Emerging actions of the nuclear receptor LRH-1 in the gut

AbstractLiver receptor homolog-1 (NR5A2) is a nuclear receptor originally identified in the liver and mostly known for its regulatory role in cholesterol and bile acid homeostasis. More recently, liver receptor homolog-1 has emerged as a key regulator of intestinal function, coordinating unanticipated actions, such as cell renewal and local immune function with important implications to common intestinal diseases, including colorectal cancer and inflammatory bowel disease. Unlike most of the other nuclear receptors, liver receptor homolog-1 acts as a constitutively active transcription factor to drive the transcription of its target genes. Liver receptor homolog-1 activity however is to a major extent regulated by different corepressors and posttranslational modifications, which may account for its tissue-specific functions. This review will provide an update on the molecular aspects of liver receptor homolog-1 action and focus on some emerging aspects of its function in normal and diseased gut. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease

Normal Proliferation and Tumorigenesis but Impaired Pancreatic Function in Mice Lacking the Cell Cycle Regulator Sei1

Sei1 is a positive regulator of proliferation that promotes the assembly of Cdk4-cyclin D complexes and enhances the transcriptional activity of E2f1. The potential oncogenic role of Sei1 is further suggested by its overexpression in various types of human cancers. To study the role of Sei1, we have generated a mouse line deficient for this gene. Sei1-null fibroblasts did not show abnormalities regarding proliferation or susceptibility to neoplastic transformation, nor did we observe defects on Cdk4 complexes or E2f activity. Sei1-null mice were viable, did not present overt pathologies, had a normal lifespan, and had a normal susceptibility to spontaneous and chemically-induced cancer. Pancreatic insulin-producing cells are known to be particularly sensitive to Cdk4-cyclin D and E2f activities, and we have observed that Sei1 is highly expressed in pancreatic islets compared to other tissues. Interestingly, Sei1-null mice present lower number of islets, decreased β-cell area, impaired insulin secretion, and glucose intolerance. These defects were associated to nuclear accumulation of the cell-cycle inhibitors p21Cip1 and p27Kip1 in islet cells. We conclude that Sei1 plays an important role in pancreatic β-cells, which supports a functional link between Sei1 and the core cell cycle regulators specifically in the context of the pancreas

Muscle or liver-specific Sirt3 deficiency induces hyperacetylation of mitochondrial proteins without affecting global metabolic homeostasis

Sirt3 is a mitochondrial sirtuin, predominantly expressed in highly metabolic tissues. Germline ablation of Sirt3 has major metabolic consequences, including increased susceptibility to metabolic damage and oxidative stress after high fat feeding. In order to determine the contribution of liver and skeletal muscle to these phenotypes, we generated muscle-specific Sirt3 (Sirt3skm−/−) and liver-specific Sirt3 (Sirt3hep−/−) knock-out mice. Despite a marked global hyperacetylation of mitochondrial proteins, Sirt3skm−/− and Sirt3hep−/− mice did not manifest any overt metabolic phenotype under either chow or high fat diet conditions. Similarly, there was no evidence for increased oxidative stress in muscle or liver when Sirt3 was ablated in a tissue-specific manner. These observations suggest that the mitochondrial hyperacetylation induced by Sirt3-deletion in a tissue specific manner is not necessarily linked to mitochondrial dysfunction and does not recapitulate the metabolic abnormalities observed in the germline Sirt3 knock-out mice

Activation of p21 limits acute lung injury and induces early senescence after acid aspiration and mechanical ventilation

The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir/ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an anti-apoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence

Intensive care unit discharge to the ward with a tracheostomy cannula as a risk factor for mortality: A prospective, multicenter propensity analysis

To analyze the impact of decannulation before intensive care unit discharge on ward survival in nonexperimental conditions. DESIGN: Prospective, observational survey. SETTING: Thirty-one intensive care units throughout Spain. PATIENTS: All patients admitted from March 1, 2008 to May 31, 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At intensive care unit discharge, we recorded demographic variables, severity score, and intensive care unit treatments, with special attention to tracheostomy. After intensive care unit discharge, we recorded intensive care unit readmission and hospital survival. STATISTICS: Multivariate analyses for ward mortality, with Cox proportional hazard ratio adjusted for propensity score for intensive care unit decannulation. We included 4,132 patients, 1,996 of whom needed mechanical ventilation. Of these, 260 (13%) were tracheostomized and 59 (23%) died in the intensive care unit. Of the 201 intensive care unit tracheostomized survivors, 60 were decannulated in the intensive care unit and 141 were discharged to the ward with cannulae in place. Variables associated with intensive care unit decannulation (non-neurologic disease [85% vs. 64%], vasoactive drugs [90% vs. 76%], parenteral nutrition [55% vs. 33%], acute renal failure [37% vs. 23%], and good prognosis at intensive care unit discharge [40% vs. 18%]) were included in a propensity score model for decannulation. Crude ward mortality was similar in decannulated and nondecannulated patients (22% vs. 23%); however, after adjustment for the propensity score and Sabadell Score, the presence of a tracheostomy cannula was not associated with any survival disadvantage with an odds ratio of 0.6 [0.3-1.2] (p=.1). CONCLUSION: In our multicenter setting, intensive care unit discharge before decannulation is not a risk factor

Sirt1 protects from K-Ras-driven lung carcinogenesis.

