[2-(sec-Butyl­imino­meth­yl)quinoline]­chlorido(η6-1-isopropyl-4-methyl­benzene)­ruthenium(II) hexa­fluorido­phosphate

In the title compound, [RuCl(C10H14)(C14H16N2)]PF6, the aromatic ring of the isopropyl­methyl­benzene fragment shows an η6-arene coordination to the ruthenium atom. Its coordination sphere is completed by a chloride ligand and 2-(sec-butyl­imino­meth­yl)quinoline. The dihedral angle between the η6-arene ring and the quinoline Schiff base is 45.64 (9)°. The sec-butyl substituent and the PF6 − anion are disordered over two positions with ratios of 0.595 (11):0.405 (11) and 0.752 (8):0.248 (8), respectively

Supplementary Appendix. All-trans retinoic acid works synergistically with the γ- secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells

Supplement Figure 1: ATRA treatment does not affect the viability of myeloma cell lines. MM.1S, OPM-2 and NCI-H929 cells were treated with ATRA for up to 72 hours. Cell viability was measured by flow cytometry and 7AAD staining (n=6). Bar diagrams show mean values +SD.Supplement Figure 2: ATRA plus crenigacestat treatment enhance BCMA expression on myeloma cell lines. Bar diagram shows BCMA expression on OPM-2 cells (n=3) after treatment with 100 nM ATRA and/or 10 nM GSI crenigacestat for 72 hours. Bar diagram shows mean values +SD. P-values between indicated groups were calculated using unpaired t-test. *p<0.05, **p<0.01.Supplement Figure 3: ATRA treatment leads to increased BCMA transcripts in OPM-2 myeloma cells. BCMA RNA levels in OPM-2 were analyzed by quantitative reverse transcription PCR (qRT-PCR) assay after incubation with increasing doses of ATRA for 48 hours (n=3). Bar diagram shows mean values +SD. P-values between indicated groups were calculated using unpaired t-test. *p<0.05.Supplement Figure 4: ATRA treatment leads to enhanced BCMA expression on primary myeloma cells. Representative flow cytometric analysis of BCMA expression on primary myeloma cells that had been cultured in the absence or presence of ATRA at different concentrations for 72 hours. 7-AAD was used to exclude dead cells from analysis.Supplement Figure 5: ATRA treatment does not impair viability of primary myeloma cells. Viability of primary myeloma cells with or without 72 hours of ATRA treatment was analyzed by flow cytometry and 7-AAD staining (n=5 biological replicates). Bar diagram shows mean values +SD.Supplement Figure 6: sBCMA does not impair BCMA CAR T cell functionality. CD8+ BCMA-CAR T-cells were co-cultured with MM.1S target cells in absence or presence of 150 ng/ml of soluble BCMA. After 4 hours, cytotoxicity was evaluated by bioluminescence- based assay. Diagram shows mean values +/-SD.Supplement Figure 7: ATRA treatment does not increase shedding of sBCMA. sBCMA concentration in the supernatant of OPM-2 and NCI-H929 after incubation with increasing doses of ATRA was analyzed by ELISA. Cell lines were cultured at 1x106/well (n=3 technical replicates). Bar diagrams show mean values +SD, P-values between indicated groups were calculated using 2way ANOVA. n.s. = not significant, *p<0.05, **p<0.01.Supplement Figure 8: BCMA-CAR T-cells confer enhanced cytotoxicity against ATRA plus crenigacestat-treated OPM-2 cells in vitro. OPM-2 cells were incubated with 100 nM ATRA and/or 10 nM GSI for 72 hours or were left untreated. Cytolytic activity of CD8+ BCMA- CAR T-cells was determined in a bioluminescence-based assay after 4h of co-incubation with target cells. Assay was performed in triplicate wells with 5,000 target cells per well. Data are presented as mean values +SD (n=4 biological replicates). P-values between indicated groups were calculated using unpaired t-test. n.s. = not significant, *p<0.05.Supplement Figure 9: Patient-derived BCMA-CAR T-cells confer enhanced cytotoxicity against ATRA-treated MM.1S cells. MM.1S cells were incubated with 50 nM ATRA for 72 hours or were left untreated. Cytolytic activity of MM patient-derived CD8+ BCMA-CAR T-cells was determined in a bioluminescence-based assay after 4h of co-incubation with target cells. Data are presented as mean values +SD of triplicate wells. P-values between indicated groups were calculated using unpaired t-test. *p<0.05, **p<0.01.Peer reviewe

