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Background and aim Extracellular matrix (ECM) components released during excessive fat mass expansion are considered potential endogenous danger/alarm signals contributing to innate immune system activation. The aim of the current study was to specifically measure plasma levels of low molecular weight (LMW) hyaluronan (HA) and to evaluate its role as pro-inflammatory damage-associated molecular pattern (DAMP) on leukocyte response in the context of human obesity. Subjects and methods Participants were selected according to their body mass index (BMI, kg/m2) as non-obese (BMI n = 18) and obese (BMI > 29.9, n = 33). Plasma samples were size-dependent fractionated using ion-exchange chromatography to specifically obtain LMW HA fractions that were subsequently quantified by ELISA. Cell incubation experiments with synthetic HA molecules were performed on freshly Ficoll-isolated neutrophils (PMN) and peripheral blood monocytes (PBMC). Leukocyte and adipose tissue gene expression was assessed by real-time PCR and NF-κB activation by western blot. Plasma cytokine levels were measured by fluorescent bead-based (Luminex) immunoassay. Results We observed a statistically significant increase in the circulating levels of HA fragments of LMW in individuals with obesity which were consistent with significant up-regulated expression of the LMW HA synthesizing enzyme hyaluronan synthase-1 (HAS-1) in obese adipose tissue. Gene expression assessment of HA receptors revealed up-regulated levels for TLR2 in both obese PMN and PBMC. Synthetic HA molecules of different sizes were tested on leukocytes from healthy donors. LMW HA fragments (15–40 kDa) and not those from intermediate molecular sizes (75–350 kDa) induced a significant up-regulation of the expression of major pro-inflammatory cytokines such as IL-1β, MCP-1 and IL-8 in PBMC. Importantly, LMW HA was able to induce the phosphorylation of IKK α/β complex supporting its pro-inflammatory role through NF-κB activation. Conclusion Circulating LMW HA molecules are elevated in obesity and may play an important role in triggering low-grade inflammation and the development of metabolic complications.

Introduction The Spanish Haematology and Haemotherapy Society organizes peripheral blood smear review scheme, focused on the evaluation of diagnostic proficiency of participants by blood cell morphology analysis. The objective was to evaluate the efficacy of this scheme as an educational tool to improve the diagnostic proficiency of the participants. Methods During 2011-2019, 54 peripheral blood smears, alongside with patient details such as age, sex, blood cell counts and relevant clinical information, were sent to an average of 125 ± 13 laboratories per year. A number of 44 shipments were selected to analyse whether successive surveys of the same disease may lead to an improvement in the diagnostic success rate proposed by the laboratories. Participants were asked to select the most relevant morphological abnormalities, alongside the diagnostic orientation. Agreement of participant responses with RR was evaluated. Results Spanish laboratories showed a diagnostic proficiency greater than 80% in acute myeloid leukaemia, including acute promyelocytic leukaemia, mature B-cell neoplasms (hairy cell leukaemia and splenic marginal zone lymphoma), chronic myeloid leukaemia, sickle cell disease, Bernard-Soulier syndrome and infectious mononucleosis. It was important to note the significant improvement over the time in the successive shipments of the same disease, with a 31% and 13% increase in their diagnostic orientation success rate for acute myeloid leukaemia and acute promyelocytic leukaemia cases, respectively, 15% for mantle cell lymphoma and 6% for sickle cell disease. Conclusions The present study provides evidence that peripheral blood smear review scheme can be a valid educational tool to improve the clinical pathologist skills in blood morphology and haematological diagnosis.

The aim of this paper is to examine the influence of the right to information laws on sustainability transparency in European local governments. This goal is novel, in that previous studies have examined the effects of various factors on the dissemination of government information (demographic, socioeconomic, political and financial) but not the contribution of legal factors to online transparency on environmental, social and economic sustainability. Our research question is this: Do information laws contribute to transparency on sustainability? Using the Global Reporting Initiative guidelines and a statistical regression analysis, we studied the websites of 106 local governments in ten European countries. The results obtained show that when transparency laws clearly stipulate the rules applicable and the procedures established for appeals, exceptions, refusals and requests, this can favour transparency on environmental, social and economic sustainability. Our findings advance understanding of this field and reinforce the basis for legal reforms to enhance sustainability transparency.

