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The longstanding ‘polyelectrolyte theory of the gene’ proposes that a multiply charged backbone is the universal signature of all genetic polymer systems that support life. Now, the first tenable challenge to this theory has been mounted, through the successful engineering of enzymes which can synthesize and reverse-transcribe from an artificial, uncharged nucleic acid analogue.

SummaryHealth and social care face growing and conflicting pressures: mounting complex needs of an ageing population, restricted funding and a workforce recruitment and retention crisis. In response, in the UK the NHS Long Term Plan promises increased investment and an emphasis on better ‘integrated’ care. We describe key aspects of integration that need addressing.Declaration of interestD.K.T. and S.S.S. are on the editorial board of the British Journal of Psychiatry and executives of the Academic Faculty at the Royal College of Psychiatrists. A.J.B.J., H.P. and Z.M. have roles at the Royal College of Psychiatrists that include evaluation of integrated care systems. A.J.B.J. is married to Dr Sarah Wollaston, Member of Parliament for Totnes and Chair of the Health Select Committee.

Although recent studies have shown that electricity systems with shares of wind and solar above 80% can be affordable, economists have raised concerns about market integration. Correlated generation from variable renewable sources depresses market prices, which can cause wind and solar to cannibalise their own revenues and prevent them from covering their costs from the market. This cannibalisation appears to set limits on the integration of wind and solar, and thus to contradict studies that show that high shares are cost effective. Here we show from theory and with simulation examples how market incentives interact with prices, revenue and costs for renewable electricity systems. The decline in average revenue seen in some recent literature is due to an implicit policy assumption that technologies are forced into the system, whether it be with subsidies or quotas. This decline is mathematically guaranteed regardless of whether the subsidised technology is variable or not. If instead the driving policy is a carbon dioxide cap or tax, wind and solar shares can rise without cannibalising their own market revenue, even at penetrations of wind and solar above 80%. The strong dependence of market value on the policy regime means that market value needs to be used with caution as a measure of market integration. Declining market value is not necessarily a sign of integration problems, but rather a result of policy choices., 24 pages, 29 figures; accepted to Energy Economics

BACKGROUND: Frequent exacerbations are an important cause of morbidity in patients with severe asthma.OBJECTIVE: Our aim was to identify factors associated with frequent exacerbations in a large well-characterized severe asthma population and determine whether factors differed in patients treated with and without maintenance oral corticosteroids (OCS).METHODS: Adults with severe asthma from specialized asthma centers across the United Kingdom were recruited to the UK Severe Asthma Registry. Demography, comorbidities and physiological measurements were collected. We conducted univariable and multivariable logistic regression analyses to identify factors associated with frequent exacerbations, defined as 3 or more exacerbations treated with high-dose systemic corticosteroids in the past year.RESULTS: Of 1,592 patients with severe asthma from the UK Severe Asthma Registry, 1,137 (71%) were frequent exacerbators and 833 (52%) were on maintenance OCS. The frequent exacerbators were more likely to be ex-smokers, have gastroesophageal reflux disease, higher Asthma Control Questionnaire-6 (ACQ-6) score, and higher blood eosinophilia. Multivariable regression analyses showed ACQ-6 score greater than 1.5 (odds ratio [OR] 4.25; P < .001), past smoking history (OR 1.55; P = .024), and fractional exhaled nitric oxide greater than 50ppb (OR 1.54; P = .044) were independently associated with frequent exacerbations. Past smoking history correlated with frequent exacerbations only in patients on maintenance OCS (OR 2.25; P = .004), whereas ACQ-6 score greater than 1.5 was independently associated with frequent exacerbations in those treated with and without maintenance OCS (OR 2.74; P = .017 and OR 6.42; P < .001, respectively).CONCLUSIONS: Several factors were associated with frequent exacerbations in a large UK severe asthma registry population. High ACQ-6 score had the strongest association with frequent exacerbations irrespective of maintenance OCS status.

