Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

Mycobacterium tuberculosis (M.tb), which requires iron for survival, acquires this element by synthesizing iron-binding molecules known as siderophores and by recruiting a host iron-transport protein, transferrin, to the phagosome. The siderophores extract iron from transferrin and transport it into the bacterium. Here we describe an additional mechanism for iron acquisition, consisting of an M.tb protein that drives transport of human holo-transferrin into M.tb cells. The pathogenic strain M.tb H37Rv expresses several proteins that can bind human holo-transferrin. One of these proteins is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Rv1436), which is present on the surface of M.tb and its relative Mycobacterium smegmatis. Overexpression of GAPDH results in increased transferrin binding to M.tb cells and iron uptake. Human transferrin is internalized across the mycobacterial cell wall in a GAPDH-dependent manner within infected macrophages

Exploring the waveform characteristics of tidal breathing carbon dioxide, measured using the N-Tidal C device in different breathing conditions (The General Breathing Record Study): protocol for an observational, longitudinal study

Background: In an increasingly comorbid population, there are significant challenges to diagnosing the cause of breathlessness, and once diagnosed, considerable difficulty in detecting deterioration early enough to provide effective intervention. The burden of the breathless patient on the health care economy is substantial, with asthma, chronic heart failure, and pneumonia affecting over 6 million people in the United Kingdom alone. Furthermore, these patients often have more than one contributory factor to their breathlessness symptoms, with conditions such as dysfunctional breathing pattern disorders—an under-recognized component. Current methods of diagnosing and monitoring breathless conditions can be extensive and difficult to perform. As a consequence, home monitoring is poorly complied with. In contrast, capnography (the measurement of tidal breath carbon dioxide) is performed during normal breathing. There is a need for a simple, easy-to-use, personal device that can aid in the diagnosis and monitoring of respiratory and cardiac causes of breathlessness.Objective: The aim of this study was to explore the use of a new, handheld capnometer (called the N-Tidal C) in different conditions that cause breathlessness. We will study whether the tidal breath carbon dioxide (TBCO2) waveform, as measured by the N-Tidal C, has different characteristics in a range of respiratory and cardiac conditions.Methods: We will perform a longitudinal, observational study of the TBCO2 waveform (capnogram) as measured by the N-Tidal C capnometer. Participants with a confirmed diagnosis of asthma, breathing pattern disorders, chronic heart failure, motor neurone disease, pneumonia, as well as volunteers with no history of lung disease will be asked to provide twice daily, 75-second TBCO2 collection via the N-Tidal C device for 6 months duration. The collated capnograms will be correlated with the underlying diagnosis and disease state (stable or exacerbation) to determine if there are different TBCO2 characteristics that can distinguish different respiratory and cardiac causes of breathlessness.Results: This study’s recruitment is ongoing. It is anticipated that the results will be available in late 2018.Conclusions: The General Breathing Record Study will provide an evaluation of the use of capnography as a diagnostic and home-monitoring tool for various diseases

E3 ligases:a ubiquitous link between DNA repair, DNA replication and human disease

Maintenance of genome stability is of paramount importance for the survival of an organism. However, genomic integrity is constantly being challenged by various endogenous and exogenous processes that damage DNA. Therefore, cells are heavily reliant on DNA repair pathways that have evolved to deal with every type of genotoxic insult that threatens to compromise genome stability. Notably, inherited mutations in genes encoding proteins involved in these protective pathways trigger the onset of disease that is driven by chromosome instability e.g. neurodevelopmental abnormalities, neurodegeneration, premature ageing, immunodeficiency and cancer development. The ability of cells to regulate the recruitment of specific DNA repair proteins to sites of DNA damage is extremely complex but is primarily mediated by protein post-translational modifications (PTMs). Ubiquitylation is one such PTM, which controls genome stability by regulating protein localisation, protein turnover, protein-protein interactions and intra-cellular signalling. Over the past two decades, numerous ubiquitin (Ub) E3 ligases have been identified to play a crucial role not only in the initiation of DNA replication and DNA damage repair but also in the efficient termination of these processes. In this review, we discuss our current understanding of how different Ub E3 ligases (RNF168, TRAIP, HUWE1, TRIP12, FANCL, BRCA1, RFWD3) function to regulate DNA repair and replication and the pathological consequences arising from inheriting deleterious mutations that compromise the Ub-dependent DNA damage response.</p

Modern innovative solutions to improve outcomes in severe asthma : Protocol for a mixed methods observational comparison of clinical outcomes in mission versus current care delivery