Besides its oncotic power, albumin exerts pleiotropic actions, including binding, transport, and detoxification of endogenous and exogenous molecules, antioxidant activity, and modulation of immune and inflammatory responses. In particular, recent studies have demonstrated that albumin reduces leukocyte cytokine production. Here, we investigated whether albumin also has the ability to protect tissues from the damaging actions of these inflammatory mediators. We circumscribed our investigation to tumor necrosis factor (TNF) α, which exemplifies the connection between immunity and tissue injury. In vivo experiments in analbuminemic mice showed that these mice exhibit a more pronounced response to a model of TNFα-mediated liver injury induced by the administration of lipopolysaccharide (LPS) and D-galactosamine (D-gal). A tissue protective action against LPS/D-gal liver injury was also observed during the administration of human albumin to humanized mice expressing the human genes for albumin and neonatal Fc receptor (hAlb+/+ /hFcRn+/+ ) with preestablished carbon tetrachloride (CCl4 )-induced early cirrhosis. The cytoprotective actions of albumin against TNFα-induced injury were confirmed ex vivo, in precision-cut liver slices, and in vitro, in primary hepatocytes in culture. Albumin protective actions were independent of its scavenging properties and were reproduced by recombinant human albumin expressed in Oryza sativa. Albumin cytoprotection against TNFα injury was related to inhibition of lysosomal cathepsin B leakage accompanied by reductions in mitochondrial cytochrome c release and caspase-3 activity. These data provide evidence that in addition to reducing cytokines, the albumin molecule also has the ability to protect tissues against inflammatory injury.

Significance Fatty liver, which is an initial step in the development of more severe complications such as liver cirrhosis, is prevalent worldwide in our society. This study demonstrates that stimulation of soluble guanylate cyclase (sGC), an enzyme producing the second messenger cGMP, protects against the most common features of fatty liver, namely inflammation and fibrosis, in animal models of the disease. Our study also provides an explanation for this protection and describes how sGC stimulation blocks the inflammasome (a protein complex responsible for the production of the potent proinflammatory cytokine interleukin-1β) in liver macrophages. The results of this study support the investigation of sGC stimulators, which are already approved for treatment in other conditions, in patients with fatty liver disease., Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3′,5′-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit.

Decompensated cirrhosis is characterized by exuberant systemic inflammation. Although the inducers of this feature remain unknown, the presence of circulating forms of oxidized albumin, namely human nonmercaptalbumin 1 (HNA1) and HNA2, is a common finding in cirrhosis. The aim of this study was to explore the ability of these oxidized albumin forms to induce systemic inflammation by triggering the activation of peripheral leukocytes. We observed significantly higher plasma levels of HNA1 and HNA2 in patients with cirrhosis (n = 256) compared to healthy volunteers (n = 48), which gradually increased during the course from compensated to decompensated to acute-on-chronic liver failure. Plasma HNA1 and HNA2 levels significantly correlated with inflammatory markers (i.e., interleukin-6 [IL-6], IL-1β, tumor necrosis factor-alpha [TNF-α] and IL-8) in patients with cirrhosis. To directly test the inflammatory effects of HNA1 and HNA2 on leukocytes, these oxidized albumin forms were prepared ex vivo and their posttranslational modifications monitored by liquid chromatography (LC)-quadrupole time-of-flight/mass spectrometry (MS). HNA1, but not HNA2, increased IL-1β, IL-6, and TNF-α mRNA and protein expression in leukocytes from both healthy volunteers and patients with cirrhosis. Moreover, HNA1 up-regulated the expression of eicosanoid-generating enzymes (i.e., cyclooxygenase-2 [COX-2] and microsomal prostaglandin E [PGE] synthase 1) and the production of inflammatory eicosanoids (PGE2 , PGF2α , thromboxane B2 , and leukotriene B4 ), as determined by LC-electrospray ionization-MS/MS. The inflammatory response to HNA1 was more pronounced in peripheral blood mononuclear cells (PBMCs) and marginal in polymorphonuclear neutrophils. Kinome analysis of PBMCs revealed that HNA1 induced the phosphorylation of p38 mitogen-activated protein kinase, the inhibition of which blocked HNA1-induced cytokine and COX-2 induction. Conclusion: HNA1 triggers an inflammatory response in PBMCs, providing a rationale for its removal and replacement by reduced albumin in the prevention of systemic inflammation in patients with advanced liver disease.

