mTORC2 Is the major second layer kinase negatively regulating FOXO3 activity

Forkhead box O (FOXO) proteins are transcription factors involved in cancer and aging and their pharmacological manipulation could be beneficial for the treatment of cancer and healthy aging. FOXO proteins are mainly regulated by post-translational modifications including phosphorylation, acetylation and ubiquitination. As these modifications are reversible, activation and inactivation of FOXO factors is attainable through pharmacological treatment. One major regulatory input of FOXO signaling is mediated by protein kinases. Here, we use specific inhibitors against different kinases including PI3K, mTOR, MEK and ALK, and other receptor tyrosine kinases (RTKs) to determine their effect on FOXO3 activity. While we show that inhibition of PI3K efficiently drives FOXO3 into the cell nucleus, the dual PI3K/mTOR inhibitors dactolisib and PI-103 induce nuclear FOXO translocation more potently than the PI3Kδ inhibitor idelalisib. Furthermore, specific inhibition of mTOR kinase activity affecting both mTORC1 and mTORC2 potently induced nuclear translocation of FOXO3, while rapamycin, which specifically inhibits the mTORC1, failed to affect FOXO3. Interestingly, inhibition of the MAPK pathway had no effect on the localization of FOXO3 and upstream RTK inhibition only weakly induced nuclear FOXO3. We also measured the effect of the test compounds on the phosphorylation status of AKT, FOXO3 and ERK, on FOXO-dependent transcriptional activity and on the subcellular localization of other FOXO isoforms. We conclude that mTORC2 is the most important second layer kinase negatively regulating FOXO activity.info:eu-repo/semantics/publishedVersio

Intrinsic Plasmon-Phonon Interactions in Highly Doped Graphene: A Near-Field Imaging Study.

Author's accepted versionFinal version available from ACS via the DOI in this recordAs a two-dimensional semimetal, graphene offers clear advantages for plasmonic applications over conventional metals, such as stronger optical field confinement, in situ tunability, and relatively low intrinsic losses. However, the operational frequencies at which plasmons can be excited in graphene are limited by the Fermi energy EF, which in practice can be controlled electrostatically only up to a few tenths of an electronvolt. Higher Fermi energies open the door to novel plasmonic devices with unprecedented capabilities, particularly at mid-infrared and shorter-wave infrared frequencies. In addition, this grants us a better understanding of the interaction physics of intrinsic graphene phonons with graphene plasmons. Here, we present FeCl3-intercalated graphene as a new plasmonic material with high stability under environmental conditions and carrier concentrations corresponding to EF > 1 eV. Near-field imaging of this highly doped form of graphene allows us to characterize plasmons, including their corresponding lifetimes, over a broad frequency range. For bilayer graphene, in contrast to the monolayer system, a phonon-induced dipole moment results in increased plasmon damping around the intrinsic phonon frequency. Strong coupling between intrinsic graphene phonons and plasmons is found, supported by ab initio calculations of the coupling strength, which are in good agreement with the experimental data.FJGA and PA-G acknowledge support from the Spanish Ministry of Economy and Competitiveness through the national programs MAT2014-59096-P and FIS2014-60195-JIN, respectively. MFC and SR acknowledge support from EPSRC (Grant no. EP/J000396/1, 281 EP/K017160/1, EP/K010050/1, EPG036101/1, EP/M001024/1, EPM- 002438/1), from Royal Society International Exchanges Scheme 2012/R3 and 2013/R2 and from European Commission (FP7-ICT-2013-613024-GRASP). SD, DNB and MF acknowledge support of ONR N00014-15-1-2671. DNB is the Moore Investigator in Quantum Materials funded by the Gordon and Betty Moore Foundation’s EPiQS Initiative through Grant GBMF4533

Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis

Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichiacoli and Acinetobacterbaumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy

Cronoestratigrafía del Paleozoico Superior de América del Sur : Primera etapa de trabajo hacia una nueva propuesta

Fil: Azcuy, Carlos L.. Departamento de Geología. Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. CABA; ArgentinaFil: Beri, Ángeles. Sección Paleontología. Departamento de Geología. Facultad de Ciencias. Montevideo; UruguayFil: Bernardes-de-Oliveira, Mary E.C.. Universidade Guarulhos. SP; BrasilFil: Carrizo, Hugo A.. Fundación Miguel Lillo. Dirección de Geología. San Miguel de Tucumán; ArgentinaFil: di Pasquo, Mercedes. Departamento de Geología. Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. CABA; ArgentinaFil: Díaz Saravia, Pamela. Fil: González, Carlos R.. Fundación Miguel Lillo. Dirección de Geología. San Miguel de Tucumán; ArgentinaFil: Iannuzzi, Roberto. Instituto de Geociências. Universidad Federal Río Grande do Sul. Porto Alegre; BrasilFil: Lemos, Valesca B.. Instituto de Geociências. Universidad Federal Río Grande do Sul. Porto Alegre; BrasilFil: Melo, José Henrique G.. PETROBRAS/CENPES/PDEXP/BPA. Rio de Janeiro; BrasilFil: Pagani, María Alejandra. Museo Paleontológico Egidio Feruglio. Trelew. Chubut; ArgentinaFil: Rhon, Rosemarie. Departamento de Geologia Aplicada, IGCE/UNESP. Rio Claro; BrasilFil: Amenabar, Cecilia. Departamento de Geología. Facultad de Ciencias Exactas y Naturales. UBA. CABA; ArgentinaFil: Sabattini, Nora María. Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Souza, Paulo. Instituto de Geociências. Universidad Federal Río Grande do Sul. Porto Alegre; BrasilFil: Taboada, Arturo C.. Laboratorio de Investigaciones en Evolución y Biodiversidad (LIEB). Facultad de Ciencias Naturales Sede Esquel. Universidad Nacional de La Patagonia San Juan Bosco. Chubut; ArgentinaFil: Vergel, María del Milagro. Fundación Miguel Lillo. Dirección de Geología. San Miguel de Tucumán; Argentin

Radiographic assessment and clinical outcome after total hip arthroplasty with a Nanos® short stem prosthesis in 147 patients

Background. New generation short stem implants have some unquestionable advantages, which make them particularly attractive. However, in order to achieve good clinical results every implant must respect the normal joint anatomy and biomechanics. Objectives. To evaluate if these implants can fulfill the normal biomechanical parameters, such as femoral offset and leg length, and to assess the clinical outcome. Methods. The main radiographic parameters (horizontal and vertical rotation centre, femoral offset, leg length) have been evaluated in 147 patients who had a short stem implanted between July 2010 and July 2012 at the Private Hospital The Avenue in Melbourne, Australia. Patients have been clinically assessed with the Harris Hip Score and the WOMAC score preoperatively and at 3 months and at 1 year follow-up. Results. Restoration of the four main radiographic parameters was achieved within 5 mm of the contralateral side in most of our patients. Clinical results are excellent, as with the standard stems. Conclusions. With the Nanos® stem we can expect only minor and probably meaningless differences concerning the biomechanical parameters and the leg length; clinical results are comparable to the standard stems. Therefore, we believe the Nanos® stem to be a very useful implant for the total hip arthroplasty

Explorative Sonophotocatalytic Study of C-H Arylation Reaction of Pyrazoles Utilizing a Novel Sonophotoreactor for Green and Sustainable Organic Synthesis

The development of a mild, general, and green method for the C-H arylation of pyrazoles with relatively unreactive aryl halides is an ongoing challenge in organic synthesis. We describe herein a novel sonophotoreactor based on an ultrasonic cleaning bath and blue LED light (visible light) that induce copper-catalyzed monoarylation for pharmacologically relevant pyrazoles. The hybrid effect of ultrasonic irradiation and blue LED is discussed to interpret the observed synergistic action. A broad array of pyrazoles coupled with iodobenzene avoids expensive palladium metal or salts, and certain designed substrates were attained. Only comparatively inexpensive copper(I)iodide and 1,10-phenanthroline were used all together as the catalyst. The presented technique is a greener way to create C-H arylation of pyrazoles. It significantly reduces the amount of energy needed

Urinary bladder matrix scaffolds strengthen esophageal hiatus repair

Background: Laparoscopic repair of the hiatal hernia is associated with a recurrence rate between 12% and 42% depending on the defect size. Although the impact of hiatal reinforcement on long-term recurrence remains controversial, the main limitation of this approach has been the risk of adverse events related with the use of synthetic materials in the vicinity of the esophagus. Methods: A total of 14 female domestic pigs underwent laparoscopic primary hiatal hernia repair of a simulated defect in the esophageal hiatus. Seven of the hiatal repairs were reinforced with an extracellular matrix (ECM) scaffold, whereas the remaining seven served as primary repair controls. Animals were survived for 8 wk. At necropsy, after gross morphologic evaluation, samples were sent for mechanical testing and histology. Results: The repaired defect site reinforced with ECM scaffolds showed a robust closure of the crura in all cases with a smooth peritoneal-like structure covering the entire repair. Average load at failure of the treated group was found to be significantly stronger than that of the controls (185.8 149.7 g versus 57.5 57.5 g, P < 0.05). Similarly, the stiffness was significantly higher in the treated animals (57.5 26.9 g/mm versus 19.1 17.5 g/mm; P < 0.01). Interestingly, there was no difference in elongation at failure (7.62 2.02 mm versus 7.87 3.28 mm; P ¼ 0.44). Conclusions: In our animal survival model, we have provided evidence that the addition of an ECM to augment a primary hiatal repair leads to tissue characteristics that may decrease the possibility of early failure of the repair. This may translate to decreased recurrence rates. Further study is necessary.Fil: Riganti, Juan Martin. Fundación Favaloro; ArgentinaFil: Citola, F. Fundación Favaloro; ArgentinaFil: Amenabar, A. Fundación Favaloro; ArgentinaFil: Craiem, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Graf, S. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Badaloni, A. Fundación Favaloro; ArgentinaFil: Gilbert, TW. University of Pittsburgh; Estados Unidos. ACell; Estados UnidosFil: Nieponice, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina. Fundación Favaloro; Argentin