Operation strategies guideline for packed bed thermal energy storage systems

Special issue research articlePacked bed thermal energy storage (TES) systems have been identified in the last years as one of the most promising TES alternatives in terms of thermal efficiency and economic viability. The relative simplicity of this storage concept opens an important opportunity to its implementation in many environments, from the renewable solar-thermal frame to the industrial waste heat recovery. In addition, its implicit flexibility allows the use of a wide variety of solid materials and heat transfer fluids, which leads to its deployment in very different applications. Its potential to overcome current heat storage system limitations regarding suitable temperature ranges or storage capacities has also been pointed out. However, the full implementation of the packed bed storage concept is still incomplete since no industrial scale units are under operation. The main underlying reasons are associated to the lack of a complete extraction of the full potential of this storage technology, derived from a successful system optimization in terms of material selection, design, and thermal management. These points have been evidenced as critical in order to attain high thermal efficiency values, comparable to the state-of-the-art storage technologies, with improved technoeconomic performance. In order to bring this storage technology to a more mature status, closer to a successful industrial deployment, this paper proposes a double approach. First, a low-cost by-product material with high thermal performance is used as heat storage material in the packed bed. Second, a complete energetic and efficiency analysis of the storage system is introduced as a function of the thermal operation. Overall, the impact of both the selected storage material and the different thermal operation strategies is discussed by means of a thermal model which permits a careful discussion about the implications of each TES deployment strategy and the underlying governing mechanisms. The results show the paramount importance of the selected operation method, able to increase the resulting cycle and material usage efficiency up to values comparable to standard currently used TES solutions.Financial support received from the European Commission through the H2020‐WASTE‐2014‐two‐stage(WASTE‐1‐2014) program (642067—RESLAG—IA) is gratefully acknowledged

Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity

Among the main complications associated with obesity are insulin resistance and altered glucose and lipid metabolism within the liver. It has previously been described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes compared with isoform B (IRB), improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high-fatdiet-induced obesity. We addressed the role of insulin receptor isoforms in glucose and lipid metabolism in vivo. We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAVs) in a mouse model of diet-induced insulin resistance and obesity. IRA, but not IRB, expression induced increased glucose uptake in the liver and muscle, improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn, Pgc1a, Acaca and Dgat2 and increasing Scd-1 expression. Taken together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB at favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease associated with obesity

Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12

Chronic hepatitis B is a major cause of liver-related death worldwide. Interleukin-12 (IL-12) induction accompanies viral clearance in chronic hepatitis B virus infection. Here, we tested the therapeutic potential of IL-12 gene therapy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), an infection that closely resembles chronic hepatitis B. The woodchucks were treated by intrahepatic injection of a helper-dependent adenoviral vector encoding IL-12 under the control of a liver-specific RU486-responsive promoter. All woodchucks with viral loads below 10(10) viral genomes (vg)/ml showed a marked and sustained reduction of viremia that was accompanied by a reduction in hepatic WHV DNA, a loss of e antigen and surface antigen, and improved liver histology. In contrast, none of the woodchucks with higher viremia levels responded to therapy. The antiviral effect was associated with the induction of T-cell immunity against viral antigens and a reduction of hepatic expression of Foxp3 in the responsive animals. Studies were performed in vitro to elucidate the resistance to therapy in highly viremic woodchucks. These studies showed that lymphocytes from healthy woodchucks or from animals with low viremia levels produced gamma interferon (IFN-gamma) upon IL-12 stimulation, while lymphocytes from woodchucks with high viremia failed to upregulate IFN-gamma in response to IL-12. In conclusion, IL-12-based gene therapy is an efficient approach to treat chronic hepadnavirus infection in woodchucks with viral loads below 10(10) vg/ml. Interestingly, this therapy is able to break immunological tolerance to viral antigens in chronic WHV carriers

CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1(-/-) mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites

Evolution of the use of corticosteroids for the treatment of hospitalised COVID-19 patients in Spain between March and November 2020: SEMI-COVID national registry

Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID- 19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years; p < 0.001), with hypertension (57.0% vs. 47.7%; p < 0.001), obesity (26.4% vs. 19.3%; p < 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%; p < 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7-160) vs. 49.3 (16-109) mg/dL; p < 0.001), ferritin (791 (393-1534) vs. 470 (236- 996) µg/dL; p < 0.001), D dimer (750 (430-1400) vs. 617 (345-1180) µg/dL; p < 0.001), and lower Sp02/Fi02 (266 (91.1) vs. 301 (101); p < 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September; p < 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%

