Drosophila gurken (TGFα) mRNA Localizes as Particles that Move within the Oocyte in Two Dynein-Dependent Steps

AbstractIn Drosophila oocytes, gurken mRNA localization orientates the TGF-α signal to establish the anteroposterior and dorsoventral axes. We have elucidated the path and mechanism of gurken mRNA localization by time-lapse cinematography of injected fluorescent transcripts in living oocytes. gurken RNA assembles into particles that move in two distinct steps, both requiring microtubules and cytoplasmic Dynein. gurken particles first move toward the anterior and then turn and move dorsally toward the oocyte nucleus. We present evidence suggesting that the two steps of gurken RNA transport occur on distinct arrays of microtubules. Such distinct microtubule networks could provide a general mechanism for one motor to transport different cargos to distinct subcellular destinations

Practical evaluation of SEEK and OpenBIS for biological data management in SynthSys; first report

Author contributions: ET and TZ evaluated systems and developed software; IC, PS and AJM provided use cases; AJM and TZ designed the evaluation; ET, TZ and AJM wrote the report with input from all authors. Acknowledgements: We gratefully acknowledge training and support from the SEEK and OpenBIS project teams, who also checked this document.The project evaluated two existing data management systems for a small set of users, who represent diverse needs within the SynthSys Centre, in order to inform wider adoption for biological research. SEEK’s strengths are support for the Investigation, Study, Assay (ISA) standard and a fine grained access control. This makes SEEK an excellent tool for collaborative work and publishing results. OpenBIS is well suited for automatic metadata processing and incorporation into analysis workflows. Both data management systems provided useful and complementary functionality, so our recommendation is that both are hosted for use in SynthSys. This also aligns well with the EU FAIRDOM project which is currently integrating SEEK and OpenBIS into one platform

Tangled terminology: what's in a name?

Ann Clark and colleagues from the SLI in Scotland SIG Committee look at the use of terminology to describe the needs of children they supportcaslpub3239pu

A sub-group of patients with hospital-acquired pneumonia do not require broad-spectrum gram-negative antimicrobial coverage

C.D.R. is supported by an Edinburgh Clinical Academic Track (ECAT)/Wellcome Trust PhD Training Fellowship for Clinicians award (214178/Z/18/Z).Among 200 patients developing hospital-acquired pneumonia (HAP) outside the intensive care unit, 61% were treated empirically without broad-spectrum Gram-negative coverage, with clinical cure in 69.7%. Lower disease severity markers (systemic inflammatory response syndrome, hypoxia, tachypnoea, neutrophilia) and the absence of diabetes mellitus and prior doxycycline treatment (but not the time to HAP onset) identified patients not requiring broad-spectrum Gram-negative coverage.Publisher PDFPeer reviewe

IL4Rα signaling abrogates hypoxic neutrophil survival and limits acute lung injury responses <i>in vivo</i>

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.  Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1a (hypoxia-inducible factor-1a)mediated neutrophil adaptation, resulting in resolution of lung injury.  Methods: Neutrophil activation of IL4Ra (IL-4 receptor a) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4.  Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1a-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis.  Conclusions: We describe an important interaction whereby IL4Ra-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

PyOmeroUpload: A Python toolkit for uploading images and metadata to OMERO

A Python toolkit for automatically extracting metadata from experiment logs and text files, processing images and uploading these payloads to OMERO servers to create fully annotated, multidimensional datasets. The toolkit comes packaged in portable, platform-independent Docker images that enable users to deploy and run the utilities easily, regardless of Operating System constraints. A selection of use cases is provided, illustrating the primary capabilities and flexibility offered with the toolkit, along with a discussion of limitations and potential future extensions. PyOmeroUpload is available from: https://github.com/SynthSys/pyOmeroUpload.Hay J, Troup E, Clark I et al. PyOmeroUpload: A Python toolkit for uploading images and metadata to OMERO. PyOmeroUpload is available from: https://github.com/SynthSys/pyOmeroUpload. Archived source code at time of publication: https://doi.org/10.5281/zenodo.374648640

Enhanced Quality and Effectiveness of Transurethral Resection of Bladder Tumour in Non–muscle-invasive Bladder Cancer:A Multicentre Real-world Experience from Scotland's Quality Performance Indicators Programme

Background: Clinical outcomes from non–muscle-invasive bladder cancer (NMIBC) are partly determined by the quality of initial interventions. To improve and standardise treatment for cancer, Scotland implemented a national Quality Performance Indicator (QPI) programme for bladder cancer (BC). Objective: To evaluate compliance with specific quality indicators (QIs) related to transurethral resection of bladder tumour (TURBT) and to understand clinical outcomes from NMIBC following the introduction of the QPI programme. Design, setting, and participants: Within a robust governance framework, 12 mandatory evidence-based QPIs were implemented nationally in April 2014. We report prospectively collected data for all new BC patients (between April 2014 and March 2017). We include follow-up data for 2689 patients. Intervention: The TURBT-related QPIs were (1) using a bladder diagram, (2) single post-TURBT instillation of mitomycin C (SPI-MMC), (3) detrusor muscle (DM) in the specimen, and (4) early re-TURBT in high-risk NMIBC. Outcome measurements and statistical analysis: We measured compliance with these QPIs and (1) recurrence rate at first follow-up cystoscopy (RRFFC), (2) rates of residual cancer, and (3) pT2 cancer at re-TURBT. Associations between QPI compliance, tumour features, and outcomes were assessed with multivariable logistic regression models. Results and limitations: Among 4246 new BC patients, SPI-MMC was used in 67% (2029/3023) NMIBC patients. In 1860 NMIBC patients undergoing TURBT, RRFFC, rate of residual cancer, and rate of pT2 at re-TURBT were 13% (116/888), 33% (212/653), and 2.9% (19/653), respectively. SPI-MMC was associated with lower RRFFC, independent of all variables including hospital volume and surgeon. Presence of DM in the specimen halved the likelihood of residual disease in pT1 cancers. The main limitation is the lack of a pre-QPI introduction cohort for comparison. Conclusions: The implementation of a QI programme in Scotland appears to facilitate high-quality TURBT, which in a real-world setting is associated with low early recurrence/residual cancer and accurate pathological staging. Patient summary: Following the first 3 yr of implementing a novel Quality Performance Indicator (QPI) programme in Scotland, we assessed compliance and outcomes in non–muscle-invasive bladder cancer. Evaluating over 4000 new bladder cancer patients, we found that the QPI programme was associated with low recurrence and accurate staging following the initial transurethral resection of bladder tumour