Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice

The study was partially presented as a poster in the 53rd Annual Meeting of the European Association for the Study of Diabetes, Lisbon 2017.The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. OBJECTIVE: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance.[Methods] We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action.[Results] L-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded.[Conclusion] IDE is not a rate-limiting regulator of plasma insulin levels in vivo.This work was supported by grants from the Ministerio de Economía, Industria y Competitividad: SAF2014-58702-C2-1-R and SAF2016-77871-C2-1-R to ICC; SAF2014-58702-C2-2-R and SAF2016-77871-C2-2-R to GP; supported by the EFSD European Research Programme on New Targets for Type 2 Diabetes supported by an educational research grant from MSD to ICC and GP; the National Institutes of Health: R01-DK054254, R01-DK083850 and RO1-HL-112248 to SMN, and R01-GM115617 to MAL; and the American Diabetes Association: Career Development Award 7-11-CD-13 to MAL.Peer reviewe

Consistent patterns of common species across tropical tree communities

Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations1,2,3,4,5,6 in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories7, we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees.Publisher PDFPeer reviewe

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Investigaciones recientes (1990-1997) en los yacimientos achelenses de Ambrona y Torralba (Soria, España). Aproximación al complejo estratigráfico inferior de Ambrona.

Resumen: El proyecto iniciado en 1990 en los yacimientos achelenses de Ambrona y Torralba (Soria, España) tiene como primer objetivo definir el marco natural en que se inscribe la actividad humana y delimitar su alcance. Junto a la descripción general de los trabajos efectuados basta 1997, presentamos aquí algunos resultados iniciales relativos a la geología, palinología, fauna e industria lítica del Complejo estratigráfico inferior de Ambrona.Abstract: In 1990 we initiated new investigations al the Lower Paleolithic sites of Ambrona and Torralba (Soria province, Spain). The purpose of the project is to define the natural framework in which human activity was inscribed and to delimit its scope. Together with the general description of the work carried out between 1990 and 1997 we present preliminary results on the geology, palinology, fauna and the lithic industry recovered in recent excavations of the Lower stratigraphic Complex of Ambrona.Peer reviewe

The Archaeo- Palaeontological sites of the Middle Pleistocene at Ambrona and Torralba (Soria).

There are not many sites supplying significant information in order to enlarge our knowledge of the activities of human groups in the Lower Palaeolithic. Most of them conserve only artefacts of stone together with chips and flakes produced in their preparation and few sites offer in addition wide-ranging sets of fauna, palaeo-environmental information and other items, such as for instance wood. Torralba and Ambrona, two sites known to scientists since the beginning of the century, correspond to this second category and are particularly distinguished by the abundant presence of faunal remains, particularly elephants. The wealth and variety of the information recovered from these two locations contribute to enlarge our knowledge on the environment of the ages in which these deposits were accumulated, of the fauna and vegetation and, in short, to a better understanding of the ecosystems in which the groups of Palaeolithic humans lived.Peer reviewe

The Torralba and Ambrona pleistocene sites and their relations with the geomorphological evolution of the Conquezuela Polje

The Ambrona and Torralba archeological sites are related to the pleistocene evolution of the Conquezuela-Ambrona-Torralba polje. A study made of the centre-south sectors of this polje, nowadays highly degraded In part though being dissected by the river Masegar, shows that Torralba and Ambrona occupy different geomorphological positions. This would mean that both the age and strati graphic formations of the sites are differen

Aproximación a los paleoambientes del hombre en el Pleistoceno medio e inferior. A.- Los yacimientos de Ambrona y Torralba.

Peer reviewe

Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome

Mosaicism is defined as the coexistence of cells with different genetic composition within an individual, caused by postzygotic somatic mutation. Although somatic mosaicism for chromosomal abnormalities is a well-established cause of developmental and somatic disorders and has also been detected in different tissues, its frequency and extent in the adult normal population are still unknown. We provide here a genome-wide survey of mosaic genomic variation obtained by analyzing Illumina 1M SNP array data from blood or buccal DNA samples of 1991 adult individuals from the Spanish Bladder Cancer/EPICURO genome-wide association study. We found mosaic abnormalities in autosomes in 1.7% of samples, including 23 segmental uniparental disomies, 8 complete trisomies, and 11 large (1.5-37 Mb) copy-number variants. Alterations were observed across the different autosomes with recurrent events in chromosomes 9 and 20. No case-control differences were found in the frequency of events or the percentage of cells affected, thus indicating that most rearrangements found are not central to the development of bladder cancer. However, five out of six events tested were detected in both blood and bladder tissue from the same individual, indicating an early developmental origin. The high cellular frequency of the anomalies detected and their presence in normal adult individuals suggest that this type of mosaicism is a widespread phenomenon in the human genome. Somatic mosaicism should be considered in the expanding repertoire of inter- and intraindividual genetic variation, some of which may cause somatic human diseases but also contribute to modifying inherited disorders and/or late-onset multifactorial traits.This work was supported by the Intramural Research Program of the NCI Division of Cancer Epidemiology and Genetics (to N.R., D.S., and S.J.C.), the Asociación Española Contra el Cáncer (to F.X.R., N.M., and L.A.P.-J.), EU-6FP grants LSHG-CT-2006-037627 (to L.A.P.-J.) and HEALTH-STREP-2006-037739-DropTop (to N.M. and F.X.R.), Fondo de Investigación Sanitaria grants PI076832 (to L.A.P.-J.) and PI061614 (to F.X.R.), Consolider ONCOBIO (to F.X.R.), National Institutes of Health grant R01 CA089715-06A2 (to N.M. and F.X.R.), Red Temática de Investigación Cooperativa en Cáncer (to N.M. and A.C.), Fundació La Marató de TV3 (to N.M.), and EU-7FP grant agreements #201663-UROMOL (to N.M. and F.X.R.) and #201333-DEC-anBIO(to N.M.). B.R.-S. and G.M.were supportedby a postdoctoral fellowship (FIS CD06/00019) and a predoctoral fellowship (FI09/00205) of the Fondo Investigación Sanitaria, respectively