Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total ...synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.
Objective To estimate the frequency with which results of large randomized clinical trials registered with ClinicalTrials.gov are not available to the public.Design Cross sectional analysisSetting ...Trials with at least 500 participants that were prospectively registered with ClinicalTrials.gov and completed prior to January 2009.Data sources PubMed, Google Scholar, and Embase were searched to identify published manuscripts containing trial results. The final literature search occurred in November 2012. Registry entries for unpublished trials were reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database.Main outcome measures The frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database.Results Of 585 registered trials, 171 (29%) remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299 763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. Non-publication was more common among trials that received industry funding (150/468, 32%) than those that did not (21/117, 18%), P=0.003. Of the 171 unpublished trials, 133 (78%) had no results available in ClinicalTrials.gov.Conclusions Among this group of large clinical trials, non-publication of results was common and the availability of results in the ClinicalTrials.gov database was limited. A substantial number of study participants were exposed to the risks of trial participation without the societal benefits that accompany the dissemination of trial results.
Single-electron circuits of the future, consisting of a network of quantum dots, will require a mechanism to transport electrons from one functional part of the circuit to another. For example, in a ...quantum computer decoherence and circuit complexity can be reduced by separating quantum bit (qubit) manipulation from measurement and by providing a means of transporting electrons between the corresponding parts of the circuit. Highly controlled tunnelling between neighbouring dots has been demonstrated, and our ability to manipulate electrons in single- and double-dot systems is improving rapidly. For distances greater than a few hundred nanometres, neither free propagation nor tunnelling is viable while maintaining confinement of single electrons. Here we show how a single electron may be captured in a surface acoustic wave minimum and transferred from one quantum dot to a second, unoccupied, dot along a long, empty channel. The transfer direction may be reversed and the same electron moved back and forth more than sixty times-a cumulative distance of 0.25 mm-without error. Such on-chip transfer extends communication between quantum dots to a range that may allow the integration of discrete quantum information processing components and devices.
Atmospheric methane grew very rapidly in 2014 (12.7 ± 0.5 ppb/year), 2015 (10.1 ± 0.7 ppb/year), 2016 (7.0 ± 0.7 ppb/year), and 2017 (7.7 ± 0.7 ppb/year), at rates not observed since the 1980s. The ...increase in the methane burden began in 2007, with the mean global mole fraction in remote surface background air rising from about 1,775 ppb in 2006 to 1,850 ppb in 2017. Simultaneously the 13C/12C isotopic ratio (expressed as δ13CCH4) has shifted, now trending negative for more than a decade. The causes of methane's recent mole fraction increase are therefore either a change in the relative proportions (and totals) of emissions from biogenic and thermogenic and pyrogenic sources, especially in the tropics and subtropics, or a decline in the atmospheric sink of methane, or both. Unfortunately, with limited measurement data sets, it is not currently possible to be more definitive. The climate warming impact of the observed methane increase over the past decade, if continued at >5 ppb/year in the coming decades, is sufficient to challenge the Paris Agreement, which requires sharp cuts in the atmospheric methane burden. However, anthropogenic methane emissions are relatively very large and thus offer attractive targets for rapid reduction, which are essential if the Paris Agreement aims are to be attained.
Plain Language Summary
The rise in atmospheric methane (CH4), which began in 2007, accelerated in the past 4 years. The growth has been worldwide, especially in the tropics and northern midlatitudes. With the rise has come a shift in the carbon isotope ratio of the methane. The causes of the rise are not fully understood, and may include increased emissions and perhaps a decline in the destruction of methane in the air. Methane's increase since 2007 was not expected in future greenhouse gas scenarios compliant with the targets of the Paris Agreement, and if the increase continues at the same rates it may become very difficult to meet the Paris goals. There is now urgent need to reduce methane emissions, especially from the fossil fuel industry.
Key Points
Atmospheric methane is rising; its carbon isotopic ratio has become more depleted in C‐13
The possible causes of the change include an increase in emissions, with changing relative proportions of source inputs, or a decline in methane destruction, or both
If this rise continues, there are significant consequences for the UN Paris Agreement
Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor ...precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes.
We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 95% CI 0.972 to 0.984; AUPRC = 0.670 95% CI 0.652 to 0.688; PPV = 0.721 95% CI 0.703 to 0.739). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 95% CI 0.838 to 0.873. Main limitations of this study included limited transportability of the model and lack of geographically independent validation.
Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.
Tobacco use is a leading preventable risk factor for many chronic disorders, which are expected to account for an increasing share of the global disease burden. As part of the Global Youth Tobacco ...Survey (GYTS), we aimed to assess the effect of tobacco use by young people on global mortality.
GYTS is a school-based survey of students aged 13–15 years. The survey was undertaken at 395 sites in 131 countries and the Gaza Strip and West Bank. We questioned students about current tobacco use, susceptibility to smoking among non-smokers, and exposure to secondhand smoke at home and in public places.
