Novel resistance functions uncovered using functional metagenomic investigations of resistance reservoirs

Rates of infection with antibiotic-resistant bacteria have increased precipitously over the past several decades, with far-reaching healthcare and societal costs. Recent evidence has established a link between antibiotic resistance genes in human pathogens and those found in non-pathogenic, commensal, and environmental organisms, prompting deeper investigation of natural and human-associated reservoirs of antibiotic resistance. Functional metagenomic selections, in which shotgun-cloned DNA fragments are selected for their ability to confer survival to an indicator host, have been increasingly applied to the characterization of many antibiotic resistance reservoirs. These experiments have demonstrated that antibiotic resistance genes are highly diverse and widely distributed, many times bearing little to no similarity to known sequences. Through unbiased selections for survival to antibiotic exposure, functional metagenomics can improve annotations by reducing the discovery of false-positive resistance and by allowing for the identification of previously unrecognizable resistance genes. In this review, we summarize the novel resistance functions uncovered using functional metagenomic investigations of natural and human-impacted resistance reservoirs. Examples of novel antibiotic resistance genes include those highly divergent from known sequences, those for which sequence is entirely unable to predict resistance function, bifunctional resistance genes, and those with unconventional, atypical resistance mechanisms. Overcoming antibiotic resistance in the clinic will require a better understanding of existing resistance reservoirs and the dissemination networks that govern horizontal gene exchange, informing best practices to limit the spread of resistance-conferring genes to human pathogens

Characterization of wild and captive baboon gut microbiota and their antibiotic resistomes

Antibiotic exposure results in acute and persistent shifts in the composition and function of microbial communities associated with vertebrate hosts. However, little is known about the state of these communities in the era before the widespread introduction of antibiotics into clinical and agricultural practice. We characterized the fecal microbiota and antibiotic resistomes of wild and captive baboon populations to understand the effect of human exposure and to understand how the primate microbiota may have been altered during the antibiotic era. We used culture-independent and bioinformatics methods to identify functional resistance genes in the guts of wild and captive baboons and show that exposure to humans is associated with changes in microbiota composition and resistome expansion compared to wild baboon groups. Our results suggest that captivity and lifestyle changes associated with human contact can lead to marked changes in the ecology of primate gut communities.Environmental microbes have harbored the capacity for antibiotic production for millions of years, spanning the evolution of humans and other vertebrates. However, the industrial-scale use of antibiotics in clinical and agricultural practice over the past century has led to a substantial increase in exposure of these agents to human and environmental microbiota. This perturbation is predicted to alter the ecology of microbial communities and to promote the evolution and transfer of antibiotic resistance (AR) genes. We studied wild and captive baboon populations to understand the effects of exposure to humans and human activities (e.g., antibiotic therapy) on the composition of the primate fecal microbiota and the antibiotic-resistant genes that it collectively harbors (the “resistome”). Using a culture-independent metagenomic approach, we identified functional antibiotic resistance genes in the gut microbiota of wild and captive baboon groups and saw marked variation in microbiota architecture and resistomes across habitats and lifeways. Our results support the view that antibiotic resistance is an ancient feature of gut microbial communities and that sharing habitats with humans may have important effects on the structure and function of the primate microbiota

Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence

On the requirements to establish a European radiological preparedness for malicious airborne dispersion scenarios

European computerised decision support systems are currently targeted for large accidental atmospheric contaminant releases from nuclear installations. To make these systems applicable also for malicious dispersion events, such as ‘dirty bomb’ blasts, a series of modifications and extensions are necessary. Also European decision support handbooks need supplementary sections to cover the features of these types of scenarios. An overview is given of the requirements

Transcript of The Dory Derby Accident

This story is an excerpt from a longer interview that was collected as part of the Launching through the Surf: The Dory Fleet of Pacific City project. In this story, Don Grotjohn recounts an accident that occurred during a Dory Derby competition

The Distinct Metamorphic Stages and Structural Styles of the 1.94–1.86 Ga Snowbird Orogen, Northwest Territories, Canada

