Expanded Diversity and Phylogeny of mer Genes Broadens Mercury Resistance Paradigms and Reveals an Origin for MerA Among Thermophilic Archaea

Mercury (Hg) is a highly toxic element due to its high affinity for protein sulfhydryl groups, which upon binding, can destabilize protein structure and decrease enzyme activity. Prokaryotes have evolved enzymatic mechanisms to detoxify inorganic Hg and organic Hg (e.g., MeHg) through the activities of mercuric reductase (MerA) and organomercury lyase (MerB), respectively. Here, the taxonomic distribution and evolution of MerAB was examined in 84,032 archaeal and bacterial genomes, metagenome assembled genomes, and single-cell genomes. Homologs of MerA and MerB were identified in 7.8 and 2.1% percent of genomes, respectively. MerA was identified in the genomes of 10 archaeal and 28 bacterial phyla previously unknown to code for this functionality. Likewise, MerB was identified in 2 archaeal and 11 bacterial phyla previously unknown to encode this functionality. Surprisingly, homologs of MerB were identified in a number of genomes (∼50% of all MerB-encoding genomes) that did not encode MerA, suggesting alternative mechanisms to detoxify Hg(II) once it is generated in the cytoplasm. Phylogenetic reconstruction of MerA place its origin in thermophilic Thermoprotei (Crenarchaeota), consistent with high levels of Hg(II) in geothermal environments, the natural habitat of this archaeal class. MerB appears to have been recruited to the mer operon relatively recently and likely among a mesophilic ancestor of Euryarchaeota and Thaumarchaeota. This is consistent with the functional dependence of MerB on MerA and the widespread distribution of mesophilic microorganisms that methylate Hg(II) at lower temperature. Collectively, these results expand the taxonomic and ecological distribution of mer-encoded functionalities, and suggest that selection for Hg(II) and MeHg detoxification is dependent not only on the availability and type of mercury compounds in the environment but also the physiological potential of the microbes who inhabit these environments. The expanded diversity and environmental distribution of MerAB identify new targets to prioritize for future research

Metagenomic investigation of the geologically unique Hellenic Volcanic Arc reveals a distinctive ecosystem with unexpected physiology

Hydrothermal vents represent a deep, hot, aphotic biosphere where chemosynthetic primary producers, fuelled by chemicals from Earth\u27s subsurface, form the basis of life. In this study, we examined microbial mats from two distinct volcanic sites within the Hellenic Volcanic Arc (HVA). The HVA is geologically and ecologically unique, with reported emissions of CO2‐saturated fluids at temperatures up to 220°C and a notable absence of macrofauna. Metagenomic data reveals highly complex prokaryotic communities composed of chemolithoautotrophs, some methanotrophs, and to our surprise, heterotrophs capable of anaerobic degradation of aromatic hydrocarbons. Our data suggest that aromatic hydrocarbons may indeed be a significant source of carbon in these sites, and instigate additional research into the nature and origin of these compounds in the HVA. Novel physiology was assigned to several uncultured prokaryotic lineages; most notably, a SAR406 representative is attributed with a role in anaerobic hydrocarbon degradation. This dataset, the largest to date from submarine volcanic ecosystems, constitutes a significant resource of novel genes and pathways with potential biotechnological applications

Simulation-Based Estimates of Effectiveness and Cost-Effectiveness of Smoking Cessation in Patients with Chronic Obstructive Pulmonary Disease