To reach ambitious European CO$_2$ emission reduction targets, most scenarios of future European electricity systems rely on large shares of wind and solar photovoltaic power generation. We interpolate between two concepts for balancing the variability of these renewable sources: balancing at continental scales using the transmission grid and balancing locally with storage. This interpolation is done by systematically restricting transmission capacities from the optimum level to zero. We run techno-economic cost optimizations for the capacity investment and dispatch of wind, solar, hydroelectricity, natural gas power generation and transmission, as well as storage options such as pumped-hydro, battery, and hydrogen storage. The simulations assume a 95% CO$_2$ emission reduction compared to 1990, and are run over a full historical year of weather and electricity demand for 30 European countries. In the cost-optimal system with high levels of transmission expansion, energy generation is dominated by wind (65%) and hydro (15%), with average system costs comparable to today's system. Restricting transmission shifts the balance in favour of solar and storage, driving up costs by a third. As the restriction is relaxed, 85% of the cost benefits of the optimal grid expansion can be captured already with only 44% of the transmission volume., 15 pages, 10 figures, accepted by Energy

The mechanism by which 5-formylcytosine (fC) is recognised by enzymes involved in epigenetic modification and reading of DNA is not known, and recently an unusual DNA structure (F-DNA) was proposed as the basis for enzyme recognition of clusters of fC. We used NMR and X-ray crystallography to compare several modified DNA duplexes with the unmodified analogues and show that in the crystal state they all belong to the A-family, but in solution they are all members of the B-family. Contrary to the previous study, we find that 5-formylcytosine does not significantly affect the structure of DNA, though there are modest local differences at the modification sites. Hence, global conformation changes are unlikely to account for the recognition of this modified base, and our structural data favour a mechanism that operates at base-pair resolution for the recognition of 5-formylcytosine by epigenome-modifying enzymes.

This work describes a new class of gold nanoparticle-based liquid-phase colorimetric assay (GNP-LPCA) termed as two dimensional (2D) GNP-LPCA. Its utility is demonstrated with the development of an aptamer-based 2D GNP-LPCA for simple, low-cost, sensitive, specific, and quantitative detection of adenosine as a model analyte in buffer and human serum samples with the naked eye.

We demonstrate the use of arrays of Teflon AF nanopillars for directing the assembly of single rectangular DNA origami scaffolds, functionalized with covalently linked fluorophore molecules, in defined positions on patterned surfaces. This is achieved by introducing Teflon AF as a non-amplified negative e-beam resist, which is exposed and chemically developed to generate arrays of hydrophobic nanopillars with a minimum feature size 40 nm. Binding of the DNA origami to the pillars is facilitated by porphyrin moieties that act as hydrophobic molecular anchors, reaching 80% coverage of the available sites. This combination of top-down lithography and bottom-up self assembly is an efficient means of fabricating hierarchically structured bio-nanointerfaces in which the positioning of functional units is precisely controlled on the molecular scale inside the DNA assembly, and on the nanoscale at pre-designed locations on the substrate.

Background Chronic obstructive pulmonary disease (COPD) is the second-leading cause of death in the United Kingdom and accounts for 1.7% of bed days in acute hospitals. An estimated two-third of patients with COPD remain undiagnosed. Objective Modern Innovative Solutions in Improving Outcomes in Chronic Obstructive Pulmonary Disease (MISSION COPD) aimed to proactively identify patients from primary care who were undiagnosed or had uncontrolled COPD and to provide a comprehensive integrated multidisciplinary clinic to address the needs of this complex group for improving diagnosis, personalizing therapy, and empowering patients to self-manage their condition. Methods This clinic was led by a respiratory specialist team from Portsmouth Hospitals NHS Trust working with five primary care surgeries in Wessex. A total of 108 patients were reviewed, with 98 patients consenting to provide additional data for research. Diagnoses were changed in 14 patients, and 32 new diagnoses were made. Results Reductions were seen across all aspects of unscheduled care as compared to the prior 12 months, including in emergency general practitioner visits (3.37-0.79 visits per patient, P Conclusions This pilot demonstrates that the MISSION model may be an effective way to provide comprehensive gold-standard care that is valued by patients and to promote integration across sectors.