Palaeoproterozoic orogenesis within the Archean southeastern Rae craton is related to the initial amalgamation of Laurentia. Characterizing the accompanying tectonic processes during this time has been complicated due to polymetamorphism, which results in the obscuring of the age record of the terranes involved. To improve the knowledge of the tectonic evolution of the South Rae Craton, petrologic and structural analyses are applied in conjunction with in situ trace element chemistry, inclusion barometry, U–Pb monazite and titanite, and Lu–Hf garnet chronology. The data robustly constrain Palaeoproterozoic pressure–temperature–time paths of major deformational events along the southeastern Rae craton margin. D1 occurred between 1.94 and 1.93 Ga in the Dodge-Snowbird domain, which included prograde burial of metasedimentary rocks, deposited at 2.2–2.0 Ga, and the development of migmatitic layering and east-southeast trending folds (S1, F1). Peak metamorphism is recorded in metasedimentary units at c. 1.93 Ga when rocks reached conditions of 9.0–10.5 kbar and 810–830°C. Within the Dodge-Snowbird domain, D2 imparted north-northeast trending open folds and associated axial planar cleavage (S2, F2) between 1.93 and 1.90 Ga during east-west compression that appears to have been synchronous with cooling and exhumation. Later D2 deformation, localized within the Wholdaia Lake shear zone (WLsz; ST1), developed in the footwall of this thrust-sense structure at 1,873 ± 5 Ma at conditions of 9.5–11.0 kbar and 820–850°C. The hangingwall Dodge-Snowbird domain had already cooled to below 300°C by then, indicating a significant structural and metamorphic break across the domain\u27s western boundary. A new phase of unroofing (D3) involved pervasive amphibolite- to greenschist facies extensional shearing (ST2) within the WLsz, which overprinted ST1 foliations between 1.87 and 1.86 Ga. Continued greenschist facies shearing younger than 1.86 Ga likely ended by c. 1.83 Ga when lamprophyre dykes cut the structure, which was followed by cooling until c. 1.80 Ga. This work highlights the utility and application of multiple chronometers (zircon, monazite, titanite, garnet) along with structural and petrologic analysis that together can resolve precise orogenic cycles in polymetamorphic terranes that may otherwise be undetected. The time-resolved P–T–D histories derived here enable more robust interpretations regarding the nature and evolution of 1.9 Ga tectonism along the southeast Rae craton margin, which may be used to refine models for Laurentian terrane amalgamation

Analytical Challenges and Metrological Approaches to Ensuring Dietary Supplement Quality: International Perspectives

The increased utilization of metrology resources and expanded application of its’ approaches in the development of internationally agreed upon measurements can lay the basis for regulatory harmonization, support reproducible research, and advance scientific understanding, especially of dietary supplements and herbal medicines. Yet, metrology is often underappreciated and underutilized in dealing with the many challenges presented by these chemically complex preparations. This article discusses the utility of applying rigorous analytical techniques and adopting metrological principles more widely in studying dietary supplement products and ingredients, particularly medicinal plants and other botanicals. An assessment of current and emerging dietary supplement characterization methods is provided, including targeted and non-targeted techniques, as well as data analysis and evaluation approaches, with a focus on chemometrics, toxicity, dosage form performance, and data management. Quality assessment, statistical methods, and optimized methods for data management are also discussed. Case studies provide examples of applying metrological principles in thorough analytical characterization of supplement composition to clarify their health effects. A new frontier for metrology in dietary supplement science is described, including opportunities to improve methods for analysis and data management, development of relevant standards and good practices, and communication of these developments to researchers and analysts, as well as to regulatory and policy decision makers in the public and private sectors. The promotion of closer interactions between analytical, clinical, and pharmaceutical scientists who are involved in research and product development with metrologists who develop standards and methodological guidelines is critical to advance research on dietary supplement characterization and health effects

Nutrient composition of selected traditional United States Northern Plains Native American plant foods

