PLANIFICACION FISCAL DE LA TRANSMISION INTERGENERACIONAL DE LA EMPRESA FAMILIAR

El principal objetivo del trabajo es, con el fin de realizar una planificación fiscal óptima, observar los aspectos fiscales que deben tener en cuenta las empresas familiares ante la posibilidad de transmitir su empresa a futuras generaciones. El trabajo de investigación se compone de dos partes, una conceptual y otra analítica. La parte conceptual se basa, en primer lugar, en explicar el término de Empresa Familiar para, posteriormente, estudiar su relevancia e importancia en la economía española. La parte analítica consistirá en analizar la planificación fiscal que deben tener en cuenta este tipo de empresas haciendo referencia a dos tributos: el Impuesto sobre el Patrimonio y el Impuesto sobre Sucesiones y Donaciones. Para realizar el análisis del Impuesto sobre Sucesiones y Donaciones nos vamos centrar en la normativa estatal y aragonesa. En definitiva, el trabajo tiene como finalidad profundizar en la siguiente pregunta ¿qué beneficios fiscales ostentan las empresas familiares aragonesas para su transmisión intergeneracional?<br /

Expression and Functionality Study of 9 Toll-Like Receptors in 33 Drug-Naïve Non-Affective First Episode Psychosis Individuals: A 3-Month Study

Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1?9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1?9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-?) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory respons

MKK6 controls T3-mediated browning of white adipose tissue

El aumento de la capacidad termogénica del tejido adiposo para mejorar el gasto de energía del organismo se considera una estrategia terapéutica prometedora para combatir la obesidad. Aquí nosotros informe que la expresión del activador MAPK p38 MKK6 está elevada en el tejido adiposo blanco de individuos obesos. Usando animales knockout y shRNA, mostramos que la eliminación de Mkk6 aumenta el gasto de energía y la capacidad termogénica del tejido adiposo blanco, protegiendo a los ratones contra la obesidad inducida por la dieta y el desarrollo de la diabetes. La eliminación de Mkk6 aumenta la expresión de UCP1 estimulada por T3 en los adipocitos, lo que aumenta su capacidad termogénica. De manera mecánica, demostramos que, en el tejido adiposo blanco, p38 se activa mediante una ruta alternativa que involucra AMPK, TAK y TAB. Nuestros resultados identifican MKK6 en los adipocitos como un posible objetivo terapéutico para reducir la obesidad.Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals. Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UCP1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically, we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB. Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.• Guadalupe Sabio Buzo y Rebeca Acin Pérez pertenecen a Programa Ramón y Cajal • Elisa Manieri pertenece a Caixa • Ministerio de Economía y Competitividad. Proyecto FPI BES-2014-069332, para Valle Montalvo Romeral • Ministerio de Economía y Competitividad. Proyecto FPI BES-2011-043428, para Edgar Bernardo • Ministerio de Economía y Competitividad y FEDER SAF2016-79126-R y Comunidad de Madrid S2010 / BMD-2326, para Guadalupe Sabio Buzo • ISCIII y FEDER, PI10 / 01692 e I3SNS-INT12 / 049, para Miguel Marcos Martín • Junta de Castilla y León GRS 681 / A / 11, para Lourdes Hernández Cosido • Ministerio de Economía y Competitividad. BFU2015-70664-R, Xunta de Galicia 2015-CP080 y PIE13 / 00024, y ERC281408, para Rubén Nogueiras Pozo • Unión Europea. Becas europeas UE0 / MCA1108 y UE0 / MCA1201; y la Comunidad de Madrid CAM / API1009, para Rubén Nogueiras Pozo • Junta de Extremadura y FEDER BR15164, para Francisco Centeno Velázquez • Ministerio de Economía y Competitividad. . BFU2013-46109-R, para Clara V. Álvarez Villamarín • European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. ERC 260464peerReviewe