Background and Purpose Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, inflammation and fibrosis. Soluble guanylate cyclase (sGC) stimulation reduces inflammation and fibrosis in experimental models of lung, kidney and heart disease. Here, we tested whether sGC stimulation is also effective in experimental NASH. Experimental Approach NASH was induced in mice by feeding a choline-deficient, l-amino acid-defined, high-fat diet. These mice received either placebo or the sGC stimulator IW-1973 at two different doses (1 and 3 mg·kg−1·day−1) for 9 weeks. IW-1973 was also tested in high-fat diet (HFD)-induced obese mice. Steatosis, inflammation and fibrosis were assessed by Oil Red O, haematoxylin–eosin, Masson's trichrome, Sirius Red, F4/80 and α-smooth muscle actin staining. mRNA expression was assessed by quantitative PCR. Levels of IW-1973, cytokines and cGMP were determined by LC-MS/MS, Luminex and enzyme immunoassay respectively. Key Results Mice with NASH showed reduced cGMP levels and sGC expression, increased steatosis, inflammation, fibrosis, TNF-α and MCP-1 levels and up-regulated collagen types I α1 and α2, MMP2, TGF-β1 and tissue metallopeptidase inhibitor 1 expression. IW-1973 restored hepatic cGMP levels and sGC expression resulting in a dose-dependent reduction of hepatic inflammation and fibrosis. IW-1973 levels were ≈40-fold higher in liver tissue than in plasma. IW-1973 also reduced hepatic steatosis and adipocyte hypertrophy secondary to enhanced autophagy in HFD-induced obese mice. Conclusions and Implications Our data indicate that sGC stimulation prevents hepatic steatosis, inflammation and fibrosis in experimental NASH. These findings warrant further evaluation of IW-1973 in the clinical setting.

Human serum albumin (HSA) is an emerging treatment for preventing excessive systemic inflammation and organ failure(s) in patients with acutely decompensated (AD) cirrhosis. Here, we investigated the molecular mechanisms underlying the immunomodulatory properties of HSA. Administration of HSA to patients with AD cirrhosis with elevated circulating bacterial DNA rich in unmethylated cytosine-phosphate-guanine dideoxynucleotide motifs (CpG-DNA) was associated with reduced plasma cytokine concentrations. In isolated leukocytes, HSA abolished CpG-DNA-induced cytokine expression and release independently of its oncotic and scavenging properties. Similar anti-inflammatory effects were observed with recombinant human albumin. HSA exerted widespread changes on the immune cell transcriptome, specifically in genes related to cytokines and type I interferon responses. Our data revealed that HSA was taken up by leukocytes and internalized in vesicles positively stained with early endosome antigen 1 and colocalized with CpG-DNA in endosomes, where the latter binds to Toll-like receptor 9 (TLR9), its cognate receptor. Furthermore, HSA also inhibited polyinosinic:polycytidylic acid- and lipopolysaccharide-induced interferon regulatory factor 3 phosphorylation and TIR domain-containing adapter-inducing interferon-β-mediated responses, which are exclusive of endosomal TLR3 and TLR4 signaling, respectively. The immunomodulatory actions of HSA did not compromise leukocyte defensive mechanisms such as phagocytosis, efferocytosis, and intracellular reactive oxygen species production. The in vitro immunomodulatory effects of HSA were confirmed in vivo in analbuminemic humanized neonatal Fc receptor transgenic mice. These findings indicate that HSA internalizes in immune cells and modulates their responses through interaction with endosomal TLR signaling, thus providing a mechanism for the benefits of HSA infusions in patients with cirrhosis.

Acute-on-chronic liver failure (ACLF) in cirrhosis is an increasingly recognized syndrome characterized by acute decompensation, organ failure(s) and high short-term mortality. Recent findings suggest that an overexuberant systemic inflammation plays a primary role in ACLF progression. In this study, we examined whether genetic factors shape systemic immune responses in patients with decompensated cirrhosis. Six single-nucleotide polymorphisms (SNPs) in inflammation-related genes (interleukin [IL]-1 beta [IL-1β], rs1143623; IL-1 receptor antagonist [IL-1ra], rs4251961; IL-10, rs1800871; suppressor of cytokine signaling-3, rs4969170; nucleotide-binding oligomerization domain-containing protein 2, rs3135500; and chemerin chemokine-like receptor 1, rs1878022) were genotyped in 279 patients with cirrhosis with (n = 178) and without (n = 101) ACLF from the CANONIC study of the CLIF consortium. Among these SNPs, we identified two polymorphisms belonging to the IL-1 gene cluster (IL-1β and IL-1ra) in strong association with ACLF. Both SNPs were protective against ACLF; IL-1β (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13-0.89; P < 0.05) and IL-1ra (OR, 0.58; 95% CI, 0.35-0.95; P < 0.05) under the recessive and overdominant inheritance models, respectively. These protective SNPs translated into reduced circulating levels of IL-1β, IL-1α, IL-6, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, and C-reactive protein at enrollment as well as after 7-14 days of admission. These findings were confirmed in vitro in leukocytes incubated with plasma from patients with decompensated cirrhosis carrying the protective SNP genotypes. Notably, a higher frequency of the protective genotypes was observed in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28-day mortality rate.CONCLUSION: These data identify two common functional polymorphisms in the IL-1 gene cluster, which are associated with the inflammatory process related to development of ACLF. (Hepatology 2017;65:202-216).

