Search

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.

Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-Methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a β-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.

Over the past decades, the luxury sector has been constantly growing; consequently, luxury products have attracted the interest of many scholars. Nevertheless, only recently research has been started to investigate possible relations between luxury and activities in terms of corporate social responsibility (CSR) and sustainability. This development was overdue: as luxury products often act as industry models, a shift towards sustainable luxury can pave the way for more sustainable mass products on a broad scope as well. Thus, a profound understanding of the mechanisms behind the successful combination of luxury and sustainability can provide insights for both enhancing individual firm success and achieving a shift towards more sustainable products, which is desirable from a societal perspective. To foster this research stream, the present paper provides a systematic literature review on luxury and sustainability in a broader sense, which, based on an inductive approach, identifies the various areas covered by existing research. This allows critical reflection of what is still missing in the ongoing discussions and shows where priorities within research have been set. We identify several major blind spots within extant research and discuss possible further research paths to close them.

The human gut microbiome is considered an organ in its entirety and has been the subject of extensive research due to its role in physiology, metabolism, digestion, and immune regulation. Disequilibria of the normal microbiome have been associated with the development of several gastrointestinal diseases, but the exact underlying interactions are not well understood. Conventional in vivo and in vitro modelling systems fail to faithfully recapitulate the complexity of the human host–gut microbiome, emphasising the requirement for novel systems that provide a platform to study human host–gut microbiome interactions with a more holistic representation of the human in vivo microenvironment. In this review, we outline the progression and applications of new and old modelling systems with particular focus on their ability to model and to study host–microbiome cross-talk.

This study explores the relationship between the detection of psychiatric illness during general practice consultations and patient satisfaction. Psychiatric illness was defined as a score of 3 on the 12-Item General Health Questionnaire (GHQ-12). The hypothesis was that patient satisfaction would be higher after consultations during which psychiatric illness was correctly identified by the GP than after those during which it was ‘missed’. Two hundred and twenty two patients attending seven doctors at one inner London practice participated. One hundred and ten patients (50%) scored 3 on the GHQ-12. The GPs classified 76 of these 110 patients as having a psychiatric component to their illness and 34 as having an entirely physical illness. Only one significant difference in satisfaction was found between these two groups-patients in whom psychiatric illness was correctly identified reported more benefit from the consultation than patients in whom psychiatric illness was present but ‘missed’. Possible explanations for the largely negative findings are discussed including the difficulties of measuring patient satisfaction and the distinction between detection and management of psychiatric illness in general practice.