Predicted Epitope Abundance Supports Vaccine-Induced Cytotoxic Protection Against SARS-CoV-2 Variants of Concern

The effect of emerging SARS-CoV-2 variants on vaccine efficacy is of critical importance. In this study, the potential impact of mutations that facilitate escape from the cytotoxic cellular immune response in these new virus variants for the 551 most abundant HLA class I alleles was analyzed. Computational prediction showed that most of these alleles, that cover >90% of the population, contain enough epitopes without escape mutations in the principal SARS-CoV-2 variants. These data suggest that the cytotoxic cellular immune protection elicited by vaccination is not greatly affected by emerging SARS-CoV-2 variants.This research was supported by grants from COV20_00679 (MPY 222-20), to MM, MPY 509/19 to AM-G, and MPY 388/18 to DL of “Acción Estratégica en Salud” from the ISCIII.S

Predicted impact of the viral mutational landscape on the cytotoxic response against SARS-CoV-2

The massive assessment of immune evasion due to viral mutations that increase COVID-19 susceptibility can be computationally facilitated. The adaptive cytotoxic T response is critical during primary infection and the generation of long-term protection. Here, potential HLA class I epitopes in the SARS-CoV-2 proteome were predicted for 2,915 human alleles of 71 families using the netMHCIpan EL algorithm. Allele families showed extreme epitopic differences, underscoring genetic variability of protective capacity between humans. Up to 1,222 epitopes were associated with any of the twelve supertypes, that is, allele clusters covering 90% population. Next, from all mutations identified in ~118,000 viral NCBI isolates, those causing significant epitope score reduction were considered epitope escape mutations. These mutations mainly involved non-conservative substitutions at the second and C-terminal position of the ligand core, or total ligand removal by large recurrent deletions. Escape mutations affected 47% of supertype epitopes, which in 21% of cases concerned isolates from two or more sub-continental areas. Some of these changes were coupled, but never surpassed 15% of evaded epitopes for the same supertype in the same isolate, except for B27. In contrast to most supertypes, eight allele families mostly contained alleles with few SARS-CoV-2 ligands. Isolates harboring cytotoxic escape mutations for these families co-existed geographically within sub-Saharan and Asian populations enriched in these alleles according to the Allele Frequency Net Database. Collectively, our findings indicate that escape mutation events have already occurred for half of HLA class I supertype epitopes. However, it is presently unlikely that, overall, it poses a threat to the global population. In contrast, single and double mutations for susceptible alleles may be associated with viral selective pressure and alarming local outbreaks. The integration of genomic, geographical and immunoinformatic information eases the surveillance of variants potentially affecting the global population, as well as minority subpopulations.This research was supported by Acción Estratégica en Salud from the ISCIII (https://www.isciii.es), grants MPY 380/18 (to MJM), 388/18 (to DL) and 509/19 (to AJM-G). AJM-G is the recipient of a Miguel Servet contract by the ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

The origin of the Acheulean: the 1.7 million-year-old site of FLK West, Olduvai Gorge (Tanzania)

The appearance of the Acheulean is one of the hallmarks of human evolution. It represents the emergence of a complex behavior, expressed in the recurrent manufacture of large-sized tools, with standardized forms, implying more advance forethought and planning by hominins than those required by the precedent Oldowan technology. The earliest known evidence of this technology dates back to c. 1.7 Ma. and is limited to two sites (Kokiselei [Kenya] and Konso [Ethiopia]), both of which lack fauna. The functionality of these earliest Acheulean assemblages remains unknown. Here we present the discovery of another early Acheulean site also dating to c. 1.7 Ma from Olduvai Gorge. This site provides evidence of the earliest steps in developing the Acheulean technology and is the oldest Acheulean site in which stone tools occur spatially and functionally associated with the exploitation of fauna. Simple and elaborate large-cutting tools (LCT) and handaxes co-exist at FLK West, showing that complex cognition was present from the earliest stages of the Acheulean. Here we provide a detailed technological study and evidence of the use of these tools on the butchery and consumption of fauna, probably by early Homo erectus sensu lato