ResumenAlgunos trabajos previos y los pronunciamientos de organismos internacionales (OTAN, GAO) han considerado el coste del ciclo de vida (LCC) como la metodología de selección de inversiones más avanzada para contribuir a la eficiencia del gasto militar, lo que representa una especial oportunidad para los investigadores considerando la obligada austeridad y las restricciones presupuestarias de los gobiernos. En cualquier país, la viabilidad del LCC exige el previo cumplimiento de los requisitos establecidos por tales organismos para la aplicación de este modelo. El objetivo del presente trabajo reside en identificar las mejoras necesarias para posibilitar la implantación del LCC en los sistemas de evaluación económica de las Fuerzas Armadas de España. A tal fin, hemos estudiado la adecuación de los actuales sistemas españoles a los requerimientos del LCC, realizando, además, un análisis comparativo con los sistemas de países europeos y norteamericanos, lo que nos ha permitido identificar reformas de adaptación dirigidas a alcanzar la factibilidad de este modelo en el Ministerio de Defensa español, sobre la base de las debilidades y fortalezas detectadas en nuestra investigación empírica.AbstractPrevious studies and the pronouncements by international organisations (NATO, GAO) have considered the Life Cycle Costing (LCC) as the most advanced methodology for the economic assesment of the efficiency of military spending. This provided a good opportunity for researchers considering the forced austerity and budget constraints of governments. In any country, the viability of LCC requires prior compliance with the requirements issued by such organisations for the implementation of this model. The aim of this paper is to identify the improvements required to enable the implementation of LCC in economic evaluation systems of the Armed Forces of Spain. A study was performed on the adequacy of current Spanish economic systems to the requirements of LCC, as well as conducting a comparative analysis with the systems of European and American countries. This enabled reforms to be identified in order to achieve the feasibility of this model in the Spanish Ministry of Defense, based on the strengths and weaknesses detected in our empirical research.

ObjectiveSystemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients.Design249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured.ResultsPatients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts.ConclusionPrevious AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.

Developers and managers of websites are key players in conveying the transparency of governments. Although previous research has highlighted the need for further progress in transparency on sustainability, very few studies have considered how websites can better contribute to providing sustainability information. This paper identifies determinant factors that can help website developers and managers enhance the online transparency on sustainability provided by regional governments. In an empirical study of 17 Spanish regional governments, we identified technological factors (such as broadband availability and the online compilation of information) and transparency-stimulating factors (such as convergence with the information society, accessibility and usability) that can be useful to increase the volume of social, economic and environmental information published on their websites.

Although the transparency and sustainability of governments are currently of great interest to researchers, few studies have specifically addressed these issues. Nevertheless, previous research has found sustainability transparency as a key issue in government–citizen relations, especially for local governments (LGs). The aim of this article is to identify factors that promote online transparency regarding the sustainability of public policies, by means of an empirical study of 62 LGs in the United Kingdom, Ireland, and Southern Europe. Our results show that the prevailing administrative tradition may influence the degree of transparency of LGs, with population, socioeconomic, and financial factors being relevant.

Meme si les organisations internationales et la litterature existante reconnaissent l’importance des rapports sur la durabilite pour les gouvernements de nos jours, certaines etudes revelent que cette question n’a pas recu l’attention qu’elle merite et qu’elle doit des lors etre examinee de plus pres. Dans le present article, nous etudions la publication par les gouvernements locaux des informations sur les questions de durabilite, en analysant la relation entre les differents niveaux de divulgation des informations sur la durabilite et certaines variables socioeconomiques, financieres et demographiques. Compte tenu du recours accru a l’Internet par les gouvernements, la methodologie appliquee dans la presente etude consiste a analyser les sites Web de 55 grandes villes espagnoles pour y rechercher 61 elements recommandes dans les lignes directrices de la Global Reporting Initiative. En appliquant une regression lineaire multiple, nous avons analyse l’influence de treize facteurs sur les rapports sur la durabilite publies par ces autorites municipales. Les resultats indiquent que les informations sociales sont les plus repandues et que la population inactive a une influence positive sur la divulgation des informations sur la durabilite. Les principaux moyens d’ameliorer les pratiques en matiere de durabilite consistent a ameliorer la divulgation des informations economiques et en matiere d’environnement, par la publication de rapports formels sur la durabilite et en ameliorant la coordination des informations publiees individuellement par differents departements.Remarques a l’intention des praticiensLes resultats obtenus font ressortir plusieurs questions particulierement interessantes pour les gestionnaires. D’une part, la crise financiere dans le secteur public a fait ressortir la necessite de legitimer les actions du gouvernement. De plus, l’incidence de la variable « population inactive » sur la divulgation des informations sur la durabilite indique qu’il existe un lien important entre la structure de la population et la divulgation de ces informations, ce qui fait ressortir la necessite de considerer l’âge de la population et son evolution au fil du temps comme la raison d’etre de la creation de rapports specifiques sur la durabilite. La demande d’informations sur la durabilite de la part du public ne depend pas du niveau d’impots payes. Enfin, le niveau d’autonomie des gouvernements locaux n’a aucune influence sur les informations divulguees a propos de leurs engagements en matiere de durabilite economique.