Revista de Vertebrados de la Estación Biológica de Doñana

Catálogo descriptivo de los anfibios y reptiles de CubaEvolución estacional de la comunidad de aves en un robledal de Sierra NevadaComposición de la comunidad de aves en pinares del Parque Nacional de Doñana (suroeste de España).Alimentación de la pagaza piconegra (Gelochelidon nilotica) en las marismas del GuadalquivirContaminación xenobiótica del Parque Nacional de Doñana. III. Residuos de insecticidas organoclorados, bifenilos policlorados y metales pesados en ciconiformesAlimentación de la lechuza común Tyto alba en la cuenca del Duero, EspañaEstudio de una población rural de (Mus musculus L.) I. La probabilidad de captura y la estima numéricLa reproducción en Gazella dorcasIncidencia del Nemátodo parásito Skrjabingylus Leuckart, 1842 sobre el Mustela en España.Desplazamientos de ungulados silvestres a través de una zona de ecotono en Doñana.Etograma de la cabra montés (Capra pyrenaica) y comparación con otras especies.Sobre comportamiento agresivo de Triturus marmoratus en época de celoEmbarrancamiento masivo de ejemplares de tortuga lad (Dermochelys coriacea L.) en las costas de Ceuta (España, norte de África)Sobre un ejemplar melánico de Podarcis hispanica (Steindachner, 1870)Nuevos datos sobre la distribución de cuatro especies de reptiles en la provincia de Cádiz.Algunos datos sobre la nidificación de Ciconia nigra L. en sierra Morena (S. España)Observación del halcón de Eleonor (Falco eleonorae) en el centro de EspañaNueva localidad de cría del pájaro moscón (Remiz pendulinus) en la Península IbéricaRegistro de aves en el sur de BoliviaNidificación del paiño de Madeira Oceanodroma castro (Harcourt, 1851) en las Islas Canarias.Observación primaveral de Phalaropus fulicarius L. en el SO de EspañaNuevos datos sobre la presencia del nóctulo gigante Nyctalus lasiopterus (Chiroptera, vespertilionidae) en EspañaNote sur l'alimentation de Martes martes a Menorca (Baleares).Peer reviewe

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of &gt;1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with &gt;1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p &lt;0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p &lt;0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p &lt;0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p &lt;0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p &lt;0.001) and more oHE development (35% vs. 49%, p &lt;0.001) than those with S-TSA. Conclusion: This study suggests that TSA &gt;83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57, CRC1382), Cellex Foundation and European Union’s Horizon 2020 research and innovation program GALAXY study (No. 668031), LIVERHOPE (No. 731875) and MICROB-PREDICT (No. 825694) and the Cellex Foundation. Joan Genescà is a recipient of a Research Intensification grant from Instituto de Salud Carlos III, Spain. The study was partially funded by grants PI15/00066, and PI18/00947 from Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Investing in your future”). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivasis supported by Instituto de Salud Carlos III. Macarena Simón-Talero is a recipient of the grant JR 17/00029 from Instituto de Salud Carlos II

