Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice.

BackgroundThe mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens.MethodsTo examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1-7.ResultsGnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1-7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away.ConclusionOur results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries

GnRH Receptor Expression and Reproductive Function Depend on JUN in GnRH Receptor‒Expressing Cells.

Gonadotropin-releasing hormone (GnRH) from the hypothalamus regulates synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gonadotropes. LH and FSH are heterodimers composed of a common α-subunit and unique β-subunits, which provide biological specificity and are limiting components of mature hormone synthesis. Gonadotrope cells respond to GnRH via specific expression of the GnRH receptor (Gnrhr). GnRH induces the expression of gonadotropin genes and of the Gnrhr by activation of specific transcription factors. The JUN (c-Jun) transcription factor binds to AP-1 sites in the promoters of target genes and mediates induction of the FSHβ gene and of the Gnrhr in gonadotrope-derived cell lines. To analyze the role of JUN in reproductive function in vivo, we generated a mouse model that lacks JUN specifically in GnRH receptor‒expressing cells (conditional JUN knockout; JUN-cKO). JUN-cKO mice displayed profound reproductive anomalies such as reduced LH levels resulting in lower gonadal steroid levels, longer estrous cycles in females, and diminished sperm numbers in males. Unexpectedly, FSH levels were unchanged in these animals, whereas Gnrhr expression in the pituitary was reduced. Steroidogenic enzyme expression was reduced in the gonads of JUN-cKO mice, likely as a consequence of reduced LH levels. GnRH receptor‒driven Cre activity was detected in the hypothalamus but not in the GnRH neuron. Female, but not male, JUN-cKO mice exhibited reduced GnRH expression. Taken together, our results demonstrate that GnRH receptor‒expression levels depend on JUN and are critical for reproductive function

Economic evaluation of bio-based supply chains with CO2 capture and utilisation

Carbon capture and storage (CCS) and carbon capture and utilisation (CCU) are acknowledged as important R&D priorities to achieve environmental goals set for next decades. This work studies biomass-based energy supply chains with CO2 capture and utilisation. The problem is formulated as a mixed-integer linear program. This study presents a flexible supply chain superstructure to answer issues on economic and environmental benefits achievable by integrating biomass-coal plants, CO2 capture and utilisation plants; i.e. location of intermediate steps, fraction of CO2 emissions captured per plant, CO2 utilisation plants' size, among others. Moreover, eventual incentives and environmental revenues will be discussed to make an economically feasible project. A large-size case study located in Spain will be presented to highlight the proposed approach. Two key scenarios are envisaged: (i) Biomass, capture or utilisation of CO2 are not contemplated; (ii) Biomass, capture and CO2 utilisation are all considered. Finally, concluding remarks are drawn.Peer ReviewedPostprint (author's final draft

Integrated game-theory modelling for multi enterprise-wide coordination and collaboration under uncertain competitive environment

In this work, an integrated Game Theory (GT) approach is developed for the coordination of multi-enterprise Supply Chains (SCs) in a competitive uncertain environment. The conflicting goals of the different participants are solved through coordination contracts using a non-cooperative non-zero-sum Stackelberg game under the leadership of the manufacturer. The Stackelberg payoff matrix is built under the nominal conditions, and then evaluated under different probable uncertain scenarios using a Monte-Carlo simulation. The competition between the Stackelberg game players and the third parties is solved through a Nash Equilibrium game. A novel way to analyze the game outcome is proposed based on a win–win Stackelberg set of “Pareto-frontiers”. The benefits of the resulting MINLP tactical models are illustrated by a case study with different vendors around a client SC. The results show that the coordinated decisions lead to higher expected payoffs compared to the standalone case, while also leading to uncertainty reduction.Peer ReviewedPostprint (author's final draft

Recommendations for headache service organisation and delivery in Europe.

Headache disorders are a major public-health priority, and there is pressing need for effective solutions to them. Better health care for headache—and ready access to it—are central to these solutions; therefore, the organisation of headache-related services within the health systems of Europe becomes an important focus. These recommendations are the result of collaboration between the European Headache Federation and Lifting The Burden: the Global Campaign against Headache. The process of development included wide consultation. To meet the very high level of need for headache care both effectively and efficiently, the recommendations formulate a basic three-level model of health-care organisation rationally spread across primary and secondary health-care sectors, taking account of the different skills and expertise in these sectors. They recognise that health services are differently structured in countries throughout Europe, and not always adequately resourced. Therefore, they aim to be adaptable to suit these differences. They are set out in five sections: needs assessment, description of the model, adaptation, standards and educational implications

Media coverage and speculation about the impact of the COVID-19 pandemic on suicide: A content analysis of UK news

