Resultados de investigación

Figure S1: Absorption spectra and standard curve of CIP at different concentrations in inorganic α-MEM solution at 25 ◦C.; Figure S2. (a,d) Optical micrographs, (b,e) 3D rendering and (c,f) variation of surface topography in 3D of (a–c) drug-free and (d–f) CIP-loaded HHC systems; Figure S3: Zwitterionic chelate complex of ciprofloxacin with Mg2+ and Ca2+ cations (M) released by PEO coating and Mg alloy; Figure S4: (a) Evolution of OCP for HHC and HH+CIP during 1 and 24 h of immersion. (b,c) Nyquist and Bode diagrams for HHC and HHC+CIP specimens after 1 h and 24 h of immersion in inorganic α-MEM solution at 37 ◦C; Table S1. Fitted electrical parameters of EIS spectra of HHC and HHC+CIP specimens after 1 h and 24 h of immersion in inorganic α-MEM solution at 37 ◦C. Chi-square range: 0.001446-0.003891, Peer reviewed

[Introduction]: Drought-associated tree mortality has been increasing worldwide since the last decades, impacting structure and functioning of forest ecosystems, with implications for energy, carbon and water fluxes. However, the understanding of the individual vulnerability to drought-induced mortality is still limited., [Methods]: We aimed to identify the factors that triggered the mortality of the widely distributed Pinus sylvestris L. in an extensive forest area in central Spain. We compared radial growth patterns in pairs of alive and recently dead individuals that co-occur in close proximity and present similar age and size, thereby isolating the effects of size and environment from the mortality process. Temporal dynamics of growth, growth synchrony, and growth sensitivity to water availability (precipitation minus potential evapotranspiration) were compared between alive and recently dead trees., [Results and discussion]: Over the last 50 years, although we did not detect significant differences in growth between alive and dead trees, an increase in the growth synchrony and sensitivity to water availability (i.e. slope of the climatic water balance in the growth model) was observed in all trees as drought intensity increased. 20 years before mortality, dead individuals showed lower growth synchrony and growth sensitivity to water availability than alive ones, without significant differences in growth. Recorded reduction in growth synchrony and growth sensitivity to water availability in dead trees suggests a decoupling between tree growth and climate, which could increase the risk of hydraulic failure and/or carbon starvation under increasingly arid conditions. Thus, the use of reduced growth sensitivity to water availability as potential early-warning signal of tree mortality, together with reduced growth synchrony, should be further explored, particularly in pine species in seasonally dry areas., Peer reviewed

The role of plant traits in shaping community assembly along environmental gradients is a topic of ongoing research. It is well accepted that plant traits of aboveground organs tend to be conservative in stressful conditions. However, there is limited understanding of how belowground traits respond. Plants may have similar strategies above and belowground, but an intriguing possibility is that there is a trade-off between above and belowground traits of communities to both ensure efficient resource-use and limit niche overlap along the gradient. To test this, we asked whether the response of above and belowground traits of communities is coordinated or not along a stress gradient in Mediterranean sand dune communities. We analyzed 80 vegetation plots in Central Italy to test for coordinated vs independent patterns in above vs belowground plant traits using community weighted mean and standardized effect size of functional richness. Our results show that plant communities close to the sea, which experience high stress, were characterized by high convergence towards aboveground resource conservation and conservative water-use strategies but belowground resource acquisition, consistent with a strong effect of habitat filtering and an above-belowground tradeoff favoring adaptation to harsh and dry conditions. At the opposite end of the gradient with lower stress, plants exhibited higher trait diversity for both above and belowground traits, but overall a dominance of aboveground fast resource acquisition and generally acquisitive water-use strategies, combined with conservative fine-root traits. This suggests that fast growth rate aboveground was compensated by more conservative fine-root strategies, but processes such as competition limited niche overlap overall. Our findings provide new insights into the relationship between functional traits and environmental gradients in plant communities, shedding light on the trade-offs between the above and belowground dimensions., Peer reviewed