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for Jorge Simon and Maria Luz Martinez-Chantar); Ministerio de Economía, Industria y Competitividad, Retos a la Sociedad AGL2017- 86927R (for F.M.); Instituto de Salud Carlos III, Proyectos de Investigación en Salud DTS20/00138 and DTS21/00094 (for Jorge Simon and Maria Luz Martinez-Chantar, and Asis Palazon. respectively); Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-founded by European Regional Development Fund/European Social Fund, “Investing in your future” PI19/00819, “Una manera de hacer Europa” FIS PI20/00765, and PI21/01067 (for Jose J. G. Marin., Pau Sancho-Bru,. and Mario F. Fraga respectively); Departamento de Industria del Gobierno Vasco (for Maria Luz Martinez-Chantar); Asturias Government (PCTI) co-funding 2018-2023/ FEDER IDI/2021/000077 (for Mario F. Fraga.); Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00, CEX2021-001136-S PID2020-117941RB-I00, PID2020-11827RB-I00 and PID2019-107956RA-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova and Asis Palazon); Ayudas Ramón y Cajal de la Agencia Estatal de Investigación RY2013-13666 and RYC2018- 024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research Foundation SFB/TRR57/P04, SFB1382-403224013/ A02 and DFG NE 2128/2-1 (for Francisco J Cubero and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism (NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru); Junta de Castilla y León SA074P20 (for Jose J. G. Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for Franz Martin); CIBERER Acciones Cooperativas y Complementarias Intramurales ACCI20-35 (for Mario F. Fraga); Ministerio de Educación, Cultura y Deporte FPU17/04992 (for Silvia Ariño); Fundació Marato TV3 201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is a fellow of the University of the Basque Country (UPV/ EHU); BIOEF (Basque Foundation for Innovation and Health Research); Asociación Española contra el Cáncer (Maria Luz Martinez-Chantar and Teresa C. Delgado.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa Foundation Program (for Maria Luz Martinez-Chantar); Proyecto Desarrollo Tecnologico CIBERehd (for Maria Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.S

Los contratos sobre el buque en Derecho Español. Análisis práctico

Prólogo / José Luis Gabaldón García (pp. 9-13). -- Introducción (pp. 15-18). -- El contrato de construcción naval: aspectos prácticos / Gonzalo Alvar Ezquerra (pp. 19-37). -- El contrato de compraventa / Carlos López-Quiroga, Luz Martínez de Azcoitia y José Sánchez-Fayos Martín-Peña (pp. 39-58). -- El contrato de arrendamiento de buque / Rodolfo González Lebrero (pp. 59-75). -- El contrato de fletamento por tiempo / José María Alcántara González (pp. 77-102). -- El contrato de fletamento por viaje: contenido obligacional / Juan Pablo Rodríguez Delgado (pp. 103-144). -- El contrato de transporte marítimo en régimen de conocimiento de embarque / Javier del Corte (pp. 145-186). -- Los documentos de transporte / Carlos Llorente (pp. 187-205). -- Contratos de utilización del buque para fines distintos del transporte de mercancías / José Manuel G. Pellicer (pp. 207-221). -- El contrato de arrendamiento náutico / León von Ondarza (pp. 223-244). -- El contrato de pasaje marítimo / Hannah de Bustos, Antonio Quirós de Sas y Julio López Quiroga (pp. 245-260). -- Los contratos de gestión naval para la dotación del buque / Bernardo Ruiz Lima (pp. 261-279). -- El contrato de gestión naval / Víctor Mata Garrido (pp. 281-302). -- El contrato de consignación de buques /Jesús Barbadillo Eyzaguirre (pp. 303-323). -- El contrato de manipulación portuaria / Carlos Pérez (pp. 325-338). -- El contrato de practicaje / Alicia Velasco Nates (pp. 339-356). -- Los contratos de mediación en la explotación del buque / Carmen Codes Cid y Martín Prieto Sulleiro (pp. 357-372). -- El contrato de remolque / Ana Sánchez Horneros (pp. 373- 392). -- El contrato de remolque / Jaime de Castro (pp. 393-412). -- El contrato de salvamento / Luis Souto (pp. 413-430). -- El contrato de remoción de restos / Verónica Meana (pp. 431-446). -- El contrato de clasificación del buque / Jaime Rodrigo de Larrucea (pp. 447-463). -- El seguro de casco y máquina / Carlos Cerdá Donat y Diego de San Simón Palacios (pp. 465-491). -- Los clubes de protección e indemnización (P&I) / Miguel Caballero (pp. 493-504). -- El seguro de protección e indemnización (P&I) / Jaime Albors (pp. 505-524). -- El seguro del acreedor hipotecario / Luis F. Gómez de Mariaca Fernández (pp. 525-540)