Objectives: Since the start of the COVID-19 pandemic, there has been much concern and speculation about rises in suicide rates, despite evidence that suicides did not in fact increase in the first year of the pandemic in most countries with real-time suicide data. This public narrative is potentially harmful, as well as misleading, and is likely to be perpetuated by sensational news coverage. Method: Using a bespoke database, we analysed the quality and content of print and online UK news (including opinion pieces) on the impact of COVID-19 on suicidality, based on adherence to international recommendations. Chi-square tests were conducted to examine variability in relation to key characteristics (e.g., type of publication) and to four ‘restriction phases’ (based on UK government official lockdown measures) over the first 14 months of the pandemic. Results: We identified 372 stories about COVID-19 and suicidality in online and print news between the first UK lockdown (March 2020) and May 2021 (when restrictions were significantly eased in the UK). Throughout this period, over a third of articles (39.2%) and headlines (41.4%) claimed or predicted a rise in suicide, often attributed to feelings of entrapment and poor mental health (especially amongst young people), and fueled by expert commentary and speculation. Almost a third of reports were rated as being of negative quality (116, 31.2%), and at least half included no signposting to help and support. However, reporting improved in phases of less stringent COVID-19 restrictions and over time, with later articles and headlines including fewer negative statements and predictions about rises in suicides, and greater reliance on academic evidence. Conclusions: As the longer-term consequences of the pandemic develop, and other national and global events unfold, it is increasingly important that the media, and the wider community of experts shaping its narratives, strive for a positive and evidence-informed approach to news coverage of suicide

Scenario-based dynamic negotiation for the coordination of multi-enterprise supply chains under uncertainty

A novel scenario-based dynamic negotiation approach is proposed for the coordination of decentralized supply chains under uncertainty. The relations between the involved organizations (client, provider and third parties) and their respective conflicting objectives are captured through a non-zero-sum and non symmetric roles SBDN negotiation. The client (leader) designs coordination agreements considering the uncertain reaction of the provider (follower) resulting from the uncertain nature of the third parties, which is modeled as a probability of acceptance function. Different negotiation scenarios are studied: (i) cooperative, and (ii) non-cooperative and (iii) standalone cases. The use of the resulting models is illustrated through a case study with different vendors around aPeer ReviewedPostprint (author's final draft

Have news reports on suicide and attempted suicide during the COVID-19 pandemic adhered to guidance on safer reporting? A UK-wide content analysis study

Background: Associations between sensational news coverage of suicide and increases in suicidal behaviour have been well documented. Amidst growing concern over the impact of the COVID-19 pandemic on suicide rates, it is especially important that news coverage adheres to recommended standards. Methods: We analysed the quality and content of print and online UK news reports of possible COVID-19 related suicides and suicide attempts in the first four months of the pandemic (N=285). Results: Most reports made explicit links between suicidal behaviour and the COVID-19 pandemic in the headline (65.5%), based on statements by family, friends or acquaintances of the deceased (60%). The impact of the pandemic on suicidal behaviour was most often attributed to feelings of isolation (27.4%), poor mental health (14.7%) and entrapment due to government-imposed restrictions (14.4%). Although rarely of poor overall quality, reporting was biased towards young people, frontline staff and relatively unusual suicides and, to varying degrees, failed to meet recommended standards (e.g. 41.1% did not signpost readers to sources of support). Limitations: This analysis cannot account for the impact of reporting on suicide. Conclusions: Careful attention must be paid to the quality and content of reports, especially as longer-term consequences of the pandemic develop

Evaluación cuantitativa del riesgo de entrada del virus de la gripe aviar altamente patógeno en la comunidad valenciana por importación de aves vivas

The Region of Valencia has had many imports of live poultry from different countries that have had several outbreaks of Highly Pathogenic Bird flu during their history. The aim of this paper is to do a quantitative assessment of the risk of entry of HPAI in the Region of Valencia and its provinces due to the importation of live poultry, and identify the countries which entail a higher risk. The results indicate that Alicante is the province with more risk and Italy is the country that represents the greatest proportion of risk due to his imports. The probability to introduce the HPAI virus to the Region of Valencia due to life poultry imports is low.En la Comunidad Valenciana (CV) se importa cantidades altas de aves vivas desde países que han sufrido algún brote de influenza aviar altamente patógena (HPAI) a lo largo de su historia. El objetivo de este trabajo es realizar una evaluación cuantitativa del riesgo que hay de que el virus HPAI entre en la CV y sus provincias por importación de aves vivas, e identificar los países desde los que es más probable introducirlo. Los resultados obtenidos muestran a Alicante como la provincia con más probabilidad de sufrir la entrada del virus y a Italia, el país desde donde hay más probabilidad que entre. La probabilidad de introducir el virus HPAI en la CV mediante importaciones de aves vivas es baja

Recommendations for headache service organisation and delivery in Europe.

Headache disorders are a major public-health priority, and there is pressing need for effective solutions to them. Better health care for headache-and ready access to it-are central to these solutions; therefore, the organisation of headache-related services within the health systems of Europe becomes an important focus. These recommendations are the result of collaboration between the European Headache Federation and Lifting The Burden: the Global Campaign against Headache. The process of development included wide consultation. To meet the very high level of need for headache care both effectively and efficiently, the recommendations formulate a basic three-level model of health-care organisation rationally spread across primary and secondary health-care sectors, taking account of the different skills and expertise in these sectors. They recognise that health services are differently structured in countries throughout Europe, and not always adequately resourced. Therefore, they aim to be adaptable to suit these differences. They are set out in five sections: needs assessment, description of the model, adaptation, standards and educational implications