The maize smut fungus Ustilago maydis is a model organism for elucidating host colonization strategies of biotrophic fungi. Here, we performed an in depth transcriptional profiling of the entire ...plant-associated development of U. maydis wild-type strains. In our analysis, we focused on fungal metabolism, nutritional strategies, secreted effectors, and regulatory networks. Secreted proteins were enriched in three distinct expression modules corresponding to stages on the plant surface, establishment of biotrophy, and induction of tumors. These modules are likely the key determinants for U. maydis virulence. With respect to nutrient utilization, we observed that expression of several nutrient transporters was tied to these virulence modules rather than being controlled by nutrient availability. We show that oligopeptide transporters likely involved in nitrogen assimilation are important virulence factors. By measuring the intramodular connectivity of transcription factors, we identified the potential drivers for the virulence modules. While known components of the b-mating type cascade emerged as inducers for the plant surface and biotrophy module, we identified a set of yet uncharacterized transcription factors as likely responsible for expression of the tumor module. We demonstrate a crucial role for leaf tumor formation and effector gene expression for one of these transcription factors.
Imaging of energetic neutral atoms coming from a trans‐Europa region and energetic proton observations by Galileo around Jupiter have previously revealed the existence of a neutral gas torus produced ...by Europa. Energetic sulfur ions observed by Galileo do not show any effect of the Europa torus for Mc Ilwain parameters L > 9.2, surely because ions are multiply charged, so that the torus first needs to bring the ions charge state to one before being able to neutralize them. Signatures of the Europa torus in energetic sulfur ion measurements obtained near the magnetic equator at L = 9.08–9.20 during Galileo orbits C10 and E11 are reported for the first time in this letter. They provide an independent confirmation of the Europa neutral gas torus. Pitch angle distributions suggest that protons might principally interact with a vertically thin neutral oxygen torus, while sulfur ions are lost by charge exchange with a vertically thicker hydrogen torus.
Plain Language Summary
The icy moon Europa around Jupiter creates a large cloud of neutral particles in space that has not been observed in situ so far. Observation of this cloud is only possible through the effect it has on energetic positively charged ions, like protons or heavier ions. Previous observations have proved the existence of the Europa neutral gas torus by looking at the protons, as the interaction with the torus simultaneously removes the protons and creates energetic neutral particles. In this article, we show never‐reported‐before depletions of the sulfur ion fluxes measured by the Galileo spacecraft that independently confirm the existence of the neutral torus. In addition, comparing the sulfur ions and protons measurements, we find that the molecular hydrogen torus is likely to be vertically thicker than the oxygen torus.
Key Points
An independent confirmation of the Europa neutral gas torus is provided based on never‐reported energetic sulfur ion observations
Protons and sulfur ions are likely to interact with two different neutral torii: a thin oxygen torus and a thick hydrogen one
Machine learning has played an essential role in the past decades and has been in lockstep with the main advances in computer technology. Given the massive amount of data generated daily, there is a ...need for even faster and more effective machine learning algorithms that can provide updated models for real-time applications and on-demand tools. This paper presents FEMa—a finite element machine classifier—for supervised learning problems, where each training sample is the center of a basis function, and the whole training set is modeled as a probabilistic manifold for classification purposes. FEMa has its theoretical basis in the finite element method, which is widely used for numeral analysis in engineering problems. It is shown FEMa is parameterless and has a quadratic complexity for both training and classification phases when basis functions are used that satisfy certain properties. The proposed classifier yields very competitive results when compared to some state-of-the-art supervised pattern recognition techniques.
Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified goal of 75% or greater ...efficacy over 12 months in the target population of African children. Here, we report the safety, immunogenicity, and efficacy results at 12 months following administration of a booster vaccination.
This double-blind phase 1/2b randomised controlled trial was done in children aged 5–17 months in Nanoro, Burkina Faso. Eligible children were enrolled and randomly assigned (1:1:1) to receive three vaccinations of either 5 μg R21/25 μg Matrix-M, 5 μg R21/50 μg Matrix-M, or a control vaccine (the Rabivax-S rabies vaccine) before the malaria season, with a booster dose 12 months later. Children were eligible for inclusion if written informed consent could be provided by a parent or guardian. Exclusion criteria included any existing clinically significant comorbidity or receipt of other investigational products. A random allocation list was generated by an independent statistician by use of block randomisation with variable block sizes. A research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants. All vaccines were prepared by the study pharmacists by use of the same type of syringe, and the contents were covered with an opaque label. Vaccine safety, efficacy, and a potential correlate of efficacy with immunogenicity, measured as anti-NANP antibody titres, were evaluated over 1 year following the first booster vaccination. The population in which the efficacy analyses were done comprised all participants who received the primary series of vaccinations and a booster vaccination. Participants were excluded from the efficacy analysis if they withdrew from the trial within the first 2 weeks of receiving the booster vaccine. This trial is registered with ClinicalTrials.gov (NCT03896724), and is continuing for a further 2 years to assess both the potential value of additional booster vaccine doses and longer-term safety.
Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 μg R21 adjuvanted with 25 μg Matrix-M, 137 received 5 μg R21 adjuvanted with 50 μg Matrix-M, and 140 received the control vaccine. R21/Matrix-M had a favourable safety profile and was well tolerated. Vaccine efficacy remained high in the high adjuvant dose (50 μg) group, similar to previous findings at 1 year after the primary series of vaccinations. Following the booster vaccination, 67 (51%) of 132 children who received R21/Matrix-M with low-dose adjuvant, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine developed clinical malaria by 12 months. Vaccine efficacy was 71% (95% CI 60 to 78) in the low-dose adjuvant group and 80% (72 to 85) in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78% (95% CI 71 to 83), and 2285 (95% CI 1911 to 2568) cases of malaria were averted per 1000 child-years at risk among vaccinated children in the second year of follow-up. Among these participants, at 28 days following their last R21/Matrix-M vaccination, titres of malaria-specific anti-NANP antibodies correlated positively with protection against malaria in both the first year of follow-up (Spearman's ρ –0·32 95% CI –0·45 to –0·19; p=0·0001) and second year of follow-up (–0·20 –0·34 to –0·06; p=0·02).
A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria. Furthermore, the booster vaccine induced antibody concentrations that correlated with vaccine efficacy. The trial is ongoing to assess long-term follow-up of these participants and the value of further booster vaccinations.
European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), Wellcome Trust, and NIHR Oxford Biomedical Research Centre.
For the French translation of the abstract see Supplementary Materials section.
In healthy individuals, virtually all blood plasma iron is bound by transferrin. However, in several diseases and clinical conditions, hazardous non-transferrin-bound iron (NTBI) species occur. NTBI ...represents a potentially toxic iron form, being a direct cause of oxidative stress in the circulating compartment and tissue iron loading. The accumulation of these species can cause cellular damage in several organs, namely, the liver, spleen, and heart. Despite its pathophysiological relevance, the chemical nature of NTBI remains elusive. This has precluded its use as a clinical biochemical marker and the development of targeted therapies. Herein, we make a critical assessment of the current knowledge of NTBI speciation. The currently accepted hypotheses suggest that NTBI is mostly iron bound to citric acid and iron bound to serum albumin, but the chemistry of this system remains fuzzy. We explore the complex chemistry of iron complexation by citric acid and its implications towards NTBI reactivity. Further, the ability of albumin to bind iron is revised and the role of protein post-translational modifications on iron binding is discussed. The characterization of the NTBI species structure may be the starting point for the development of a standardized analytical assay, the better understanding of these species' reactivity or the identification of NTBI uptake mechanisms by different cell types, and finally, to the development of new therapies.
The cornerstone of standard treatment for patients with primary bone metastatic prostate cancer (mPCa) is androgen deprivation therapy (ADT). Retrospective studies suggest a survival benefit for ...treatment of the primary prostatic tumour in mPCa, but to date, no randomised-controlled-trials (RCTs) have been published addressing this issue.
To determine whether overall survival is prolonged by adding local treatment of the primary prostatic tumour with external beam radiation therapy (EBRT) to ADT.
The HORRAD trial is a multicentre RCT recruiting 432 patients with prostate-specific antigen (PSA) >20ng/ml and primary bone mPCa on bone scan between 2004 and 2014.
Patients were randomised to either ADT with EBRT (radiotherapy group) or ADT alone (control group).
Primary endpoint was overall survival. Secondary endpoint was time to PSA progression. Crude and adjusted analyses were applied to evaluate treatment effect.
Median PSA level was 142ng/ml and 67% of patients had more than five osseous metastases. Median follow up was 47 mo. Median overall survival was 45 mo (95% confidence interval CI, 40.4–49.6) in the radiotherapy group and 43 mo (95% CI: 32.6–53.4) in the control group (p=0.4). No significant difference was found in overall survival (hazard ratio HR: 0.90; 95% CI: 0.70–1.14; p=0.4). Median time to PSA progression in the radiotherapy group was 15 mo (95% CI: 11.8–18.2), compared with 12 mo (95% CI: 10.6–13.4) in the control group. The crude HR (0.78; 95% CI: 0.63–0.97) was statistically significant (p=0.02).
The current RCT comparing ADT to ADT with EBRT to the prostate in patients with primary bone mPCa did not show a significant difference in overall survival, although the CI cannot exclude a substantial survival benefit. Further research is needed to confirm our findings.