1 file, Supporting information for the article https://doi.org/10.1029/2019GB006229, Text S1 to S6.-- Figures S1 to S16, Peer reviewed

[Introduction]: Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation., [Methods]: In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells’ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality., [Results]: In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells., [Discussion]: The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL., Peer reviewed

[Background]: Little is known about whether the overlap syndrome (OS) combining features of chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome increases the risk of stroke associated with COPD itself., [Methods]: We prospectively studied 74 COPD patients and 32 subjects without lung disease. Spirometry and cardiorespiratory polygraphy were used to assess the pulmonary function of the study population and ultrasound measurements of intima media thickness (IMT) as well as the volume of plaques in both carotid arteries were also evaluated., [Results]: Polygraphic criteria of OS were met in 51% of COPD patients. We found that 79% of patients with OS and 50% of COPD patients without OS had atherosclerotic plaques in the left carotid artery (p = 0.0509). Interestingly, the mean volume of atherosclerotic plaques was significantly higher in the left carotid artery of COPD patients with OS (0.07 ± 0.02 ml) than in those without OS (0.04 ± 0.02 ml, p = 0.0305). However, regardless of the presence of OS, no significant differences were observed in both presence and volume of atherosclerotic plaques in the right carotid artery of COPD patients. Adjusted-multivariate linear regression revealed age, current smoking and the apnea/hypopnea index (OR = 4.54, p = 0.012) as independent predictors of left carotid atherosclerotic plaques in COPD patients., [Conclusions]: This study suggests that the presence of OS in COPD patients is associated with larger left carotid atherosclerotic plaques, indicating that OS might be screened in all COPD patients to identify those with higher risk of stroke., Peer reviewed

[Background]: Little is known about whether the overlap syndrome (OS) combining features of chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome increases the risk of stroke associated with COPD itself., [Methods]: We prospectively studied 74 COPD patients and 32 subjects without lung disease. Spirometry and cardiorespiratory polygraphy were used to assess the pulmonary function of the study population and ultrasound measurements of intima media thickness (IMT) as well as the volume of plaques in both carotid arteries were also evaluated., [Results]: Polygraphic criteria of OS were met in 51% of COPD patients. We found that 79% of patients with OS and 50% of COPD patients without OS had atherosclerotic plaques in the left carotid artery (p = 0.0509). Interestingly, the mean volume of atherosclerotic plaques was significantly higher in the left carotid artery of COPD patients with OS (0.07 ± 0.02 ml) than in those without OS (0.04 ± 0.02 ml, p = 0.0305). However, regardless of the presence of OS, no significant differences were observed in both presence and volume of atherosclerotic plaques in the right carotid artery of COPD patients. Adjusted-multivariate linear regression revealed age, current smoking and the apnea/hypopnea index (OR = 4.54, p = 0.012) as independent predictors of left carotid atherosclerotic plaques in COPD patients., [Conclusions]: This study suggests that the presence of OS in COPD patients is associated with larger left carotid atherosclerotic plaques, indicating that OS might be screened in all COPD patients to identify those with higher risk of stroke., Peer reviewed

[Background]: Little is known about whether the overlap syndrome (OS) combining features of chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome increases the risk of stroke associated with COPD itself., [Methods]: We prospectively studied 74 COPD patients and 32 subjects without lung disease. Spirometry and cardiorespiratory polygraphy were used to assess the pulmonary function of the study population and ultrasound measurements of intima media thickness (IMT) as well as the volume of plaques in both carotid arteries were also evaluated., [Results]: Polygraphic criteria of OS were met in 51% of COPD patients. We found that 79% of patients with OS and 50% of COPD patients without OS had atherosclerotic plaques in the left carotid artery (p = 0.0509). Interestingly, the mean volume of atherosclerotic plaques was significantly higher in the left carotid artery of COPD patients with OS (0.07 ± 0.02 ml) than in those without OS (0.04 ± 0.02 ml, p = 0.0305). However, regardless of the presence of OS, no significant differences were observed in both presence and volume of atherosclerotic plaques in the right carotid artery of COPD patients. Adjusted-multivariate linear regression revealed age, current smoking and the apnea/hypopnea index (OR = 4.54, p = 0.012) as independent predictors of left carotid atherosclerotic plaques in COPD patients., [Conclusions]: This study suggests that the presence of OS in COPD patients is associated with larger left carotid atherosclerotic plaques, indicating that OS might be screened in all COPD patients to identify those with higher risk of stroke., Peer reviewed

