New insights about the Upper Jurassic – Lower Cretaceous sedimentary successions from Asturias (NW Iberian Peninsula)

Detailed mapping of the Jurassic to pre-Albian deposits of central and eastern Asturias (NW of the Iberian Peninsula) has enabled several Upper Jurassic and Lower Cretaceous outcrops, previously assigned to other ages, to be identified. Where possible, these outcrops have been correlated with the well-known sequences outcropping on the Asturian coast. A new Jurassic unit, the Miyares Formation, has been defined, which consists of a Lower conglomerate Unit, a Middle Unit composed mainly of oolitic limestones and an Upper Unit comprising bioclastic and marly limestones with a rich fauna of larger foraminifera. The Lower Unit is interpreted as having been deposited in a fan delta, the Middle Unit represents a shallow marine high-energy environment, and the Upper Unit was deposited on a restricted shallow marine platform. The shallow-water foraminiferal assemblage from the Upper Unit is attributed to the Tithonian and the oldest Cretaceous rocks are Barremian; there is therefore a stratigraphic gap recorded in the study area, which might correspond to the latest Jurassic to Early Cretaceous p. p. timespan.Una cartografía geológica detallada de los depósitos jurásicos y cretácicos pre-albienses ha permitido identificar varios afloramientos del Jurásico Superior y del Cretácico Inferior, asignados previamente a otras edades. Donde ha sido posible, estos afloramientos han sido correlacionados con las sucesiones bien conocidas que afloran en la costa asturiana. Se ha definido una nueva unidad, la Formación Miyares, formada por una Unidad Inferior conglomerática, una Unidad Media mayoritariamente de calizas oolíticas y una Unidad Superior de calizas bioclásticas y margosas con abundantes macroforaminíferos. La Unidad Inferior se interpreta como depósitos de fan delta, la Unidad Media representa un ambiente marino somero de alta energía, y la Unidad Superior fue depositada en una plataforma marina somera restringida. El conjunto de foraminíferos de agua somera de la Unidad Superior se atribuye al Titoniense y las rocas más antiguas del Cretácico son del Barremiense; existe por lo tanto, en el área de estudio, una laguna estratigráfica que abarca la parte terminal del Jurásico y una parte del Cretácico Inferior

Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia

The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes

Introducing Hyaluronic Acid into Supramolecular Polymers and Hydrogels

[Abstract] The use of supramolecular polymers to construct functional biomaterials is gaining more attention due to the tunable dynamic behavior and fibrous structures of supramolecular polymers, which resemble those found in natural systems, such as the extracellular matrix. Nevertheless, to obtain a biomaterial capable of mimicking native systems, complex biomolecules should be incorporated, as they allow one to achieve essential biological processes. In this study, supramolecular polymers based on water-soluble benzene-1,3,5-tricarboxamides (BTAs) were assembled in the presence of hyaluronic acid (HA) both in solution and hydrogel states. The coassembly of BTAs bearing tetra(ethylene glycol) at the periphery (BTA-OEG4) and HA at different ratios showed strong interactions between the two components that led to the formation of short fibers and heterogeneous hydrogels. BTAs were further covalently linked to HA (HA-BTA), resulting in a polymer that was unable to assemble into fibers or form hydrogels due to the high hydrophilicity of HA. However, coassembly of HA-BTA with BTA-OEG4 resulted in the formation of long fibers, similar to those formed by BTA-OEG4 alone, and hydrogels were produced with tunable stiffness ranging from 250 to 700 Pa, which is 10-fold higher than that of hydrogels assembled with only BTA-OEG4. Further coassembly of BTA-OEG4 fibers with other polysaccharides showed that except for dextran, all polysaccharides studied interacted with BTA-OEG4 fibers. The possibility of incorporating polysaccharides into BTA-based materials paves the way for the creation of dynamic complex biomaterials.The authors acknowledge the ICMS Animation Studio for providing the artwork. S.V.-A. and G.M. acknowledge the funding received by Gravitation Program “Materials Driven Regeneration,” funded by the Netherlands Organization for Scientific Research (024.003.013). J.M. acknowledges a Marie Skłodowska-Curie postdoctoral fellowship (794016) for financial support. G.M. acknowledges the funding received by the Swiss National Science Foundation (SNSF “Early PostDoc Mobility” P2EZP2-178435). R.C. acknowledges TA Instruments for providing the DHR-3 rheometer under the Young Distinguished Rheologist Award instrument grant. S.S. and E.W.M acknowledge the European Research Council (H2020-EU.1.1., SYNMAT project, ID 788618).Netherlands Organisation for Scientific Research; 024.003.013Swiss National Science Foundation; P2EZP2-17843

COPD classification models and mortality prediction capacity

Our aim was to assess the impact of comorbidities on existing COPD prognosis scores. Patients and methods: A total of 543 patients with COPD (FEV1 < 80% and FEV1/ FVC <70%) were included between January 2003 and January 2004. Patients were stable for at least 6 weeks before inclusion and were followed for 5 years without any intervention by the research team. Comorbidities and causes of death were established from medical reports or information from primary care medical records. The GOLD system and the body mass index, obstruction, dyspnea and exercise (BODE) index were used for COPD classification. Patients were also classified into four clusters depending on the respiratory disease and comorbidities. Cluster analysis was performed by combining multiple correspondence analyses and automatic classification. Receiver operating characteristic curves and the area under the curve (AUC) were calculated for each model, and the DeLong test was used to evaluate differences between AUCs. Improvement in prediction ability was analyzed by the DeLong test, category-free net reclassification improvement and the integrated discrimination index. Results: Among the 543 patients enrolled, 521 (96%) were male, with a mean age of 68 years, mean body mass index 28.3 and mean FEV1% 55%. A total of 167 patients died during the study follow-up. Comorbidities were prevalent in our cohort, with a mean Charlson index of 2.4. The most prevalent comorbidities were hypertension, diabetes mellitus and cardiovascular diseases. On comparing the BODE index, GOLDABCD, GOLD2017 and cluster analysis for pre-dicting mortality, cluster system was found to be superior compared with GOLD2017 (0.654 vs 0.722, P=0.006), without significant differences between other classification models. When cardiovascular comorbidities and chronic renal failure were added to the existing scores, their prognostic capacity was statistically superior (P<0.001). Conclusion: Comorbidities should be taken into account in COPD management scores due to their prevalence and impact on mortalit

