Identificación de componentes moleculares sinápticos que contribuyen a la vulnerabilidad de los terminales nerviosos motores en un modelo múrido de atrofia muscular espinal

La Atrofia Muscular Espinal (AME), la causa genética más frecuente de mortalidad infantil, es una enfermedad neurodegenerativa autosómica recesiva caracterizada por la pérdida de las motoneuronas α de la médula espinal, debilidad muscular y parálisis progresiva de los músculos axiales y proximales. La AME está causada por la pérdida o mutación en homocigosis del gen de Supervivencia de Motoneuronas 1 (SMN1), que codifica para la proteína de Supervivencia de Motoneuronas (SMN). Esta proteína se expresa ubicuamente y es importante en el ensamblaje de las ribonucleoproteínas pequeñas nucleares (snRNP). En modelos de ratón de AME, la liberación de neurotransmisor está gravemente alterada. Sin embargo, los mecanismos moleculares de la disfunción sináptica y las bases de la vulnerabilidad muscular selectiva se desconocen. Los objetivos del presente estudio fueron obtener una visión más profunda del origen del déficit de la liberación de neurotransmisor en los terminales nerviosos motores, e investigar las bases moleculares de la vulnerabilidad muscular selectiva en AME. Con este fin, se compararon las propiedades moleculares y funcionales de los terminales nerviosos en músculos con diferente grado de vulnerabilidad en el modelo de ratón SMNΔ7 usando técnicas electrofisiológicas, inmunomarcaje, microscopia de fluorescencia confocal y análisis cuantitativo de imágenes. Los resultados muestran que los niveles de expresión de sinaptotagmina-2 (Syt2), y su proteína de interacción, la proteína de la vesícula sináptica 2 (SV2) B, estaban muy reducidos en los terminales AME en comparación con los controles, mientras que otras proteínas sinápticas, como sintaxina-1B ( Stx1B) y sinaptotagmina-7 (Syt7), no se vieron afectados. También se encontró que sinaptotagmina-1 (Syt1) se somete a un proceso de regulación fisiológica a la baja durante el desarrollo postnatal en los terminales nerviosos de los músculos más vulnerables, pero no en los menos afectados, lo que podría ser particularmente crítico cuando Syt2 está también patológicamente disminuida. Además, los ratones SMN7 muestran una reducción en la densidad de los canales de Ca2+ dependientes de voltaje tipo P/Q en la unión neuromuscular. En consonancia con la reducción de los canales de Ca2+ y el bajo contenido de Syt2, Syt1 y SV2B en las sinapsis neuromusculares más afectadas, el análisis funcional de la neurotransmisión reveló una gran reducción en la liberación evocada, una alteración de la plasticidad a corto plazo, una baja probabilidad de liberación y la incapacidad para modular normalmente el número de sitios de liberación activos. Por último, a pesar de las alteraciones estructurales y funcionales que caracterizan a los terminales nerviosos motores en AME, todavía conservan la capacidad de regular positivamente, en cierta medida, la neurotransmisión en presencia de moduladores de la liberación sináptica. Conjuntamente, proponemos que la gran reducción de Syt2 y SV2B es un factor clave en el déficit funcional sináptico y que la regulación fisiológica de Syt1 juega un papel determinante en la vulnerabilidad muscular selectiva en AME.Spinal Muscular Atrophy (SMA), the most frequent genetic cause of infant mortality, is an autosomal recessive neurodegenerative motor neuron disease characterized by the loss of spinal cord α-motoneurons, muscle weakness and progressive paralysis of axial and proximal limb muscles. SMA is caused by the homozygous loss or mutation of the Survival Motorneuron 1 (SMN1) gene, which codes for the Survival Motor Neuron (SMN) protein. This protein is ubiquitously expressed, and it is important in the assembly of small nuclear ribonucleoproteins (snRNPs). In SMA mouse models, neurotransmitter release is greatly impaired. However, the molecular mechanisms of the synaptic dysfunction and the basis of the selective muscle vulnerability are unknown. The aims of the present study were to get a deeper insight into the origin of the neurotransmitter release deficit at motor nerve terminals, and investigate the molecular basis of selective muscle vulnerability in SMA. To this end, we compared the molecular and functional properties of nerve terminals in muscles with different degree of vulnerability in the SMNΔ7 mouse model using electrophysiological techniques, immunostaining, confocal fluorescent microscopy, and quantitative imaging analysis. The results show that the expression levels of synaptotagmin-2 (Syt2), and its interacting protein, synaptic vesicle protein 2 (SV2) B, were highly reduced in SMA terminals in comparison with controls, while other synaptic proteins, as syntaxin-1B (Stx1B) and synaptotagmin-7 (Syt7) were unaffected. We also found that synaptotagmin-1 (Syt1) undergoes a process of physiological downregulation during the postnatal development in nerve terminals of the most vulnerable muscles, but not in the least affected, what could be particularly critical when Syt2 is also pathologically decreased. Additionally, SMN7 mice show a reduction in the density of P/Q-type voltage dependent Ca2+ channels in the neuromuscular junction. Consistently with the reduction of Ca2+ channels and the low content of Syt2, Syt1, and SV2B in most affected neuromuscular synapses, functional analysis of neurotransmission revealed a great reduction in evoked release, impaired short term plasticity, low release probability and inability to modulate normally the number of active release sites. Finally, despite the structural and functional alterations which characterize the motor nerve terminals in SMA, they still retain the ability to upregulate, to certain extend, neurotransmission in the presence of modulators of synaptic release. Together, we propose that the large reduction of Syt2 and SV2B are crucial factors of the functional synaptic deficit and that the physiological downregulation of Syt1 plays a determinant role in selective muscle vulnerability in SMA.Premio Extraordinario de Doctorado U