The NAD+-dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K-RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K-RasG12V-driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1-Tg pneumocytes, isolated shortly after K-RasG12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K-RAS-driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1-K-RAS axis could be a therapeutic target for NSCLCs.We thank Jesus Herranz for his biostatistical advice; and Alba de Martino, Patricia Gonzalez, Maria Gomez, and Zaira Vega, from the Histopathology Unit at the CNIO, for their work in mouse histopathology. Work in the laboratory of P.J.F.-M. was funded by the IMDEA Food, the Spanish Association against Cancer (aecc) and the Ramon Areces (CIVP18A3891) Foundation. Work in the laboratory of M.S. was funded by the CNIO and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (SAF project), the European Research Council (ERC Advanced Grant), the European Union (RISK-IR project), and the Botin Foundation and Banco Santander (Santander Universities Global Division). Work in the laboratory of DH was funded by Rutgers Cancer Institute of New Jersey, the Alex's Lemonade Stand Foundation Shark Tank Award and by the National Institutes of Health Grant K99/R00 CA197869. Work in the laboratory of M.S.C. was supported by a grant (SAF2012-40026) from the Spanish Ministry of Science and Innovation. L.F.C-M. was supported by a PhD Fellowship from the Portuguese Foundation for Science and Technology (FCT-MCTES, SFRH/BD/124022/2016).S

Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity.

Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.General: We thank Prof. Jose Maria. Ordovas for his kind suggestions; nutritionists Helena Marcos-Pasero, Elena Aguilar-Aguilar and Isabel Espinosa-Salinas for their help with volunteers management; Rosa Serrano for her help with animal experiments; Susana Molina for her advice with PBMC isolation; Luisa Mariscal, Domingo Fernandez, Lola Martinez, Diego Megias, Patricia Gonzalez, Fernando Pelaez, Anabel Sanz, Carolina Pola, Celia de la Calle, Ana Ortega, Ana Sagrera, Jose Miguel Frade, Elena Lopez-Guadamillas, Maribel Munoz, Susana Llanos, Andres Fernandez, Aranzazu Sierra, Andres Lopez, Noemi Haro and Ildefonso Rodriguez for their excellent technical and scientific support. Work at the laboratory of P.J.F.M. is funded by the Ramon Areces Foundation, (CIVP18A3891), Asociacion Espanola contra el Cancer-AECC (SIRTBIO-LABAE18008FERN), a Ramon y Cajal Award from the Spanish Ministry of Science, Innovation and Universities (MICINN) (RYC-2017-22335), RETOS projects Program of MICINN (SAF2017-85766-R) and the Portuguese Foundation for Science and Technology (FCT-MCTES, SFRH/BD/124022/2016). Work at the laboratory of ARM was funded by the MICINN (PID2019-110183RB-C21), Regional Government of Community of Madrid (P2018/BAA-4343-ALIBIRD2020-CM) and the Ramon Areces Foundation. Work at the laboratory of A.D.R. Funded by the Comunidad de Madrid-Talento Grant 2018-T1/BMD-11966 and the MICINN PID-2019-106893RA-100. Work at the laboratory of L.D. is funded by projects from the Health Research Fund (ISCIII FIS PI14/01374 and FISPI17/00508) and from a Manuel de Oya research fellowship from the Beer and Health Foundation. Work at the laboratory of A.E. is funded by a Ramon y Cajal Award from MICINN (RYC-2013-13546) and RETOS projects Program of the MICINN, co-funded by the European Regional Development Fund (ERDF) (SAF2015-67538-R). Work in the laboratory of M.S. was funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and the "laCaixa" Foundation.S

Search for nonresonant Higgs boson pair production in the four leptons plus twob jets final state in proton-proton collisions at √s = 13 TeV