Background: Asthma that is poorly controlled and undertreated can progress to more severe disease that is associated with high levels of unscheduled care that requires high-cost therapy, leading to a significant health economic burden. The identification and appropriate referral to a specialist asthma service is also often delayed by several months or years because of poor recognition and understanding of symptom severity. Current severe asthma services may take several months to provide a comprehensive multidisciplinary assessment, often necessitating multiple hospital visits and costing up to £5000 per patient. Objective: This study aims to evaluate whether a new service model could identify poorly controlled and potentially severe asthma much earlier in the patient pathway, and then compare clinical outcomes between this new care model with standard care. Methods: Modern Innovative Solutions to Improve Outcomes in (MISSION) Severe Asthma is a novel service model developed by asthma specialists from Portsmouth and Southampton severe asthma services. MISSION Severe Asthma identified patients with poorly controlled disease from general practice databases who had not been under secondary outpatient care in the last 12 months or who were not known to secondary care. In 1- or 2-stop assessments, a thorough review of diagnosis, disease phenotype, and control is undertaken, and clinical outcomes collected at baseline. Results: A variety of clinical outcomes will be collected to assess the service model. The results will be reported in February 2020. Conclusions: This protocol outlines a mixed methods study to assess the impact on disease control, unscheduled health care usage, and quality of life in patients seen in the MISSION clinic compared with a closely matched cohort who declined to attend

Symptom burden and unmet needs in MPM:exploratory analyses from the RESPECT-Meso study

© The Author(s) 2020. Objective: Malignant Pleural Mesothelioma (MPM) has a poor prognosis and high symptom burden. RESPECT-Meso was a multicenter randomized study examining the role of early specialist palliative care (SPC) on quality of life (QoL) with MPM. This is a post-hoc exploratory analysis of the symptom burden and unmet needs identified from RESPECT-Meso participants. Methods: Exploratory analysis from 174 participants using the General Health Status (GHS) measure (from the EORTC QLQ-C30 QoL questionnaire) and 87 participants using validated assessment questionnaires in those randomized to SPC. Eligibility for the study included confirmed MPM with diagnosis \u3c 6 weeks prior, performance score (PS) 0 or 1, no significant physical or psychological comorbidity. Cox proportional hazards models were derived to examine for relationships with survival. Free text was assessed using content analysis, looking for common themes and words. Results: Participants were predominantly male (79.9%), mean age 72.8 years, PS was 0 in 38%, 78% of MPM was epithelioid. At least 3 symptoms were reported in 69.8% of participants, including fatigue (81%), dyspnea (73.3%), pain (61.2%), weight loss (59.3%). Anxiety was reported by 54.7% of participants, 52.3% low mood and 48.8% anhedonia symptoms. After multivariable adjustment, only pain remained statistically significant with a hazard ratio (HR) 2.9 (95% CI 1.3-6.7; p = 0.01). For each 1 unit increase in GHS score, the HR for death was 0.987 (0.978-0.996; p = 0.006), indicating a worse reported QoL is related to shorter survival. Unmet needs were common: 25.9% wanted more information about their condition, 24.7% about their care and 21.2% about their treatment. 79.1% were concerned about the effect of their illness on family. Conclusion: There is a high symptom burden in mesothelioma despite good baseline performance status. A worse QoL is associated with a worse survival. Unmet needs are common, perhaps highlighting a need for improved communication and information sharing

Clinical severity classes in COVID-19 pneumonia have distinct immunological profiles, facilitating risk stratification by machine learning

ObjectiveClinical triage in coronavirus disease 2019 (COVID-19) places a heavy burden on senior clinicians during a pandemic situation. However, risk stratification based on serum biomarker bioprofiling could be implemented by a larger, nonspecialist workforce.MethodMeasures of Complement Activation and inflammation in patientS with CoronAvirus DisEase 2019 (CASCADE) patients (n = 72), (clinicaltrials.gov: NCT04453527), classified as mild, moderate, or severe (by support needed to maintain SpO2 &gt; 93%), and healthy controls (HC, n = 20), were bioprofiled using 76 immunological biomarkers and compared using ANOVA. Spearman correlation analysis on biomarker pairs was visualised via heatmaps. Linear Discriminant Analysis (LDA) models were generated to identify patients likely to deteriorate. An X-Gradient-boost (XGB) model trained on CASCADE data to triage patients as mild, moderate, and severe was retrospectively employed to classify COROnavirus Nomacopan Emergency Treatment for covid 19 infected patients with early signs of respiratory distress (CORONET) patients (n = 7) treated with nomacopan.ResultsThe LDA models distinctly discriminated between deteriorators, nondeteriorators, and HC, with IL-27, IP-10, MDC, ferritin, C5, and sC5b-9 among the key predictor variables during deterioration. C3a and C5 were elevated in all severity classes vs. HC (p &lt; 0.05). sC5b-9 was elevated in the “moderate” and “severe” categories vs. HC (p &lt; 0.001). Heatmap analysis shows a pairwise increase of negatively correlated pairs with IL-27. The XGB model indicated sC5b-9, IL-8, MCP1, and prothrombin F1 and F2 were key discriminators in nomacopan-treated patients (CORONET study).ConclusionDistinct immunological fingerprints from serum biomarkers exist within different severity classes of COVID-19, and harnessing them using machine learning enabled the development of clinically useful triage and prognostic tools. Complement-mediated lung injury plays a key role in COVID-19 pneumonia, and preliminary results hint at the usefulness of a C5 inhibitor in COVID-19 recovery