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Apoptosi; Motoneurones; Atròfia muscular espinal Apoptosis; Motoneuronas; Atrofia muscular espinal Apoptosis; Motoneurons; Spinal muscular atrophy Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder caused by loss of the Survival Motor Neuron 1 gene (SMN1). Due to this depletion of the survival motor neuron (SMN) protein, the disease is characterized by the degeneration of spinal cord motoneurons (MNs), progressive muscular atrophy, and weakness. Nevertheless, the ultimate cellular and molecular mechanisms leading to cell loss in SMN-reduced MNs are only partially known. We have investigated the activation of apoptotic and neuronal survival pathways in several models of SMA cells. Even though the antiapoptotic proteins FAIM-L and XIAP were increased in SMA MNs, the apoptosis executioner cleaved-caspase-3 was also elevated in these cells, suggesting the activation of the apoptosis process. Analysis of the survival pathway PI3K/Akt showed that Akt phosphorylation was reduced in SMA MNs and pharmacological inhibition of PI3K diminished SMN and Gemin2 at transcriptional level in control MNs. In contrast, ERK phosphorylation was increased in cultured mouse and human SMA MNs. Our observations suggest that apoptosis is activated in SMA MNs and that Akt phosphorylation reduction may control cell degeneration, thereby regulating the transcription of Smn and other genes related to SMN function. This work was supported by grants from Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias, Unión Europea, Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” (PI17/00231 and PI20/00098) to RMS and AG; CERCA Program/Generalitat de Catalunya; and Spanish Agency of Research (Agencia Estatal de Investigacion-PID2019-107286RB-I00) and CIBERNED to JXC. AS holds a fellowship from Universitat de Lleida and SdF holds a fellowship from “Ajuts de Promoció de la Recerca en Salut” (IRBLleida-Diputació de Lleida). We thank Elaine Lilly, PhD, for English language revision of the paper.

A high level of transposon-mediated genome rearrangement is a common trait among microorganisms isolated from thermal environments, probably contributing to the extraordinary genomic plasticity and horizontal gene transfer (HGT) observed in these habitats. In this work, active and inactive insertion sequences (ISs) spanning the sequenced members of the genus Thermus were characterized, with special emphasis on three T. thermophilus strains: HB27, HB8, and NAR1. A large number of full ISs and fragments derived from different IS families were found, concentrating within megaplasmids present in most isolates. Potentially active ISs were identified through analysis of transposase integrity, and domestication-related transposition events of ISTth7 were identified in laboratory-adapted HB27 derivatives. Many partial copies of ISs appeared throughout the genome, which may serve as specific targets for homologous recombination contributing to genome rearrangement. Moreover, recruitment of IS1000 32 bp segments as spacers for CRISPR sequence was identified, pointing to the adaptability of these elements in the biology of these thermophiles. Further knowledge about the activity and functional diversity of ISs in this genus may contribute to the generation of engineered transposons as new genetic tools, and enrich our understanding of the outstanding plasticity shown by these thermophiles., This work was supported by grants BIO2016-77031-R from the Spanish Ministry of Economy and Competitiveness and grant nº 685474 from Horizon 2020 research and innovation program of the European Union. An institutional grant from Fundación Ramón Areces to the CBMSO is also acknowledged., We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is caused by the loss of survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration and loss of spinal cord motoneurons (MNs), muscular atrophy, and weakness. SMN2 is the centromeric duplication of the SMN gene, whose numbers of copies determine the intracellular levels of SMN protein and define the disease onset and severity. It has been demonstrated that elevating SMN levels can be an important strategy in treating SMA and can be achieved by several mechanisms, including promotion of protein stability. SMN protein is a direct target of the calcium-dependent protease calpain and induces its proteolytic cleavage in muscle cells. In this study, we examined the involvement of calpain in SMN regulation on MNs. In vitro experiments showed that calpain activation induces SMN cleavage in CD1 and SMA mouse spinal cord MNs. Additionally, calpain 1 knockdown or inhibition increased SMN level and prevent neurite degeneration in these cells. We examined the effects of calpain inhibition on the phenotype of two severe SMA mouse models. Treatment with the calpain inhibitor, calpeptin, significantly improved the lifespan and motor function of these mice. Our observations show that calpain regulates SMN level in MNs and calpeptin administration improves SMA phenotype demonstrating the potential utility of calpain inhibitors in SMA therapy. This work was financially supported by grants from the Instituto de Salud Carlos III, Fondo de Inversiones Sanitarias, Unión Europea, Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” (PI14/00060 and PI17/00231).

Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in motoneurons. NF-κB is one of the main regulators of motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF-κB pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-κB members and RelA phosphorylation. We describe the alteration of NF-κB pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-κB pathway as a candidate in this new therapeutic approach. This work was supported by grants from Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI14/00060), Unión Europea, Fondo europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa", and Generalitat de Catalunya (SGR740). AP holds a fellowship from Comissionat d’Universitats i Recerca, Departament d’Innovació, Universitats i Empresa de la Generalitat de Catalunya i Fons Social Europeu, SA and SdF hold a fellowship from Universitat de Lleida. We thank Elaine Lilly, Ph.D., for the English language revision of the manuscript.

Aim: To study whether mortality and cardiovascular morbidity differ in non-invasive ventilation (NIV)-treated patients with severe obesity-hypoventilation syndrome (OHS) as compared with CPAP-treated patients with obstructive sleep apnea syndrome (OSAS), and to identify independent predictors of mortality in OHS. Material and methods: Two retrospective cohorts of OHS and OSAS were matched 1:2 according to sex, age (±10 year) and length of time since initiation of CPAP/NIV therapy (±6 months). Results: Three hundred and thirty subjects (110 patients with OHS and 220 patients with OSAS) were studied. Mean follow-up time was 7±4 years. The five year mortality rates were 15.5% in OHS cohort and 4.5% in OSAS cohort (p< 0.05). Patients with OHS had a 2-fold increase (OR 2; 95% CI: 1.11–3.60) in the risk of mortality and 1.86 fold (OR 1.86; 95% CI: 1.14–3.04) increased risk of having a cardiovascular event. Diabetes, baseline diurnal SaO2 < 83%, EPAP < 7 cmH2O after titration and adherence to NIV < 4 hours independently predicted mortality in OHS. Conclusion: Mortality of severe OHS is high and substantially worse than that of OSAS. Severe OHS should be considered a systemic disease that encompasses respiratory, metabolic and cardiovascular components that require a multimodal therapeutic approach. SI

The Fourier-transform infrared (FTIR) technique has been used for both qualitative and quantitative determination in mineral species (McMillan et al., 1988; Pandya et al., 1992; Schroeder, 1992; Yanagisawa et al., 1997; Zhang et al., 1997). The method presents a number of important advantages: simple preparation, high sensitivity, and rapid analysis. The quantitative determination of minerals in the presence of glass is an interesting problem in mineralogy because X-ray diffraction (XRD) methods do not provide accurate results, especially for small mineral components. In this paper, we present a method for quantitative analysis of Al-rich smectite, mixed-layer illite-smectite (I-S), or illite in the presence of volcanic glass using FTIR. A series of hydrothermal-alteration reactions were made on volcanic tuff from the Cabo de Gata region, southeast Spain. The glass was crushed, ground, and calcined at 900°C for 2 h. After calcination, the fraction of 10–200 μm in size was selected. XRD and differential thermal and thermogravimetric analysis did not detect any phase other than glass. The glass chemical composition is: 72.89% SiO2, 14.47% Al2O3, 1.25% Fe2O3, 1.44% MgO, 0.86% CaO, 3.34% Na2O, 4.97% K2O. The hydrothermal reactions were made at 80, 120, and 160°C, for 60, 90, 180, and 360 d, in both deionized water and in solutions with K/Na ratios of 0.01, 0.1, 1, 10, and 100. The total ion concentrations were 1.01, 0.33, 0.20, 0.33, and 1.01 M. Five grams of glass were placed in 25 mL of solution for each reaction. The products of reaction were separated from the solutions and washed repeatedly with deionized water by centrifugation. The fraction of

ABO histo-blood group system is widely acknowledged as one of the antigenic systems most relevant to blood transfusion, but also cells, tissues and organs transplantation. This chapter will illustrate a series of subjects related to blood transfusion but will also give an overview of ABO related topics such as its genetics, biochemistry and its association to human disease as well as a historical section. We decided not to include much detail about the related Lewis oligosaccharide antigens which have been reviewed extensively elsewhere (Soejima & Koda 2005) in order to focus on ABO and allow the inclusion of novel and exciting developments.

