The In Vivo Role of the RP-Mdm2-p53 Pathway in Signaling Oncogenic Stress Induced by pRb Inactivation and Ras Overexpression

The Mdm2-p53 tumor suppression pathway plays a vital role in regulating cellular homeostasis by integrating a variety of stressors and eliciting effects on cell growth and proliferation. Recent studies have demonstrated an in vivo signaling pathway mediated by ribosomal protein (RP)-Mdm2 interaction that responds to ribosome biogenesis stress and evokes a protective p53 reaction. It has been shown that mice harboring a Cys-to-Phe mutation in the zinc finger of Mdm2 that specifically disrupts RP L11-Mdm2 binding are prone to accelerated lymphomagenesis in an oncogenic c-Myc driven mouse model of Burkitt's lymphoma. Because most oncogenes when upregulated simultaneously promote both cellular growth and proliferation, it therefore stands to reason that the RP-Mdm2-p53 pathway might also be essential in response to oncogenes other than c-Myc. Using genetically engineered mice, we now show that disruption of the RP-Mdm2-p53 pathway by an Mdm2C305F mutation does not accelerate prostatic tumorigenesis induced by inactivation of the pRb family proteins (pRb/p107/p130). In contrast, loss of p19Arf greatly accelerates the progression of prostate cancer induced by inhibition of pRb family proteins. Moreover, using ectopically expressed oncogenic H-Ras we demonstrate that p53 response remains intact in the Mdm2C305F mutant MEF cells. Thus, unlike the p19Arf-Mdm2-p53 pathway, which is considered a general oncogenic response pathway, the RP-Mdm2-p53 pathway appears to specifically suppress tumorigenesis induced by oncogenic c-Myc

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

Not All Sperm Are Equal: Functional Mitochondria Characterize a Subpopulation of Human Sperm with Better Fertilization Potential

Human sperm samples are very heterogeneous and include a low amount of truly functional gametes. Distinct strategies have been developed to characterize and isolate this specific subpopulation. In this study we have used fluorescence microscopy and fluorescence-activated cell sorting to determine if mitochondrial function, as assessed using mitochondrialsensitive probes, could be employed as a criterion to obtain more functional sperm from a given ejaculate. We first determined that mitochondrial activity correlated with the quality of distinct human samples, from healthy donors to patients with decreased semen quality. Furthermore, using fluorescence-activated cell sorting to separate sperm with active and inactive mitochondria we found that this was also true within samples. Indeed, sperm with active mitochondria defined a more functional subpopulation, which contained more capacitated and acrosome intact cells, sperm with lower chromatin damage, and, crucially, sperm more able to decondense and participate in early development using both chemical induction and injection into mature bovine oocytes. Furthermore, cell sorting using mitochondrial activity produced a more functional sperm subpopulation than classic swim-up, both in terms of improvement in a variety of functional sperm parameters and in statistical significance. In conclusion, whatever the true biological role of sperm mitochondria in fertilization, mitochondrial activity is a clear hallmark of human sperm functionality.Fundação para a Ciência e Tecnologia (POCTI/CVT/49102/2002; SFRH/BD/23571/2005; SFRH/BPD/63120/2009; SFRH/BD/46002/2008; SFRH/BD/46078/2008)Instituto de Investigação Interdisciplinar da Universidade de Coimbra (III/BIO/50/2005

Impact of antibiotic resistance on outcomes of neutropenic cancer patients with Pseudomonas aeruginosa bacteraemia (IRONIC study) : Study protocol of a retrospective multicentre international study

Introduction Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe sepsis and death among neutropenic cancer patients. There has been a recent increase of multidrug-resistant PA (MDRPA) isolates that may determine a worse prognosis, particularly in immunosuppressed patients. The aim of this study is to establish the impact of antibiotic resistance on the outcome of neutropenic onco-haematological patients with PA bacteraemia, and to identify the risk factors for MDRPA bacteraemia and mortality. Methods and analysis This is a retrospective, observational, multicentre, international study. All episodes of PA bacteraemia occurring in neutropenic onco-haematological patients followed up at the participating centres from 1 January 2006 to 31 May 2018 will be retrospectively reviewed. The primary end point will be overall case-fatality rate within 30 days of onset of PA bacteraemia. The secondary end points will be to describe the following: the incidence and risk factors for multidrug-resistant and extremely drug-resistant PA bacteraemia (by comparing the episodes due to susceptible PA with those produced by MDRPA), the efficacy of ceftolozane/tazobactam, the rates of persistent bacteraemia and bacteraemia relapse and the risk factors for very early (48 hours), early (7 days) and overall (30 days) case-fatality rates. Ethics and dissemination The Clinical Research Ethics Committee of Bellvitge University Hospital approved the protocol of the study at the primary site. To protect personal privacy, identifying information of each patient in the electronic database will be encrypted. The processing of the patients' personal data collected in the study will comply with the Spanish Data Protection Act of 1998 and with the European Directive on the privacy of data. All data collected, stored and processed will be anonymised. Results will be reported at conferences and in peer-reviewed publications

Resultados de Pesquisa em Nutrição de Aves no Brasil: Resumo dos Ultimos 5 anos Results of Poultry Nutrition Research in Brazil: A Summary of the Last 5 years

Foi realizada uma revisão bibliográfica sobre as pesquisas brasileiras na área de nutrição avícola, entre 1994 a l999. Nesse período, foi publicado um total de 496 trabalhos, com uma média de 82,7 trabalhos/ ano. Os trabalhos na área de nutrição revelaram que 64,52% foram realizados com frangos de corte; 24,19%, com poedoiras e aves de reposição; 3,93%, com matrizes pesadas; e 7,66%, com outras aves. Com relação às publicações em forma de resumos expandidos, foram publicados 226 e 163 resumos, nos Anais das Reuniões Anuais da Fundação APINCO de Ciência e Tecnologia Avícolas e da Sociedade Brasileira de Zootecnia, respectivamente. Na Revista da Sociedade Brasileira de Zootecnia e no Arquivo Brasileiro de Medicina Veterinária e Zootecnia foram publicados, respectivamente, 65 e 34 trabalhos completos. Os pesquisadores das instituições UFV, UNESP-Jaboticabal e UFRGS publicaram no total 104, 92 e 46 trabalhos. As pesquisas concentraram-se principalmente nas áreas de proteína/aminoácidos (21,77%), avaliação de alimentos (21,77%), minerais (19,15%) e aditivos (16,33%).<br>A literature review of the papers published in the area of poultry nutrition was done considering Brazilian publications from the period of 1994 to 1999. During this period a total of 496 papers were published, with an average of 82. 7 papers/year. The publications in nutrition revealed that 64. 52% were made with broiler chickens, 24. 19% with laying hens and replacement birds, 3.93% with broiler breeders and 7.66% with other type of birds. Considering the publications in the form of summary, 226 and 163, were published in the Proceedings of Fundação APINCO de Ciência e Tecnologia Avícola and Sociedade Brasileira de Zootecnia, respectively. In the Revista da Sociedade Brasileira de Zootecnia and Arquivo Brasileiro de Medicina Veterinária e Zootecnia were published, 65 and 34 papers, respectively. Researches in the Universities UFV, UNESP-Jaboticabal and UFRGS, accounted for a total 104, 92 and 46 papers, respectively. The papers in poultry nutrition concentrated mainly in the area of protein/amino acid (21.77%), feedstuffs evaluation (21.77%), minerals (19.15%) and additives (16.33%)