pH-triggered endosomal escape of pore-forming Listeriolysin O toxin-coated gold nanoparticles

The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (ERC grant agreement n° 338133)Background: A major bottleneck in drug delivery is the breakdown and degradation of the delivery system through the endosomal/lysosomal network of the host cell, hampering the correct delivery of the drug of interest. In nature, the bacterial pathogen Listeria monocytogenes has developed a strategy to secrete Listeriolysin O (LLO) toxin as a tool to escape the eukaryotic lysosomal system upon infection, allowing it to grow and proliferate unharmed inside the host cell. Results: As a “proof of concept”, we present here the use of purifed His-LLO H311A mutant protein and its conjuga tion on the surface of gold nanoparticles to promote the lysosomal escape of 40 nm-sized nanoparticles in mouse embryonic fbroblasts. Surface immobilization of LLO was achieved after specifc functionalization of the nanoparti cles with nitrile acetic acid, enabling the specifc binding of histidine-tagged proteins. Conclusions: Endosomal acidifcation leads to release of the LLO protein from the nanoparticle surface and its self-assembly into a 300 Å pore that perforates the endosomal/lysosomal membrane, enabling the escape of nanoparticles.Depto. de Química FísicaFac. de Ciencias QuímicasTRUEUnión Europea. FP7Ministerio de Ciencia e Innovación (MICINN)Comunidad de MadridUniversidad Complutense de Madridpu

Predictive factors for overactive bladder symptoms after pelvic organ prolapse surgery

Contains fulltext : 89696.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: This study focussed on the factors which predict the presence of symptoms of overactive bladder (OAB) after surgery for pelvic organ prolapse (POP). METHODS: Consecutive women who underwent POP surgery with or without the use of vaginal mesh materials in the years 2004-2007 were included. Assessments were made preoperatively and at follow-up, including physical examination (POP-Q) and standardised questionnaires (IIQ, UDI and DDI). RESULTS: Five hundred and five patients were included with a median follow-up of 12.7 (6-35) months. Bothersome OAB symptoms decreased after POP surgery. De novo bothersome OAB symptoms appeared in 5-6% of the women. Frequency and urgency were more likely to improve as compared with urge incontinence and nocturia. The best predictor for the absence of postoperative symptoms was the absence of preoperative bothersome OAB symptoms. CONCLUSION: The absence of bothersome OAB symptoms preoperatively was the best predictor for the absence of postoperative symptoms.1 september 201

The InterPro protein families and domains database: 20 years on

The InterPro database (https://www.ebi.ac.uk/interpro/) provides an integrative classification of protein sequences into families, and identifies functionally important domains and conserved sites. InterProScan is the underlying software that allows protein and nucleic acid sequences to be searched against InterPro's signatures. Signatures are predictive models which describe protein families, domains or sites, and are provided by multiple databases. InterPro combines signatures representing equivalent families, domains or sites, and provides additional information such as descriptions, literature references and Gene Ontology (GO) terms, to produce a comprehensive resource for protein classification. Founded in 1999, InterPro has become one of the most widely used resources for protein family annotation. Here, we report the status of InterPro (version 81.0) in its 20th year of operation, and its associated software, including updates to database content, the release of a new website and REST API, and performance improvements in InterProScan

Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC

The Vigilance Decrement in Executive Function Is Attenuated When Individual Chronotypes Perform at Their Optimal Time of Day

Time of day modulates our cognitive functions, especially those related to executive control, such as the ability to inhibit inappropriate responses. However, the impact of individual differences in time of day preferences (i.e. morning vs. evening chronotype) had not been considered by most studies. It was also unclear whether the vigilance decrement (impaired performance with time on task) depends on both time of day and chronotype. In this study, morning-type and evening-type participants performed a task measuring vigilance and response inhibition (the Sustained Attention to Response Task, SART) in morning and evening sessions. The results showed that the vigilance decrement in inhibitory performance was accentuated at non-optimal as compared to optimal times of day. In the morning-type group, inhibition performance decreased linearly with time on task only in the evening session, whereas in the morning session it remained more accurate and stable over time. In contrast, inhibition performance in the evening-type group showed a linear vigilance decrement in the morning session, whereas in the evening session the vigilance decrement was attenuated, following a quadratic trend. Our findings imply that the negative effects of time on task in executive control can be prevented by scheduling cognitive tasks at the optimal time of day according to specific circadian profiles of individuals. Therefore, time of day and chronotype influences should be considered in research and clinical studies as well as real-word situations demanding executive control for response inhibition.This work was supported by the Spanish Ministerio de Ciencia e Innovación (Ramón y Cajal programme: RYC-2007-00296 and PLAN NACIONAL de I+D+i: PSI2010-15399) and Junta de Andalucía (SEJ-3054)

