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Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes underlying the pathology of NAFLD remain poorly understood. Hepatic intracellular lipid accumulation may lead to dysregulated tricarboxylic acid (TCA) cycle activity and associated alterations in metabolite levels. The TCA cycle metabolites alpha-ketoglutarate, succinate and fumarate are allosteric regulators of the alpha-ketoglutarate-dependent dioxygenase family of enzymes. The enzymes within this family have multiple targets, including DNA and chromatin, and thus may be capable of modulating gene transcription in response to intracellular lipid accumulation through alteration of the epigenome. In this review, we discuss what is currently understood in the field and suggest areas for future research which may lead to the development of novel preventative or therapeutic interventions for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes underlying the pathology of NAFLD remain poorly understood. Hepatic intracellular lipid accumulation may lead to dysregulated tricarboxylic acid (TCA) cycle activity and associated alterations in metabolite levels. The TCA cycle metabolites alpha-ketoglutarate, succinate and fumarate are allosteric regulators of the alpha-ketoglutarate-dependent dioxygenase family of enzymes. The enzymes within this family have multiple targets, including DNA and chromatin, and thus may be capable of modulating gene transcription in response to intracellular lipid accumulation through alteration of the epigenome. In this review, we discuss what is currently understood in the field and suggest areas for future research which may lead to the development of novel preventative or therapeutic interventions for NAFLD.

Supreme Audit Institutions (SAIs) have an important role in ensuring public sector accountability; their main activities being managing the audit of public sector entities’ financial statements and assessing probity/compliance, providing advice to parliamentary committees, and undertaking performance audits. Standards issued by the International Organization of SAIs encourage SAIs to recognize the value they deliver through their activities and to demonstrate that to citizens, Parliament, and other stakeholders. The recognition of the need to be democratically accountable for efficiency and effectiveness is one aspect of public value, which is also concerned with the just use of authority (Moore, 2013). The purpose of this article is to develop the components of a SAI's public value and, through a comparative international study, to analyze how SAIs’ report on the public value they deliver. Analyzing reporting against the model developed in this article indicates that SAIs reporting prioritizes critiques to increase public sector efficiency and effectiveness, rather than government policy. In addition, it finds SAIs generally fail to discuss any negative consequences of their work. SAIs are encouraged to develop new ways to demonstrate their ongoing relevance.

Summary The Hippo pathway plays major roles in development, regeneration, and cancer. Its activity is tightly regulated by both diffusible chemical ligands and mechanical stimuli. The pathway consists of a series of kinases that can control the sub-cellular localization and stability of YAP or TAZ, homologous transcriptional co-factors. Caveolae, small (60–100 nm) bulb-like invaginations of the plasma membrane, are comprised predominantly of caveolin and cavin proteins and can respond to mechanical stimuli. Here, we show that YAP/TAZ, the major transcriptional mediators of the Hippo pathway, are critical for expression of caveolae components and therefore caveolae formation in both mammalian cells and zebrafish. In essence, without YAP/TAZ, the cell loses an entire organelle. CAVEOLIN1 and CAVIN1, the two essential caveolar genes, are direct target genes of YAP/TAZ, regulated via TEA domain (TEAD) transcription factors. Notably, YAP/TAZ become nuclear enriched and facilitate target gene transcription in cells with diminished levels of caveolae. Furthermore, caveolar-mediated shear stress response activates YAP/TAZ. These data link caveolae to Hippo signaling in the context of cellular responses to mechanical stimuli and suggest activity-based feedback regulation between components of caveolae and the outputs of the Hippo pathway., Graphical Abstract, Highlights • YAP/TAZ are critical for CAVIN1 and CAVEOLIN1 expression and caveolae formation • The essential caveolar genes CAVIN1 and CAVEOLIN1 are direct YAP/TAZ-TEAD target genes • YAP/TAZ are hyperactivated in caveolae-deficient cells • Caveolae facilitate YAP/TAZ-mediated shear stress response, Rausch et al. identifies that the Hippo pathway regulates caveolae abundance via YAP/TAZ-TEAD-mediated transcriptional regulation of the two essential caveolar genes CAVEOLIN1 and CAVIN1. In essence, without YAP/TAZ, the cell loses an entire cellular organelle. In addition, caveolae facilitate shear-stress-mediated signaling via the Hippo pathway.

Guaranteeing a high availability of network services is a crucial part of network management. In this study, we show how to compute the availability of network services under earthquakes, by using empirical data. We take a multi-disciplinary approach and create an earthquake model based on seismological research and historical data. We then show how to integrate this empirical disaster model into existing network resiliency models to obtain the vulnerability and availability of a network under earthquakes. While previous studies have applied their models to ground shaking hazard models or earthquake scenarios, we compute (1) earthquake activity rates and (2) a relation between magnitude and disaster area, and use both as input data for our modeling. This approach is more in line with existing network resiliency models: it provides better information on the correlation between link failures than ground shaking hazard models and a more comprehensive view than a fixed set of scenarios.