Background: The aim of this study was to evaluate the role of serum and sputum YKL-40 measurements as biomarkers in severe asthma phenotypes. Material and Methods: 243 adult subjects (48.9±14.2 years) from the Wessex Severe Asthma Cohort (WSAC), spirometry according to BTS/SIGN guidelines; sputum induction with inhaled hypertonic saline in 99 subjects. Serum and sputum levels of YKL-40 were determined by ELISA (Quidel corporation, San Diego, California, USA). Statistical analysis used SPSS (version 22) ; statistical significance at p Results: We observed correlation between markers of airway neutrophilia and sputum YKL-40 levels. Sputum YKL-40 was strongly correlated with both sputum MPO (Spearman’s rho 0.733; p≤0.001) and sputum absolute neutrophil count (Spearman’s rho 0.663; p≤0.001), but not serum levels of YKL-40. Sputum (p=0,025), but not serum(p=0,753), YKL-40 levels were also significantly different across the inflammatory cell subtypes in sputum. When comparing YKL-40 levels in serum and sputum between SARP clusters, serum ( p=0.002), but not sputum (p=0.081) YKL-40 levels were significantly different between phenotypes (namely differentiating clusters 1 and 2 from 3, 4 and 5). Conclusions: It is thus apparent that serum YKL-40 and sputum YKL-40 are reflecting different processes within the airways. Serum YKL-40 might reflect a more systemic inflammation opposed to sputum YKL-40 that might reflect more local: airway inflammation.

We report the design and optimisation of novel oligonucleotide substrates for a sensitive fluorescence assay for high-throughput screening and functional studies of the DNA repair enzyme, XPF-ERCC1, with a view to accelerating inhibitor and drug discovery.

Governments across the world are planning to increase the share of renewables in their energy systems. The siting of new wind and solar power plants requires close coordination with grid planning, and hence co-optimization of investment in generation and transmission expansion in spatially and temporally resolved models is an indispensable but complex problem. Particularly considerations of transmission expansion planning (TEP) add to the problem's complexity. Even if the power flow equations are linearized, the optimization problem is still bilinear and mixed-integer due to the dependence of line expansion on line impedance and a discrete set of line expansion options. While it is possible to linearize this mixed-integer nonlinear program (MINLP) by applying a big-M disjunctive relaxation, the resulting MILP is still hard to solve using state-of-the-art solvers for large-scale energy system models. In this paper we therefore develop heuristics to incorporate integer transmission expansion and responsive line impedances in energy system models, while retaining the lower computational effort of continuous linear programming (LP) by applying sequential linear programming (SLP) techniques, relaxation and discretization approaches. We benchmark their performance against the results of the exact formulation for a policy-relevant case study of the German transmission system in terms of their speed-up in computation time, deviation from optimal total system cost, and similarity of line expansion. Using heuristics we reduce computation times of joint generation and transmission optimisation by 82% with a maximal total system cost deviation of only 1.5%. The heuristics closely mirror optimal integer line investment of the exact MINLP with considerable time savings for policy-relevant low-carbon energy system optimization models., 8 pages, 7 figures, conference, EEM 2019

H3K4me3 is a near-universal histone modification found predominantly at the 5’ region of genes, with a well-documented association with gene activity. H3K4me3 has been ascribed roles as both an instructor of gene expression and also a downstream consequence of expression, yet neither has been convincingly proven on a genome-wide scale. Here we test these relationships using a combination of bioinformatics, modelling and experimental data from budding yeast in which the levels of H3K4me3 have been massively ablated. We find that loss of H3K4me3 has no effect on the levels of nascent transcription or transcript in the population. Moreover, we observe no change in the rates of transcription initiation, elongation, mRNA export or turnover, or in protein levels, or cell-to-cell variation of mRNA. Loss of H3K4me3 also has no effect on the large changes in gene expression patterns that follow galactose induction. Conversely, loss of RNA polymerase from the nucleus has no effect on the pattern of H3K4me3 deposition and little effect on its levels, despite much larger changes to other chromatin features. Furthermore, large genome-wide changes in transcription, both in response to environmental stress and during metabolic cycling, are not accompanied by corresponding changes in H3K4me3. Thus, despite the correlation between H3K4me3 and gene activity, neither appear to be necessary to maintain levels of the other, nor to influence their changes in response to environmental stimuli. When we compare gene classes with very different levels of H3K4me3 but highly similar transcription levels we find that H3K4me3-marked genes are those whose expression is unresponsive to environmental changes, and that their histones are less acetylated and dynamically turned-over. Constitutive genes are generally well-expressed, which may alone explain the correlation between H3K4me3 and gene expression, while the biological role of H3K4me3 may have more to do with this distinction in gene class.