Tectonic evolution of Variscan Iberia: Gondwana–Laurussia

An integrated interpretation of the late Paleozoic structural and geochronological record of the Iberian Massif is presented and discussed under the perspective of a Gondwana-Laurussia collision giving way to the Variscan orogen. Compressional and extensional structures developed during the building of the Variscan orogenic crust of Iberia are linked together into major tectonic events operating at lithosphere scale. A review of the tectonometamorphic and magmatic evolution of the IberianMassif reveals backs and forths in the overall conver- gence between Gondwana and Laurussia during theamalgamation of Pangea in late Paleozoic times. Stages dom- inated by lithosphere compression are characterized by subduction, both oceanic and continental, development of magmatic arcs, (over- and under-) thrusting of continental lithosphere, and folding. Variscan convergence re- sulted in the eventual transference of a large allochthonous set of peri-Gondwanan terranes, the Iberian Allochthon, onto the Gondwana mainland. The Iberian Allochthon bears the imprint of previous interaction be- tween Gondwana and Laurussia, including their juxtaposition after the closure of the Rheic Ocean in Lower De- vonian times. Stages governed by lithosphere extension are featured by the opening of two short-lived oceanic basins that dissected previous Variscan orogenic crust, first in the Lower-Middle Devonian, following the closure of the Rheic Ocean, and then in the early Carboniferous, following the emplacement of the peri-Gondwanan allochthon. An additional, major intra-orogenic extensional event in the early-middle Carboniferous dismem- bered the Iberian Allochthon into individual thrust stacks separated by extensional faults and domes. Lateral tec- tonics played an important role through the Variscan orogenesis, especially during the creation of new tectonic blocks separated by intracontinental strike-slip shear zones in the late stages of continental convergence

HIFI observations of warm gas in DR21: Shock versus radiative heating

The molecular gas in the DR21 massive star formation region is known to be affected by the strong UV field from the central star cluster and by a fast outflow creating a bright shock. The relative contribution of both heating mechanisms is the matter of a long debate. By better sampling the excitation ladder of various tracers we provide a quantitative distinction between the different heating mechanisms. HIFI observations of mid-J transitions of CO and HCO+ isotopes allow us to bridge the gap in excitation energies between observations from the ground, characterizing the cooler gas, and existing ISO LWS spectra, constraining the properties of the hot gas. Comparing the detailed line profiles allows to identify the physical structure of the different components. In spite of the known shock-excitation of H2 and the clearly visible strong outflow, we find that the emission of all lines up to > 2 THz can be explained by purely radiative heating of the material. However, the new Herschel/HIFI observations reveal two types of excitation conditions. We find hot and dense clumps close to the central cluster, probably dynamically affected by the outflow, and a more widespread distribution of cooler, but nevertheless dense, molecular clumps.Comment: Accepted for publication by A&

A novel class of CoA-transferase involved in short-chain fatty acid metabolism in butyrate-producing human colonic bacteria

Peer reviewedPublisher PD

Elective Open Suprarenal Aneurysm Repair in England from 2000 to 2010 an Observational Study of Hospital Episode Statistics

Background: Open surgery is widely used as a benchmark for the results of fenestrated endovascular repair of complex abdominal aortic aneurysms (AAA). However, the existing evidence stems from single-centre experiences, and may not be reproducible in wider practice. National outcomes provide valuable information regarding the safety of suprarenal aneurysm repair. Methods: Demographic and clinical data were extracted from English Hospital Episodes Statistics for patients undergoing elective suprarenal aneurysm repair from 1 April 2000 to 31 March 2010. Thirty-day mortality and five-year survival were analysed by logistic regression and Cox proportional hazards modeling. Results: 793 patients underwent surgery with 14% overall 30-day mortality, which did not improve over the study period. Independent predictors of 30-day mortality included age, renal disease and previous myocardial infarction. 5-year survival was independently reduced by age, renal disease, liver disease, chronic pulmonary disease, and known metastatic solid tumour. There was significant regional variation in both 30-day mortality and 5-year survival after risk-adjustment. Regional differences in outcome were eliminated in a sensitivity analysis for perioperative outcome, conducted by restricting analysis to survivors of the first 30 days after surgery. Conclusions: Elective suprarenal aneurysm repair was associated with considerable mortality and significant regional variation across England. These data provide a benchmark to assess the efficacy of complex endovascular repair of supra-renal aneurysms, though cautious interpretation is required due to the lack of information regarding aneurysm morphology. More detailed study is required, ideally through the mandatory submission of data to a national registry of suprarenal aneurysm repair

