y las causas que la llevaron a su disolución en 1923. El artículo muestra que la ciencia y la moral fueron dos elementos centrales que la Sociedad buscó promover, pues sus integrantes asumieron que las enfermedades venéreas eran un problema sanitario y moral, que debía prevenirse con el control de la voluntad y las pasiones, y llegado el caso, tratarse con la ayuda de médicos calificados (AU)

The Mexican Society for Sanitary and Moral Prophylaxis was founded in 1908 for the purpose of fighting against venereal diseases. Unlike previous prevention initiatives that focused on sanitary control of prostitution, the Society promoted the creation of dispensaries for medical care for the sick, and the dissemination of knowledge through lectures and printed propaganda. This article analyzes the ideas that led to the founding of the Society, the main messages which it sought to spread, obstacles and criticism it faced, and the causes that led to its dissolution in 1923. The article shows that science and morality were two core elements that the Society sought to promote, since its members assumed that venereal diseases concerned to public health and morals, and that they could be prevented by the control of the will and passions, and if necessary, treated with the help of qualified physicians (AU)

El empoderamiento en el ámbito de la gerontología clínica y social / Empowerment in a social and clinical gerontology context

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Evaluation of extracts from potato and tomato wastes as natural antioxidant additives

The industrialization of potato and tomato produces large amount of wastes. Previous studies have demonstrated that these by-products are rich in antioxidant compounds. In this study, the composition and antioxidant efficacy of extracts from potato and tomato by-products were determined in order to evaluate their potential as food additives. Potato and tomato wastes showed to be good sources of fiber, protein and antioxidants. The antioxidant activity and total phenolic, carotenoid and lycopene contents were determined in methanol, ethanol and acetone extracts of the residues. Methanol was the best solvent for the extraction of phenolics while acetone was the best in the extraction of carotenoids in both residues. The greatest antioxidant activity (14.10 µmol Trolox/g) resulted when potato peels were extracted with ethanol. The oxidative stability of canola oil containing either ethanol extracts of potato and tomato wastes (200 and 400 mg/kg) or the synthetic antioxidant BHT (200 mg/kg), compared to oil without antioxidants, was evaluated by measuring their peroxide values, conjugated dienes and p-anisidine value after 72 and 144 h storage at 65 °C. The order of antioxidant efficacy was as follows: potato peels > BHT > tomato residues. The results showed that ethanol extracts of potato and tomato waste could be used as natural antioxidant additives in the protection of vegetable oils(AU)

La industrialización de la papa y el jitomate genera grandes cantidades de desechos. Estudios previos han demostrado que estos subproductos son ricos en compuestos antioxidantes. En este trabajo se determinaron la composición y la eficacia antioxidante de subproductos de papa y jitomate con el fin de evaluar su potencial como aditivos alimentarios. Los desechos de papa y jitomate demostraron ser buenas fuentes de fibra, proteína y antioxidantes. Se determinó la actividad antioxidante y el contenido de compuestos fenólicos, carotenoides y licopeno en extractos metanólicos, etanólicos y acetónicos de los residuos. El mejor disolvente para la extracción de compuestos fenólicos fue el metanol mientras que la acetona fue el mejor disolvente para extraer los carotenoides. La mayor actividad antioxidante (14.10 µmol Trolox/g) se obtuvo cuando las cáscaras de papa se extrajeron con etanol. La estabilidad oxidativa de aceite de canola adicionado con los extractos etanólicos de desechos de papa o jitomate (200 y 400 mg/kg) o con el antioxidante sintético BHT (200 mg/kg), comparándolos con aceite sin antioxidantes, se evaluó mediante la medición de su índice de peróxidos, dienos conjugados e índice de anisidina, después de almacenarlo a 65°C durante 72 y 144 h. El orden de eficacia antioxidante fue como sigue: cáscara de papa > BHT > residuos de jitomate. Los resultados demostraron que los extractos etanólicos de los desperdicios de papa y jitomate podrían ser usados como aditivos antioxidantes naturales en la protección de aceites vegetales(AU)

Molecular Basis of Orb2 Amyloidogenesis and Blockade of Memory Consolidation.

Amyloids are ordered protein aggregates that are typically associated with neurodegenerative diseases and cognitive impairment. By contrast, the amyloid-like state of the neuronal RNA binding protein Orb2 in Drosophila was recently implicated in memory consolidation, but it remains unclear what features of this functional amyloid-like protein give rise to such diametrically opposed behaviour. Here, using an array of biophysical, cell biological and behavioural assays we have characterized the structural features of Orb2 from the monomer to the amyloid state. Surprisingly, we find that Orb2 shares many structural traits with pathological amyloids, including the intermediate toxic oligomeric species, which can be sequestered in vivo in hetero-oligomers by pathological amyloids. However, unlike pathological amyloids, Orb2 rapidly forms amyloids and its toxic intermediates are extremely transient, indicating that kinetic parameters differentiate this functional amyloid from pathological amyloids. We also observed that a well-known anti-amyloidogenic peptide interferes with long-term memory in Drosophila. These results provide structural insights into how the amyloid-like state of the Orb2 protein can stabilize memory and be nontoxic. They also provide insight into how amyloid-based diseases may affect memory processes.

Physico-chemical, nutritional and infrared spectroscopy evaluation of an optimized soybean/corn flour extrudate.

A central composite design using RMS (Response Surface Methodology) successfully described the effect of independent variables (feed moisture, die temperature and soybean proportion) on the specific parameters of product quality as expansion index (EI), water absorption index (WAI), water solubility index (WSI) and total color difference (ΔE) studied. The regression model indicated that EI, WAI, WSI and ΔE were significant (p < 0.05) with coefficients of determination (R(2)) of 0.7371, 0.7588, 0.7622, 0.8150, respectively. The optimized processing conditions were obtained with 25.8 % feed moisture, 160 °C die temperature and 58 %/42 % soybean/corn proportion. It was not found statistically changes in amino acid profile due to extrusion process. The electrophoretic profile of extruded soybean/corn mix presented low intensity molecular weight bands, compared to the unprocessed sample. The generation of low molecular weight polypeptides was associated to an increased in In vitro protein digestibility (IVPD) of the extrudate. The FTIR spectra of the soybean/corn mix before and after extrusion showed that the α-helix structure remained unchanged after extrusion. However, the band associated with ß-sheet structure showed to be split into two bands at 1624 and 1640 cm(-1) . The changes in the ß-sheet structures may be also associated to the increased in IVPD in the extruded sample.

Effect of germinated soy protein on the growth of HeLa cervical cancer cells in female athymic mice.

Previous studies showed that germination could improve the antiproliferative effect of soy protein on cervical cancer cells and that a peptide fraction (MAPF) from germinated soybeans decreases the expression of PTTG1 and TOP2A (2 genes considered as therapeutic targets) causing apoptosis of cancer cells. The aim of this work was to study the effect of feeding germinated soybean protein diets on the tumor growth in nude mice inoculated with cervical cancer cells and identify the bioactive component. Mice were randomly assigned to 1 of the 6 dietary groups based in AIN-93G formulation with 6 protein sources: casein, ungerminated soy protein (SP), and SP from 2 and 6 days of germination, with and without ethanol-soluble phytochemicals (ESPC). Compared with casein-fed controls, the tumor volumes after 5 wk were reduced by 44.6% by ungerminated SP, 98.9% by 2-day-germinated SP, 97.7% by 2-day-germinated SP without ESPC, 94.7% by 6-day-germinated SP, and 92.7% by 6-day-germinated SP without ESPC (P < 0.05). Liquid chromatography coupled with tandem mass spectrometry analysis of MAPF showed that the bioactive peptide might be the leginsulin, a peptide involved in signal transduction of soybean cells. Germination is a simple procedure that could help to increase the anticancer activity of soy protein probably through generation of biologically active peptides.

Mesenchymal dental stem cells in regenerative dentistry

In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration (AU)

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Mesenchymal dental stem cells in regenerative dentistry.

In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration.

A peptide fraction from germinated soybean protein down-regulates PTTG1 and TOP2A mRNA expression, inducing apoptosis in cervical cancer cells.

The aim of this study was to evaluate the effect of a peptide fraction, obtained from a germinated soybean protein hydrolysate, on the viability, apoptosis and cancer related gene expression in HeLa cells. Soybean was germinated for 0-6 days and proteins were isolated from the seeds. Protein isolates, without ethanol-soluble phytochemicals, were hydrolyzed with digestive enzymes and their effect on growth in HeLa cells was evaluated. The most active hydrolysate was separated by ultrafiltration into five peptide fractions. A >10 kDa fraction was the most active against cancer cells. This fraction down-regulated PTTG1 and TOP2A mRNA expression (two genes considered as therapeutic targets) and induced apoptosis in cancer cells activating the caspase cascade and causing DNA fragmentation. Germinated soy protein isolates could be a bioactive ingredient of functional food.