Calcium is reduced in presynaptic mitochondria of motor nerve terminals during neurotransmission in SMA mice

Spinal muscular atrophy (SMA) is an autosomal recessive degenerative motor neuron disease characterized by symmetrical muscle weakness and atrophy of limb and trunk muscles being the most severe genetic disease in children. In SMA mouse models, motor nerve terminals display neurotransmitter release reduction, endocytosis decrease and mitochondria alterations. The relationship between these changes is, however, not well understood. In the present study, we investigated whether the endocytosis impairment could be related to the functional alteration of the presynaptic mitochondria during action potential (AP) firing. To this aim, we generated a Synaptophysin-pHluorin (SypHy) transgenic mouse, crossed it with Taiwanese SMA mice, and recorded exo- and endocytosis and mitochondria Ca2+ signaling in real-time at ex vivo motor nerve terminals of Taiwanese-SypHy mice. The experiments were performed at the beginning of the motor symptoms to get an integrated view of the nerve terminal’s functional state before degeneration. Our electrophysiological and live imaging results demonstrated that the mitochondria’s capacity to increase matrix-free Ca2+ in SMA mice was significantly limited during nerve AP firing, except when the rate of Ca2+ entry to the cytosol was considerably reduced. These results indicate that both the mitochondrial Ca2+ signaling alterations and the secretion machinery defects are significant players in the dysfunction of the presynaptic terminal in SMA

