IR characterization of Ln2−xSrxCoO4 (x≥1; Ln=La, Nd) oxides

[Abstract] We have recorded the FTIR spectra of powder samples of Ln2−xSrxCoO4 (Ln=La, Nd) at room temperature. We have identified the infrared active modes (3A2u+4Eu), and analyzed how they change as a function of Ln and the Sr doping. We correlate the obtained results with structural data obtained from powder X-ray diffraction studies and with the electronic properties displayed by these samples

Ionoluminescence induced by swift heavy ions in silica and quartz: A comparative analysis

Ionoluminescence (IL) of the two SiO 2 phases, amorphous silica and crystalline quartz, has been comparatively investigated in this work, in order to learn about the structural defects generated by means of ion irradiation and the role of crystalline order on the damage processes. Irradiations have been performed with Cl at 10 MeV and Br at 15 MeV, corresponding to the electronic stopping regime (i.e., where the electronic stopping power S e is dominant) and well above the amorphization threshold. The light-emission kinetics for the two main emission bands, located at 1.9 eV (652 nm) and 2.7 eV (459 nm), has been measured under the same ion irradiation conditions as a function of fluence for both, silica and quartz. The role of electronic stopping power has been also investigated and discussed within current views for electronic damage. Our experiments provide a rich phenomenological background that should help to elucidate the mechanisms responsible for light emission and defect creationThis work has been supported by Spanish Ministry MICINN through the project MAT-2008-06794-C03-03, JCI-2009-05681, and by Madrid Community through the project TECHNOFUSION (S2009/ENE-1679). OPR is grateful to CONACyT, Mexico, for extending a postdoctoral fellowshi

Nuclear receptor NR5A2 and bone: gene expression and association with bone mineral density

ObjectiveThere is growing evidence for a link between energy and bone metabolism. The nuclear receptor subfamily 5 member A2 (NR5A2) is involved in lipid metabolism and modulates the expression of estrogen-related genes in some tissues. The objective of this study was to explore the influence of NR5A2 on bone cells and to determine whether its allelic variations are associated with bone mineral density (BMD).DesignAnalyses of gene expression by quantitative PCR and inhibition of NR5A2 expression by siRNAs were used to explore the effects of NR5A2 in osteoblasts. Femoral neck BMD and 30 single nucleotide polymorphisms (SNPs) were first analyzed in 935 postmenopausal women and the association of NR5A2 genetic variants with BMD was explored in other 1284 women in replication cohorts.ResultsNR5A2 was highly expressed in bone. The inhibition of NR5A2 confirmed that it modulates the expression of osteocalcin, osteoprotegerin, and podoplanin in osteoblasts. Two SNPs were associated with BMD in the Spanish discovery cohort (rs6663479, P=0.0014, and rs2816948, P=0.0012). A similar trend was observed in another Spanish cohort, with statistically significant differences across genotypes in the combined analysis (P=0.03). However, the association in a cohort from the United States was rather weak. Electrophoretic mobility assays and studies with luciferase reporter vectors confirmed the existence of differences in the binding of nuclear proteins and the transcriptional activity of rs2816948 alleles.ConclusionsNR5A2 modulates gene expression in osteoblasts and some allelic variants are associated with bone mass in Spanish postmenopausal women

Acoustic detection of larval fish aggregations in Galician waters (NW Spain)

14 páginas, 3 tablas, 7 figurasAn acoustic study was conducted on the Galician shelf (NW Spain) during late winter 2012 to detect and assess larval fish abundance. An echo sounder operating with 18, 38, 70, 120 and 200 kHz split-beam, hull-mounted transducers was employed. We analysed the acoustic records in order to describe vertical and horizontal distribution patterns of larval fish aggregations. Regressions between acoustic backscattered energy and density of the most abundant species (Micromesistius poutassou) indicated that larvae with a swimbladder incremented notably the acoustic response at 38, 70 and 120 kHz. However, the predicted acoustic resonance at larval size and depth shows that the frequency of 120 kHz was likely ineffective in detecting fish larvae. The contribution of zooplankton (fish larvae excluded) to total scattering was negligible, even at the higher frequencies, except for several groups of fluid-like zooplankton, such as chaetognaths and polychaetes. Horizontal and vertical distributions of acoustic backscattering also indicated that larval fish aggregations can be detected in Galician waters with acoustics and suggest that this technique is a useful tool for overcoming difficulties associated with larval ecology and fish recruitment studiesVersión del editor2,483

Fatty liver and fibrosis in glycine N-methyltransferase knockout mice is prevented by nicotinamide

Deletion of glycine N-methyltransferase (GNMT) in mice, the main gene involved in liver S-adenosylmethionine (SAMe) catabolism, leads to the hepatic accumulation of this molecule and the development of fatty liver and fibrosis. To demonstrate that the excess of hepatic SAMe is the main agent contributing to liver disease in GNMT-KO mice, we treated 1.5-month old GNMT-KO mice for 6 weeks with nicotinamide (NAM), a substrate of the enzyme NAM N-methyltransferase. NAM administration markedly reduced hepatic SAMe content, prevented DNA-hypermethylation and normalized the expression of critical genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis. More important, NAM treatment prevented the development of fatty liver and fibrosis in GNMT-KO mice. Because GNMT expression is down-regulated in patients with cirrhosis and there are subjects with GNMT mutations who have spontaneous liver disease, the clinical implication of the present findings is obvious at least with respect to these latter individuals. Especially since NAM has been used for many years to treat a broad spectrum of diseases including pellagra and diabetes without significant side effects, it should be considered in subjects with GNMT mutations.ConclusionsThese results indicate that the anomalous accumulation of SAMe in GNMT-KO mice can be corrected by NAM treatment leading to the normalization of the expression of many genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation and apoptosis, and to the reversion of the appearance of the pathologic phenotype

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

© 2021 The Authors.[Background]: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established.[Methods]: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response.[Results]: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition.[Conclusions]: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/006

Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ACC signaling increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis and inflammation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-β-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.This work was supported by grants PID2019-104233RB-I00 and PID2022-136703OB-I00 funded by MCIN /AEI/10.13039/501100011033 / FEDER, Spanish National Research Council CSIC–COV19-096/PIE202020E160, Comunidad de Madrid “NOVELREN” B2017/BMD-3751 and Fundación Renal “Íñigo Alvarez de Toledo”, all from Spain. The CBMSO receives institutional support from Fundación “Ramón Areces”. VM and EA hold a Juan de la Cierva-Formación fellowship from the Spanish Ministry of Science and Innovation (FJC2020-043505-I and FJC2021-046602-I, respectively). VM was supported by a Postdoctoral Long-Term Fellowship from the Federation of European Biochemical Societies (FEBS). CR and BS are recipients of a pre-doctoral fellowship of the FPI Program (BES-2016-076735 and PRE-2020-093831, respectively) from the Spanish Research State Agenc

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

[EN]Background Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established. Methods We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response. Results Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition. Conclusions Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL

Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer

The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma

Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer

The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma