Challenges of ultra large scale integration of biomedical computing systems

The NCRI Informatics Initiative is overseeing the implementation of an informatics framework for the UK cancer research community. The framework advocates an integrated multidisciplinary method of working between scientific and medical communities. Key to this process is community adoption of high quality acquisition, storage, sharing and integration of diverse data elements to improve knowledge of the causes, prevention and treatment of cancer. The integration of the complex data and meta-data used by these multiple communities is a significant challenge and there are technical, resource-based and sociological issues to be addressed. In this paper we review progress aimed at establishing the framework and outline key challenges in ultra large scale integration of biomedical computing systems

Synthesis and biological activity of alpha-L-fucosyl ceramides, analogues of the potent agonist, alpha-D-galactosyl ceramide KRN7000

Several L-fucoglycolipids are associated with diseases such as cancer, cystic fibrosis and rheumatoid arthritis. Activation of iNKT cells is known to lead to the production of cytokines that can help alleviate or exacerbate these conditions. a-Galactosyl ceramide (a-GalCer) is a known agonist of iNKT cells and it is believed that its fucosyl counterpart might have similar immunogenic properties. We herein report the synthesis of a-L-fucosyl ceramide derivatives and describe their biological evaluation. The key challenge in the synthesis of the target molecules involved the stereoselective synthesis of the a-glycosidic linkage. Of the methods examined, the per-TMS-protected glycosyl iodide donor was completely aselective,and could be scaled up to provide gram quantities of the azide precursor 11, from which a range of N-acylated a-L-fucosyl ceramides were readily obtained and evaluated for ex vivo expansion of human iNKT cells

Library Design in Combinatorial Chemistry by Monte Carlo Methods

Strategies for searching the space of variables in combinatorial chemistry experiments are presented, and a random energy model of combinatorial chemistry experiments is introduced. The search strategies, derived by analogy with the computer modeling technique of Monte Carlo, effectively search the variable space even in combinatorial chemistry experiments of modest size. Efficient implementations of the library design and redesign strategies are feasible with current experimental capabilities.Comment: 5 pages, 3 figure

Seafloor incubation experiment with deep-sea hydrothermal vent fluid reveals effect of pressure and lag time on autotrophic microbial communities

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Fortunato, C. S., Butterfield, D. A., Larson, B., Lawrence-Slavas, N., Algar, C. K., Zeigler Allen, L., Holden, J. F., Proskurowski, G., Reddington, E., Stewart, L. C., Topçuoğlu, B. D., Vallino, J. J., & Huber, J. A. Seafloor incubation experiment with deep-sea hydrothermal vent fluid reveals effect of pressure and lag time on autotrophic microbial communities. Applied and Environmental Microbiology, 87, (2021): e00078-21, https://doi.org/10.1128/AEM.00078-21Depressurization and sample processing delays may impact the outcome of shipboard microbial incubations of samples collected from the deep sea. To address this knowledge gap, we developed a remotely operated vehicle (ROV)-powered incubator instrument to carry out and compare results from in situ and shipboard RNA stable isotope probing (RNA-SIP) experiments to identify the key chemolithoautotrophic microbes and metabolisms in diffuse, low-temperature venting fluids from Axial Seamount. All the incubations showed microbial uptake of labeled bicarbonate primarily by thermophilic autotrophic Epsilonbacteraeota that oxidized hydrogen coupled with nitrate reduction. However, the in situ seafloor incubations showed higher abundances of transcripts annotated for aerobic processes, suggesting that oxygen was lost from the hydrothermal fluid samples prior to shipboard analysis. Furthermore, transcripts for thermal stress proteins such as heat shock chaperones and proteases were significantly more abundant in the shipboard incubations, suggesting that depressurization induced thermal stress in the metabolically active microbes in these incubations. Together, the results indicate that while the autotrophic microbial communities in the shipboard and seafloor experiments behaved similarly, there were distinct differences that provide new insight into the activities of natural microbial assemblages under nearly native conditions in the ocean.This work was funded by Gordon and Betty Moore Foundation grant GBMF3297; the NSF Center for Dark Energy Biosphere Investigations (C-DEBI) (OCE-0939564), contribution number 562; NOAA/PMEL, contribution number 5182; and the Joint Institute for the Study of the Atmosphere and Ocean (JISAO) under NOAA cooperative agreement NA15OAR4320063, contribution number 2020-1113. The RNA-SIP methodology used in this work was developed during cruise FK010-2013 aboard the R/V Falkor supported by the Schmidt Ocean Institute. The NOAA/PMEL supported this work with ship time in 2014 and through funding to the Earth Ocean Interactions group. NSF provided ship time for the 2015 expedition through OCE-1546695 to D.A.B. and OCE-1547004 to J.F.H

Understanding the impact of antibiotic therapies on the respiratory tract resistome: A novel pooled-template metagenomic sequencing strategy

Determining the effects of antimicrobial therapies on airway microbiology at a population-level is essential. Such analysis allows, for example, surveillance of antibiotic-induced changes in pathogen prevalence, the emergence and spread of antibiotic resistance, and the transmission of multi-resistant organisms. However, current analytical strategies for understanding these processes are limited. Culture- and PCR-based assays for specific microbes require the a priori selection of targets, while antibiotic sensitivity testing typically provides no insight into either the molecular basis of resistance, or the carriage of resistance determinants by the wider commensal microbiota. Shotgun metagenomic sequencing provides an alternative approach that allows the microbial composition of clinical samples to be described in detail, including the prevalence of resistance genes and virulence traits. While highly informative, the application of metagenomics to large patient cohorts can be prohibitively expensive. Using sputum samples from a randomised placebo-controlled trial of erythromycin in adults with bronchiectasis, we describe a novel, cost-effective strategy for screening patient cohorts for changes in resistance gene prevalence. By combining metagenomic screening of pooled DNA extracts with validatory quantitative PCR-based analysis of candidate markers in individual samples, we identify population-level changes in the relative abundance of specific macrolide resistance genes. This approach has the potential to provide an important adjunct to current analytical strategies, particularly within the context of antimicrobial clinical trials