The outcome of transobturator anterior vaginal wall prolapse repair using porcine dermis graft: intermediate term follow-up

Introduction and Hypothesis We evaluated the anatomical success and complications of Perigee® with porcine dermis Graft in the repair of anterior vaginal wall prolapse (AVWP) Materials and Methods After Institutional Review Board (IRB) approval, the charts of all patients who underwent AVWP repair using the Perigee/InteXen® kit from July 2005 to July 2009 were reviewed. Patients who had less than 6-month follow-up were excluded. Preoperative data including patient age, previous AVWP repairs, hysterectomy status, preoperative dyspareunia and pertinent physical findings were collected and recorded. Postoperative success was defined as anatomical stage 0 or I using the Pelvic Organ Prolapse Quantification (POP-Q) scoring system. Graft related complications were also recorded. Results Out of 89 patients, 69 completed at least 6-month follow-up. Median follow-up was 13 (6-48) months. Seventeen patients (25%) had previous AVWP repair and 32 (46%) had previous hysterectomy. Preoperatively, AVWP stage II was found in 9 (13%), stage III in 27 (39%) and stage IV in 33 (48%) patients. Anatomic success was found in 48 (69%) patients, with 23 (33%) having stage 0 and 25 (36%) stage I AVWP. Intraoperative complications included incidental cystotomy in one patient and bladder perforation in one. Postoperative complications included vaginal exposure and dyspareunia in one case, wound dehiscence in one and tenderness over the graft arm with dyspareunia in one. conclusions The use of porcine dermis in AVWP repair is safe with minimal graft related complications; however, anatomical success is lower than that reported with the use of synthetic grafts

Season of Birth and Dopamine Receptor Gene Associations with Impulsivity, Sensation Seeking and Reproductive Behaviors

Season of birth (SOB) has been associated with many physiological and psychological traits including novelty seeking and sensation seeking. Similar traits have been associated with genetic polymorphisms in the dopamine system. SOB and dopamine receptor genetic polymorphisms may independently and interactively influence similar behaviors through their common effects on the dopaminergic system.Based on a sample of 195 subjects, we examined whether SOB was associated with impulsivity, sensation seeking and reproductive behaviors. Additionally we examined potential interactions of dopamine receptor genes with SOB for the same set of traits. Phenotypes were evaluated using the Sociosexual Orientation Inventory, the Barratt Impulsivity Scale, the Eysenck Impulsivity Questionnaire, the Sensation Seeking Scale, and the Delay Discounting Task. Subjects were also asked about their age at first sex as well as their desired age at the birth of their first child. The dopamine gene polymorphisms examined were Dopamine Receptor D2 (DRD2) TaqI A and D4 (DRD4) 48 bp VNTR. Primary analyses included factorial genderxSOB ANOVAs or binary logistic regression models for each dependent trait. Secondary analysis extended the factorial models by also including DRD2 and DRD4 genotypes as independent variables. Winter-born males were more sensation seeking than non-winter born males. In factorial models including both genotype and season of birth as variables, two previously unobserved effects were discovered: (1) a SOBxDRD4 interaction effect on venturesomeness and (2) a DRD2xDRD4 interaction effect on sensation seeking.These results are consistent with past findings that SOB is related to sensation seeking. Additionally, these results provide tentative support for the hypothesis that SOB modifies the behavioral expression of dopaminergic genetic polymorphism. These findings suggest that SOB should be included in future studies of risky behaviors and behavioral genetic studies of the dopamine system

InterPro in 2019: improving coverage, classification and access to protein sequence annotations

The InterPro database (http://www.ebi.ac.uk/interpro/) classifies protein sequences into families and predicts the presence of functionally important domains and sites. Here, we report recent developments with InterPro (version 70.0) and its associated software, including an 18% growth in the size of the database in terms on new InterPro entries, updates to content, the inclusion of an additional entry type, refined modelling of discontinuous domains, and the development of a new programmatic interface and website. These developments extend and enrich the information provided by InterPro, and provide greater flexibility in terms of data access. We also show that InterPro's sequence coverage has kept pace with the growth of UniProtKB, and discuss how our evaluation of residue coverage may help guide future curation activities