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Acknowledgements: The authors are grateful to the other members of the Boletta laboratory for useful discussions and to L. Tronci for helpful suggestions on data analysis. This work was supported by the Italian Ministry of Health (RF-2018-12368254; RF-2016-02361267 to A.B.; GR-2016-02364851 to C.P. and R.P.), the Italian association of patients with PKD (AIRP to A.B.), the PKD Foundation (218G18 to A.B.), the European Community (H-2020-MSCA-ITN-2019#SCiLS to A.B. and R.R.), by the Italian association for research on cancer (AIRC, IG2019-23513 to A.B.), by Q12 grant (MRC_MC_UU_12022/6 to C.F.), the European Research Council (ERC819920 to C.F.), and the CRUK Programme Foundation (Award C51061/A27453 to C.F.). The authors are grateful to S. Bramani for her continuous support. Part of this work was carried out in ALEMBIC, an advanced microscopy laboratory established by IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele. Part of the present work was performed by M.E.S. and A.K.N. in fulfilment of the requirements for obtaining a PhD degree at Vita-Salute San Raffaele University, Milano, Italy., Funder: EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011264; Grant(s): H2020-MSCA-ITN-2019#SCiLS, H2020-MSCA-ITN-2019#SCiLS, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): ERC819920, Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.

Este artigo tem como objetivo analisar as respostas dos Estados Unidos e da China em termos de políticas públicas de combate à pandemia da COVID-19, com ênfase no contexto atual de acirramento das tensões geopolíticas, na competição tecnológica e nos modelos de desenvolvimento de ambos os países. Considerando a importância da internet na contemporaneidade para áreas essenciais como economia, política, segurança e defesa, daremos destaque à corrida pela liderança no desenvolvimento das redes 5G. A questão principal que propomos é: qual foi o papel da pandemia na disputa geopolítica entre China e Estados Unidos, considerando sua dimensão tecnológica? A metodologia de pesquisa adotada é a análise qualitativa de documentos oficiais e bibliografia especializada sobre o tema. Nossa hipótese é que a pandemia pode ter conferido vantagem à China na corrida pela liderança no 5G, considerando o maior foco dado pelo governo chinês aos investimentos nessa tecnologia e sua importância no combate à pandemia no país asiático, em que a internet foi essencial para o controle do isolamento social como forma de conter a disseminação do vírus. Os Estados Unidos, por sua vez, concentraram seus esforços no setor de biotecnologia para combater a pandemia.

Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS-010759. Mechanistically, IACS-010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC-overexpressing cells. In line with these findings, the BCL2-inhibitory compound venetoclax synergized with IACS-010759 against double-hit lymphoma (DHL), a high-grade malignancy with concurrent activation of MYC and BCL2. In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.

Polycystin-1 (PC-1) is a transmembrane protein, encoded by the PKD1 gene, mutated in autosomal dominant polycystic kidney disease (ADPKD). This common genetic disorder, characterized by cyst formation in both kidneys, ultimately leading to renal failure, is still waiting for a definitive treatment. The overall function of PC-1 and the molecular mechanism responsible for cyst formation are slowly coming to light, but they are both still intensively studied. In particular, PC-1 has been proposed to act as a mechanosensor, although the precise signal that activates the mechanical properties of this protein has been long debated and questioned. In this review, we report studies and evidence of PC-1 function as a mechanosensor, starting from the peculiarity of its structure, through the long journey that progressively shed new light on the potential initiating events of cystogenesis, concluding with the description of PC-1 recently shown ability to sense the mechanical stimuli provided by the stiffness of the extracellular environment. These new findings have potentially important implications for the understanding of ADPKD pathophysiology and potentially for designing new therapies.NEW & NOTEWORTHY Polycystin-1 has recently emerged as a possible receptor able to sense extracellular stiffness and to negatively control the cellular actomyosin contraction machinery. Here, we revisit a large body of literature on autosomal dominant polycystic kidney disease providing a new possible mechanistic view on the topic.

MYC is a key oncogenic driver and an adverse prognostic factor in multiple types of cancer, including diffuse large B-cell lymphoma (DLBCL). Yet, MYC activation also endows cancer cells with a series of metabolic dependencies, which can provide strategic points for targeted pharmacological intervention. We recently reported that targeting the mitochondrial electron transport chain (ETC) complex I with the small molecule inhibitor IACS-010759 selectively killed MYC-overexpressing lymphoid cells. Here, we unravel the mechanistic basis for this synthetic-lethal interaction and exploit it to improve the anti-tumoral effects of ETC inhibition. In a mouse B-cell line, MYC hyperactivation and IACS-010759 treatment added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced by targeted pharmacological intervention, with either inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to contribute pro-oxidant effects when administered at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, ETC inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and other MYC-driven cancers.Key point #1MYC and the ETC complex I inhibitor IACS-010759 elicit different reactive oxygen species (ROS) that cooperate to disrupt redox homeostasis.Key point #2Further boosting of oxidative stress with high doses of ascorbate increases the killing of MYC-driven lymphoma xenografts by IACS-010759.

Equity crowdfunding platforms allow small ventures to raise money and find new investors among retail individuals. In this work we aim at analysing the relationship between the number of equity investors registered in the crowdfunding round and the follow-up growth of revenues reported by investee firms. We find support for the ‘curse of the crowd’ hypothesis, according to which a larger number of investors registered at the end of the equity crowdfunding campaign is associated to lower growth in the revenues, in the short run. We posit that this effect is attributable to coordination costs, possible conflicts and low incentive for investors to spend efforts in value-adding activities.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder, characterized by bilateral renal cyst formation. Multiple pathways are de-regulated in cystic epithelia offering good opportunities for therapy. Others and we have previously reported that metabolic reprogramming, including alterations of the TCA cycle, are prominent features of ADPKD. Several lines of evidence suggest that mitochondrial impairment might be responsible for the metabolic alterations. Here, we performed morphologic and morphometric evaluation of mitochondria by TEM in an orthologous mouse model of PKD caused by mutations in the Pkd1 gene (Ksp-Cre;Pkd1flox/- ). Furthermore, we measured mitochondrial respiration by COX and SDH enzymatic activity in situ. We found several alterations including reduced mitochondrial mass, altered structure and fragmentation of the mitochondrial network in cystic epithelia of Ksp-Cre;Pkd1flox/- mice. At the molecular level, we found reduced expression of the pro-fusion proteins OPA1 and MFN1 and up-regulation of the pro-fission protein DRP1. Importantly, administration of Mdivi-1, which interferes with DRP1 rescuing mitochondrial fragmentation, significantly reduced kidney/body weight, cyst formation, and improved renal function in Ksp-Cre;Pkd1flox/- mice. Our data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease.

Summary Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.