Interactive comment on CO2 radiative forcing during the Holocene Thermal Maximum revealed by stomatal frequency of Iberian oak leaves (2)

Here we analyse radiocarbon-dated Quercus leaf assemblages from northern Spain to obtain past atmospheric CO2 mixing ratios for the time period 9000–1100 cal BP by means of stomatal frequency analysis. Normalized, stomata based CO2 records show fluctuations of 20 ppmv during the Holocene that parallel Northern 5 Hemisphere palaeotemperature reconstructions. The calculated radiative forcing of CO2 indicates a CO2 contribution of +0.1_C to the Holocene Thermal Maximum from 7 to 5 kyr BP, and −0.05_C to the Neoglacial cooling around 4 kyr BP. Derived northern hemispheric air-temperature anomalies forced by atmospheric CO2 variation suggest an active role 10 of this trace gas as an amplifier of initial orbital forcing of Holocene climate

Functional evolution of ADAMTS genes: Evidence from analyses of phylogeny and gene organization

BACKGROUND: The ADAMTS (A Disintegrin-like and Metalloprotease with Thrombospondin motifs) proteins are a family of metalloproteases with sequence similarity to the ADAM proteases, that contain the thrombospondin type 1 sequence repeat motifs (TSRs) common to extracellular matrix proteins. ADAMTS proteins have recently gained attention with the discovery of their role in a variety of diseases, including tissue and blood disorders, cancer, osteoarthritis, Alzheimer's and the genetic syndromes Weill-Marchesani syndrome (ADAMTS10), thrombotic thrombocytopenic purpura (ADAMTS13), and Ehlers-Danlos syndrome type VIIC (ADAMTS2) in humans and belted white-spotting mutation in mice (ADAMTS20). RESULTS: Phylogenetic analysis and comparison of the exon/intron organization of vertebrate (Homo, Mus, Fugu), chordate (Ciona) and invertebrate (Drosophila and Caenorhabditis) ADAMTS homologs has elucidated the evolutionary relationships of this important gene family, which comprises 19 members in humans. CONCLUSIONS: The evolutionary history of ADAMTS genes in vertebrate genomes has been marked by rampant gene duplication, including a retrotransposition that gave rise to a distinct ADAMTS subfamily (ADAMTS1, -4, -5, -8, -15) that may have distinct aggrecanase and angiogenesis functions

Engraftment characterization of risk-stratified AML in NSGS mice

The authors thank Paola Romecin and Virginia Rodriguez-Cortez for technical assistance. This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2016-80481R, PID2019-108160RBI00), the Obra Social La Caixa (LCF/PR/HR19/52160011), Interreg V-A programme (POCTEFA) 2014-2020 (grant PROTEOblood EFA360/19), Health Canada (H4080-144541), and Deutsche Josep Carreras Leukämie Stiftung (P.M.). Additional funding was provided by Consejería de Salud y Familia (PI- 0119-2019) (R.D.d.l.G.), Health Institute Carlos III (ISCIII/FEDER, PI17/01028) and Asociación Española Contra el Cáncer (C.B.), Health Institute Carlos III/FEDER (CPII17/00032) (V.R.-M.), and Fundación Hay Esperanza (E.A.). CERCA/Generalitat de Catalunya and Fundación Josep Carreras-Obra Social la Caixa provided institutional support. B.L.-M. was supported by a Lady Tata Memorial Trust International Award and Asociación Española Contra el Cáncer (INVES20011LÓPE). O.M. and T.V.-H. were supported by Asociación Española Contra el Cáncer (INVES211226MOLI) and a Marie Sklodowska Curie Fellowship (792923), respectively. P.M. is an investigator in the Spanish Cell Therapy Network.Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment robustness/kinetics of 28 AML patient samples grouped according to molecular/ cytogenetic classification and assessed whether the orthotopic coadministration of patientmatched bone marrow mesenchymal stromal cells (BM MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85-94%) of the mice were engrafted in bone marrow (BM) independently of the risk group, although HR AML patients showed engraftment levels that were significantly superior to those of FR or IR AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable over time. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR AML patients, fitter leukemia-initiating cells (LICs) in HR AML samples, and the presence of AML LICs in the CD342 leukemic fraction, regardless of the risk group. Finally, orthotopic coadministration of patient-matched BM MSCs and AML cells was dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.Spanish Ministry of Economy and Competitiveness (SAF2016-80481R, PID2019-108160RBI00)Obra Social La Caixa (LCF/PR/HR19/52160011)Interreg V-A programme (POCTEFA) 2014-2020 (grant PROTEOblood EFA360/19)Health Canada (H4080-144541)Deutsche Josep Carreras Leukämie StiftungConsejer ıa de Salud y Familia (PI- 0119-2019)Health Institute Carlos III (ISCIII/FEDER, PI17/01028)Asociación Española Contra el CáncerHealth Institute Carlos III/FEDER (CPII17/00032)Fundación Hay EsperanzaCERCA/Generalitat de CatalunyaFundació Josep Carreras-Obra Social la CaixaLady Tata Memorial Trust International AwardAsociación Española Contra el Cáncer (INVES20011LÓPE)Asociación Española Contra el Cáncer (INVES211226MOLI)Marie Sklodowska Curie Fellowship (792923

Paleoflora y Paleovegetación Ibérica III: Holoceno

International audienc

Paleoflora y Paleovegetación Ibérica III: Holoceno

International audienc

Hypoxia and extracellular matrix remodeling

International audienceHypoxia regulates composition of both the vascular basement membrane (BM) and the extracellular matrix (ECM) by modulating deposition, cross-linking, posttranslational modifications, and rearrangement events but also degradation. Hypoxia-driven remodeling of the ECM includes highly temporally and spatially coordinated processes that eventually affect angiogenesis leading to blood vessel formation from existing blood vessels. Hypoxia thereby affects the mechanical properties of the vascular milieu as well as matricellular proteins expression and function and availability of angiogenesis-regulating growth factors such as vascular endothelial growth factor (VEGF). ECM composition and stiffness may be required for optimal VEGFR2 expression and vascular development in vitro and in vivo (Mammoto et al. Nature 2009), but how it might control signaling pathways such as VEGFR2 signaling is not fully appreciated yet. Thus, vascular BM and ECM composition affects vascular microenvironment architecture and interaction with angiogenic growth factors but also exerts mechanical forces controlled by physical interactions between vascular cells and the ECM that cooperate in regulating angiogenesis