Antisense oligonucleotides (ASOs) are becoming important drugs for hard to treat diseases. Modifications to their DNA backbones are essential to inhibit degradation in vivo, but they can reduce binding affinity to RNA targets. To address this problem we have combined the enzymatic resistance of carbamate (CBM) DNA backbone analogues with the thermodynamic stability conferred by locked nucleic acid sugars (LNA). Using a dinucleotide phosphoramidite strategy and automated solid phase synthesis, we have synthesised a set of oligonucleotides modified with multiple LNA-CBM units. The LNA sugars restore binding affinity to RNA targets, and in this respect LNA position with respect to the CBM linkage is important. Oligonucleotides containing carbamate flanked on its 5'and 3'-sides by LNA form stable duplexes with RNA and unstable duplexes with DNA, which is desirable for antisense applications. Carbamate-LNA modified oligonucleotides also show increased stability in the presence of snake venom and foetal bovine serum compared to LNA or CBM backbones alone.

DNA-mediated self-assembly of nanoparticles has been of great interest because it enables access to nanoparticle superstructures that cannot be synthesized otherwise. However, the programmability of higher order nanoparticle structures can be easily lost under DNA denaturing conditions. Here, we demonstrate that light can be employed as an external stimulus to master the stability of nanoparticle superlattices (SLs) via the promotion of a reversible photoligation of DNA in SLs. The oligonucleotides attached to the nanoparticles are encoded to ligate using 365 nm light, effectively locking the SLs and rendering them stable under DNA denaturing conditions. The reversible process of unlocking these structures is possible by irradiation with light at 315 nm, recovering the structures to their natural state. Our work inspires an alternative research direction toward postassembly manipulation of nanoparticle superstructures using external stimuli as a tool to enrich the library of additional material forms and their application in different media and environments.

BACKGROUND: Hypereosinophilic syndrome is a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils. METHODS: In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome and an absolute eosinophil count of at least 1000 cells per cubic millimeter; all the patients were receiving stable therapy (drugs or dietary changes) for this disease. This regimen was followed by an open-label phase, during which the patient’s background therapy could be tapered as tolerated, and an extension phase. The primary end point of the randomized phase was a reduction of at least 50% in the absolute eosinophil count at week 12. RESULTS: During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P = 0.02). During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with benralizumab therapy. The most common drug-related adverse events, headache and an elevated lactate dehydrogenase level, occurred in 32% of the patients after the first dose of benralizumab and resolved within 48 hours in all patients. Other adverse events occurred with similar frequency in the two groups. Of the many potential predictors of response that were examined, only clinical disease subtype appeared to be associated with the initial response or relapse. CONCLUSIONS: In this small phase 2 trial, patients with PDGFRA-negative hypereosinophilic syndrome who received benralizumab for 12 weeks had lower absolute eosinophil counts than those who received placebo. During the open-label phase, clinical and hematologic responses were sustained for 48 weeks in 74% of the patients. Adverse events did not limit treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov numbers, NCT00001406 and NCT02130882.)

Energy systems integration, or sector coupling, has several drivers that span climate impact mitigation and economics to social and regulatory considerations. A key question is what is sector coupling, and how does it impact the flexibility of the energy system? Here, the energy system includes several sectors - electricity, gas, heat, and transportation - that have been independent for decades in most countries except for their coupling via combined heat and power (CHP) units. In energy systems integration, some sectors may provide flexibility to other sectors, while other sectors will require flexibility when interlinking. To support these synergies among sectors, it is important to explore and quantify mutual interactions as well as seek examples of how these integrations can provide flexibility and other benefits. From the perspective of the electricity sector, it is important to ensure that there is enough flexibility in the interconnected systems to support decarbonization goals, such as those set in the Paris Agreement, while ensuring operational reliability.