Additional file 1: Supplementary Figure S1. Expression of RMPs in prostate tumours. A) mRNA expression of RMPs is significantly altered in human normal prostate tissue (N), primary (PT), and metastatic tumour (M). Y-axis shows log2-normalised expression data from Grasso et al. [7],Taylor et al. [6], and Varambally et al. [42] datasets (left panels). Kaplan–Meier curves showing disease-free survival (DFS) of patient groups selected according to decile expression of the indicated RMP genes (middle panel). The right panel shows differential expression in disease-free (DF) and recurrent patient samples from TCGA dataset [3]. B, C) Kaplan–Meier curves representing the disease-free survival (DFS) of patient groups selected according to the decile expression, data from the TCGA dataset [6] (TCGA: n = 491). D, E) PCa cell lines show increased METTL1 protein and mRNA levels. Western blotting showing METTL1, WDR4, AR, PTEN and phosphor-S6K expression (D), and qPCR (E) of normalised mRNA expression (lower panel) in prostate epithelial cell lines (PWR-1E and RWPE-1), benign prostatic hyperplasia cell lines (BPH1), and prostate cancer cell lines (VCap, C4-2, LNCaP, 22Rv1, DU145, and PC3). Mean ± SD (D, E). Statistical tests: ANOVA test (A), log-rank Cox test (A, B); Student’s t-test with Welch’s correction, grouping all data from benign vs. all data from tumour cells ****p < 0.0001 (E)., Consejo Superior de Investigaciones Cientificas (CSIC), Peer reviewed

Additional file 2: Supplementary Figure S2. Regulation of METTL1 expression in PCa. A) Correlation analysis between METTL1 and KLK3 expression, and METTL1 and AR expression in the human primary PCa expression datasets. The plotted values correspond to the log2-normalised expression values. Black line represents linear regression, grey area indicates the limits of the confidence intervals. Pearson's correlation coefficient (R) and p-values are indicated. Grasso n = 88; Taylor n = 183; TCGA n = 497. B) No effect on mRNA expression levels of METTL1 upon dihydrotestosterone (DHT) treatment in LNCaP cells. Mean ± SD, n = 3. C) Graphical representation of PI3K inhibition by different compounds. Small molecule inhibitors used: pan-PI3K inhibitor BKM-120 (BKM), AKT inhibitor MK2206 (MK), mTORC1 inhibitor rapamycin (RAPA), and mTORC1/2 inhibitor Torin (TOR). D, E) METTL1 expression is affected by the inhibition of downstream PI3K pathway members. Western blotting (D) and RT-qPCR (E) analyses of METTL1 expression upon PI3K pathway inhibition in PC3 cells. The cells were treated for 48 h (D) or 8 h (E). Mean ± SD, n = 2 (D) and n = 6 (E). F) Representative images of immune stained sections for Mettl1 and markers for luminal (AR), and basal (K14) cells in Pten-KO prostates (dorsal and ventral lobes) in invasive carcinoma (6 months old mice) and in aged-match wild-type (WT) prostates. Scale bars represent 50 μm. Statistical tests: One-tailed Student’s t-test (B, D, E). *p < 0.05, **p < 0.01, ***p < 0.001., Consejo Superior de Investigaciones Cientificas (CSIC), Peer reviewed