Citizens increasingly demand an active role in public affairs and decision-making processes. From a critical standpoint, this chapter consolidates existing knowledge and, in turn, provides a better understanding on how social media tools promote the citizens' engagement and participation. The main aim is to assist researchers in the development of their future analyses, identifying trends of research and the methodology used. In so doing, a systematic literature review has been used to examine social media and e-participation research in journals listed in ISI in the field of public administration and information science and library science during the period 2000-2016. The findings reveal that although research on social media and e-participation has increased in the last year, it remains immature. Therefore, further research is needed in order to understand the true impacts of social media tools and their involvement in e-participation.

Obesity comorbidities are closely associated with chronic low-grade adipose tissue inflammation. A number of SNPs associated with inflammation has been identified, underscoring the impact of genetic determinants on this process. Here, we screened SNPs in genes with pro-inflammatory (IL-1β, IL-6, STAT3 and JAK2), anti-inflammatory (IL-10 and SOCS3) and pro-resolving (ERV1/ChemR23) properties in 101 obese and 99 non-obese individuals. Among the SNPs analyzed, we identified that individuals carrying a C allele in the rs1878022 polymorphism of the ERV1/ChemR23 gene, which encodes for the receptor of the pro-resolving mediator RvE1, had increased ERV1/ChemR23 protein expression and reduced levels of the inflammatory cytokine IL-6 in adipose tissue. Moreover, patients carrying the C allele in homozygosity had lower plasma levels of IL-6, IFN-α2, IL-15, IL-1ra, IL-10, GM-CSF, G-CSF and VEGF and enhanced leukocyte responsiveness to RvE1. C-carriers also exhibited decreased TAG to HDL ratio, a surrogate marker of insulin resistance and a predictor of incident fatty liver. Finally, we confirmed in vivo that the ERV1/ChemR23 receptor regulates systemic and tissue inflammation since mice lacking ERV1/ChemR23 expression showed increased IL-6 levels in adipose tissue and peritoneal macrophages. Together, our study identified an ERV1/ChemR23 variant that protects patients with obesity from excessive inflammatory burden.

In several European countries decentralization has promoted the creation of Regional Governments (RGs) with high levels of competence and responsibilities, such as promoting good governance and sustainability. Information and communication technologies (ICTs), and hence, the adoption of e-government has contributed to the adoption and dissemination of government transparency in a usable and accessible way. In this chapter, we study the transparency, accessibility and usability of websites of Spanish RGs.

E-government has enhanced the availability of government information, and expanding access to services, offering greater transparency and accountability for public administrations. However, previous research indicates that there are significant barriers for citizens, assuming major obstacles. In this sense, the EU and, in particular, the Spanish government has formulated policies and legal frameworks to introduce in the field of the provision of public sector services, in order to customize and to access these services. These initiatives seek to promote the development of networks and services, to improve the e-administration and the adoption of digital solutions for efficient delivery of public services, and to promote the inclusion and digital literacy. Therefore, the purpose of this chapter is to obtain a vision of government strategies adopted by Spanish regional governments to reduce the digital divide.