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia

Background and aims: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3?,7?,12?-trihydroxy-5?-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods and results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAX? expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusions: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.Funding information: This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI-100, PID2020-115055RB-I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A-2015-9456; FPU-14/00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the article

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.BGT and MC were fellows of the FPI: Severo Ochoa CNIC program (SVP-2013–067639) and (BES-2017–079711) respectively. IN was funded by EFSD/Lilly grants (2017 and 2019), the CNIC IPP FP7 Marie Curie Programme (PCOFUND-2012–600396), EFSD Rising Star award (2019), JDC-2018-Incorporación (MIN/JDC1802). T-L was a Juan de la Cierva fellow (JCI2011–11623). C.F has a Sara Borrell contract (CD19/00078). RJD is an Investigator of the Howard Hughes Medical Institute. This work was funded by the following grants to GS: funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n˚ ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017) IN[17] _BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R and PID2019-104399RB-I00 , EUIN201785875, Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and Fundación AECC AECC PROYE19047SABI and AECC: INVES20026LEIV to ML. MM was funded by ISCIII and FEDER PI16/01548 and Junta de Castilla y León GRS 1362/A/16 and INT/M/17/17 and JL-T by Junta de Castilla y León GRS 1356/A/16 and GRS 1587/A/17. The study was additionally funded by MEIC grants to ML (MINECO-FEDER-SAF2015-74112-JIN) AT-L (MINECO-FEDERSAF2014-61233-JIN), RJD: Grant DK R01 DK107220 from the National Institutes of Health. AH: (SAF2015-65607-R). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015–0505).S

Specialized proresolving mediators protect against experimental autoimmune myocarditis by modulating Ca2+ handling and NRF2 activation

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum–adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (SAF-2017-84777R), Instituto de Salud Carlos III (ISCIII) (PI17/01093, PI17/01344, and PI20/01482), Sociedad Española de Cardiología, Proyecto Traslacional 2019 and Asociación del Ritmo Cardiaco (SEC, España), Proyecto Asociación Insuficiencia Cardiaca (Trasplante Cardiaco) 2020, Fondo Europeo de Desarrollo Regional, Fondo Social Europeo, and CIBERCV, a network funded by ISCIII, Spanish Ministry of Science, Innovation and Universities (PGC2018-097019-B-I00), Ministerio de Economía, Industria y Competitividad/Agencia Estatal de Investigación 10.13039/501100011033 PID2020-113238RB-I00, PID2019-105600RB-I00, the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria grant PRB3 [PT17/0019/0003-ISCIII-SGEFI/ERDF, ProteoRed]), and “la Caixa” Foundation (project code HR17-00247). The Centro Nacional de Investigaciones Cardiovasculares is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades. Dr Ruiz-Hurtado is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). Dr Tamayo and R.I. Jaén, and M. Gil-Fernández were or currently are PhD students funded by the Formación de Profesorado Universitario program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135; FPU16/00827, FPU1901973)

Parenteral Nutrition: Current Use, Complications, and Nutrition Delivery in Critically Ill Patients