Reversal of infall in SgrB2(M) revealed by Herschel/HIFI observations of HCN lines at THz frequencies

To investigate the accretion and feedback processes in massive star formation, we analyze the shapes of emission lines from hot molecular cores, whose asymmetries trace infall and expansion motions. The high-mass star forming region SgrB2(M) was observed with Herschel/HIFI (HEXOS key project) in various lines of HCN and its isotopologues, complemented by APEX data. The observations are compared to spherically symmetric, centrally heated models with density power-law gradient and different velocity fields (infall or infall+expansion), using the radiative transfer code RATRAN. The HCN line profiles are asymmetric, with the emission peak shifting from blue to red with increasing J and decreasing line opacity (HCN to H$^{13}$CN). This is most evident in the HCN 12--11 line at 1062 GHz. These line shapes are reproduced by a model whose velocity field changes from infall in the outer part to expansion in the inner part. The qualitative reproduction of the HCN lines suggests that infall dominates in the colder, outer regions, but expansion dominates in the warmer, inner regions. We are thus witnessing the onset of feedback in massive star formation, starting to reverse the infall and finally disrupting the whole molecular cloud. To obtain our result, the THz lines uniquely covered by HIFI were critically important.Comment: A&A, HIFI special issue, accepte

Genetic architecture and major genes for backfat thickness in pig lines of diverse genetic backgrounds

Background Backfat thickness is an important carcass composition trait for pork production and is commonly included in swine breeding programmes. In this paper, we report the results of a large genome-wide association study for backfat thickness using data from eight lines of diverse genetic backgrounds. Methods Data comprised 275,590 pigs from eight lines with diverse genetic backgrounds (breeds included Large White, Landrace, Pietrain, Hampshire, Duroc, and synthetic lines) genotyped and imputed for 71,324 single-nucleotide polymorphisms (SNPs). For each line, we estimated SNP associations using a univariate linear mixed model that accounted for genomic relationships. SNPs with significant associations were identified using a threshold of p < 10(-6) and used to define genomic regions of interest. The proportion of genetic variance explained by a genomic region was estimated using a ridge regression model. Results We found significant associations with backfat thickness for 264 SNPs across 27 genomic regions. Six genomic regions were detected in three or more lines. The average estimate of the SNP-based heritability was 0.48, with estimates by line ranging from 0.30 to 0.58. The genomic regions jointly explained from 3.2 to 19.5% of the additive genetic variance of backfat thickness within a line. Individual genomic regions explained up to 8.0% of the additive genetic variance of backfat thickness within a line. Some of these 27 genomic regions also explained up to 1.6% of the additive genetic variance in lines for which the genomic region was not statistically significant. We identified 64 candidate genes with annotated functions that can be related to fat metabolism, including well-studied genes such as MC4R, IGF2, and LEPR, and more novel candidate genes such as DHCR7, FGF23, MEDAG, DGKI, and PTN. Conclusions Our results confirm the polygenic architecture of backfat thickness and the role of genes involved in energy homeostasis, adipogenesis, fatty acid metabolism, and insulin signalling pathways for fat deposition in pigs. The results also suggest that several less well-understood metabolic pathways contribute to backfat development, such as those of phosphate, calcium, and vitamin D homeostasis