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are hallmarks of nonalcoholic fatty liver disease (NAFLD), which is the hepatic manifestation of the metabolic syndrome associated with obesity. The specialized proresolving lipid mediator maresin 1 (MaR1) preserves tissue homeostasis by exerting cytoprotective actions, dampening inflammation, and expediting its timely resolution. Here, we explored whether MaR1 protects liver cells from lipotoxic and hypoxia-induced ER stress. Mice were rendered obese by high-fat diet feeding, and experiments were performed in primary hepatocytes, Kupffer cells, and precision-cut liver slices (PCLSs). Palmitate-induced lipotoxicity increased ER stress and altered autophagy in hepatocytes, effects that were prevented by MaR1. MaR1 protected hepatocytes against lipotoxicity-induced apoptosis by activating the UPR prosurvival mechanisms and preventing the excessive up-regulation of proapoptotic pathways. Protective MaR1 effects were also seen in hepatocytes challenged with hypoxia and TNF-α-induced cell death. High-throughput microRNA (miRNA) sequencing revealed that MaR1 actions were associated with specific miRNA signatures targeting both protein folding and apoptosis. MaR1 also prevented lipotoxic-triggered ER stress and hypoxia-induced inflammation in PCLSs and enhanced Kupffer cell phagocytic capacity. Together, these findings describe the ability of MaR1 to oppose ER stress in liver cells under conditions frequently encountered in NAFLD.-Rius, B., Duran-Güell, M., Flores-Costa, R., López-Vicario, C., Lopategi, A., Alcaraz-Quiles, J., Casulleras, M., Lozano, J. J., Titos, E., Clària, J. The specialized proresolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress.

Although international organizations and prior literature have recognized the importance of sustainability reporting for governments nowadays, some studies have revealed that this is an issue that has received little attention and thus needs further investigation. This article studies the publication of information on sustainability issues by local governments, analysing the relationship between diverse levels of sustainability information disclosure and some socioeconomic, financial and population variables. Based on the increased use of the Internet by governments, the methodology applied in this study is to analyse the websites of 55 major towns and cities in Spain, seeking 61 items that are recommended in the Global Reporting Initiative guidelines. By applying multiple linear regression analysis, we analysed the influence of 13 factors on the sustainability reporting provided by these municipal authorities. The results show that social information is the most widespread, and that the dependent population has a positive impact on the sustainability disclosures. The major opportunities to improve sustainability practices lie in improving the disclosure of economic and environmental information, through the publication of formal sustainability reports and the enhanced coordination of information published individually by different departments. Points for practitioners The results obtained highlight several issues of particular interest for managers. On the one hand, the public sector financial crisis has heightened the need to legitimize government actions. Moreover, the incidence of the variable ‘dependent population’ on the disclosure of sustainability information suggests that there is an important relation between the population structure and such disclosure, highlighting the need to consider the age of the population and its evolution over time as the basis for creating specific reports on sustainability. The public demand for information on sustainability does not depend on the level of taxes paid. Finally, local governments are not motivated by their level of financial autonomy with respect to information about their commitments on economic sustainability.

International organisations such as the EU, the OECD and the WBG have recommended that governments provide information to citizens about the sustainability of their public policies. Furthermore, previous studies have concluded that while stakeholders are demanding greater transparency from public entities about the sustainability of their actions, little research has been conducted into governmental information disclosure concerning sustainability. Accordingly, the aim of the present paper is to contribute to our understanding of sustainability practices and information transparency in this respect in governmental institutions, and thus enable improvements to be made in this field. In the view that e-government, based on information and communication technologies, is a key element in good governance aimed at achieving sustainable development, we identify factors that may promote the disclosure of information on the sustainability of public entities, by analysing the information content of regional governments' websites and its relationship with certain variables. Our main findings are that socio-economic factors such as education, population density and access to internet, and e-government factors such as the provision of public information online, the percentage of procedures completed after online start, the level of online services provided and broadband availability, are all relevant to the disclosure of sustainability information by regional governments.

Resumen Introduccion Para asegurar la fiabilidad de los resultados de las magnitudes bioquimicas en muestras conservadas durante varios dias, se aconseja realizar estudios de estabilidad segun las condiciones de conservacion empleadas. Con el presente estudio queremos conocer los limites de estabilidad de 27 magnitudes bioquimicas bajo las condiciones de conservacion utilizadas en nuestro laboratorio. Material y metodos Se recogieron 20 muestras de suero en tubos con gel separador y se conservaron a 4 °C. Las magnitudes bioquimicas se midieron 2 veces al dia, con un intervalo de 6 h, durante 5 dias. El cambio de concentracion de las magnitudes a cada uno de los tiempos (X t ) respecto al valor inicial (X 0 ) se expreso como cambio porcentual (X t %) = (X t /X 0 )*100 y se calculo la media de dicho cambio (Xm t %). La estabilidad se evaluo segun 3 criterios. Criterio metrologico segun la variacion analitica interdia (CV a ), por el que la Xm t % no podria superar al cambio significativo minimo (CSM = ±1,65*CV a ). Criterio biologico basado en la variacion biologica intraindividual (CV b ), por el que la Xm t % no podria superar al cambio significativo deseable (CSD = ±0,5*CV b ). Y criterio combinado de ambos, por el que la Xm t % no podria superar el limite de cambio total (LCT = ±√(1,65*CV a ) 2 + (0,5*CV b ) 2 ). Resultados Veinte magnitudes se consideraron no estables segun CSM y 14 segun CSD. Al final del estudio, 9 magnitudes se consideraron no estables segun el criterio LCT. Conclusion Los criterios CSM y CSD resultan demasiados restrictivos. La combinacion de ambos se ajusta mas a las necesidades de nuestro laboratorio. Cada laboratorio deberia estudiar la estabilidad de sus muestras con sus propias condiciones de conservacion.