After nearly four years of study, evaluation, and deliberation, the Madison, Wisconsin, Ad Hoc Committee charged with undertaking a comprehensive review of the Madison Police Department (MPD) has completed its work and issued its final report. The report contains 177 specific recommendations to chart a path for the future that will help bring together Madison's diverse communities and its police department, build mechanisms for collaboration and trust through enhanced civilian input and oversight of the policing function, and ensure that the Madison Police Department continues its long-standing ideals of community policing and problem-oriented policing. The centerpiece of the report and its recommendations is that Madison should create structures for civilian oversight of police through a new Office of an Independent Monitor that responds to a Civilian Review Board, composed of civilians who reflect all of Madison's diverse communities and the lived experiences of those members of the community who frequently come into contact with the police. That recommendation was submitted to the Common Council separately on August 6, 2019, and was accepted by the Council. The Mayor's budget includes $200,000 to implement that recommendation. Other recommendations include proposals aimed at improving the MPD's relations with the Madison Community, including addressing race and equity concerns; enhancing the MPD's commitment to and practice of community policing and problem-oriented policing; enhancing the MPD's ability to respond effectively and sensitively to individuals in mental health crises; minimizing the need to resort to and the frequency of incidents of police use of force, including deadly force; improving accountability and transparency; creating processes for learning from bad outcomes, including police or civilian fatalities; and others.

Measures to reduce carbon dioxide emissions are often considered separately, in terms of electricity, heating, transport, and industry. This can lead to the measures being prioritised in the wrong sectors, and neglects interactions between the sectors. In addition, studies often focus on specific greenhouse gas reduction targets, despite the uncertainty regarding what targets are desirable and when. In this paper, these issues are examined for the period after 2030 in an existing openly-available, hourly-resolved, per-country, and highly-renewable model of the European energy system, PyPSA-Eur-Sec-30, that includes electricity, land transport, and space and water heating. A parameter sweep of different reduction targets for direct carbon dioxide emissions is performed, ranging from no target down to zero direct emissions. The composition of system investments, the interactions between the energy sectors, shadow prices, and the market values of the system components are analysed as the carbon dioxide limit changes. Electricity and land transport are defossilised first, while the reduction of emissions in space and water heating is delayed by the expense of new components and the difficulty of supplying heat during cold spells with low wind and solar power generation. For deep carbon dioxide reduction, power-to-gas changes the system dynamics by reducing curtailment and increasing the market values of wind and solar power. Using this model setup, cost projections for 2030, and optimal cross-border transmission, the costs of a zero-direct-emission system in these sectors are marginally cheaper than today’s system, even before the health and environmental benefits are taken into account.

Models for long-term investment planning of the power system typically return a single optimal solution per set of cost assumptions. However, typically there are many near-optimal alternatives that stand out due to other attractive properties like social acceptance. Understanding features that persist across many cost-efficient alternatives enhances policy advice and acknowledges structural model uncertainties. We apply the modeling-to-generate-alternatives (MGA) methodology to systematically explore the near-optimal feasible space of a completely renewable European electricity system model. While accounting for complex spatio-temporal patterns, we allow simultaneous capacity expansion of generation, storage and transmission infrastructure subject to linearized multi-period optimal power flow. Many similarly costly, but technologically diverse solutions exist. Already a cost deviation of 0.5% offers a large range of possible investments. However, either offshore or onshore wind energy along with some hydrogen storage and transmission network reinforcement are essential to keep costs within 10% of the optimum., Comment: Accepted to the 21st Power Systems Computation Conference (PSCC 2020); 9 pages, 8 figures, 3 tables

We use an open, hourly-resolved, networked model of the European energy system to investigate the storage requirements under decreasing CO$_2$ emissions targets and several sector-coupling scenarios. For the power system, significant storage capacities only emerge for CO$_2$ reductions higher than 80% of 1990 level in that sector. For 95% CO$_2$ reductions, the optimal system includes electric batteries and hydrogen storage energy capacities equivalent to 1.4 and 19.4 times the average hourly electricity demand. Coupling heating and transport sectors enables deeper global CO$_2$ reductions before the required storage capacities become significant, which highlights the importance of sector coupling strategies in the transition to low carbon energy systems. A binary selection of storage technologies is consistently found, i.e., electric batteries act as short-term storage to counterbalance solar photovoltaic generation while hydrogen storage smooths wind fluctuations. Flexibility from the electric vehicle batteries provided by coupling the transport sector avoid the need for additional stationary batteries and reduce the usage of pumped hydro storage. Coupling the heating sector brings to the system large capacities of thermal energy storage to compensate for the significant seasonal variation in heating demand., Comment: 22 pages, 13 figures

Advances in nanoparticle design have led to the development of nanoparticulate systems that can sense intracellular molecules, alter cellular processes, and release drugs to specific targets in vitro. In this work we demonstrate that oligonucleotide - coated gold nanoparticles are suitable for the detection of mRNA in live Hydra vulgaris - a model organism - without affecting the animal's integrity. We specifically focus on the detection of Hymyc1 mRNA, which is responsible for the regulation of the balance between stem cell self-renewal and differentiation. Myc deregulation is found in more than half of human cancers, thus the ability to detect in vivo related mRNAs through innovative fluorescent systems is of outmost interest.