espanolObjetivo: El objetivo de este estudio es determinar la repercusion de una consulta monografica para insuficiencia cardiaca cronica (ICC) y comorbilidad asociada,dirigida por internistas y enfermeria cualificada, sobre la hospitalizacion de estos pacientes. Material y Metodos: Estudio de cohortes prospectivo que incluye 456 pacientes ingresados en la unidad de Medicina Interna con ICC. Al alta los pacientes fueron distribuidos en dos grupos homogeneos, uno control que realizo seguimiento habitual, y otro de intervencion que fue seguido en consulta monografica de ICC. Se realizo un seguimiento desde en-06 hasta abril-09 y se compara en ambas cohortes el numero de visitas que realizan a urgencias, reingresos hospitalarios, promedio de reingresos y mortalidad en los ingresos. Resultados : Los pacientes del grupo intervenido frente a los del grupo control, acudieron a Urgencias significativamente menos (66% vs 155%) (p Conclusiones: El seguimiento por internistas y enfermeria de los pacientes con ICC y comorbilidad, basado en una atencion continuada e integral, en la informacion y en la disponibilidad; es un buen metodo para disminuir las visitas a urgencias y los reingresos, ademas de reducir la estancia y mortalidad hospitalaria. EnglishObjetive: The target of this study is to determine the impact of a monographic consultation for Chronic Heart Failure (CHF) which internists and specialized nursing have a main role, on the hospitalization of those patients. Material and Methods: Prospective cohort study included 456 patients admitted to the Internal Medicine Unit with CHF. Upon discharge patients were divided into two similar groups, one control group that went through routine monitoring, and one intervention group made of patients subject to monitoring through monographic consultation for CHF. The study was conducted from January 6th to April 9th. Both cohorts were compared in terms of the number of urgent service visits, hospital readmissions, readmission rates and mortality average at hospital admission. Results : The number of ER visits of patients subject to monitoring through monographic consultation as opposed to control group was considerably lower (66% vs 155%) (p Conclusion: In CHF and comorbility patients, following a health program in which internists and specialized nursing have a main role and which is based on a continuous and integral tracking, information / training and availability, is a good way to reducing urgents visits and readmissions, as well as reducing hospital stay and mortality.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by loss of the survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motoneurons (MNs), progressive skeletal muscle atrophy, and weakness. The cellular and molecular mechanisms causing MN loss of function are only partially known. Recent advances in SMA research postulate the role of calpain protease regulating survival motor neuron (SMN) protein and the positive effect on SMA phenotype of treatment with calpain inhibitors. We analyzed the level of calpain pathway members in mice and human cellular SMA models. Results indicate an increase of calpain activity in SMN-reduced MNs. Spinal cord analysis of SMA mice treated with calpeptin, a calpain inhibitor, showed an increase of SMN, calpain, and its endogenous inhibitor calpastatin in MNs. Finally, in vitro calpeptin treatment prevented microtubule-associated protein 1A/1B-light chain 3 (LC3) increase in MNs neurites, indicating that calpain inhibition may reduce autophagosome accumulation in neuron prolongations, but not in soma. Thus, our results show that calpain activity is increased in SMA MNs and its inhibition may have a beneficial effect on SMA phenotype through the increase of SMN in spinal cord MNs. This work was supported by grants from Instituto de Salud Carlos III, Fondo de Inversiones Sanitarias, Unión Europea, Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” (PI17/00231 and PI17/00134). CERCA Program/Generalitat de Catalunya. SdF holds a fellowship from Universitat de Lleida and “Ajuts de Promoció de la Recerca en Salut 2018” (IRBLLEIDA-Diputació de Lleida). AS holds a fellowship from Universitat de Lleida. AG holds a postdoctoral fellowship from Universitat de Lleida. We thank Dr. Manuel Portero from Metabolic Physiopathology Group, Universitat de Lleida-IRBLLEIDA for human iPSC differentiation protocol and assistance. We thank Elaine Lilly, PhD, for English language revision of the paper.

Spinal Muscular Atrophy (SMA), a neurodegenerative disorder primarily affecting motoneurons (MNs), is caused by the loss of the Survival Motor Neuron 1 (SMN1) gene and reduced levels of full-length survival motor neuron (SMN) protein. The exact cellular/molecular mechanisms involved in SMN-induced MN degeneration are under study. Autophagy is a degradation pathway whose precise roles in neurodegeneration remain largely unknown, but abnormal autophagy has a central role in some neurodegenerative diseases, including MN disorders. The analysis of the autophagy response in SMA and its role in the development of the disease could be essential to understand the disease. In the present work, we describe an increase of autophagosomes and LC3-II protein in spinal cord MNs of severe SMA mouse model. A time-course experiment demonstrated increased LC3-II levels from embryonic to postnatal stage, suggesting a deregulation of the autophagy process as the disease progressed. Using an in vitro model of MN culture, we analyzed the effect of autophagy modulators on Smn (murine survival motor neuron) protein level. Results suggest that the inhibitors of the autophagy flux cause reduction of Smn protein, whereas autophagy inducers increase the level of Smn protein in MNs. In order to evaluate other proteolytic systems involved to SMN degradation, we also studied the effect of the inhibition of the calcium-dependent protease, calpain, on Smn protein level. Our results demonstrate that calpain reduction increases Smn and LC3-II level in cultured MNs. Collectively, these results provide new insight into the role of autophagy and its modulation in SMN protein regulation.