Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA

Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA.This work was supported by Instituto de Salud Carlos III (ISCIII) [PI18/0919], the Spanish Ministerio de Ciencia e Innovación (MICINN) [RTI2018-094727-B-100 and PID2019-108489RB-100], the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) [2017-SGR-00333], Sociedad Española de Arteriosclerosis [Beca FEA 2020 Investigación Básica], and Sociedad Española de Cardiología [SEC/FEC-INV-BAS 20/005]. The study was co-founded by Fondo Europeo de Desarrollo Regional (FEDER), “A way to make Europe”. L.C. was supported by a FI (AGAUR). The CNIC is supported by MICINN, ISCIII, and the Pro-CNIC Foundation

Combining biocatalysts to achieve new phase change materials. Application to non-edible animal fat

"Formerly known as Journal of Molecular Catalysis A: Chemical"The thermal properties of various alkyl threo-9, 10-dihydroxystearates (DHSEs) prepared from non-edible fat were studied. Non-edible animal fat was hydrolyzed in a 93% yield with R. oryzae resting cells. Crude unsaturated fatty acids were recovered from the matter liquor resulting from a crystallization performed to achieve the saturated fatty acids. These unsaturated free fatty acids were epoxidized with 30% H2O2 using immobilized Candida antarctica Lipase-B (CAL-B) as biocatalyst. The epoxy ring was cleaved with hot water in the presence of tert-butanol (t-BuOH). Pure threo-9, 10-dihydroxystearic acid (DHSA) from animal fat was recovered by crystallization (51% yield). Subsequently, DHSA was esterified in alpha-limonene using biocatalysts yielding twelve DHSEs (58-90% yield). Differential scanning calorimetry (DSC) analysis of these esters revealed potential latent heats ranging from 136.83 kJ kg−1 to 234.22 kJ kg−1 and melting temperatures from 52.45 ◦C to 76.88 ◦C. Finally, the compounds with enthalpies above 200 kJ kg−1 were subjected to 100 and 1000 thermal cycles. These experiments showed that these products present good thermal reliability.GREA and DBA are certified agents TECNIO in the category of technology developers from the Government of Catalonia. We thanks to Subproductos Cárnicos Echevarria y Asociados S.L (Cervera, Spain) for supplying the non-edible fat. Moreover, the research leading to these results has received funding from the European Commission Seventh Framework Programme (FP/2007-2013) under grant agreement no PIRSES-GA-2013-610692 (INNOSTORAGE) and from the European Union’s Horizon 2020 research and innovation program under grant agreement no 657466 (INPATH-TES). The authors would like to thank the Catalan Government for the quality accreditation given to their research groups GREA (2014 SGR 123) and Agricultural Biotechnology Research Group (2014 SGR 1296). This work has been partially funded by the Spanish government (CTQ2015-70982-C3-1-R (MINECO/FEDER) and ENE2015-64117-C5-1-R (MINECO/FEDER). Aran Solé would like to thank Ministerio de Economía y Competitividad de España for Grant Juan de la Cierva, FJCI-2015-25741

GasLib — A Library of Gas Network Instances

The development of mathematical simulation and optimization models and algorithms for solving gas transport problems is an active field of research. In order to test and compare these models and algorithms, gas network instances together with demand data are needed. The goal of GasLib is to provide a set of publicly available gas network instances that can be used by researchers in the field of gas transport. The advantages are that researchers save time by using these instances and that different models and algorithms can be compared on the same specified test sets. The library instances are encoded in an XML (extensible markup language) format. In this paper, we explain this format and present the instances that are available in the library

Individuals With SARS-CoV-2 Infection During the First and Second Waves in Catalonia, Spain: Retrospective Observational Study Using Daily Updated Data

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiologia; ComparacióCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiología; ComparaciónCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiology; ComparisonA description of individuals with SARS-CoV-2 infection comparing the first and second waves could help adapt health services to manage this highly transmissible infection.Objective: We aimed to describe the epidemiology of individuals with suspected SARS-CoV-2 infection, and the characteristics of patients with a positive test comparing the first and second waves in Catalonia, Spain. Methods: This study had 2 stages. First, we analyzed daily updated data on SARS-CoV-2 infection in individuals from Girona (Catalonia). Second, we compared 2 retrospective cohorts of patients with a positive reverse-transcription polymerase chain reaction or rapid antigen test for SARS-CoV-2. The severity of patients with a positive test was defined by their admission to hospital, admission to intermediate respiratory care, admission to the intensive care unit, or death. The first wave was from March 1, 2020, to June 24, 2020, and the second wave was from June 25, 2020, to December 8, 2020.Results: The numbers of tests and cases were lower in the first wave than in the second wave (26,096 tests and 3140 cases in the first wave versus 140,332 tests and 11,800 cases in the second wave), but the percentage of positive results was higher in the first wave than in the second wave (12.0% versus 8.4%). Among individuals with a positive diagnostic test, 818 needed hospitalization in the first wave and 680 in the second; however, the percentage of hospitalized individuals was higher in the first wave than in the second wave (26.1% versus 5.8%). The group that was not admitted to hospital included older people and those with a higher percentage of comorbidities in the first wave, whereas the characteristics of the groups admitted to hospital were more alike.This work was supported by grants from the European Union ERDF funds (Network for Prevention and Health Promotion in Primary Care, RedIAPP–CARDIOCAT; RD16/0007/0004) and from the Agency for Management of University and Research Grants (AGAUR; 2017-SGR 1146). We thank Eric Tornabell for his technical support. We also thank all health care professionals for their ceaseless work to care for COVID-19 patients in this pandemic