Telomerase is expressed in the majority (>85%) of tumors, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterization of radiolabeled oligonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic activity and delivering radiation intracellularly. Oligonucleotides complementary (Match) and noncomplementary (Scramble or Mismatch) to hTR were conjugated to diethylenetriaminepentaacetic dianhydride (DTPA), allowing radiolabeling with the Auger electron-emitting radionuclide indium-111 (111In). Match oligonucleotides inhibited telomerase activity with high potency, which was not observed with Scramble or Mismatch oligonucleotides. DTPA-conjugation and 111In-labeling did not change telomerase inhibition. In telomerase-positive cancer cells, unlabeled Match oligonucleotides had no effect on survival, however, 111In-labeled Match oligonucleotides significantly reduced clonogenic survival and upregulated the DNA damage marker γH2AX. Minimal radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to 111In-Match oligonucleotides. Match oligonucleotides localized in close proximity to nuclear Cajal bodies in telomerase-positive cells. In comparison with Match oligonucleotides, 111In-Scramble or 111In-Mismatch oligonucleotides demonstrated reduced retention and negligible impact on cell survival. This study indicates the therapeutic activity of radiolabeled oligonucleotides that specifically target hTR through potent telomerase inhibition and DNA damage induction in telomerase-expressing cancer cells and paves the way for the development of novel oligonucleotide radiotherapeutics targeting telomerase-positive cancers. Significance: These findings present a novel radiolabeled oligonucleotide for targeting telomerase-positive cancer cells that exhibits dual activity by simultaneously inhibiting telomerase and promoting radiation-induced genomic DNA damage.

Phosphate groups are often crucial to biological activity and interactions of oligonucleotides, but confer poor membrane permeability. In addition, the group's lability to enzymatic hydrolysis is an obstacle to its use in therapeutics and in biological tools. We present the synthesis of N‐oxyamide and squaramide modifications at the 5’‐end of oligonucleotides as phosphate replacements and their biological evaluation using the 5’‐exonuclease SNM1A. The squaryl diamide modification showed minimal recognition as a 5’‐phosphate mimic; however, modest inhibition of SNM1A, postulated to occur through metal coordination at the active site, was observed. Their facile incorporation after solid‐phase synthesis and recognition by the exonuclease makes squaryl diamides attractive neutral 5’‐phosphate replacements for oligonucleotides. This work is the first example of squaryl diamide modifications at the 5’‐terminal position of oligonucleotides and of the potential use of modified oligonucleotides to bind to the metal center of SNM1A.

Glucocorticoids are first-line agents for the treatment of many eosinophil-associated disorders; however, their effects on human eosinophils remain poorly understood. To gain an unbiased, genome-wide view of the early transcriptional effects of glucocorticoids on human eosinophils in vivo, RNA sequencing was performed on purified blood eosinophils obtained before and 30, 60, and 120 minutes after administration of a single dose of oral prednisone (1 mg/kg) to three unrelated healthy subjects with hypereosinophilia of unknown significance. The resulting dataset is of high quality and suitable for differential expression analysis. Flow cytometry and qPCR were then performed on three additional cohorts of human subjects, to validate the key findings at the transcript and protein levels. The resulting datasets provide a resource for understanding the response of circulating human eosinophils to glucocorticoid administration. Machine-accessible metadata file describing the reported data (ISA-Tab format)