Reduced horn size in two wild trophy-hunted species of Caprinae

Factors affecting horn size in wild Caprinae are of biological and socio-economic interest because several species are selectively harvested on the basis of this heritable character. We analysed temporal trends in horn size in two mountain ungulates from south-eastern Spain, the Iberian wild goat Capra pyrenaica and the aoudad Ammotragus lervia. Trophy harvest is the main way in which these two species are exploited, although 'poor-quality' aoudads are also selectively removed. In recent years, both populations have suffered drastic decreases in number due to outbreaks of sarcoptic mange that led to the suspension of hunting for several years. Horn length in harvested male wild goats and aoudads declined during our study period. Over an 18-year period, the mean age of male goats shot as trophies rose by four years, while the age of trophy-harvested aoudads decreased by around six months over a 9-year period. Age and environmental conditions during the first few years of life explained 20% of variance in horn size in Iberian wild goat and 53% in aoudad. Population density early in life explained much of the reduction in goat horn size over time. Nevertheless, the major fall in population densities after the sarcoptic mange outbreaks did not lead to a recovery in horn size in either species. We suggest that the selective removal of large-horned animals may contribute to a decline in horn size. Other factors that may also explain the observed pattern include changes in interspecific competition, longlasting maternal effects and reduced carrying capacity due to overgrazing during high density periods. Unfortunately, our data sets did not allow us to account for the possible effects of these factors

Geographic patterns of tree dispersal modes in Amazonia and their ecological correlates

Unidad de excelencia María de Maeztu CEX2019-000940-MAim: To investigate the geographic patterns and ecological correlates in the geographic distribution of the most common tree dispersal modes in Amazonia (endozoochory, synzoochory, anemochory and hydrochory). We examined if the proportional abundance of these dispersal modes could be explained by the availability of dispersal agents (disperser-availability hypothesis) and/or the availability of resources for constructing zoochorous fruits (resource-availability hypothesis). Time period: Tree-inventory plots established between 1934 and 2019. Major taxa studied: Trees with a diameter at breast height (DBH) ≥ 9.55 cm. Location: Amazonia, here defined as the lowland rain forests of the Amazon River basin and the Guiana Shield. Methods: We assigned dispersal modes to a total of 5433 species and morphospecies within 1877 tree-inventory plots across terra-firme, seasonally flooded, and permanently flooded forests. We investigated geographic patterns in the proportional abundance of dispersal modes. We performed an abundance-weighted mean pairwise distance (MPD) test and fit generalized linear models (GLMs) to explain the geographic distribution of dispersal modes. Results: Anemochory was significantly, positively associated with mean annual wind speed, and hydrochory was significantly higher in flooded forests. Dispersal modes did not consistently show significant associations with the availability of resources for constructing zoochorous fruits. A lower dissimilarity in dispersal modes, resulting from a higher dominance of endozoochory, occurred in terra-firme forests (excluding podzols) compared to flooded forests. Main conclusions: The disperser-availability hypothesis was well supported for abiotic dispersal modes (anemochory and hydrochory). The availability of resources for constructing zoochorous fruits seems an unlikely explanation for the distribution of dispersal modes in Amazonia. The association between frugivores and the proportional abundance of zoochory requires further research, as tree recruitment not only depends on dispersal vectors but also on conditions that favour or limit seedling recruitment across forest types

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <<1um, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term "secular" dimming, which may be caused by independent processes, or probe different regimes of a single process