Although the importance of sustainability reporting in the public sector is widely recognized, there are few studies about this issue. This paper analyzed the practices of diffusion of information on sustainability in local governments. So, we observed the Websites of the largest local governments in Spain using a list of items from the guidelines of GRI and comparing the results with the results of the Spanish regional governments. Our findings show that local governments reported some information (50% of the items), but less than regional governments (60%). Social information is the most widespread and environmental information is the least reported.

espanolEn el actual contexto de crisis, los ciudadanos demandan al sector publico mayor transparencia y rendicion de cuentas. Este trabajo pretende avanzar en el conocimiento de las practicas de sostenibilidad en la administracion publica. Para ello proponemos comparar la divulgacion de informacion sobre sostenibilidad realizada por distintos gobiernos regionales, analizando las webs de los mismos mediante un analisis de contenido, usando para ello un listado de items basado en las guias del Global Reporting Initiative (GRI).Nuestros resultados muestran que los gobiernos regionales espanoles difunden dos tercios de la informacion requerida por el GRI, presentando la informacion social un nivel de respuesta mayor y la informacion general un menor nivel de difusion. Ademas, aquellos gobiernos regionales con mayor compromiso ambiental publican mas informacion sobre sostenibilidad. De nuestras conclusiones podemos destacar que la mala situacion financiera que atraviesan no parece impulsar a los gobiernos regionales espanoles a divulgar informacion sobre sostenibilidad EnglishIn the current crisis, citizens are demanding greater public sector transparency and accountability. In this paper, we advance the understanding of sustainability practices in public administration. We propose to compare the dissemination of sustainability of various regional governments, analyzing the websites of these regional governments through a content analysis, using for this purpose a list of items obtained from the Global Reporting Initiative (GRI) guidelines. Our results show that Spanish regional governments, spread two-thirds of the information in the GRI guidelines, being the social information which presents a higher level of response and corresponding general aspects which has a lower level of dissemination. In addition, those regional governments with greater environmental commitment are those who publish more information about sustainability. From our conclusions, we emphasize that the poor financial situation of the Spanish regional governments does not seem to promote them to disseminate information about sustainability

Persistent activation of the innate immune system greatly influences the risk of developing metabolic complications associated with obesity. In this study, we explored the therapeutic potential of the specialized pro-resolving mediator (SPM) resolvin D1 (RvD1) to actively promote the resolution of inflammation in human visceral adipose tissue from obese patients. By means of LC-MS/MS-based metabololipidomic analysis we identified unbalanced production of SPMs (i.e. D- and E-series resolvins, protectin D1, maresin 1 and lipoxins) with respect to inflammatory lipid mediators (i.e. leukotriene B4 and prostaglandins) in omental adipose tissue from obese patients. In parallel, high-throughput transcriptomic analysis revealed a unique signature in this tissue characterized by an overactivation of the interleukin (IL)-10 signaling pathway. Incubation of inflamed obese visceral adipose tissues and human macrophages with RvD1 limited the excessive activation of the IL-10 pathway by reducing phosphorylation of signal transducer and activator of transcription (STAT) proteins. Of interest, RvD1 blocked STAT-1 and its target inflammatory genes (i.e. CXCL9) as well as persistent STAT3 activation without affecting the IL-10 anti-inflammatory response characterized by inhibition of IL-6, IL-1β, IL-8 and TNFα. Furthermore, RvD1 promoted resolution by enhancing the expression of the IL-10-target gene heme oxygenase-1 by mechanisms depending on p38 mitogen-activated protein kinase (MAPK) activity. Together, our data show that RvD1 can tailor the quantitative and qualitative responses of human inflamed adipose tissue to IL-10 and provide a mechanistic basis for the immunoresolving actions of RvD1 in this tissue. These findings may have potential therapeutic implications in obesity-related insulin resistance and other metabolic complications.