Background Exacerbations of COPD are one of the commonest causes of admission to hospital in the UK. Re-admission is also a significant problem and is currently the fifth most common cause of hospitalisation. Self-management interventions have shown benefits in improving health related quality of life and reducing hospital admissions. We explored the potential for an online self-management system to improve outcomes for COPD patients recently admitted to hospital with an exacerbation. Methods We conducted a feasibility randomised controlled trial of a digital health platform ‘myCOPD’. 41 Patients were recruited following an admission to hospital with an acute exacerbation of COPD. Patients gave written informed consent and were randomised to either receive usual care (n=21) (including written self-management plan) or the myCOPD app (n=20) for 3 months. Patients attended 2 visits and received monthly telephone contacts to capture AEs. Exacerbations, readmission, CAT and PAM scores were captured. Inhaler technique was assessed for critical errors, pre and post intervention by a blinded team. Analysis was performed by an independent blinded statistician to an a priori SAP. Results The overall cohort had a mean (SD) age of 66.6 (7) years, and had moderate to very severe disease FEV1 44 (17.6)% predicted. Exacerbations were less frequent in the digital arm compared to usual care over 3 m; 18 vs 34, p=0.047 for mean difference. Hospital readmissions were lower in the digital intervention arm than in usual care 4 vs 13. Patients’ inhaler technique (total critical error count) improved in the digital intervention arm (101 improving to 20 errors) compared to usual care (100 and 72) p=0.008.As did CAT scores, with a differential improvement of −4.8 (CI −8.8 to −0.7) p=0.021 in favour of digitally enhanced care. No differences were seen between treatment arms for HAD, MRC, SGRQ or PAM scores. Conclusion In this early clinical study of the digital self- management platform myCOPD, its use has been shown to significantly improve exacerbation rates, lower re-admission numbers, improve symptom control and reduce the number of critical errors in inhaler technique compared to usual written self-management. This provides a strong basis for the design of a large multicentred trial.

International audience; The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received 12 million s funding under the European Union Framework Programme 7 from 1st June 2008 to 30th November 2012. The 19 project partners from both academia and industry from in total 7 countries had a project budget of 16 Ms with which they have discovered, created and developed a huge body of insights into nucleic acid analysis. Results have been presented widely in publications and in innumerous public presentations. Results have been moved to spin-offs such as the Olink enrichment kits (now sold by Agilent as Haloplex) and are findingtheir way to the market, such as the Oxford Nanopore MinIon sequencer that was first released to early-access user sites in 2014.

To spur Europe to meet ambitious CO2 emission reduction targets, Greenpeace has developed scenarios for each country to increase its electricity generation from renewable sources. Energynautics was commissioned by Greenpeace to model and optimise the grid extensions in Europe necessary to integrate these large shares of renewables (77% of the total electricity supply by 2030, including 53% from wind and solar). The results and further analysis of the data are presented here. It was found that by preferring high voltage direct current rather than alternating current network extensions, the overall grid upgrades in Europe (measured as the length of new transmission lines) can be reduced by a third. By allowing a small amount of curtailment of variable renewable sources, a disproportionately large number of the necessary grid extensions can be avoided. In addition, the accuracy of decoupling active from reactive power flows is analysed.

The tensegrity triangle is a robust DNA motif that can self-assemble to generate macroscopic three-dimensional crystals. However, the stability of these crystals is dependent on the high ionic conditions used for crystal growth. Here we demonstrate that a triplex-forming oligonucleotide can be used to direct the specific intercalation, and subsequent photo-cross-linking, of 4,5',8-trimethylpsoralen to single or multiple loci within or between the tiles of the crystal. Cross-linking between the tiles of the crystal improves their thermal stability. Such an approach is likely to facilitate the removal of crystals from their mother liquor and may prove useful for applications that require greater crystal stability.

Single-molecule fluorescence and Förster resonance energy transfer (smFRET) are important tools for studying molecular heterogeneity, cellular organization, and protein structure in living cells. However, in vivo smFRET studies are still very challenging, and a standardized approach for robust in vivo smFRET measurements is still missing. Here, we synthesized protected DNAs with chemically linked ends as robust in vivo nano-rulers. We efficiently internalized doubly-labeled end-sealed DNA standards into live bacteria using electroporation and obtained stable and long-lasting smFRET signatures. Single-molecule fluorescence signals could be extended to ∼1 min by studying multi-fluorophore DNA standards. The high stability of protected DNA standards offers a general approach to evaluate single-molecule fluorescence and FRET signals, autofluorescence background, and fluorophore density, and hence, quality check the workflow for studying single-molecule trajectories and conformational dynamics of biomolecules in vivo.

