Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase.

Bacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. Here we report cryo-EM structures of a hyperactive ClpB variant bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS, which reveal the translocation mechanism. Distinct substrate-gripping interactions are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent to the topmost NBD1 contact. NBD conformations at the seam interface reveal how ATP hydrolysis-driven substrate disengagement and re-binding are precisely tuned to drive a directional, stepwise translocation cycle

A mass threshold in the number density of passive galaxies at z∼\sim2

The process that quenched star formation in galaxies at intermediate and high redshift is still the subject of considerable debate. One way to investigate this puzzling issue is to study the number density of quiescent galaxies at z~2, and its dependence on mass. Here we present the results of a new study based on very deep Ks-band imaging (with the HAWK-I instrument on the VLT) of two HST CANDELS fields (the UKIDSS Ultra-deep survey (UDS) field and GOODS-South). The new HAWK-I data (taken as part of the HUGS VLT Large Program) reach detection limits of Ks>26 (AB mag). We select a sample of passively-evolving galaxies in the redshift range 1.4<z<2.5. Thanks to the depth and large area coverage of our imaging, we have been able to extend the selection of quiescent galaxies a magnitude fainter than previous analyses. Through extensive simulations we demonstrate, for the first time, that the observed turn-over in the number of quiescent galaxies at K>22 is real. This has enabled us to establish unambiguously that the number counts of quiescent galaxies at z~2 flatten and slightly decline at magnitudes fainter than Ks~22(AB mag.). We show that this trend corresponds to a stellar mass threshold $M_*10^{10.8}\,{\rm M_{\odot}}$ below which the mechanism that halts the star formation in high-redshift galaxies seems to be inefficient. Finally we compare the observed pBzK number counts with those of quiescent galaxies extracted from four different semi-analytic models. We find that none of the models provides a statistically acceptable description of the number density of quiescent galaxies at these redshifts. We conclude that the mass function of quiescent galaxies as a function of redshift continues to present a key and demanding challenge for proposed models of galaxy formation and evolution.Comment: Accepted for publication on Astronomy and Astrophysic

CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”

Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients

Overcoming PLK1 inhibitor resistance by targeting mevalonate pathway to impair AXL-TWIST axis in colorectal cancer

© 2021 The Author(s).New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients’ outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29R, RKOR, SW837R and HCT116R, were generated in vitro and validated by IG50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKOR. AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29R, SW837R and HCT116R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors.This study has been funded by Instituto de Salud Carlos III (ISCIII) -Fondos FEDER proyects PI16/01468 and PI19/01231

IMAGINE study protocol of a clinical trial: a multi-center, investigator-blinded, randomized, 36-month, parallel-group to compare the effectiveness of motivational interview in rehabilitation of older stroke survivors

Background: Rehabilitation pathways are crucial to reduce stroke-related disability. Motivational Interviewing (MI), as a person-centered complex intervention, aimed to empower and motivate, and could be a resource to improve rehabilitation outcomes for older stroke survivors. The IMAGINE project aims to assess the impact of MI, as a complement to standard geriatric rehabilitation, on functional improvement at 30 days after admission, compared to standard geriatric rehabilitation alone, in persons admitted to geriatric rehabilitation after a stroke. Secondary objectives include assessing the impact of MI on physical activity and performance, self-efficacy, safety, cost-utility, participants' experiences and functional status at 3 months. Methods: We will conduct a multicenter randomized clinical trial in three geriatric rehabilitation hospitals in Spain. Older adults after mild-moderate stroke without previous severe cognitive impairment or disability will be randomized into the control or intervention group (136 per group, total N = 272). The intervention group will receive 4 sessions of MI by trained nurses, including the design of a personalized rehabilitation plan agreed between stroke survivors and nurses based on stroke survivors´ goals, needs, preferences and capabilities. Main outcome will be the Functional Independence Measure (FIM). In-hospital physical activity will be measured through accelerometers and secondary outcomes using validated scales. The study includes a process evaluation and cost-utility analysis. Discussion: Final results are expected by end of 2020. This study will provide relevant information on the implementation of MI as a rehabilitation reinforcement tool in older stroke survivors. A potential reduction in post-stroke disability and dependence would increase person's health-related quality of life and well-being and reduce health and social care costs. IMAGINE has the potential to inform practice and policymakers on how to move forward towards shared decision-making and shared responsibilities in the vulnerable population of older stroke survivors

Co-designing implementation strategies to promote remote physical activity programs in frail older community-dwellers