The difference in current cigarette smoking between boys and girls is narrower than expected in many regions of the world. Use of tobacco products other than cigarettes by students is as high as cigarette smoking in many regions. Almost one in five never-smokers reported they were susceptible to smoking in the next year. Student exposure to secondhand smoke was high both at home (more than four in ten) and in public places (more than five in ten). Never-smokers were significantly less likely than current smokers to be exposed to secondhand smoke at home (prevalence 39·1% 95% CI 36·6–41·6
vs 72·8% 64·0–81·6) and in public places (49·5% 46·7–52·3
vs 81·2% 74·2–88·2).
Our findings are troubling for the future of chronic disease and tobacco-related mortality. Reduction of tobacco consumption will require a redoubling of efforts to prevent initiation and promote cessation among the large proportion of young people who currently use tobacco. High exposure to secondhand smoke suggests a need for countries to pass strong and effective smoke-free policies.
An enantioselective total synthesis of the Strychnos alkaloid (+)-minfiensine has been accomplished. Prominent features of this synthesis include (i) a new enantioselective organocatalytic ...Diels−Alder/amine cyclization sequence to build the central tetracyclic pyrroloindoline framework in four steps from commercial materials and (ii) a 6-exo-dig radical cyclization to forge the final piperidinyl ring system. This total synthesis of (+)-minfiensine was completed in nine chemical steps and 21% overall yield.
Underplatform dampers (UPD) are commonly used in aircraft engines to mitigate the risk of high-cycle fatigue failure of turbine blades. The energy dissipated at the friction contact interface of the ...damper reduces the vibration amplitude significantly, and the couplings of the blades can also lead to significant shifts of the resonance frequencies of the bladed disk. The highly nonlinear behaviour of bladed discs constrained by UPDs requires an advanced modelling approach to ensure that the correct damper geometry is selected during the design of the turbine, and that no unexpected resonance frequencies and amplitudes will occur in operation. Approaches based on an explicit model of the damper in combination with multi-harmonic balance solvers have emerged as a promising way to predict the nonlinear behaviour of UPDs correctly, however rigorous experimental validations are required before approaches of this type can be used with confidence.
In this study, a nonlinear analysis based on an updated explicit damper model having different levels of detail is performed, and the results are evaluated against a newly-developed UPD test rig. Detailed linear finite element models are used as input for the nonlinear analysis, allowing the inclusion of damper flexibility and inertia effects. The nonlinear friction interface between the blades and the damper is described with a dense grid of 3D friction contact elements which allow accurate capturing of the underlying nonlinear mechanism that drives the global nonlinear behaviour. The introduced explicit damper model showed a great dependence on the correct contact pressure distribution. The use of an accurate, measurement based, distribution, better matched the nonlinear dynamic behaviour of the test rig. Good agreement with the measured frequency response data could only be reached when the zero harmonic term (constant term) was included in the multi-harmonic expansion of the nonlinear problem, highlighting its importance when the contact interface experiences large normal load variation. The resulting numerical damper kinematics with strong translational and rotational motion, and the global blades frequency response were fully validated experimentally, showing the accuracy of the suggested high detailed explicit UPD modelling approach.
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•Double blade underplatform damper test rig for turbine applications.•Nondimensional parameters defined to mimic the dynamics of a real turbine blade.•Advanced modelling approach based on an FE explicit model of the damper and a dense grid of 3D friction contact elements.•New insights into the required contact pressure distribution accuracy and harmonics required for correct predictions.•Experimentally validated UPD modelling approach achieved.
Plant development is highly responsive to ambient temperature, and this trait has been linked to the ability of plants to adapt to climate change 1. The mechanisms by which natural populations ...modulate their thermoresponsiveness are not known 2. To address this, we surveyed Arabidopsis accessions for variation in thermal responsiveness of elongation growth and mapped the corresponding loci. We find that the transcriptional regulator EARLY FLOWERING3 (ELF3) controls elongation growth in response to temperature. Through a combination of modeling and experiments, we show that high temperature relieves the gating of growth at night, highlighting the importance of temperature-dependent repressors of growth. ELF3 gating of transcriptional targets responds rapidly and reversibly to changes in temperature. We show that the binding of ELF3 to target promoters is temperature dependent, suggesting a mechanism where temperature directly controls ELF3 activity.
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•Temperature specifically affects growth at night•Arabidopsis accessions display natural variation in thermoresponsiveness•ELF3 is necessary for mediating temperature control of growth•Binding of ELF3 to target loci is temperature dependent
Box et al. discover extensive natural variation in the thermoresponsive growth of plants. They find that a nighttime transcriptional repressor of growth, ELF3, has a temperature-dependent DNA-binding activity. In this way, warm temperature releases nighttime gene repression of the growth-promoting transcription factor PIF4.
Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and ...efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.
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