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Info WebApp

Desenvolupament d'Info WebApp, una aplicació web per a una escola d'informàtica que permet donar una nova visió a la programació d'esdeveniments, permet informar de manera original al consumidor i llueix de manera moderna amb un model gràfic actual.Desarrollo de Info WebApp, una aplicación web para una escuela de informática que permite dar una nueva visión a la programación de eventos, permite informar de manera original al consumidor y luce de forma moderna con un modelo gráfico actual.Bachelor thesis for the Computer Science program on Multimedia

Comparison between Native and Cross-Platform Apps

The primary purpose of this study is to determine in which technology we have to develop an application depending on the features that we would like to include, in order to deliver the best value for a good price to the customers. Consequently, in this research we have described the capabilities, performance and limitations that we have found while using the different technologies. The empirical part of this study was conducted in the first semester of 2014/2015 at the Linnaeus University in Växjö (Sweden), supported by Softwerk Company. In conclusion, the thesis shows that the user experience with native apps is always better than using the web-based technologies, especially using maps, although the time and effort spent to develop them is higher. Cross-platform solutions can be very useful for simple apps, and also if the developer does not have a lot of time to develop them. The problem with this last kind of applications is that the performance is less than the native ones

Atypical IκB proteins - nuclear modulators of NF-κB signaling.

Nuclear factor κB (NF-κB) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-κB governs embryogenesis, tissue homeostasis and the functions of innate and adaptive immune cells it represents one of the most important and versatile signaling networks known. Its activity is regulated via the inhibitors of NF-κB signaling, the IκB proteins. Classical IκBs, like the prototypical protein IκBα, sequester NF-κB transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-κB to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of IκBα. Phosphorylation of the conserved serine residues 32 and 36 leads to polyubiquitination and subsequent proteasomal degradation. This process marks the central event of canonical NF-κB activation. Once their NLS is accessible, NF-κB transcription factors translocate into the nucleus, bind to the DNA and regulate the transcription of their respective target genes. Several studies described a distinct group of atypical IκB proteins, referred to as the BCL-3 subfamily. Those atypical IκBs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-κB transcription factors takes place in the nucleus in contrast to classical IκBs, whose binding to NF-κB predominantly occurs in the cytoplasm. Secondly, atypical IκBs are strongly induced after NF-κB activation, for example by LPS and IL-1β stimulation or triggering of B cell and T cell antigen receptors, but are not degraded in the first place like their conventional relatives. Finally, the interaction of atypical IκBs with DNA-associated NF-κB transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-κB activity. The capacity to modulate NF-κB transcription either positively or negatively, represents their most important and unique mechanistic difference to classical IκBs. Several reports revealed the importance of atypical IκB proteins for immune homeostasis and the severe consequences following their loss of function. This review summarizes insights into the physiological processes regulated by this protein class and the relevance of atypical IκB functioning

Novel pharmacological approaches in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA

Lysyl oxidase (LOX) limits VSMC proliferation and neointimal thickening through its extracellular enzymatic activity

Lysyl oxidase (LOX) plays a critical role in extracellular matrix maturation and limits VSMC proliferation and vascular remodeling. We have investigated whether this anti-proliferative effect relies on the extracellular catalytically active LOX or on its biologically active propeptide (LOX-PP). High expression levels of both LOX and LOX-PP were detected in the vascular wall from transgenic mice over-expressing the full-length human LOX cDNA under the control of SM22α promoter (TgLOX), which targets the transgene to VSMC without affecting the expression of mouse LOX isoenzymes. TgLOX VSMC also secrete high amounts of both mature LOX and LOX-PP. Wild-type (WT) mouse VSMC exposed to VSMC supernatants from transgenic animals showed reduced proliferative rates (low [H]-thymidine uptake and expression of PCNA) than those incubated with conditioned media from WT cells, effect that was abrogated by β-aminopropionitrile (BAPN), an inhibitor of LOX activity. Lentiviral over-expression of LOX, but not LOX-PP, decreased human VSMC proliferation, effect that was also prevented by BAPN. LOX transgenesis neither impacted local nor systemic inflammatory response induced by carotid artery ligation. Interestingly, in this model, BAPN normalized the reduced neointimal thickening observed in TgLOX mice. Therefore, extracellular enzymatically active LOX is required to limit both VSMC proliferation and vascular remodeling