International audienceBACKGROUND: The medico-economic impact of smoking cessation considering a smoking patient with chronic obstructive pulmonary disease (COPD) is poorly documented. OBJECTIVE: Here, considering a COPD smoking patient, the specific burden of continuous smoking was estimated, as well as the effectiveness and the cost-effectiveness of smoking cessation. METHODS: A multi-state Markov model adopting society's perspective was developed. Simulated cohorts of English COPD patients who are active smokers (all severity stages combined or patients with the same initial severity stage) were compared to identical cohorts of patients who quit smoking at cohort initialization. Life expectancy, quality adjusted life-years (QALY), disease-related costs, and incremental cost-effectiveness ratio (ICER: £/QALY) were estimated, considering smoking cessation programs with various possible scenarios of success rates and costs. Sensitivity analyses included the variation of model key parameters. PRINCIPAL FINDINGS: At the horizon of a smoking COPD patient's remaining lifetime, smoking cessation at cohort intitialization, relapses being allowed as observed in practice, would result in gains (mean) of 1.27 life-years and 0.68 QALY, and induce savings of -1824 £/patient in the disease-related costs. The corresponding ICER was -2686 £/QALY. Smoking cessation resulted in 0.72, 0.69, 0.64 and 0.42 QALY respectively gained per mild, moderate, severe, and very severe COPD patient, but was nevertheless cost-effective for mild to severe COPD patients in most scenarios, even when hypothesizing expensive smoking cessation intervention programmes associated with low success rates. Considering a ten-year time horizon, the burden of continuous smoking in English COPD patients was estimated to cost a total of 1657 M£ while 452516 QALY would be simultaneously lost. CONCLUSIONS: The study results are a useful support for the setting of smoking cessation programmes specifically targeted to COPD patients

Review of MRI positioning devices for guiding focused ultrasound systems

Background: This article contains a review of positioning devices that are currently used in the area of magnetic resonance imaging (MRI) guided focused ultrasound surgery (MRgFUS). Methods: The paper includes an extensive review of literature published since the first prototype system was invented in 1991. Results: The technology has grown into a fast developing area with application to any organ accessible to ultrasound. The initial design operated using hydraulic principles, while the latest technology incorporates piezoelectric motors. Although, in the beginning there were fears regarding MRI safety, during recent years, the deployment of MR-safe positioning devices in FUS has become routine. Many of these positioning devices are now undergoing testing in clinical trials. Conclusion: Existing MRgFUS systems have been utilized mostly in oncology (fibroids, brain, liver, kidney, bone, pancreas, eye, thyroid, and prostate). It is anticipated that, in the near future, there will be a positioning device for every organ that is accessible by focused ultrasound

Removing atherosclerotic plaque created using high cholesterol diet in rabbit using ultrasound

Background: The aim of the proposed study was to conduct a feasibility study using a flat rectangular (3 × 10 mm2) transducer operating at 5 MHz for removing atherosclerotic plaque in an in vivo model. The proposed method can be used in the future for treating atherosclerotic plaques in humans. Methods and results: The plaque in the rabbits was created using high cholesterol diet for 4 months. The amount of plaque removed was studied as a function of intensity, with a fixed pulse repetition frequency (PRF), and duty factor (DF). Conclusions: The amount of plaque removed is directly related to the acoustic intensity. It was found that the presence of bubbles accelerates the removal of plaque. In order to ensure that pure mechanical mode ultrasound was used, the intensity used does not produce temperatures that exceed 1°C

MRI-compatible positioning device for guiding a focused ultrasound system for transrectal treatment of prostate cancer

Background   : High-intensity focused ultrasound (HIFU) is a promising treatment method for many common cancers, including prostate cancer. Magnetic resonance image (MRI) guidance of HIFU permits targeting and monitoring of therapy. A prototype MRI-compatible positioning device that navigates a HIFU transducer was designed, fabricated and tested. Materials and methods   : The positioning device has two PC-controlled and one manually driven stage that allow endorectal access to the prostate. The positioning device was constructed using a 3-D rapid prototype manufacturing device. Software was developed that controls the motion of the positioning device and enables activation of a HIFU transducer. In vitro testing of the system was performed in a 1.5T MRI scanner using ex vivo turkey tissue. Optical encoders were employed to enhance the accuracy of this positioning device. Result   : The positioning device was successfully tested for MRI compatibility. The movement error of the positioning device is approximately 20 μm. The robot has the ability to accurately move the transducer for creation of discrete and overlapping lesions. Conclusion   : An MRI-compatible HIFU positioning system was developed that has the ability to create thermal lesions with MRI guidance for endorectal treatment of prostate cancer