In the current socioeconomic context, the question of local government sustainability transparency is of great interest to policymakers, managers, citizens and other stakeholders, and yet one to which previous research has devoted little specific attention. At the same time, the Internet has become an instrument of good governance worldwide and government entities in Europe have strived to promote e-government to improve transparency towards citizens. The aim of this study was to identify factors that can help politicians and managers improve practices of sustainability information disclosed by European local governments. To do so, an empirical study was conducted of 91 municipalities in nine countries, comparing three main administrative cultures. Our analysis of the study results highlights various demographic, socioeconomic, financial and legal factors that may be useful to policymakers and managers in promoting the online provision of sustainability information in Anglo-Saxon, Nordic and Southern European countries.

A novel genus of pro-resolving lipid mediators endogenously generated from omega-3 polyunsaturated fatty acids has been identified in exudates obtained during the resolution phase of acute inflammation. The term specialized pro-resolving mediators (SPM) has been coined for these lipid mediators, comprising four novel chemical mediator families designated resolvins of the E series (if derived from eicosapentaenoic acid) and resolvins of the D series, protectins and maresins (if generated from docosahexaenoic acid). These SPM act not only as “stop-signals” of inflammatory response, but also as facilitators of the ability of macrophages to clear apoptotic cells (efferocytosis) and migrate to peripheral lymph nodes (efflux), thus, expediting their removal from sites of inflammation. In this review, we provide an overview of the current efforts to elucidate the structure-function, biosynthesis and actions of these omega-3-derived SPM in the context of inflammatory diseases. We specifically highlight the role of these SPM as endogenous counter-regulators of the persistent inflammatory status present in adipose tissue of obese individuals and describe the potential therapeutic impact of these bioactive lipid autacoids on the prevention of hepatic co-morbidities associated with obesity and the metabolic syndrome.

Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases.

Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions driving uncontrolled inflammation and fibrosis and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT.

The prototypic proinflammatory cytokine IL-1β plays a central role in innate immunity and inflammatory disorders. The formation of mature IL-1β from an inactive pro-IL-1β precursor is produced via nonconventional multiprotein complexes called the inflammasomes, of which the most common is the nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome composed by NLRP3, (ASC) apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD), and caspase-1. Specialized proresolving mediators (SPMs) promote resolution of inflammation, which is an essential process to maintain host health. SPMs prevent excessive inflammation by terminating the inflammatory response and returning to tissue homeostasis without immunosupression. This study tested the hypothesis that modulation of the NLRP3 inflammasome in macrophages is one mechanism involved in the SPM-regulated processes during resolution. Our findings demonstrate that the SPM resolvin D2 (RvD2) suppressed the expression of pro-IL-1β and reduced the secretion of mature IL-1β in bone marrow-derived macrophages challenged with LPS+ATP (classical NLRP3 inflammasome model) or LPS+palmitate (lipotoxic model). Similar findings were observed in thioglycolate-elicited peritoneal macrophages, in which RvD2 remarkably reduced ASC oligomerization, inflammasome assembly, and caspase-1 activity. In vivo, in a self-resolving zymosan A-induced peritonitis model, RvD2 blocked the NLRP3 inflammasome leading to reduced release of IL-1β into the exudates, repression of osteopontin, and MCP-1 expression and induction of M2 markers of resolution (i.e., CD206 and arginase-1) in peritoneal macrophages. RvD2 inhibitory actions were receptor mediated and were abrogated by a selective GPR18 antagonist. Together, these findings support the hypothesis that SPMs have the ability to inhibit the priming and to expedite the deactivation of the NLRP3 inflammasome in macrophages during the resolution process. Resolvin D2 modulates the NLRP3 inflammasome and the production of IL-1β in macrophages during resolution of inflammation.

White adipose tissue is recognized as an active endocrine organ implicated in the maintenance of metabolic homeostasis. However, adipose tissue function, which has a crucial role in the development of obesity-related comorbidities including insulin resistance and non-alcoholic fatty liver disease, is dysregulated in obese individuals. This review explores the physiological functions and molecular actions of bioactive lipids biosynthesized in adipose tissue including sphingolipids and phospholipids, and in particular fatty acids derived from phospholipids of the cell membrane. Special emphasis is given to polyunsaturated fatty acids of the omega-6 and omega-3 families and their conversion to bioactive lipid mediators through the cyclooxygenase and lipoxygenase pathways. The participation of omega-3-derived lipid autacoids in the resolution of adipose tissue inflammation and in the prevention of obesity-associated hepatic complications is also thoroughly discussed.