The NAE Pathway : autobahn to the nucleus for cell surface receptors

Various growth factors and full-length cell surface receptors such as EGFR are translocated from the cell surface to the nucleoplasm, baffling cell biologists to the mechanisms and functions of this process. Elevated levels of nuclear EGFR correlate with poor prognosis in various cancers. In recent years, nuclear EGFR has been implicated in regulating gene transcription, cell proliferation and DNA damage repair. Different models have been proposed to explain how the receptors are transported into the nucleus. However, a clear consensus has yet to be reached. Recently, we described the nuclear envelope associated endosomes (NAE) pathway, which delivers EGFR from the cell surface to the nucleus. This pathway involves transport, docking and fusion of NAEs with the outer membrane of the nuclear envelope. EGFR is then presumed to be transported through the nuclear pore complex, extracted from membranes and solubilised. The SUN1/2 nuclear envelope proteins, Importin-beta, nuclear pore complex proteins and the Sec61 translocon have been implicated in the process. While this framework can explain the cell surface to nucleus traffic of EGFR and other cell surface receptors, it raises several questions that we consider in this review, together with implications for health and disease

In-Orbit Trend Analysis of Galileo Satellites for Power Sources Degradation Estimation

This paper presents the IOV and FOC Battery in orbit trend analysis and degradation modelling based on the Galileo experience in the frame of the ESPC 2016. Galileo provides a unique opportunity to study a constellation of satellites in the Medium Earth Orbit (MEO) to make a statistical analysis of power sources degradations due to its environment. From a project point of view the objective of the study is to establish a process to obtain the in-orbit battery degradations. Accurate battery degradation knowledge will allow precise battery management from operation teams (battery fade strategy and combined Earth Lunar eclipse power estimations). Another key feature of this study is to be able to assess different battery performance (Saft and ABSL) under very similar mission requirements over a long period (electrical profile, temperature, and environment). This paper reports on the first four years in orbit of IOV PFM satellite (10 eclipse seasons and still running) and on-going FOC satellite telemetry (TM) analysis (starting with two years of data from FOC GSAT201 and GSAT202). The results are in all cases better than the predictions, which is expected due to the usage of conservatives assumptions in the design to cover (for both IOV and FOC) worst case scenario for the entire constellation. It should be noted that the FOC GSAT201 and GSAT202 batteries are degrading slightly faster than the 6 others FOC batteries identified GSAT203, GSAT204, GSAT205, GSAT206, GSAT208 and GSAT209, but still below predictions due to their peculiar unexpected orbit reached after launch (higher DoD up to 42% measured due to longer eclipses). These 2 satellites will require specific degradation monitoring

Regulation of O-glycosylation through Golgi-to-ER relocation of initiation enzymes

Growth factor stimulation moves O-glycosylation initiation enzymes (GalNac-Ts) from the Golgi to the ER in a Src-dependent fashion, increasing protein O-glycosylation

Survival of patients treated with extended-hours haemodialysis in Europe : an analysis of the ERA-EDTA Registry

Background. Previous US studies have indicated that haemodialysis with >= 6-h sessions [extended-hours haemodialysis (EHD)] may improve patient survival. However, patient characteristics and treatment practices vary between the USA and Europe. We therefore investigated the effect of EHD three times weekly on survival compared with conventional haemodialysis (CHD) among European patients. Methods. We included patients who were treated with haemodialysis between 2010 and 2017 from eight countries providing data to the European Renal Association-European Dialysis and Transplant Association Registry. Haemodialysis session duration and frequency were recorded once every year or at every change of haemodialysis prescription and were categorized into three groups: CHD (three times weekly, 3.5-4h/treatment), EHD (three times weekly, >= 6h/treatment) or other. In the primary analyses we attributed death to the treatment at the time of death and in secondary analyses to EHD if ever initiated. We compared mortality risk for EHD to CHD with causal inference from marginal structural models, using Cox proportional hazards models weighted for the inverse probability of treatment and censoring and adjusted for potential confounders. Results. From a total of 142 460 patients, 1338 patients were ever treated with EHD (three times, 7.10.8h/week) and 89 819 patients were treated exclusively with CHD (three times, 3.9 +/- 0.2h/week). Crude mortality rates were 6.0 and 13.5/100 person-years. In the primary analyses, patients treated with EHD had an adjusted hazard ratio (HR) of 0.73 [95% confidence interval (CI) 0.62-0.85] compared with patients treated with CHD. When we attributed all deaths to EHD after initiation, the HR for EHD was comparable to the primary analyses [HR 0.80 (95% CI 0.71-0.90)]. Conclusions. EHD is associated with better survival in European patients treated with haemodialysis three times weekly.Peer reviewe

GREAT3 results I: systematic errors in shear estimation and the impact of real galaxy morphology

We present first results from the third GRavitational lEnsing Accuracy Testing (GREAT3) challenge, the third in a sequence of challenges for testing methods of inferring weak gravitational lensing shear distortions from simulated galaxy images. GREAT3 was divided into experiments to test three specific questions, and included simulated space- and ground-based data with constant or cosmologically-varying shear fields. The simplest (control) experiment included parametric galaxies with a realistic distribution of signal-to-noise, size, and ellipticity, and a complex point spread function (PSF). The other experiments tested the additional impact of realistic galaxy morphology, multiple exposure imaging, and the uncertainty about a spatially-varying PSF; the last two questions will be explored in Paper II. The 24 participating teams competed to estimate lensing shears to within systematic error tolerances for upcoming Stage-IV dark energy surveys, making 1525 submissions overall. GREAT3 saw considerable variety and innovation in the types of methods applied. Several teams now meet or exceed the targets in many of the tests conducted (to within the statistical errors). We conclude that the presence of realistic galaxy morphology in simulations changes shear calibration biases by $\sim 1$ per cent for a wide range of methods. Other effects such as truncation biases due to finite galaxy postage stamps, and the impact of galaxy type as measured by the S\'{e}rsic index, are quantified for the first time. Our results generalize previous studies regarding sensitivities to galaxy size and signal-to-noise, and to PSF properties such as seeing and defocus. Almost all methods' results support the simple model in which additive shear biases depend linearly on PSF ellipticity.Comment: 32 pages + 15 pages of technical appendices; 28 figures; submitted to MNRAS; latest version has minor updates in presentation of 4 figures, no changes in content or conclusion

Data from the ERA-EDTA Registry were examined for trends in excess mortality in European adults on kidney replacement therapy

The objective of this study was to investigate whether the improvement in survival seen in patients on kidney replacement therapy reflects the enhanced survival of the general population. Patient and general population statistics were obtained from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry and the World Health Organization databases, respectively. Relative survival models were composed to examine trends over time in all-cause and cause-specific excess mortality, stratified by age and modality of kidney replacement therapy, and adjusted for sex, primary kidney disease and country. In total, 280,075 adult patients started kidney replacement therapy between 2002 and 2015. The excess mortality risk in these patients decreased by 16% per five years (relative excess mortality risk (RER) 0.84; 95% confidence interval 0.83-0.84). This reflected a 14% risk reduction in dialysis patients (RER 0.86; 0.85-0.86), and a 16% increase in kidney transplant recipients (RER 1.16; 1.07-1.26). Patients on dialysis showed a decrease in excess mortality risk of 28% per five years for atheromatous cardiovascular disease as the cause of death (RER 0.72; 0.70-0.74), 10% for non-atheromatous cardiovascular disease (RER 0.90; 0.88-0.92) and 10% for infections (RER 0.90; 0.87-0.92). Kidney transplant recipients showed stable excess mortality risks for most causes of death, although it did worsen in some subgroups. Thus, the increase in survival in patients on kidney replacement therapy is not only due to enhanced survival in the general population, but also due to improved survival in the patient population, primarily in dialysis patients.Peer reviewe

Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells

Embryonic stem cells (ESCs) repress the expression of exogenous proviruses and endogenous retroviruses (ERVs). Here, we systematically dissected the cellular factors involved in provirus repression in embryonic carcinomas (ECs) and ESCs by a genome-wide siRNA screen. Histone chaperones (Chaf1a/b), sumoylation factors (Sumo2/Ube2i/Sae1/Uba2/Senp6), and chromatin modifiers (Trim28/Eset/Atf7ip) are key determinants that establish provirus silencing. RNA-seq analysis uncovered the roles of Chaf1a/b and sumoylation modifiers in the repression of ERVs. ChIP-seq analysis demonstrates direct recruitment of Chaf1a and Sumo2 to ERVs. Chaf1a reinforces transcriptional repression via its interaction with members of the NuRD complex (Kdm1a, Hdac1/2) and Eset, while Sumo2 orchestrates the provirus repressive function of the canonical Zfp809/Trim28/Eset machinery by sumoylation of Trim28. Our study reports a genome-wide atlas of functional nodes that mediate proviral silencing in ESCs and illuminates the comprehensive, interconnected, and multi-layered genetic and epigenetic mechanisms by which ESCs repress retroviruses within the genome

GREAT3 results - I. Systematic errors in shear estimation and the impact of real galaxy morphology

We present first results from the third GRavitational lEnsing Accuracy Testing (GREAT3) challenge, the third in a sequence of challenges for testing methods of inferring weak gravitational lensing shear distortions from simulated galaxy images. GREAT3 was divided into experiments to test three specific questions, and included simulated space- and ground-based data with constant or cosmologically varying shear fields. The simplest (control) experiment included parametric galaxies with a realistic distribution of signal-to-noise, size, and ellipticity, and a complex point spread function (PSF). The other experiments tested the additional impact of realistic galaxy morphology, multiple exposure imaging, and the uncertainty about a spatially varying PSF; the last two questions will be explored in Paper II. The 24 participating teams competed to estimate lensing shears to within systematic error tolerances for upcoming Stage-IV dark energy surveys, making 1525 submissions overall. GREAT3 saw considerable variety and innovation in the types of methods applied. Several teams now meet or exceed the targets in many of the tests conducted (to within the statistical errors). We conclude that the presence of realistic galaxy morphology in simulations changes shear calibration biases by ∼1percent for a wide range of methods. Other effects such as truncation biases due to finite galaxy postage stamps, and the impact of galaxy type as measured by the Sérsic index, are quantified for the first time. Our results generalize previous studies regarding sensitivities to galaxy size and signal-to-noise, and to PSF properties such as seeing and defocus. Almost all methods' results support the simple model in which additive shear biases depend linearly on PSF ellipticit

VAMP3/Syb and YKT6 are required for the fusion of constitutive secretory carriers with the plasma membrane

The cellular machinery required for the fusion of constitutive secretory vesicles with the plasma membrane in metazoans remains poorly defined. To address this problem we have developed a powerful, quantitative assay for measuring secretion and used it in combination with combinatorial gene depletion studies in Drosophila cells. This has allowed us to identify at least three SNARE complexes mediating Golgi to PM transport (STX1, SNAP24/29 and Syb; STX1, SNAP24/29 and YKT6; STX4, SNAP24 and Syb). RNAi mediated depletion of YKT6 and VAMP3 in mammalian cells also blocks constitutive secretion suggesting that YKT6 has an evolutionarily conserved role in this process. The unexpected role of YKT6 in plasma membrane fusion may in part explain why RNAi and gene disruption studies have failed to produce the expected phenotypes in higher eukaryotes

322. Evaluation of the BioFire® Bone and Joint Infection (BJI) Panel for the Detection of Microorganisms and Antimicrobial Resistance Genes in Synovial Fluid Specimens

Background Bone and Joint Infections (BJIs) present with non-specific symptoms that may include pain, swelling, and fever and are associated with high morbidity and significant risk of mortality. BJIs can be caused by a variety of bacteria and fungi, including anaerobes and microorganisms that can be challenging to culture or identify by traditional microbiological methods. Clinicians primarily rely on culture to identify the pathogen(s) responsible for infection. The BioFire® Bone and Joint Infection (BJI) Panel (BioFire Diagnostics, Salt Lake City, UT) is designed to detect 15 gram-positive bacteria (including seven anaerobes), 14 gram-negative bacteria (including one anaerobe), two yeast, and eight antimicrobial resistance (AMR) genes from synovial fluid specimens in about an hour. The objective of this study was to evaluate the performance of an Investigational Use Only (IUO) version of the BioFire BJI Panel compared to various reference methods. Methods Remnant synovial fluid specimens, which were collected for routine clinical care at 13 study sites in the US and Europe, underwent testing using an IUO version of the BioFire BJI Panel. Performance of this test was determined by comparison to Standard of Care (SoC) consisting of bacterial culture performed at each study site according to their routine procedures. Results A total of 1544 synovial fluid specimens were collected and tested with the BioFire BJI Panel. The majority of specimens were from knee joints (77.9%) and arthrocentesis (79.4%) was the most common collection method. Compared to SoC culture, overall sensitivity was 90.2% and specificity was 99.8%. The BioFire BJI Panel yielded a total of 268 Detected results, whereas SoC yielded a total of 215 positive results for on-panel analytes. Conclusion The BioFire BJI Panel is a sensitive, specific, and robust test for rapid detection of a wide range of analytes in synovial fluid specimens. The number of microorganisms and resistance genes included in the BioFire BJI Panel, together with a reduced time-to-result and increased diagnostic yield compared to culture, is expected to aid in the timely diagnosis and appropriate management of BJIs