Recent freshening and cooling of Biscay subsurface waters

The monitoring program Radiales (https://www.seriestemporales-ieo.net/) by the Spanish Institute of Oceanography, has been providing hydrographical and biogeochemical series in marine waters around Spain on a monthly basis from early 90's. The proximity of the shelf-break in front of the city of Santander (SE Bay of Biscay) allowed tracking intermediate and deep waters along the standard section perpendicular to this city for three decades (sampling was limited to 1000 meter until late 2007, then extended to 1500 m, and full-depth 2400 m since 2014). From the start of the sampling in nearly 90`s, subsurface waters showed unabated warming and salt-increase. Warming was linked to isopycnal sinking (heave) during the 90`s and early 00`s until the occurrence of very strong winter mixing in 2005 that shifted quickly the salinity down to lower East North Atlantic Central Waters (ENACW) levels (ca. 400 m). Overall, warming and salt-increase at the core of ENACW added up to 0.3ºC and 0.08 in salinity within only two and a bit decades. In 2014, the upper central waters showed freshening and cooling for the first time in the series, a process that enhanced in the following years especially in salinity that currently (2021) presents the lowest value of the overall timeseries. This shift in regional hydrography follows the large salinity drop observed in the subpolar gyre around 2012 and its subsequent expansion downstream into the subtropical gyre and subarctic seas. This regime shift implies that subsurface environmental conditions in the region have returned back to 90`s state, contrasting to the uppermost waters which continue to show large positive anomalies. The effects of this cold and freshwater inflow in the regional circulation of southern Biscay are discussed

An elicitor isolated from smut teliospores (Sporisorium scitamineum) enhances lignin deposition on the cell wall on both sclerenchyma and xylem in sugarcane leaves

Sugarcane leaf shows the classical arrangement of cells which defines a C4 species. Vascular bundles consist of xylem, phloem and fibres, surrounded by an outer layer of sclereids and an inner ring of stone cells associated with the phloem. Some sclereids located below and above the vascular bundles act as docking cells and connect the vascular bundle to the internal surfaces of upper and lower layers of the epidermis. A compact mass of sclereids occupies the total internal volume of the leaf edge. Neither docking cells nor the internal mass of sclereids in the edge were markedly coloured by acriflavin or phloroglucinol, indicating the absence of lignin in their cell walls. However, such staining indicated that fibres of the vascular bundle and the external layer of sclereids were strongly lignified. Incubation of leaf discs with an elicitor produced by the pathogen Sporisorium scitamineum increased the thickness of the lignified cell walls of sclereids as well as the mid and small xylem vessels, as a possible mechanical defense response to the potential entry of the pathogen

¿Son el bajo nivel de condición física y la obesidad dos características del adolescente con síndrome de Down?

Introduction: “Obesity” is considered a feature of youth with DS but whether “low physical fitness” is also a feature is unknown. Objective: The aim of this case-control study was to compare the levels of fatness and fitness in adolescents with and without DS. Methods: Participants included 17 (5 girls) adolescents with DS aged 12-18 years and a control group of 94 (45 girls) adolescents without DS aged 12-16 years. The ALPHA health-related fitness test battery for children and adolescents was selected to assess fatness and fitness in both groups. Results: There were no differences in levels of fatness between groups (all P > 0.27). Adolescents with DS had lower levels of fitness in all the tests than adolescents without DS (all P < 0.001). Conclusion: Adolescents with DS have similar levels of fatness and lower levels of fitness than their peers without DSIntroducción: La obesidad es considerada una característica de los jóvenes con SD, sin embargo se desconoce si la “baja condición física” también lo es. Objetivo: Comparar los niveles de obesidad y condición física en adolescentes con y sin SD. Métodos: Participaron 17 adolescentes (5 niñas) con SD de 12 a 18 años y un grupo control de 94 (45 niñas) adolescentes sin SD de 12-16 años de edad. La batería de condición física ALPHA relacionada con la salud para niños y adolescentes fue seleccionada para evaluar la obesidad y la condición física en ambos grupos. Resultados: No se encontraron diferencias en los niveles de obesidad entre grupos (P > 0,27). Los adolescentes con SD tuvieron niveles más bajos de condición física en todos los test en comparación con los adolescentes sin SD (P < 0,001). Conclusión: Los adolescentes con SD tienen niveles similares de obesidad y menores de condición física que sus compañeros sin SD.The UP&DOWN study was supported by the Spanish Ministry of Economy and Competitiveness (DEP 2010-21662-C04). JRR was supported by a contract from the Spanish Ministry of Science and Innovation (RYC-2010-05957