Development of the advanced genetic therapies for Primary Hyperoxaluria type I

Primary Hyperoxaluria type I (PH1) is an inherited inborn error of the glyoxylate metabolism in the liver. It is caused by mutations in the AGXT gene, a gene that codes the peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). As a result of AGT deficiency oxalate, which is an end-product of glyoxylate metabolism, is overproduced in the liver. In healthy individuals, oxalate is excreted into urine, but when it is produced at high concentration there is a tendency for calcium oxalate (CaOx) crystals to be generated and deposited in the renal parenchyma, where kidney stones can form. As a consequence, PH1 patients present with severe kidney damage and poor survival of kidneys, developing end-stage renal disease (ESRD) in most of the cases. The only curative treatment is liver transplantation, which is usually combined with kidney transplantation because of the loss of renal function. The main goal of this study was to develop new therapeutic alternatives for PH1 based on advanced genetic treatment. In the initial part of this thesis we tried to improve PH1 gene therapy using adeno-associated viral (AAV) vectors. First, human AGXT was codon optimized in order to improve the expression levels of the protein. In this case, the optimization of the sequence of the AGXT gene resulted in no therapeutic advantage in comparison to the WT version of the gene. Second, we worked on the optimization of AAV gene delivery to the liver in non-human primates (NHP) changing the route of administration. It was demonstrated that the direct administration of AAV vectors into the hepatic blood flow resulted in a higher transduction of the liver in comparison to the systemic intravenous route. In addition, a completely novel approach based on gene editing using the recently discovered clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system was designed and characterized. This treatment was focused on a substrate reduction therapy (SRT) strategy, i.e. the reduction of glyoxylate production (the precursor of oxalate). Glycolate oxidase (GO) enzyme is a liver peroxisomal enzyme in charge of the production of glyoxylate. The inhibition of GO synthesis is known to reduce oxalate production. Therefore, a specific CRISPR/Cas9 system was designed to target and disrupt the Hao1 gene (the gene that codes GO) in hepatocytes. Using this strategy we were able to efficiently reduce GO protein levels. Moreover, the treatment resulted in a significant reduction of oxalate production and of renal damage in PH1 mice challenge with oxalate precursors, in absence of toxicity. In conclusion, several strategies to treat PH1 were developed and optimized during this project, which were able to reduce oxalate excretion in the urine of the PH1 mouse model

Development of the advanced genetic therapies for Primary Hyperoxaluria type I

Primary Hyperoxaluria type I (PH1) is an inherited inborn error of the glyoxylate metabolism in the liver. It is caused by mutations in the AGXT gene, a gene that codes the peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). As a result of AGT deficiency oxalate, which is an end-product of glyoxylate metabolism, is overproduced in the liver. In healthy individuals, oxalate is excreted into urine, but when it is produced at high concentration there is a tendency for calcium oxalate (CaOx) crystals to be generated and deposited in the renal parenchyma, where kidney stones can form. As a consequence, PH1 patients present with severe kidney damage and poor survival of kidneys, developing end-stage renal disease (ESRD) in most of the cases. The only curative treatment is liver transplantation, which is usually combined with kidney transplantation because of the loss of renal function. The main goal of this study was to develop new therapeutic alternatives for PH1 based on advanced genetic treatment. In the initial part of this thesis we tried to improve PH1 gene therapy using adeno-associated viral (AAV) vectors. First, human AGXT was codon optimized in order to improve the expression levels of the protein. In this case, the optimization of the sequence of the AGXT gene resulted in no therapeutic advantage in comparison to the WT version of the gene. Second, we worked on the optimization of AAV gene delivery to the liver in non-human primates (NHP) changing the route of administration. It was demonstrated that the direct administration of AAV vectors into the hepatic blood flow resulted in a higher transduction of the liver in comparison to the systemic intravenous route. In addition, a completely novel approach based on gene editing using the recently discovered clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system was designed and characterized. This treatment was focused on a substrate reduction therapy (SRT) strategy, i.e. the reduction of glyoxylate production (the precursor of oxalate). Glycolate oxidase (GO) enzyme is a liver peroxisomal enzyme in charge of the production of glyoxylate. The inhibition of GO synthesis is known to reduce oxalate production. Therefore, a specific CRISPR/Cas9 system was designed to target and disrupt the Hao1 gene (the gene that codes GO) in hepatocytes. Using this strategy we were able to efficiently reduce GO protein levels. Moreover, the treatment resulted in a significant reduction of oxalate production and of renal damage in PH1 mice challenge with oxalate precursors, in absence of toxicity. In conclusion, several strategies to treat PH1 were developed and optimized during this project, which were able to reduce oxalate excretion in the urine of the PH1 mouse model