Scanning the electrochemical potential negative results in the gradual denaturation of dsDNA immobilised at a nanostructure gold electrode, the DNA melting is monitored by SERS. We demonstrate the effect of the experimental temperature on the electrochemically driven melting (E-melting) by carrying out experiments between 10 and 28°C using two DNA duplexes (20 and 21 base pairs). Significant temperature dependence for both the melting potentials, Em, and the steepness of the melting curves was found over the range 10 to 18°C. Above 18°C the results were found to be independent of temperature. The relative temperature insensitivity of the melting potentials above 18°C is advantageous for the application of the electrochemically driven melting technique because precise temperature control is not necessary for measurements that are carried out around room temperature. Conversely temperature dependence below 18°C offers a way to improve discrimination for highly similar DNA sequences.

Variable generation (VG) in China is primarily wind and photovoltaic (PV) power. By the end of 2014, the cumulative installed capacity of VG in China reached 123.86 GW, accounting for 9.1% of the country?s total generation capacity. The cumulative installed capacity of wind and PV power were, 95.81 GW and 28.05 GW, respectively. The total amount of energy generated from VG in 2014 was 181 TWh (of which wind power was 156 TWh and PV power 25 TWh), accounting for 3.3% of total electricity generation. The newly installed capacity of wind and PV power in 2014 was 19.5 GW and 10.6 GW, respectively, accounting for 28% of the newly installed capacity of all generation types. Following coal-fired power and hydropower, wind has already become China?s third-largest power source both by capacity and by power generation, after nine years of high-speed growth. A rapid development of PV power generation has been experienced since 2010. The newly installed PV capacity in 2013 and 2014 reached over 10 GW for two consecutive years, accounting for about one-third of newly installed PV capacity worldwide over the same period. By capacity, PVs have become China?s fifth largest generation source after natural gas based generation.

DNA strands can be designed to assemble into stable three-dimensional structures, based on Watson-Crick base pairing rules. The simplest of these is the DNA tetrahedron that is composed of four oligonucleotides. We have re-designed the sequence of a DNA tetrahedron so that it contains a single (AATT) binding site for the minor groove binding ligand Hoechst 33258. We examined the stability of this structure by placing fluorescent groups within each of its edges and have shown that all the edges melt at the same temperature in the absence of the ligand. The minor groove ligand still binds to its recognition sequence within the tetrahedron and increases the melting temperature of the folded complex. This ligand-induced stabilisation is propagated into the adjacent helical arms and the tetrahedron melts as a single entity in a cooperative fashion.

Deep decarbonization of the electricity sector can be provided by a high penetration of renewable sources such as wind, solar PV and hydro power. Flexibility from hydro and storage complements the high temporal variability of wind and solar, and transmission infrastructure helps the power balancing by moving electricity in the spatial dimension. We study cost-optimal highly-renewable Chinese power systems under ambitious CO2 emission reduction targets, by deploying a 31-node hourly-resolved techno-economic optimization model supported by a validated weather-converted 38-year-long renewable power generation and electricity demand dataset. With a new realistic reservoir hydro model, we find that if CO2 emission reduction goes beyond 70%, storage facilities such as hydro, battery and hydrogen become necessary for a moderate system cost. Numerical results show that these flexibility components can lower renewable curtailment by two thirds, allow higher solar PV share by a factor of two and contribute to covering summer cooling demand. We show that expanding unidirectional high-voltage DC lines on top of the regional inter-connections is technically sufficient and more economical than ultra-high-voltage-AC-connected “One-Net” grid. Finally, constraining transmission volume from the optimum by up to 25% does not push total costs much higher, while the significant need for battery storage remains even with abundant interconnectivity.

International audience; Conjugation of RNA with multiple partners to obtain mimics of complex biomolecules is limited by the identification of orthogonal reactions. Here, lipid-carbohydrate-peptidyl-RNA conjugates were obtained by post-functionalization reactions, solid-phase synthesis, and enzymatic steps, to generate molecules mimicking the substrates of FmhB, an essential peptidoglycan synthesis enzyme of Staphylococcus aureus. Mimics of Gly-tRNAGly and lipid intermediate II (undecaprenyl-diphospho-disaccharide-pentapeptide) were combined in a single "bi-substrate" inhibitor (IC50 =56 nm). The synthetic route was exploited to generate substrates and inhibitors containing d-lactate residue (d-Lac) instead of d-Ala at the C-terminus of the pentapeptide stem, a modification responsible for vancomycin resistance in the enterococci. The substitution impaired recognition of peptidoglycan precursors by FmhB. The associated fitness cost may account for limited dissemination of vancomycin resistance genes in S. aureus.