Spanish Teacher Education Students’ Values and Satisfaction with Life

The main purposes of this study were to describe teacher education students’ values and degree of satisfaction with life, to analyze whether any differences by educational program, gender or living standard and to analyze the association between values and satisfaction with life. A total of 565 students of teacher degree programs (girls 415 (73.5%)) answered a self-administered questionnaire composed by two validates scales about their values (Portrait Values Questionnaire (PVQ) and satisfaction with life (Satisfaction with Life Scale)). The results showed that the most important values were self-direction, benevolence and hedonism, while the least important values were power, tradition and achievements. Females reported higher importance for benevolence, universalism, self-direction, stimulation, hedonism and security. Males reported higher importance for power. Students who live with family reported also more high values for power. Concerning satisfaction with life, it was associated to higher values of power. Current intervention programs have focused different approaches by gender and living standard. Programs focus on increasing satisfaction with life should consider the values structure of students

BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases

Correction: A feasible pathway to stabilize monoclinic and tetragonal phase coexistence in barium titanate-based ceramics

Depto. de Física de MaterialesFac. de Ciencias FísicasTRUEpu

In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/β-catenin activation

The present study investigates the differential effect of two vitamin D receptor agonists, calcitriol and paricalcitol, on human aortic smooth muscle cells calcification in vitro. Human vascular smooth muscle cells were incubated in a high phosphate (HP) medium alone or supplemented with either calcitriol 10−8M (HP + CTR) or paricalcitol 3·10−8 M (HP + PC). HP medium induced calcification, which was associated with the upregulation of mRNA expression of osteogenic factors such as bone morphogenetic protein 2 (BMP2), Runx2/Cbfa1, Msx2, and osteocalcin. In these cells, activation of Wnt/β-catenin signaling was evidenced by the translocation of β-catenin into the nucleus and the increase in the expression of direct target genes as cyclin D1, axin 2, and VCAN/versican. Addition of calcitriol to HP medium (HP + CTR) further increased calcification and also enhanced the expression of osteogenic factors together with a significant elevation of nuclear β-catenin levels and the expression of cyclin D1, axin 2, and VCAN. By contrast, the addition of paricalcitol (HP + PC) not only reduced calcification but also downregulated the expression of BMP2 and other osteoblastic phenotype markers as well as the levels of nuclear β-catenin and the expression of its target genes. The role of Wnt/β-catenin on phosphate- and calcitriol-induced calcification was further demonstrated by the inhibition of calcification after addition of Dickkopf-related protein 1 (DKK-1), a specific natural antagonist of the Wnt/β-catenin signaling pathway. In conclusion, the differential effect of calcitriol and paricalcitol on vascular calcification appears to be mediated by a distinct regulation of the BMP and Wnt/β-catenin signaling pathways

A feasible pathway to stabilize monoclinic and tetragonal phase coexistence in barium titanate-based ceramics

Multiphase coexistence has attracted significant interest in recent years because its control has entailed a significant breakthrough for the piezoelectric activity enhancement of lead-free piezoelectric oxides. However, the comprehension of phase coexistence still has many controversies including an adequate synthesis process and/or the role played by crystalline phases in functional properties. In this study, functional barium titanate [BaTiO_(3), (BTO)]-based materials with tunable functional properties were obtained by compositional modification via Bismuth (Bi) doping. Towards this aim, we systematically synthesized BTO-based materials by a sol-gel method, focusing on the control of Bi substitution in the BaTiO_(3) structure. In particular, we found that the substitution of Bi^(+3) leads to the stabilization of a monoclinic-tetragonal (M-T) phase boundary close to room temperature, which facilities the polarization process of the system. As a surprising result, we believe that the simple and cost-effective strategy and design principles described in this work open up the possibility of obtaining BTO-based lead-free ceramics with enhanced properties induced by the stabilization of the phase coexistence, expanding their application range