Frailty; Integrated care; Older adultsFragilidad; Atención integrada; Personas mayoresFragilitat; Atenció integrada; AnciansBackground: The “AGIL Barcelona (AGILBcn)” community-based integrated care program is a multicomponent healthy aging intervention for frail older adults. In this context, the present study aimed to identify implementation strategies to optimize the accessibility, acceptability, and adaptability of mobile health (mhealth) interventions to enhance physical activity in frail older adults, and to prioritize action points according to their importance and feasibility, through a co-design process. Material and methods: A mixed methods approach was used. In the qualitative phase, a method adapted from the World Café was applied in 6 virtual groups to identify strategies to facilitate the virtual physical activity program. In the quantitative phase, prioritization and feasibility of the strategies was analyzed through surveys. Strategies were ranked based on priority vs. feasibility, revealing if strategies should either be: implemented first; if possible; taken into account for future consideration; or directly disregarded. The convenience sample included older adults (n = 7), community professionals (n = 9) and health professionals (n = 13). Qualitative data were analyzed by summative content analysis and quantitative data by nonparametric descriptive analyses. Results: A total of 27 strategies were identified and grouped into four categories: general strategies for reducing barriers; specific strategies for facilitating the use of a digital application; specific strategies for facilitating participation in virtual exercise groups; and specific strategies for facilitating external support. According to the ranking of strategies, the first ones to be implemented included: digital literacy, digital capability assessment, family technology support, weekly telephone follow-up by professionals, personalizing exercises, and virtual exercises in small groups. Conclusion: The active participation of all stakeholders enabled us to identify potential strategies for implementing person-oriented technology in physical activity programs and for engaging older adults.LV-G was funded by the Industrial Doctorates Program [reference 2020 DI 76], promoted by the Government of Catalonia, Spain. This study received funding by the Barcelona Science Plan of the Cultural Institute of Barcelona-Barcelona City Council and by la Caixa Foundation [19S01576-006]

On The Detection Of Ionizing Radiation Arising From Star-Forming Galaxies At Redshift z ~ 3-4 : Looking For Analogs Of "Stellar Reionizers"

We use the spatially-resolved, multi-band photometry in the GOODS South field acquired by the CANDELS project to constrain the nature of candidate Lyman continuum (LyC) emitters at redshift z~3.7 identified using ultra-deep imaging below the Lyman limit (1-sigma limit of ~30 AB in a 2" diameter aperture). In 18 candidates, out of a sample of 19 with flux detected at >3-sigma level, the light centroid of the candidate LyC emission is offset from that of the LBG by up to 1.5". We fit the SED of the LyC candidates to spectral population synthesis models to measure photometric redshifts and the stellar population parameters. We also discuss the differences in the UV colors between the LBG and the LyC candidates, and how to estimate the escape fraction of ionizing radiation (f_esc) in cases, like in most of our galaxies, where the LyC emission is spatially offset from the host galaxy. In all but one case we conclude that the candidate LyC emission is most likely due to lower redshift interlopers. Based on these findings, we argue that the majority of similar measurements reported in the literature need further investigation before it can be firmly concluded that LyC emission is detected. Our only surviving LyC candidate is a LBG at z=3.795, which shows the bluest (B-V) color among LBGs at similar redshift, a stellar mass of M~2 x 10^9 Msun, weak interstellar absorption lines and a flat UV spectral slope with no Lya in emission. We estimate its f_esc to be in the range 25%-100%, depending on the dust and intergalactic attenuation.Comment: Submitted to The Astrophysical Journal, 20 pages, 8 figures, 1 tabl

Evaluación de la eficacia de los procesos de esterilización de consultorios odontológicos del distrito VI de la provincia de buenos aires, argentina 2006 - 2007, mediante la utilización de indicadores biológicos

En un consultorio odontológico, diversas fuentes de posible infección, como saliva, sangre, instrumentos contaminados, etc., pueden ser transmisores de microorganismos tanto a pacientes como al personal odontológico. El objeti vo del presente trabajo fue evaluar la eficacia de los procesos de esterilización de los consultorios odontológicos del Distrito VI de la Provincia de Buenos Aires mediante la utilización de Indicadores Biológicos. Participaron del estudio 283 odontólogos que llevaron a cabo un total de 320 procesos de esterilización por calor seco y 19 por calor húmedo. En base a los resultados obtenidos se observó que el 35 % (112/320) de los procesos de esterilización por calor seco controlados no cumplieron con los requ isitos, de los cuales 63 repitieron el control y, 55/63 (87%) resolvieron el problema mediante distintas acciones correctivas. Con respecto a la esterilización por calor húmedo, el 32 % (6/19) de los procesos no cumplieron con los requisitos, en 3 de los 6 positivos se efectuaron correcciones simples obteniéndose resultados satisfactorios. El presente trabajo muestra la importancia para la comunidad, de la implementación de rutina de un sistema de control que permita garantizar la esterilidad de los materi ales utilizados en los consultorios odontológicos