Background: Parenteral nutrition (PN) is needed to avoid the development of malnutrition when enteral nutrition (EN) is not possible. Our main aim was to assess the current use, complications, and nutrition delivery associated with PN administration in adult critically ill patients, especially when used early and as the initial route. We also assessed the differences between patients who received only PN and those in whom EN was initiated after PN (PN-EN). Methods: A multicenter (n = 37) prospective observational study was performed. Patient clinical characteristics, outcomes, and nutrition-related variables were recorded. Statistical differences between subgroups were analyzed accordingly. Results: From the entire population (n = 629), 186 (29.6%) patients received PN as initial nutrition therapy. Of these, 74 patients (11.7%) also received EN during their ICU stay (i.e., PNEN subgroup). PN was administered early (<48 h) in the majority of patients (75.3%; n = 140) and the mean caloric (19.94 +/- 6.72 Kcal/kg/day) and protein (1.01 +/- 0.41 g/kg/day) delivery was similar to other contemporary studies. PN showed similar nutritional delivery when compared with the enteral route. No significant complications were associated with the use of PN. Thirty-two patients (43.3%) presented with EN-related complications in the PN-EN subgroup but received a higher mean protein delivery (0.95 +/- 0.43 vs 1.17 +/- 0.36 g/kg/day; p = 0.03) compared with PN alone. Once adjusted for confounding factors, patients who received PN alone had a lower mean protein intake (hazard ratio (HR): 0.29; 95% confidence interval (CI): 0.18-0.47; p = 0.001), shorter ICU stay (HR: 0.96; 95% CI: 0.91-0.99; p = 0.008), and fewer days on mechanical ventilation (HR: 0.85; 95% CI: 0.81-0.89; p = 0.001) compared with the PN-EN subgroup. Conclusion: The parenteral route may be safe, even when administered early, and may provide adequate nutrition delivery. Additional EN, when possible, may optimize protein requirements, especially in more severe patients who received initial PN and are expected to have longer ICU stays. NCT Registry: 03634943

A Study of Learning-by-Doing in MOOCs through the Integration of Third-Party External Tools:Comparison of Synchronous and Asynchronous Running Modes

Many MOOCs are being designed replicating traditional passive teaching approaches but using video lectures as the means of transmitting information. However, it is well known that learning-by-doing increases retention rates and, thus, allows achieving a more effective learning. To this end, it is worth exploring which tools fit best in the context of each MOOC to enrich learners' experience, including built-in tools already available in the MOOC platform, and third-party external tools which can be integrated in the MOOC platform. This paper presents an example of the integration of a software development tool, called Codeboard, in three MOOCs which serve as an introduction to programming with Java. We analyze the effect this tool has on learners' interaction and engagement when running the MOOCs in synchronous (instructor-paced) or asynchronous (self-paced) modes. Results show that the overall use of the tool is similar, regardless of the course running mode, although in the case of the synchronous mode the use of the tool is concentrated in a shorter period of time. Results also show that in the synchronous mode there is a higher percentage of accesses to the tool from registered learners (who can save their advances and continue the work later); this finding suggests that learners in the synchronous running mode are more engaged with the MOOC.The authors acknowledge the eMadrid Network, which is funded by the Madrid Regional Government (Comunidad de Madrid) with grant No. S2013/ICE-2715. This work also received partial support from the Spanish Ministry of Economy, Industry and Competitiveness, Project RESET (TIN2014-53199-C3-1-R), Project SYMBHYO-TIC (PTQ-15-07505), Project SIMLAP (RTC-2014-2811-1), Project SMARTLET (TIN2017-85179-C3-1-R), and from the European Commission through Erasmus+ projects MOOC-Maker (561533-EPP-1-2015-1-ESEPPKA2-CBHE-JP), SHEILA (562080-EPP-1-2015-1-BEEPPKA3-PI-FORWARD), COMPASS (2015-1-EL01-KA203-014033), and COMPETEN-SEA (574212-EPP-1-2016-1-NLEPPKA2-CBHE-JP)

Beneficial Effect of Ursodeoxycholic Acid in Patients with ACOX2 Deficiency-Associated Hypertransaminasemia

Background: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly trihydroxycholestanoic acid (THCA). Aims: To investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods & results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals, and 13 of their relatives, 7 individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by HPLC-MS/MS. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in 2 patients and 3 family members. Two additional non-related patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In ADAH patients, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized transaminases levels. Incubation of HuH-7 liver cells with THCA, which was efficiently taken up, but not through BA transporters, increased ROS production (flow cytometry), ER stress biomarkers (GRP78, CHOP and XBP1-S/XBP1-U ratio), and BAX¿ expression (RT-qPCR and immunoblot), whereas cell viability was decreased (MTT). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusion: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a non-invasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI- 100, PID2020-115055RB- I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017- 1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A- 2015- 9456; FPU-14/ 00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the articl