The Enhancing Effect of Focused Ultrasound on TNK-Tissue Plasminogen Activator-Induced Thrombolysis Using an In Vitro Circulating Flow Model

Background The limited efficacy of thrombolytic therapy in patients with ischemic stroke has created the need to use focused ultrasound (FUS) energy as a way to enhance thrombolysis efficacy (sonothrombolysis). Using an in vitro circulating flow model, we evaluated the role of physical parameters on tenecteplase (TNK-tPA)-mediated thrombolysis. Materials and Methods Fully retracted porcine blood clots were used for the proposed experimental study. To provide a more realistic clinical environment of stroke, the study was conducted under realistic flow conditions and TNK-tPA concentrations. Two spherically FUS transducers (4-cm diameter), focusing at 10 cm and operating at .6 and 1.05 MHz, respectively, were used. Pulsed ultrasound protocols that maintained a localized temperature elevation at the focus of 1°C were applied. Thrombolysis efficacy was measured in milligram of mass clot removed. Results The effect of physical parameters such as temperature, FUS frequency, acoustic power (AP), FUS energy, and microbubble (MB) administration on thrombolysis efficacy was examined. Conclusions Study findings established that higher FUS frequencies (1 MHz) are associated with enhanced thrombolysis compared to lower FUS frequencies (.6 MHz). Furthermore, an increase in the linear relationship between AP and thrombolysis efficacy was exhibited. Also, the outcome of the study showed that the combination of 1-MHz FUS pulses with MBs strongly enhanced the enzymatic thrombolytic efficacy of TNK-tPA, because with 30 minutes of treatment, 1050 mg of clot was removed through nonthermal mechanisms. Taking into consideration that stroke is time dependent, this thrombolytic rate should be sufficient for timely recanalization of the occluded cerebral artery

MRI-guided coupling for a focused ultrasound system using a top-to-bottom propagation

Background: A novel magnetic resonance imaging (MRI)-conditional coupling system was developed that accommodates a focused ultrasound (FUS) transducer. With this coupling system, the transducer can access targets from top to bottom. The intended clinical application is treatment of fibroids using FUS with the patient placed in supine position. Methods: The coupling system was manufactured using a rapid prototyping device using acrylonitrile butadiene styrene (ABS) plastic. Coupling to a gel phantom was achieved using a water bag filled with degassed water. The FUS transducer was immersed in the water bag. Results: The coupling system was successfully tested for MRI compatibility using fast-gradient pulse sequences in a gel phantom. The robotic system with its new coupling system was evaluated for its functionality for creating discrete and multiple (overlapping) lesions in the gel phantom. Conclusions: An MRI-conditional FUS coupling system integrated with an existing robotic system was developed that has the potential to create thermal lesions in targets using a top-to-bottom approach. This system has the potential to treat fibroid tumors with the patient lying in supine position

MRI-guided focused ultrasound robotic system for the treatment of bone cancer

Background: A novel MRI-conditional robot was developed that navigates a focused ultrasound (FUS) transducer. With this robotic system the transducer can access bones. The intended application is pain palliation from bone cancer using thermal ablation using FUS. Methods: The robotic system has four computer-controlled axes (three linear and one angular). The robotic system was manufactured using a digital manufacturing 3D printer, using acrylonitrile butadiene styrene (ABS) plastic. MRI-conditional optical encoders were used to accurately control the robotic system. Results: The robotic system was successfully tested for MRI safety and compatibility, using fast-gradient pulse sequences and a liquid phantom. The robotic system has been tested for its functionality for creating discrete and multiple (overlapping) lesions in a gel phantom. Conclusions: An MRI-conditional FUS robotic system was developed that has the potential to create thermal lesions with the intention of treating bone cancer for the purpose of pain palliation