From Galena to Lead: Divergent Paths in Early Metallurgy in the Western Mediterranean

This paper examines the use of galena, beginning in the Middle Paleolithic, before the onset of metallurgy in the Iberian Peninsula, and shows that it was a well-known raw material during the Neolithic, both in funeral and in household contexts. The identification of probable provenance suggests a non-long distance movement, with the Molar-Bellmunt-Falset mining district in Tarragona as the main source area for extracting this ore since the Palaeolithic. Although southern France and other European regions share a similar use of galena in Neolithic times, each took different approaches to the use of the raw material. In some areas (southern France, Sardinia) lead was used for metal production, while in others (Iberia, continental Italy) it was not. These differences can be explained by different social choices in each region, reinforcing the idea that innovation is not simply a question of technology.The elemental and lead isotope analysis have been funded through several projects:“Inici i desenvolupament de les comunitats neolítiques a la plana occidental de Catalunya (c. 5500-3000 cal ANE)“ (núm. exp. CLT009/18/00021 -Generalitat de Catalunya, España)‘Territorios, producciones técnicas e innovaciones tecnológicas en la transición Mesolítico-Neolítico’ (PID2019-109254GB-C22). Metal y ambar II: Metal y Ambar II: Circulación de Bronce y Ambar en el Sur-este Peninsular durante la Edad del Bronce (PID2019-108289GB-I00 - Ministerio de Ciencia e Innovación).“Recursos Minerometalicos, Intercambio y Comercio en la Prehistoria y la Protohistoria Peninsular (Cataluña y el Norte del Pais Valenciano)” (HAR2014-54012-P - Ministerio de Ciencia e Innovación)Les Comunitats Prehistòriques del Massís de Garraf Nord. Fase 2. Orígens, genètica, dieta, patrons d’assentament, trets culturals i recursos durant la prehistòria recent (CLT903/2018/92 -Generalitat de Catalunya, España)Grant PGC2018-096943-B-C21: “CHRONOEVOL: High resolution chronology and cultural evolution in the east of the Iberian Peninsula (circa 7000-4000 cal BC): a multiscalar approach”. PGC2018-096943-B-C21- Min-isterio de Ciencia e Innovación and European Regional Development Fund “A way of making Europe”)Peer reviewe

The effect of hypoxia on the lipidome of recombinant Pichia pastoris

Cultivation of recombinant Pichia pastoris (Komagataella sp.) under hypoxic conditions has a strong positive effect on specific productivity when the glycolytic GAP promoter is used for recombinant protein expression, mainly due to upregulation of glycolytic conditions. In addition, transcriptomic analyses of hypoxic P. pastoris pointed out important regulation of lipid metabolism and unfolded protein response (UPR). Notably, UPR that plays a role in the regulation of lipid metabolism, amino acid metabolism and protein secretion, was found to be upregulated under hypoxia. To improve our understanding of the interplay between lipid metabolism, UPR and protein secretion, the lipidome of a P. pastoris strain producing an antibody fragment was studied under hypoxic conditions. Furthermore, lipid composition analyses were combined with previously available transcriptomic datasets to further understand the impact of hypoxia on lipid metabolism. Chemostat cultures operated under glucose-limiting conditions under normoxic and hypoxic conditions were analyzed in terms of intra/extracellular product distribution and lipid composition. Integrated analysis of lipidome and transcriptome datasets allowed us to demonstrate an important remodeling of the lipid metabolism under limited oxygen availability. Additionally, cells with reduced amounts of ergosterol through fluconazole treatment were also included in the study to observe the impact on protein secretion and its lipid composition. Our results show that cells adjust their membrane composition in response to oxygen limitation mainly by changing their sterol and sphingolipid composition. Although fluconazole treatment results a different lipidome profile than hypoxia, both conditions result in higher recombinant protein secretion levels. The online version of this article (doi:10.1186/s12934-017-0699-4) contains supplementary material, which is available to authorized users

Effectiveness of a training intervention to improve the management of vertigo in primary care: a multicentre cluster-randomised trial, VERTAP

Background: Benign paroxysmal positional vertigo (BPPV) is the most common type of vertigo. While BPPV is best treated with canalicular repositioning manoeuvres, they are not routinely performed in primary care (PC). Methods: To evaluate the effectiveness of blended training (online and face-to-face) on the diagnosis and management of vertigo to improve adherence of family doctors to clinical practice guidelines, we designed a community multicentre cluster-randomised open-label trial with an intervention (IG) and a control (GC) group of 10 primary care teams (PCT) each. Outcome variables will be ICD-10 diagnostic codes (proportion of nonspecific diagnoses such as dizziness and vertigo versus specific diagnoses such as BPPV, vestibular neuritis, and Meniere's disease); number of referrals to ENT or neurology specialists; prescription of antivertigo agents; and duration of sick leave due to vertigo. The baseline comparability of the two study groups will be analysed to ensure homogeneity. A description of all baseline variables will be performed. Student's t-test will be used to evaluate the differences between the groups. Logistic regression multivariate analysis will be performed to study the relationship between baseline variables of professionals and centres with outcome variables. Discussion: With the improvement of the diagnosis and management of vertigo by family doctors after this training, we expect an increase in the proportion of specific diagnoses, a decrease in the prescription of antivertigo agents, a decrease in referrals to ENT or neurology specialists and a reduction in the duration of sick leave due to temporary disability. The blended training will be easily expanded within primary care services, since it is mainly delivered online, with a single face-to-face session to ensure that the manoeuvres have been adequately learned

Mobilizing in borderline citizenship regimes : a comparative analysis of undocumented migrants’ collective actions

This article seeks to explain how and why groups and networks of undocumented migrants mobilizing in Berlin, Montréal, and Paris since the beginning of the 2000s construct different types of claims. The authors explore the relationship between undocumented migrants and state authorities at the local level through the concept of the citizenship regime and its specific application to undocumented migrants (which they describe as the “borderline citizenship regime”). Despite their common formal exclusion from citizenship, nonstatus migrants experience different degrees and forms of exclusion in their daily lives, in terms of access to certain rights and services, recognition, and belonging within the state (whether through formally or nonformally recognized means). As a result, they have an opportunity to create different, specific forms of leeway in the society in which they live. The concurrence of these different degrees of exclusion and different forms of leeway defines specific conditions of mobilization. The authors demonstrate how the content of their claims is influenced by these conditions of mobilization

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease