Capra alba Moyà-Solà, 1987 del Pleistoceno Inferior de la Sierra de Quibas (Albanilla, Murcia, España)

A finales de la década de los 90 se realizó el primer estudio paleontológico del yacimiento de la Sierra de Quibas (Montoya et al., 1999) en el que se describieron más de 60 taxones de vertebrados. Uno de ellos fue el de un caprino asignado como Capra sp. aff Capra alba. Las últimas campañas de excavación han librado nuevos restos de este taxón, lo que ha permitido poder estudiarlo con mayor profundidad y asignarlo a Capra alba. Esta atribución se basa en la comparación morfológica y métrica de los cráneos, núcleos óseos, dentición y metápodos con los ejemplares de C. alba de Venta Micena (Orce, Granada).The first palaeontological study of the locality of Quibas dates from the end of the 1990ties (Montoya et al., 1999), describing over 60 vertebrate taxa. One of these was a caprine assigned to Capra sp. aff. Capra alba. Recent excavations yielded new remains of this taxon, which permits a more profound study of its affinities and an assignation to Capra alba, without reservation. This assignation is based on the morphological and metrical comparison of the skulls, horn cores, dentition and metapodials from Quibas with those of Capra alba from Venta Micena (Orce Granada)[email protected]

Presence of Mammuthus sp. from Caravaca (Murcia)

In Rambla del Pizcalejo (Caravaca, Murcia, Spain) new Proboscidea fossil remains were found. In this paper are described all postcranial bones belonging to a 2-4 years old Mammuthus. Stratigraphycal and mollusc data confirm the lacustrine paleoenvironment. The remains shouldn’t have suffered a hard transport; neither should their time of exposure have been long. The date of the remains is not precise due to the lack of chronostratigraphic and biostratigraphic data. It is only the assignment of the remains to the genus Mammuthus that allows to surmise a period about Plio-Pleistocen

Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice

BACKGROUND AND AIMS: New options are needed for the management and prevention of colorectal cancer liver metastases. Interleukin 12 (IL-12) is an immunostimulatory cytokine with proven antitumour effect in animal models. Despite evidence indicating its biological effect in humans, neither the recombinant protein nor gene therapy vectors expressing IL-12 have shown a relevant benefit in patients with cancer. OBJECTIVE: To develop a new approach to overcome the difficulties in obtaining a suitable expression pattern and the immunosuppressive milieu in the tumours which contribute to this poor performance. METHODS: A high-capacity ('gutless') adenoviral vector carrying a liver-specific, mifepristone (Mif)-inducible system for the expression of IL-12 (HC-Ad/RUmIL-12) was used in combination with chemotherapy. Tumours were established in the liver of C57BL/6 mice by inoculation of MC38 colon cancer cells. RESULTS: Intrahepatic injection of HC-Ad/RUmIL-12 and tailored induction regimens allowed the maintenance of safe and efficient levels of IL-12 in vivo. An individualised, stepwise increase in the dose of Mif (125-4000 μg/kg) was needed to compensate for the progressive but transient downregulation of the inducible system. Repeated cycles of Mif induction (every 24 h for 10 days) were needed for optimal tumour eradication. However, complete protection against tumour rechallenge was seen in < 25% of the animals. The administration of oxaliplatin (5 mg/kg intraperitoneally) 3 days before starting the induction regimen achieved efficient elimination of liver metastases with a single cycle of IL-12 induction, and improved protection against tumour rechallenge. This was associated with a shift in the tumour microenvironment towards a more pro-immunogenic phenotype, with an increase in the CD8+/T regulatory cell ratio and a reduction in myeloid-derived suppressor cells. These effects were not seen with 5-fluorouracil, irinotecan or gemcitabine

Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates

BACKGROUND: Adeno-associated vectors (rAAV) have been used to attain long-term liver gene expression. In humans, the cellular immune response poses a serious obstacle for transgene persistence while neutralizing humoral immunity curtails re-administration. Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria) benefits from liver gene transfer in mouse models and clinical trials are about to begin. In this study, we sought to study in non-human primates the feasibility of repeated gene-transfer with intravenous administration of rAAV5 vectors under the effects of an intensive immunosuppressive regimen and to analyze its ability to circumvent T-cell immunity and thereby prolong transgene expression. METHODS: Three female Macaca fascicularis were intravenously injected with 1x1013 genome copies/kg of rAAV5 encoding the human PBGD. Mycophenolate mofetil (MMF), anti-thymocyte immunoglobulin, methylprednisolone, tacrolimus and rituximab were given in combination during 12 weeks to block T- and B-cell mediated adaptive immune responses in two macaques. Immunodeficient and immunocompetent mice were intravenously injected with 5x1012 genome copies/kg of rAAV5-encoding luciferase protein. Forty days later MMF, tacrolimus and rituximab were daily administrated to ascertain whether the immunosuppressants or their metabolites could interfere with transgene expression. RESULTS: Macaques given a rAAV5 vector encoding human PBGD developed cellular and humoral immunity against viral capsids but not towards the transgene. Anti-AAV humoral responses were attenuated during 12 weeks but intensely rebounded following cessation of the immunosuppressants. Accordingly, subsequent gene transfer with a rAAV5 vector encoding green fluorescent protein was impossible. One macaque showed enhanced PBGD expression 25 weeks after rAAV5-pbgd administration but overexpression had not been detected while the animal was under immunosuppression. As a potential explanation, MMF decreases transgene expression in mouse livers that had been successfully transduced by a rAAV5 several weeks before MMF onset. Such a silencing effect was independent of AAV complementary strand synthesis and requires an adaptive immune system. CONCLUSIONS: These results indicate that our transient and intensive pharmacological immunosuppression fails to improve AAV5-based liver gene transfer in non-human primates. The reasons include an incomplete restraint of humoral immune responses to viral capsids that interfere with repeated gene transfer in addition to an intriguing MMF-dependent drug-mediated interference with liver transgene expression

SN 2018bsz: a Type I superluminous supernova with aspherical circumstellar material

We present a spectroscopic analysis of the most nearby Type I superluminous supernova (SLSN-I), SN 2018bsz. The photometric evolution of SN 2018bsz has several surprising features, including an unusual pre-peak plateau and evidence for rapid formation of dust ≳200 d post-peak. We show here that the spectroscopic and polarimetric properties of SN 2018bsz are also unique. While its spectroscopic evolution closely resembles SLSNe-I, with early O II absorption and C II P Cygni profiles followed by Ca, Mg, Fe, and other O features, a multi-component Hα profile appearing at ∼30 d post-maximum is the most atypical. The Hα is at first characterised by two emission components, one at ∼+3000 km s−1 and a second at ∼ − 7500 km s−1, with a third, near-zero-velocity component appearing after a delay. The blue and central components can be described by Gaussian profiles of intermediate width (FWHM ∼ 2000–6000 km s−1), but the red component is significantly broader (FWHM ≳ 10 000 km s−1) and Lorentzian. The blue Hα component evolves towards a lower-velocity offset before abruptly fading at ∼ + 100 d post-maximum brightness, concurrently with a light curve break. Multi-component profiles are observed in other hydrogen lines, including Paβ, and in lines of Ca II and He I. Spectropolarimetry obtained before (10.2 d) and after (38.4 d) the appearance of the H lines shows a large shift on the Stokes Q – U plane consistent with SN 2018bsz undergoing radical changes in its projected geometry. Assuming the supernova is almost unpolarised at 10.2 d, the continuum polarisation at 38.4 d reaches P ∼ 1.8%, implying an aspherical configuration. We propose that the observed evolution of SN 2018bsz can be explained by highly aspherical, possibly disk-like, circumstellar material (CSM) with several emitting regions. After the supernova explosion, the CSM is quickly overtaken by the ejecta, but as the photosphere starts to recede, the different CSM regions re-emerge, producing the peculiar line profiles. Based on the first appearance of Hα, we can constrain the distance of the CSM to be less than ∼6.5 × 1015 cm (430 AU), or even lower (≲87 AU) if the pre-peak plateau is related to an eruption that created the CSM. The presence of CSM has been inferred previously for other SLSNe-I, both directly and indirectly. However, it is not clear whether the rare properties of SN 2018bsz can be generalised for SLSNe-I, for example in the context of pulsational pair instability, or whether they are the result of an uncommon evolutionary path, possibly involving a binary companion

Short-term local expression of a PD-L1 blocking antibody from a self-replicating RNA vector induces potent antitumor responses

Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFVaPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and

Evolution of the use of corticosteroids for the treatment of hospitalised COVID-19 patients in Spain between March and November 2020: SEMI-COVID national registry

Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID- 19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years; p < 0.001), with hypertension (57.0% vs. 47.7%; p < 0.001), obesity (26.4% vs. 19.3%; p < 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%; p < 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7-160) vs. 49.3 (16-109) mg/dL; p < 0.001), ferritin (791 (393-1534) vs. 470 (236- 996) µg/dL; p < 0.001), D dimer (750 (430-1400) vs. 617 (345-1180) µg/dL; p < 0.001), and lower Sp02/Fi02 (266 (91.1) vs. 301 (101); p < 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September; p < 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%

Geological characteristics of the Sierra de Quibas (Abanilla, Murcia). Relationship with a Pleistocene paleontological site

The Sierra de Quibas is mainly a Lower Jurassic carbonated relief. Its main structure is a klippe of Middle Subbeticon Southern Prebetic. The internal structure is a NE-SW anticlinorium. Detailed geological mapping (E. 1:25,000) has pointed to anomalous folds (almost N-S) caused by the halokinétic action ofTriassic materials. Also has been detected a Neotectonic activity starting in the Upper Miocene with almost N-S stresses which have reactivated some faults; the N-S faults previously compressive are now distensive. In the SE edge of the Sierra de Quibas there is an important Pleistocene paleontological site in a karstic cave filled up with reddish detritic material within the Lower Jurassic dolomites, controlled by NE-SW fault

Synergistic Effect of Covalent Bonding and Physical Encapsulation of Sulfur in the Pores of a Microporous COF to Improve Cycling Performance in Li-S Batteries

This is the peer reviewed version of the following article: Royuela, S., Almarza, J., Mancheño, M. J., Pérez Flores, J. C., Michel, E. G., Ramos, M. M., Zamora, F., Ocón, P. & Segura, J. L. (2019). Synergistic effect of covalent bonding and physical encapsulation of sulfur in the pores of a microporous COF to improve cycling performance in Li‐S batterie. Chemistry - A European Journal 25.53 (2019): 12394-12404, which has been published in final form at https://doi.org/10.1002/chem.201902052. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsLithium-sulfur batteries stands out as a promising technology for energy storage owing to a combination of favorable characteristics including a high theoretical gravimetric capacity, energy density, inexpensive character, and environmental benignity. Covalent organic frameworks (COFs) are a rapidly developing family of functional nanostructures which combine porosity and crystallinity, and which have been already used in these kinds of batteries to build sulfur electrodes, by embedding sulfur into porous COFs in order to enhance cycle lifetimes. In this contribution, this is taken one step forward and a COF endowed with vinyl groups is used, in order to graft sulfur to the COF skeleton through inverse vulcanization. The main aim of the article is to show the synergistic effect of covalent bonding and physical encapsulation of sulfur in the pores of the COF in order to alleviate the fatal redox shuttling process, to improve the cycling performance, and to provide faster ion diffusion pathways. In addition, it is shown how the material with covalently-bound S provides better electrochemical performance under demanding and/or changeable charge conditions than a parent analogue material with sulfur physically confined, but without covalent linkageFinancial support from Spanish Government (Projects MAT2016‐77608‐C3‐1‐P, MAT2016‐77608‐C3‐2‐P, FIS2017‐82415‐R, ENE2016‐77055‐C3‐1‐R), the “María de Maeztu” Programme for Units of Excellence in R&D (MDM‐2014‐0377) and the UCM (INV.GR.00.1819.10759) is acknowledged. We thank the BACH beamline team at Elettra for technical assistance with XPS measurements. The research leading to these results has received funding from the European Community's Horizon 2020 Framework Programme under grant agreement No 73087

Direct C–H Bond Imidation with Benzoyl Peroxide as a Mild Oxidant and a Reagent

A simple and mild Cu-catalyzed oxidative three component oxidative Ugi-type method for the synthesis of a variety of substituted imides has been developed. In this direct imidation approach, benzoyl peroxide serves as both the oxidant and the carboxylate source, allowing not only the functionalization of C(sp(3))-H bonds in alpha-position to an amine but also benzylic substrates. This procedure presents a wide substrate-type and functional group tolerance. Moreover, the mildness of the method permitted us to extend its application to the late stage functionalization of complex natural products such as the alkaloids brucine and strychnine, leading to interesting highly functionalized imide derivatives. On the basis of experimental and computational studies, a plausible mechanism has been proposed