This study investigated the effect of adding radiation therapy to the prostate to hormonal therapy in prostate cancer patients with metastasis to the bone at diagnosis. In our patient group, additional radiotherapy did not improve overall survival. Further research is needed to confirm our findings.
Adding radiotherapy to the prostate in patients with bone metastatic prostate cancer does not improve overall survival.
In the current randomised controlled trial, there is no improvement in overall survival when comparing androgen deprivation therapy alone to androgen deprivation therapy with concurrent radiotherapy to the prostate in patients with primary bone metastatic prostate cancer.
•In 2020, COVID-19 dislodged TB as the top infectious disease cause of mortality globally.•Globally, an estimated 10.0 million people developed active TB disease in 2019, with 1.4 million TB ...deaths.•The WHO regions of South-East Asia, Africa, and the Western Pacific had the most cases of TB.•Progress in achieving the United Nations (UN) General Assembly End TB targets remains slow.•TB services need to be ramped up, and underlying drivers of TB need be addressed.
The October 2020 Global TB report reviews TB control strategies and United Nations (UN) targets set in the political declaration at the September 2018 UN General Assembly high-level meeting on TB held in New York. Progress in TB care and prevention has been very slow. In 2019, TB remained the most common cause of death from a single infectious pathogen. Globally, an estimated 10.0 million people developed TB disease in 2019, and there were an estimated 1.2 million TB deaths among HIV-negative people and an additional 208, 000 deaths among people living with HIV. Adults accounted for 88% and children for 12% of people with TB. The WHO regions of South-East Asia (44%), Africa (25%), and the Western Pacific (18%) had the most people with TB. Eight countries accounted for two thirds of the global total: India (26%), Indonesia (8.5%), China (8.4%), the Philippines (6.0%), Pakistan (5.7%), Nigeria (4.4%), Bangladesh (3.6%) and South Africa (3.6%). Only 30% of the 3.5 million five-year target for children treated for TB was met. Major advances have been development of new all oral regimens for MDRTB and new regimens for preventive therapy. In 2020, the COVID-19 pandemic dislodged TB from the top infectious disease cause of mortality globally. Notably, global TB control efforts were not on track even before the advent of the COVID-19 pandemic. Many challenges remain to improve sub-optimal TB treatment and prevention services. Tuberculosis screening and diagnostic test services need to be ramped up. The major drivers of TB remain undernutrition, poverty, diabetes, tobacco smoking, and household air pollution and these need be addressed to achieve the WHO 2035 TB care and prevention targets. National programs need to include interventions for post-tuberculosis holistic wellbeing. From first detection of COVID-19 global coordination and political will with huge financial investments have led to the development of effective vaccines against SARS-CoV2 infection. The world now needs to similarly focus on development of new vaccines for TB utilizing new technological methods.
Abstract
Aims
Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE−/− FPNwt/C326S), ...which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI).
Methods and results
Compared with normo-ferremic ApoE−/− mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE−/− FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE−/− FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation.
Conclusion
Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis.
Anemia is frequent among patients with traumatic brain injury (TBI) and is associated with an increased risk of poor outcome. The optimal hemoglobin concentration to trigger red blood cell (RBC) ...transfusion in patients with TBI is not clearly defined.
All eligible consecutive adult patients admitted to the intensive care unit (ICU) with moderate or severe TBI were randomized to a "restrictive" (hemoglobin transfusion threshold of 7 g/dL), or a "liberal" (threshold 9 g/dL) transfusion strategy. The transfusion strategy was continued for up to 14 days or until ICU discharge. The primary outcome was the mean difference in hemoglobin between groups. Secondary outcomes included transfusion requirements, intracranial pressure management, cerebral hemodynamics, length of stay, mortality and 6-month neurological outcome.
A total of 44 patients were randomized, 21 patients to the liberal group and 23 to the restrictive group. There were no baseline differences between the groups. The mean hemoglobin concentrations during the 14-day period were 8.4 ± 1.0 and 9.3 ± 1.3 (p < 0.01) in the restrictive and liberal groups, respectively. Fewer RBC units were administered in the restrictive than in the liberal group (35 vs. 66, p = 0.02). There was negative correlation (r = - 0.265, p < 0.01) between hemoglobin concentration and middle cerebral artery flow velocity as evaluated by transcranial Doppler ultrasound and the incidence of post-traumatic vasospasm was significantly lower in the liberal strategy group (4/21, 3% vs. 15/23, 65%; p < 0.01). Hospital mortality was higher in the restrictive than in the liberal group (7/23 vs. 1/21; p = 0.048) and the liberal group tended to have a better neurological status at 6 months (p = 0.06).
The trial reached feasibility criteria. The restrictive group had lower hemoglobin concentrations and received fewer RBC transfusions. Hospital mortality was lower and neurological status at 6 months favored the liberal group.
ClinicalTrials.gov, NCT02203292 . Registered on 29 July 2014.
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