Effect of protein hydrolysates from germinated soybean on cancerous cells of the human cervix: an in vitro study.

Consumption of soybeans can reduce the risk of different types of cancer. Little is known about the effect of germination on the anticancer properties of soya. This study was done to determine if germination improves the anticancer properties of soybean protein through generation of amino acids or bioactive peptides. Soybean was germinated for 0, 2, 3, 4, 5, and 6 days and proteins were isolated from the seeds. Isolates with and without ethanol-soluble phytochemicals were hydrolyzed with digestive enzymes and their effect on growth in HeLa and C-33 (epidermoid cervical carcinoma) and HaCaT (non-cancerous human keratinocytes) cells were evaluated with the Alamar Blue method. Germination induced degradation of the alpha and alpha' fractions of beta-conglycinin and acid fraction of glycinin, generating low molecular weight peptides. Degrees of hydrolysis ranged from 73-77%. Hydrolysates inhibited the growth of HeLa cells and C-33 at concentrations exceeding 1.25 mg/ml. Major inhibition was observed with the hydrolysate germinated for 2 days and containing ethanolsoluble phytochemicals (IC(50) 2.15 and 2.27 mg/ml for HeLa and C-33, respectively). Interestingly, hydrolysate cytoxicity for normal cells was minimal in comparison to cancer cells.

Exogenous nucleosides accelerate differentiation of rat intestinal epithelial cells.

Several studies have reported differing data on the effect of exogenous nucleosides and nucleotides on the proliferation and differentiation in various intestinal cell lines and explants. To study whether exogenous nucleosides modulate intestinal cell differentiation, IEC-6 cells were differentiated in the presence or absence of a nucleoside mixture (cytidine, uridine, guanosine and inosine, 30 microM each), and the concentrations of nucleoside derivatives were determined by HPLC. Cell differentiation was assessed by electron microscopy, alkaline phosphatase activity and Rnd3 gene expression. The present results showed that uridine, guanosine and inosine were cleared from culture media (up to 32, 63 and 100 % in proliferating cells, and 31, 80 and 94 % in differentiated cells, respectively) whereas cytidine concentrations increased. Differentiation of IEC-6 cells was associated with a significant increase in intracellular nucleotide concentrations. Clearance of nucleosides correlated with a significant increase in the intracellular nucleotide pool in proliferating and differentiated IEC-6 cells. Intracellular guanosine nucleotides increased 2.5- and 5-fold in nucleoside-supplemented proliferating and differentiated cells, respectively. At 24 h, nucleoside-supplemented differentiated IEC-6 cells had significantly higher energy charge and GTP levels than non-supplemented ones. These modifications paralleled changes in cell differentiation as indicated by increased alkaline phosphatase activity, prolonged microvilli formation and accelerated down-regulation of Rnd3 gene expression. The present findings suggest that exogenous nucleosides were selectively taken up by IEC-6 cells, increased the intracellular nucleotide pool, GTP and energy charge, and favoured cell morphological and functional changes during differentiation.

Pharmacological study of antispasmodic activity of Mirabilis jalapa Linn flowers.

INTRODUCTION: Mirabilis jalapa Linn is a well-studied plant. The indigenous people of Mexico use Mirabilis jalapa to cure many infirmities including dysentery, diarrhea, muscular pain and abdominal colic. In the present investigation, we have further characterized some pharmacological properties of an extract of Mirabilis jalapa flowers; therefore, we intend to contribute to understand the pharmacological effects and clarify the complex use of this medicinal plant. RESULTS: The extract of Mirabilis jalapa (1-1000 mug/mL) exhibits an inhibitory effect (IC(50)=18+/-0.7 micorg/mL) on gut smooth muscle contractility whereas it stimulates the contraction of rabbit aortic muscle (EC(50)=11.60+/-0.26 micorg/mL) in a concentration-dependent manner. CONCLUSIONS: These effects were not due to either ACh or HIS receptors blockage, IP(3), cAMP, cGMP, Ca(2+) release from intracellular storage, or protein kinase mediated contraction-relaxation mechanisms. The effects inducted by the Mirabilis jalapa extract may involve a serotoninergic mechanism, which, in turn, interacts with other adrenergic systems. Further studies are necessary to identify the active compounds within the extract and to elucidate the mechanism of action.