Post-tectonic landscape evolution in NE Iberia using staircase terraces: Combined effects of uplift and climate

© 2017 Elsevier B.V.River incision into bedrock resulting from the combined effects of tectonic uplift and climate governs long-term regional landscape evolution. We determined spatial and temporal patterns of post-orogenic stream incision from a sequence of well-preserved staircase terraces developed over the last 1 Ma in the Central Pyrenees and its southern foreland Ebro basin (NE Spain). Extensive remnants of ten vertically separated terraces (Qt1 to Qt10, from oldest to youngest) were mapped along 170 km of the Cinca River valley, transverse to the Pyrenean mountain belt. Multiple outcrops appear in the upper reach of the valley (Ainsa sector, 50 km from headwaters) as well as in the lower reach (Albalate sector, 125 km from headwaters). Fluvial incision into bedrock was calculated using (i) differentially corrected GPS measurements of the altitude of straths and (ii) numerical dating of alluvial sediments from the lower terraces (Qt5 to Qt9) by Optically Stimulated Luminescence, previously reported by Lewis et al. (2009), and supplemented with new dates for the upper terraces (Qt1, Qt2 and Qt3) based on paleomagnetism and supported by soil development. Considering altitude differences and the elapsed time between successive well preserved terrace couples (Qt3–Qt7, Qt7–Qt9 and Qt9-Active channel), mean bedrock incision rates ranged from 0.76 to 0.38 m ka− 1, at the upper reach of the valley (Ainsa section), and from 0.61 to 0.20 m ka− 1, at the lower reach (Albalate section). River incision along the valley produced vertically separated, near-parallel longitudinal terrace profiles evidencing a rapid near-uniform regional uplift as response to (i) the tectonic lithospheric thickening in NE Iberia and (ii) the erosional download rebound related to the Ebro basin exorheism. Moreover, a subtle upstream divergence of strath profiles may have been a consequence of an increase in uplift rate toward the head of the valley. Additionally, incision rates changed over time as indicate results from the lower reach (Albalate section); the maximum rate was 1.48 m ka− 1 between Qt7 (61 ka) and Qt8 (47 ka), and the minimum rate was 0.11 m ka− 1 between Qt3 (401 ka) and Qt5 (178 ka). The highest incision rates were produced after the Marine Isotope Stage 4 most likely in response to (i) an increased snowmelt discharge during the subsequent deglaciation related to the last maximum advance of glaciers in the southern Pyrenees, and (ii) a limited width of the valley after Qt7 formation, resulting from the deactivation of the westward river migration. Therefore, incision rates over the last 1 Ma in the Cinca River valley were basically controlled by near-uniform bedrock uplift, in the context of climate variability. The results reported in this study represent significant data on fluvial incision in NE Iberia, and provide an assessment of the regional post-tectonic landscape evolution

Structure des grands bassins glaciaires dans le nord de la péninsule ibérique: comparaison entre les vallées d'Andorre (Pyrénées orientales), du Gállego (Pyrénées centrales) et du Trueba (Chaîne Cantabrique).

Les grandes vallées glaciaires de la Péninsule Ibérique sont situées dans la chaîne pyrénéo-cantabrique, principalement dans le bassin de l'Èbre. Ainsi, les vallées d'Andorre, de la Noguera Pallaresa et de la haute vallée du Gállego, dans les Pyrénées, ont eu des appareils glaciaires longs de 42, 50 et 40 km respectivement. Dans les vallées du Sil (bassin du Miño) et du Trueba, dans la Chaîne Cantabrique, ils atteignaient 42 et 16,5 km (Serrano-Cañadas, 1996 ; Gómez-Ortiz et al., 2001 ; Turu & Peña, 2006a et b ; Redondo-Vega et al., 2006). L'une des caractéristiques géomorphologiques de la plupart de ces vallées est l'existence d'une dépression morphologique du substratum dans les parties moyennes et terminales, interprétée comme la conséquence de l'érosion glaciaire. Dans tous les cas, on observe une architecture litho-stratigraphique commune (Vilaplana & Casas, 1983 ; Bordonau et al., 1989 ; Bordonau, 1992 ; Turu et al., 2002) représentée par trois unités géoélectriques : une unité inférieure très épaisse, avec des résistivités électriques basses (70 - 200 Ohms par mètre), qui traduit la présence de matériaux fins considérés comme d'origine lacustre ; une unité intermédiaire, moins épaisse, avec des valeurs de résistivité plus élevées (400 - 800 Ohms par mètre), pouvant être interprétée comme un système fluvio-deltaïque pro-glaciaire et une unité géoélectrique supérieure, avec des valeurs de résistivité très variables (100 - 1500 Ohms par mètre), constituée de sédiments alluviaux subactuels. La comparaison des données de type géophysique et géomécanique (sismique à réfraction et essais pressiométriques) montre que l'unité intermédiaire, considérée comme d'origine fluvio-deltaïque, présente des valeurs de vitesse sismique anormalement élevées, ainsi que de hautes valeurs de consolidation. Cette observation effectuée pour la première fois dans la vallée d'Andorre (Turu, 2000) montre des remarquables corrélations entre les hautes vitesses sismiques et les valeurs élevées de consolidation, ainsi que la très nette corrélation entre les hautes valeurs de consolidation et les tills sous-glaciaires. Elle permet d'interpréter l'unité intermédiaire comme essentiellement glaciaire et de remettre en question le modèle simple d'une séquence de comblement lacustre et deltaïque proposé jusqu´à maintenant

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

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

Cross-disease Meta-analysis of Genome-wide Association Studies for Systemic Sclerosis and Rheumatoid Arthritis Reveals IRF4 as a New Common Susceptibility Locus

Objectives: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc- RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods: We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposingdirection allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results: The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 x 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 x 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions: Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci

GWAS for Systemic Sclerosis Identifies Multiple Risk Loci and Highlights Fibrotic and Vasculopathy Pathways

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Funding: This work was supported by Spanish Ministry of Economy and Competitiveness (grant ref. SAF2015-66761-P), Consejeria de Innovacion, Ciencia y Tecnologia, Junta de Andalucía (P12-BIO-1395), Ministerio de Educación, Cultura y Deporte through the program FPU, Juan de la Cierva fellowship (FJCI-2015-24028), Red de Investigación en Inflamación y Enfermadades Reumaticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013), and Scleroderma Research Foundation and NIH P50-HG007735 (to H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. PopGen 2.0 is supported by a grant from the German Ministry for Education and Research (01EY1103). M.D.M and S.A. are supported by grant DoD W81XWH-18-1-0423 and DoD W81XWH-16-1-0296, respectively

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic