Rationalizing the permeation of polar antibiotics into Gram-negative bacteria

The increasing level of antibiotic resistance in Gram-negative bacteria, together with the lack of new potential drug scaffolds in the pipeline, make the problem of infectious diseases a global challenge for modern medicine. The main reason that Gram-negative bacteria are particularly challenging is the presence of an outer cell-protecting membrane, which is not present in Gram-positive species. Such an asymmetric bilayer is a highly effective barrier for polar molecules. Several protein systems are expressed in the outer membrane to control the internal concentration of both nutrients and noxious species, in particular: (i) water-filled channels that modulate the permeation of polar molecules and ions according to concentration gradients, and (ii) efflux pumps to actively expel toxic compounds. Thus, besides expressing specific enzymes for drugs degradation, Gram-negative bacteria can also resist by modulating the influx and efflux of antibiotics, keeping the internal concentration low. However, there are no direct and robust experimental methods capable of measuring the permeability of small molecules, thus severely limiting our knowledge of the molecular mechanisms that ultimately control the permeation of antibiotics through the outer membrane. This is the innovation gap to be filled for Gram-negative bacteria. This review is focused on the permeation of small molecules through porins, considered the main path for the entry of polar antibiotics into Gram-negative bacteria. A fundamental understanding of how these proteins are able to filter small molecules is a prerequisite to design/optimize antibacterials with improved permeation. The level of sophistication of modern molecular modeling algorithms and the advances in new computer hardware has made the simulation of such complex processes possible at the molecular level. In this work we aim to share our experience and perspectives in the context of a multidisciplinary extended collaboration within the IMI-Translocation consortium. The synergistic combination of structural data, in vitro assays and computer simulations has proven to give new insights towards the identification and description of physico–chemical properties modulating permeation. Once similar general rules are identified, we believe that the use of virtual screening techniques will be very helpful in searching for new molecular scaffolds with enhanced permeation, and that molecular modeling will be of fundamental assistance to the optimization stage

Access of patients with breast and lung cancer to chemotherapy treatment in public and private hospitals in the city of Buenos Aires

Objectives: Describe the time elapsed from the diagnosis to treatment with chemotherapy for patients with breast and lung cancer at public and private hospitals in Buenos Aires. Design: Retrospective cohort study. Setting: Three public and three private academic hospitals in Buenos Aires. Participants: Patients with breast (n = 168) or lung cancer (n = 100) diagnosis treated with chemotherapy. Main outcomes measures: Clinical and sociodemographic data were collected in a stratified sample. We used the Kaplan–Meier estimator to analyse the time elapsed and the log rank test to compare both groups Results: For breast cancer patients, median time elapsed between diagnosis and treatment with chemotherapy was 76 days (95% CI: 64–86) in public and 60 days (95% CI: 52–65) in private hospitals (P = 0.0001). For adjuvant and neoadjuvant treatments, median time was 130 (95% CI: 109–159) versus 64 (95% CI: 56–73) days (P < 0.0001) and 57 days (95% CI: 49–75) versus 26 (95% CI: 16–41) days, respectively (P = 0.0002). There were no significant differences in the time from first consultation to diagnosis. In patients with lung cancer, median time from diagnosis to treatment was 71 days (95% CI: 60–83) in public hospitals and 31 days (95% CI: 24–39) in private hospitals (P = 0.0002). In the metastatic setting, median time to treatment was 63 days (95% CI: 45–83) in public and 33 (95% CI: 26–44) days in private hospitals (P = 0.005). Conclusions: There are significant disparity in the access to treatment with chemotherapy for patients in Buenos Aires, Argentina.Fil: Recondo, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Cosacow, César. Centro de Educación Medica E Invest.clinicas; ArgentinaFil: Cutuli, Hernán Javier. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Cermignani, Luciano. Hospital Alemán; ArgentinaFil: Straminsky, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Naveira, Martin. Hospital Británico de Buenos Aires; ArgentinaFil: Pitzzu, Martin. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: De Ronato, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Nacuzzi, Gabriela. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Taetti, Gonzalo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Corsico, Santiago. Hospital Británico de Buenos Aires; ArgentinaFil: Berrueta, Mabel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Colucci, Giuliana. Centro de Educación Medica E Invest.clinicas; ArgentinaFil: Gibbons, Luz. Centro de Educación Medica E Invest.clinicas; ArgentinaFil: Gutierrez, Laura. Centro de Educación Medica E Invest.clinicas; ArgentinaFil: García Elorrio, Ezequiel. Centro de Educación Medica E Invest.clinicas; Argentin

Healthy Vegan

En la actualidad, si bien es cierto muchas personas se preocupan por cuidar de su salud, muchos también tienen mayor conciencia ambiental y buscan el bienestar y cuidado de los animales. Es así que este segmento de la población ha aumentado con los años tanto a nivel nacional como mundial. En el Perú, los consumidores que llevan este estilo de vida se dividen en varias categorías, un 10% se considera vegetariana, el 23% de la población es flexitariana, un 6% es vegana y solo un 5% son pescetarianos, cifras que siguen creciendo años tras años. Ante el inminente crecimiento de este sector de la población, hemos planteado crear un sistema que brinde asesoría culinaria para los usuarios que sean autosuficientes y también ofrecerá un servicio de venta de productos ya elaborados para quienes busquen platos más sofisticados. El desarrollo del aplicativo ayudará y optimizará la preparación de diversos platos vegetarianos y veganos. Para ello, se elaboró un trabajo de investigación con la colaboración de potenciales consumidores, profesionales de la salud y programadores para la viabilidad del proyecto. Encontramos que los consumidores saludables optan por comer casi lo mismo y/o elaboran menestras. Asimismo, que existe un fuerte desconocimiento de tiendas saludables y que el alcance geográfico de tiendas saludables es limitado. Por ello, también aplicamos la venta de productos saludables, actuando como intermediarios. Con la finalidad de maximizar el alcance geográfico y que el cliente obtenga sus productos de manera eficiente.Nowadays, although it is true that many people are concerned about taking care of their health, many are also more environmentally aware and seek the well-being and care of animals. As a result, this segment of the population has increased over the years both nationally and globally. In Peru, the consumers who lead this lifestyle are divided into several categories: 10% consider themselves vegetarian, 23% of the population is flexitarian, 6% is vegan and only 5% are pescetarians, figures that continue growing year by year. Given the imminent growth of this sector of the population, we have proposed the creation of a system that will provide culinary advice for self-sufficient users and will also offer a service for the sale of ready-made products for those who are looking for more sophisticated dishes. The development of the application will help and optimize the preparation of various vegetarian and vegan dishes. For this, a research work was developed with the collaboration of potential consumers, health professionals and programmers for the viability of the project. We found that healthy consumers choose to eat almost the same and/or make stews. Also, that there is a strong lack of awareness of healthy stores and that the geographical scope of healthy stores is limited. Therefore, we also apply the sale of healthy products, acting as intermediaries. With the purpose of maximizing the geographical scope and that the client obtains his products in an efficient way.Trabajo de investigació

A avaliação do risco de parto prematuro através da medida do colo uterino por ultrassonografia transvaginal

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CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity

This work has been supported by the European Research Council (CoG-2014-646903, PoC-2018-811220) to PM, the Spanish Ministry of Economy and Competitiveness (MINECO, SAF-SAF2016-80481- R, BIO2017-85364-R) to PM and EE, the Generalitat de Catalunya (SGR330, SGR102 and PERIS) to PM and EE, the Spanish Association against cancer (AECC-CI-2015) to CB, and the Health Institute Carlos III (ISCIII/FEDER, PI14-01191) to CB. PM also acknowledges financial support from the Obra Social La Caixa-Fundaciò Josep Carreras. SRZ and TV are supported by a Marie Curie fellowships. OM is supported by the Catalan Government through a Beatriu de Pinos fellowship. MB is supported by MINECO through a PhD scholarship. PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL)

Elliptic flow of charged particles in Pb-Pb collisions at 2.76 TeV

We report the first measurement of charged particle elliptic flow in Pb-Pb collisions at 2.76 TeV with the ALICE detector at the CERN Large Hadron Collider. The measurement is performed in the central pseudorapidity region (|$\eta$|<0.8) and transverse momentum range 0.2< $p_{\rm T}$< 5.0 GeV/$c$. The elliptic flow signal v$_2$, measured using the 4-particle correlation method, averaged over transverse momentum and pseudorapidity is 0.087 $\pm$ 0.002 (stat) $\pm$ 0.004 (syst) in the 40-50% centrality class. The differential elliptic flow v$_2(p_{\rm T})$ reaches a maximum of 0.2 near $p_{\rm T}$ = 3 GeV/$c$. Compared to RHIC Au-Au collisions at 200 GeV, the elliptic flow increases by about 30%. Some hydrodynamic model predictions which include viscous corrections are in agreement with the observed increase.Comment: 10 pages, 4 captioned figures, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/389

Two-pion Bose-Einstein correlations in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The first measurement of two-pion Bose-Einstein correlations in central Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.Comment: 17 pages, 5 captioned figures, 1 table, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Avaliação ultra-sonográfica do colo uterino entre 22 e 24 semanas de gestação : correlações com características demográficas e com a história obstétrica

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