Pseudo-Jahn-Teller origin of the low barrier hydrogen bond in N2H7+

The microscopic origin and quantum effects of the low barrier hydrogen bond (LBHB) in the proton-bound ammonia dimer cation N2H7+ were studied by means of ab initio and density-functional theory(DFT) methods. These results were analyzed in the framework of vibronic theory and compared to those obtained for the Zundel cation H5O2+. All geometry optimizations carried out using wavefunction-based methods [Hartree–Fock, second and fourth order Möller–Plesset theory (MP2 and MP4), and quadratic configuration interaction with singles and doubles excitations (QCISD)] lead to an asymmetrical H3N–H+⋯NH3 conformation (C3v symmetry) with a small energy barrier (1.26kcal/mol in MP4 and QCISD calculations) between both equivalent minima. The value of this barrier is underestimated in DFT calculations particularly at the local density approximation level where geometry optimization leads to a symmetric H3N⋯H+⋯NH3 structure (D3d point group). The instability of the symmetric D3d structure is shown to originate from the pseudo-Jahn–Teller mixing of the electronic A1g1ground state with five low lying excited states of A2u symmetry through the asymmetric α2u vibrational mode. A molecular orbital study of the pseudo-Jahn–Teller coupling has allowed us to discuss the origin of the proton displacement and the LBHB formation in terms of the polarization of the NH3 molecules and the transfer of electronic charge between the proton and the NH3 units (rebonding). The parallel study of the H5O2+ cation, which presents a symmetric single-well structure, allows us to analyze why these similar molecules behave differently with respect to proton transfer. From the vibronic analysis, a unified view of the Rudle–Pimentel three-center four-electron and charge transfer models of LBHBs is given. Finally, the large difference in the N–N distance in the D3d and C3v configurations of N2H7+ indicates a large anharmonic coupling between α2u-α1g modes along the proton-transfer dynamics. This issue was explored by solving numerically the vibrational Schrödinger equation corresponding to the bidimensional E[Q(α2u),Q(α1g)] energy surface calculated at the MP4/6-311++G** level of theory

Chronic obstructive pulmonary disease subtypes. transitions over time

Background Although subtypes of chronic obstructive pulmonary disease are recognized, it is unknown what happens to these subtypes over time. Our objectives were to assess the stability of cluster-based subtypes in patients with stable disease and explore changes in clusters over 1 year. Methods Multiple correspondence and cluster analysis were used to evaluate data collected from 543 stable patients included consecutively from 5 respiratory outpatient clinics. Results Four subtypes were identified. Three of them, A, B, and C, had marked respiratory profiles with a continuum in severity of several variables, while the fourth, subtype D, had a more systemic profile with intermediate respiratory disease severity. Subtype A was associated with less dyspnea, better health-related quality of life and lower Charlson comorbidity scores, and subtype C with the most severe dyspnea, and poorer pulmonary function and quality of life, while subtype B was between subtypes A and C. Subtype D had higher rates of hospitalization the previous year, and comorbidities. After 1 year, all clusters remained stable. Generally, patients continued in the same subtype but 28% migrated to another cluster. Together with movement across clusters, patients showed changes in certain characteristics (especially exercise capacity, some variables of pulmonary function and physical activity) and changes in outcomes (quality of life, hospitalization and mortality) depending on the new cluster they belonged to Conclusions Chronic obstructive pulmonary disease clusters remained stable over 1 year. Most patients stayed in their initial subtype cluster, but some moved to another subtype and accordingly had different outcomes

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, δ- and κ-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and δ-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and δ-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. κ-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1.7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development

Revisión bioestratigráfica de las pizarras del Ordovícico Medio en el noroeste de España (zonas Cantábrica, Asturoccidental-leonesa y Centroibérica septentrional)

A complete review of more than one hundred Middle Ordovician fossil localities, distributed within the north western part of the Hesperian Massif, shows that the sedimentation of the dark shales (Luarca Fo rmation and equivalents) that overlie Arenig quartzites with Cruziana (the 'Armorican Quartzite' facies) was not as uniform as it has been supposed for the whole NW Spain. These shales were mainly deposited during the Oretanian in the West Asturian-Leonese Zone and in nort h e rn Central-Iberian Zone (Domain of the Ollo de Sapo Antiform). In these zones, the top of the unit is close to the Oretanian/Dobrotivian boundary, without any fossils with proved Dobrotivian age. In the Cantabrian Zone, clay sedimentation started in the latest Oretanian and continued during the Dobrotivian. Several local or regional stratigraphic gaps are proposed and characterized for the whole study area. In addition, the most recent paleog e ographical reconstructions proposed are discussed, in accordance with new paleoecological and paleobiog e ographical data. These data indicate that sedimentation took place in open shelf areas, relative ly deeper than in the southern Central Iberian shelf, and with trough areas where some mesopelagic elements are recorded. We identified a total of 97 different fossil taxa (67 from Oretanian rocks and 45 from Dobrotivian rocks), remarkable among which are the first known appearance of certain trilobites and ostracodes, the latest record of other taxa, and also the presence of some taxa in common with Avalonia and Baltica, that were previously unknown from any area of SW Europe