A novel miR-328-Bace1 axis ensures brown adipose tissue homeostasis and energy metabolism in mice

In the last decades brown adipose tissue (BAT) rose to attention as therapeutic target to counteract obesity and its related diseases. In both rodents and humans, activated BAT protects from diet-induced obesity and the associated deterioration of glucose metabolism via enhancing energy expenditure. Interestingly, BAT-related features can also be promoted in skeletal muscle (SM) progenitor cells due to the common cell lineage that these tissue share. Differentiation and function of BAT has been shown to be under control of noncoding RNA networks. In particular, various microRNAs (miRNAs) are able to drive both brown fat homeostasis and BAT/SM cell fate regulation. Here we show a novel miR-328–Bace1 axis involved in metabolic homeostasis through a mechanism that promotes brown adipocyte differentiation and activation. We found miR-328 expression to correlate to BAT activity and to promote brown adipogenesis to the detriment of myogenesis in vitro. This process is dependent on the inhibition by the miRNA of the β-secretase BACE1, a protease known for its detrimental role in Alzheimer’s disease (AD). We could show this protein to act antagonistically to miR-328. Indeed, both knock-down and knock-out of Bace1 resulted in a pro-adipogenic phenotype in both brown adipogenic and even myogenic cell lines. Moreover, conditioned medium from Bace1 knock-out myoblasts revealed paracrine effects by stimulating the adipogenic potential of wild-type myoblasts. Complementary proteomic analyses determined potential substrates of BACE1 involved in this process. In particular, AOC3, a pro-inflammatory, type 2 diabetes-related transmembrane protein, was identified as a putative BACE1 target, with potential paracrine and endocrine functions due to its soluble form sAOC3. This mechanism could be responsible for the beneficial metabolic effects of BACE1 inhibition observed in obese mice. In fact, we showed that diminished BACE1 activity, known to reduce the pathophysiology of AD, enhanced whole-body homeostasis, leading to decreased body weight gain and ameliorated glucose metabolism. BACE1 inhibition was furthermore associated with increased BAT marker expression in the adipose tissue and a global decrease in SM-associated differentiation pathways. Taken together, BACE1 and its substrates, potentially including AOC3, are promising therapeutic targets against obesity, AD and their sequelae. This warrants the broadening of the scientific scope for BACE1 investigation beyond AD and towards BAT and metabolism regulation

Antifungal prophylaxis and pre-emptive therapy: When and how?

The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii. In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system. In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies. Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology. The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches

Neither slugs nor snails: a molecular reappraisal of the gastropod family Velutinidae

The systematics of the marine mollusc family Velutinidae has long been neglected by taxonomists, mainly because their often internal and fragile shells offer no morphological characters. Velutinids are usually undersampled owing to their cryptic mantle coloration on the solitary, social or colonial ascidians on which they feed and lay eggs. In this study, we address the worldwide diversity and phylogeny of Velutinidae based on the largest molecular dataset (313 specimens) to date, accounting for > 50% of the currently accepted genera, coupled with morphological and ecological data. Velutinids emerge as a diverse group, encompassing four independent subfamily-level lineages, two of which are newly described herein: Marseniopsinae subfam. nov. and Hainotinae subfam. nov. High diversity was found at genus and species levels, with two newly described genera (Variolipallium gen. nov. and Pacifica gen. nov.) and ≥ 86 species in the assayed dataset, 58 of which are new to science (67%). Velutinidae show a remarkable morphological plasticity in shell morphology, mantle extension and chromatic patterns. This variability is likely to be the result of different selective forces, including habitat, depth and trophic interactions

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease

Nuovi usi di vecchi concetti. Contributi alla filosofia e alle scienze sociali contemporanee

Il volume, che raccoglie alcune delle maggiori voci del pragmatismo europeo contemporaneo, esplora il modo in cui tale scuola filosofica ha ricostruito alcuni concetti chiave delle scienze sociali e della filosofia, argomentando al contempo che si possa leggere il suo gesto teorico fondamentale nei termini della nozione di ex-aptation

Nuovi usi di vecchi concetti

"Un nuovo nome per alcuni vecchi modi di pensare": così recita il sottotitolo di Pragmatism, il celebre volume di William James datato 1907. Un'espressione apparentemente modesta, che sembra sminuire la portata innovatrice della scuola pragmatista. In realtà, è proprio sulla continuità creativa tra passato, presente e futuro che si articola il potenziale rivoluzionario del pensiero di William James, John Dewey, George Herbert Mead e Charles Sanders Peirce. Come insegna la teoria dell'evoluzione, le novità più radicali hanno spesso origine da un uso innovativo di strumenti e oggetti che in precedenza svolgevano funzioni differenti. È così che opera il meccanismo di ex-aptazione, intuito già dagli autori pragmatisti. I saggi che compongono il presente volume traggono ispirazione da questo spirito "ex-aptivo". In ognuno dei contributi, vecchi concetti vengono esplorati e rivisitati in modi inediti al fine di gettare luce sopra alcuni ambiti cruciali della nostra esperienza: religione, economia/diritto, politica, comunicazione, etica ed estetica, psicologia, educazione. "Nuovi usi di vecchi concetti" vuole così dimostrare nel concreto come si possa mettere all'opera il metodo pragmatista e farne il perno di indagini interdisciplinari sulle difficili e complesse questioni della nostra epoca

Nuovi usi di vecchi concetti

"Un nuovo nome per alcuni vecchi modi di pensare": così recita il sottotitolo di Pragmatism, il celebre volume di William James datato 1907. Un'espressione apparentemente modesta, che sembra sminuire la portata innovatrice della scuola pragmatista. In realtà, è proprio sulla continuità creativa tra passato, presente e futuro che si articola il potenziale rivoluzionario del pensiero di William James, John Dewey, George Herbert Mead e Charles Sanders Peirce. Come insegna la teoria dell'evoluzione, le novità più radicali hanno spesso origine da un uso innovativo di strumenti e oggetti che in precedenza svolgevano funzioni differenti. È così che opera il meccanismo di ex-aptazione, intuito già dagli autori pragmatisti. I saggi che compongono il presente volume traggono ispirazione da questo spirito "ex-aptivo". In ognuno dei contributi, vecchi concetti vengono esplorati e rivisitati in modi inediti al fine di gettare luce sopra alcuni ambiti cruciali della nostra esperienza: religione, economia/diritto, politica, comunicazione, etica ed estetica, psicologia, educazione. "Nuovi usi di vecchi concetti" vuole così dimostrare nel concreto come si possa mettere all'opera il metodo pragmatista e farne il perno di indagini interdisciplinari sulle difficili e complesse questioni della nostra epoca

Filosofia dell’economia e pratica filosofica di comunità.

La relazione contribuisce alla contemporanea riflessione su una filosofia dell’economia, esplorando come l’approccio della Philosophy for Children possa aiutare a promuovere un’educazione al pensiero economico