Ten wild plants (cattail broad leaf shoots, chokecherries, beaked hazelnuts, lambsquarters, plains prickly pear, prairie turnips, stinging nettles, wild plums, raspberries, and rose hips) from three Native American reservations in North Dakota were analyzed to expand composition information of traditional foraged plants. Proximates, dietary fiber (DF), vitamins, minerals, carotenoids, and folate vitamers were assayed using standard methods and reference materials. Per serving, all were rich in Mn (100–2808 mg). Several provided \u3e10% DRI of Fe (cattail shoots, steamed lambsquarters, and prairie turnips), Ca (steamed lambsquarters, prickly pear, and prairie turnips), Mg (cattail shoots, lambsquarters, prickly pear, and prairie turnips), vitamins B6 (chokecherries, steamed lambsquarters, broiled prickly pear, and prairie turnips), C (raw prickly pear, plums, raspberries, rose hips (426 mg/100 g), and K (cattail shoots, chokecherries, lambsquarters, plums, rose hips, and stinging nettles). DF was \u3e10 g/serving in chokecherries, prairie turnips, plums and raspberries. Rose hips, plums, lambsquarters, and stinging nettles were carotenoid-rich (total, 3.2–11.7 mg/100 g; b-carotene, 1.2–2.4 mg/100 g; lutein/zeaxan- thin, 0.9–6.2 mg/100 g) and lycopene (rose hips only, 6.8 mg/100 g). Folate (primarily 5-methylte- trahydrofolate) was highest in raw lambsquarters (97.5 mg/100 g) and notable in cattail shoots, raw prairie turnips, and blanched stinging nettles (10.8, 11.5, and 24.0 mg/100 g, respectively). Results, provided to collaborating tribes and available in the National Nutrient Database of the United States Department of Agriculture (USDA) (www.ars.usda.gov/nutrientdata), support reintroduction or increased consumption of foraged plants

Reliability and validity of the adapted Greek version of scoliosis research society – 22 (SRS-22) questionnaire

<p>Abstract</p> <p>Background</p> <p>The SRS-22 is a valid instrument for the assessment of the health related quality of life of patients with Idiopathic scoliosis. The SRS-22 questionnaire was developed in USA and has been widely used in the English speaking countries. Recently it has been translated and validated in many other languages. The purpose of this study is to evaluate the reliability and validity of the adapted Greek version of the refined Scoliosis Research Society-22 Questionnaire.</p> <p>Methods</p> <p>Following the steps of cross – cultural adaptation the adapted Greek version of the SRS-22 questionnaire and a validated Greek version of the SF-36 questionnaire were mailed to 68 patients treated surgically for Idiopathic Scoliosis. 51 out of the 68 patients returned the 1^stset of questionnaires, while a second set was emailed to 30 randomly selected patients of the first time responders. 20 out of the 30 patients returned the 2^ndset. The mean age at the time of operation was16,2 years and the mean age at the time of evaluation was 21,2 years. Descriptive statistics for content analysis were calculated. Reliability assessment was determined by estimating Cronbach's α and intraclass correlation coefficient (ICC) respectively. Concurrent validity was evaluated by comparing SRS-22 domains with relevant domains in the SF-36 questionnaire using Pearson's Correlation Coefficient (r).</p> <p>Results</p> <p>The calculated Cronbach's α of internal consistency for three of the corresponding domains (pain 0.85; mental health 0.87; self image 0.83) were very satisfactory and for two domains (function/activity 0.72 and satisfaction 0.67) were good. The ICC of all domains of SRS-22 questionnaire was high (ICC>0.70), demonstrating very satisfactory or excellent test/retest reproducibility. Considering concurrent validity all correlations were found to be statistically significant at the 0.01 level among related domains and generally demonstrated high correlation coefficient.</p> <p>Conclusion</p> <p>The adapted Greek version of the SRS-22 questionnaire is valid and reliable and can be used for the assessment of the outcome of the treatment of the Greek speaking patients with idiopathic scoliosis.</p