CMS Collaboration: et al.The first search for nonresonant production of Higgs boson pairs (HH) with one H decaying into four leptons and the other into a pair of b quarks is presented, using proton-proton collisions recorded at a center-of-mass energy of √s = 13 TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 138 fb−1. A 95% confidence level upper limit of 32.4 is set on the signal strength modifier µ, defined as the ratio of the observed HH production rate in the HH → ZZ∗bb → 4`bb decay channel to the standard model (SM) expectation. Possible modifications of the H trilinear coupling λHHH with respect to the SM value are investigated. The coupling modifier κλ, defined as λHHH divided by its SM prediction, is constrained to be within the observed (expected) range −8.8 (−9.8) < κλ < 13.4 (15.0) at 95% confidence level.Article funded by SCOAP3.Individuals have received support from the Marie-Curie programme and the European Research Council and Horizon 2020 Grant, contract Nos. 675440, 724704, 752730, 758316, 765710, 824093, 884104, and COST Action CA16108 (European Union); the Leventis Foundation; the Alfred P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the F.R.S.-FNRS and FWO (Belgium) under the “Excellence of Science – EOS" – be.h project n. 30820817; the Beijing Municipal Science & Technology Commission, No. Z191100007219010; the Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; the Hellenic Foundation for Research and Innovation (HFRI), Project Number 2288 (Greece); the Deutsche Forschungsgemeinschaft (DFG), under Germany’s Excellence Strategy – EXC 2121 “Quantum Universe" – 390833306, and under project number 400140256 - GRK2497; the Hungarian Academy of Sciences, the New National Excellence Program - ÚNKP, the NKFIH research grants K 124845, K 124850, K 128713, K 128786, K 129058, K 131991, K 133046, K 138136, K 143460, K 143477, 2020-2.2.1-ED-2021-00181, and TKP2021-NKTA-64 (Hungary); the Council of Science and Industrial Research, India; the Latvian Council of Science; the Ministry of Education and Science, project no. 2022/WK/14, and the National Science Center, contracts Opus 2021/41/B/ST2/01369 and 2021/43/B/ST2/01552 (Poland); the Fundação para a Ciência e a Tecnologia, grant CEECIND/01334/2018 (Portugal); the National Priorities Research Program by Qatar National Research Fund; MCIN/AEI/10.13039/501100011033, ERDF “a way of making Europe", and the Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia María de Maeztu, grant MDM-2017-0765 and Programa Severo Ochoa del Principado de Asturias (Spain); the Chulalongkorn Academic into Its 2nd Century Project Advancement Project, and the National Science, Research and Innovation Fund via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation, grant B05F650021 (Thailand); the Kavli Foundation; the Nvidia Corporation; the SuperMicro Corporation; the Welch Foundation, contract C-1845; and the Weston Havens Foundation (USA).Peer reviewe

Search for CP violation using t¯t events in the lepton+jets channel in pp collisions at √s = 13 TeV

CMS collaboration: et al.Results are presented on a search for CP violation in the production and decay of top quark-antiquark pairs in the lepton+jets channel. The search is based on data from proton-proton collisions at √s = 13 TeV, collected with the CMS detector, corresponding to an integrated luminosity of 138 fb−1. Possible CP violation effects are evaluated by measuring asymmetries in observables constructed from linearly independent four-momentum vectors of the final-state particles. The dimensionless chromoelectric dipole moment of the top quark obtained from the observed asymmetries is measured to be 0.04±0.10 (stat)±0.07(syst), and the asymmetries exhibit no evidence for CP-violating effects, consistent with expectations from the standard model.Individuals have received support from the Marie-Curie program and the European Research Council and Horizon 2020 Grant, contract Nos. 675440, 724704, 752730, 758316, 765710, 824093, 884104, and COST Action CA16108 (European Union); the Leventis Foundation; the Alfred P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the F.R.S.-FNRS and FWO (Belgium) under the “Excellence of Science — EOS" — be.h project n. 30820817; the Beijing Mu nicipal Science & Technology Commission, No. Z191100007219010; the Ministry of Ed ucation, Youth and Sports (MEYS) of the Czech Republic; the Hellenic Foundation for Research and Innovation (HFRI), Project Number 2288 (Greece); the Deutsche Forschungs gemeinschaft (DFG), under Germany’s Excellence Strategy — EXC 2121 “Quantum Universe" — 390833306, and under project number 400140256 - GRK2497; the Hungarian Academy of Sciences, the New National Excellence Program — ÚNKP, the NKFIH re search grants K 124845, K 124850, K 128713, K 128786, K 129058, K 131991, K 133046, K 138136, K 143460, K 143477, 2020-2.2.1-ED-2021-00181, and TKP2021-NKTA-64 (Hun gary); the Council of Science and Industrial Research, India; the Latvian Council of Science; the Ministry of Education and Science, project no. 2022/WK/14, and the Na tional Science Center, contracts Opus 2021/41/B/ST2/01369 and 2021/43/B/ST2/01552 (Poland); the Fundação para a Ciência e a Tecnologia, grant CEECIND/01334/2018 (Portugal); the National Priorities Research Program by Qatar National Research Fund; MCIN/AEI/10.13039/501100011033, ERDF “a way of making Europe", and the Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia María de Maeztu, grant MDM-2017-0765 and Programa Severo Ochoa del Principado de Asturias (Spain); the Chulalongkorn Academic into Its 2nd Century Project Advancement Project, and the National Science, Research and Innovation Fund via the Program Management Unit for Hu man Resources & Institutional Development, Research and Innovation, grant B05F650021 (Thailand); the Kavli Foundation; the Nvidia Corporation; the SuperMicro Corporation; the Welch Foundation, contract C-1845; and the Weston Havens Foundation (USA).Article funded by SCOAP3.Peer reviewe