Current opportunities to catalyze research in nutrition and cancer prevention – an interdisciplinary perspective

Cancer Research UK and Ludwig Cancer Research convened an inaugural international Cancer Prevention and Nutrition Conference in London on December 3–4, 2018. Much of the discussion focused on the need for systematic, interdisciplinary approaches to better understand the relationships of nutrition, exercise, obesity and metabolic dysfunction with cancer development. Scientists at the meeting underscored the importance of studying the temporal natural history of exposures that may cumulatively impact cancer risk later in life. A robust dialogue identified obesity as a major risk for cancer, and the food environment, especially high energy and low nutrient processed foods, as strong and prevalent risk factors for obesity. Further engagement highlighted challenges in the post-diagnostic setting, where similar opportunities to understand the complex interplay of nutrition, physical activity, and weight will inform better health outcomes. Going forward, holistic research approaches, encompassing insights from multiple disciplines and perspectives, will catalyze progress urgently needed to prevent cancer and improve public health

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

The impact of European legislative and technology measures to reduce air pollutants on air quality, human health and climate

European air quality legislation has reduced emissions of air pollutants across Europe since the 1970s, affecting air quality, human health and regional climate. We used a coupled composition-climate model to simulate the impacts of European air quality legislation and technology measures implemented between 1970 and 2010. We contrast simulations using two emission scenarios; one with actual emissions in 2010 and the other with emissions that would have occurred in 2010 in the absence of technological improvements and end-of-pipe treatment measures in the energy, industrial and road transport sectors. European emissions of sulphur dioxide, black carbon (BC) and organic carbon in 2010 are 53%, 59% and 32% lower respectively compared to emissions that would have occurred in 2010 in the absence of legislative and technology measures. These emission reductions decreased simulated European annual mean concentrations of fine particulate matter(PM2.5) by 35%, sulphate by 44%, BC by 56% and particulate organic matter by 23%. The reduction in PM2.5 concentrations is calculated to have prevented 80 000 (37 000–116 000, at 95% confidence intervals) premature deaths annually across the European Union, resulting in a perceived financial benefit to society of US$232 billion annually (1.4% of 2010 EU GDP). The reduction in aerosol concentrations due to legislative and technology measures caused a positive change in the aerosol radiative effect at the top of atmosphere, reduced atmospheric absorption and also increased the amount of solar radiation incident at the surface over Europe. We used an energy budget approximation to estimate that these changes in the radiative balance have increased European annual mean surface temperatures and precipitation by 0.45 ± 0.11 °C and by 13 ± 0.8 mm yr−1 respectively. Our results show that the implementation of European legislation and technological improvements to reduce the emission of air pollutants has improved air quality and human health over Europe, as well as having an unintended impact on the regional radiative balance and climate

Global atmospheric particle formation from CERN CLOUD measurements

Fundamental questions remain about the origin of newly formed atmospheric aerosol particles because data from laboratory measurements have been insufficient to build global models. In contrast, gas-phase chemistry models have been based on laboratory kinetics measurements for decades. Here we build a global model of aerosol formation using extensive laboratory-measured nucleation rates involving sulfuric acid, ammonia, ions and organic compounds. The simulations and a comparison with atmospheric observations show that nearly all nucleation throughout the present-day atmosphere involves ammonia or biogenic organic compounds in addition to sulfuric acid. A significant fraction of nucleation involves ions, but the relatively weak dependence on ion concentrations indicates that for the processes studied variations in cosmic ray intensity do not significantly affect climate via nucleation in the present-day atmosphere

Current opinions and recommendations of paediatric healthcare professionals - The importance of tablets:Emerging orally disintegrating versus traditional tablets

The appropriate prescribing of paediatric dosage forms is paramount in providing the desired therapeutic effect alongside successful medication adherence with the paediatric population. Often it is the opinion of the healthcare practitioner that dictates which type of dosage form would be most appropriate for the paediatric patient, with liquids being both the most commonly available and most commonly used. Orally disintegrating tablets (ODTs) are an emerging dosage form which provide many benefits over traditional dosage forms for paediatric patients, such as rapid disintegration within the oral cavity, and the reduction in the risk of choking. However the opinion and professional use of healthcare practitioners regarding ODT's is not known. This study was designed to assess the opinions of several types of healthcare professionals (n = 41) regarding ODTs, using a survey across two hospital sites. Results reaffirmed the popularity of liquids for prescribing in paediatrics, with 58.0% of participants preferring this dosage form. ODTs emerged as the second most popular dosage form (30.0%), with healthcare practitioners indicating an increasing popularity amongst patients in the hospital setting, belief with 63.0% of practitioners agreeing that many liquid formulations could be substituted with a suitable ODT. The desired properties of an ideal ODT were also identified by healthcare practitioners preferring a small, fast disintegrating tablet (90.2% and 95.1% respectively), with the taste, disintegration time and flavour being the three most important attributes identified (29.5%, 28.7% and 21.7% respectively). This study provided a pragmatic approach in assessing healthcare professional's opinions on ODTs, highlighting the ideas and thoughts of practitioners who are on the frontline of paediatric prescribing and treatment and gave an indication to their preference for ODT properties