The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as important molecular players in ...metabolic diseases. Here we summarize evidence that dysregulation of sphingolipid metabolism correlates with pathogenesis of metabolic diseases in humans. This review discusses the current understanding of how ceramide regulates signaling and metabolic pathways to exacerbate metabolic diseases and the Janus faces for its further metabolite S1P, the kinases that produce it, and the multifaceted and at times opposing actions of S1P receptors in various tissues. Gaps and limitations in current knowledge are highlighted together with the need to further decipher the full array of their actions in tissue dysfunction underlying metabolic pathologies, pointing out prospects to move this young field of research toward the development of effective therapeutics.
Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate, have emerged as important mediators in the development of metabolic diseases. In this review, Green et al. discuss the multifacted, tissue-specific roles of these sphingolipid metabolites and how their dysregulation contributes to the pathogenesis of metabolic diseases.
Global contamination of the marine environment by plastic has led to the discovery of microplastics in a range of marine species, including those for human consumption. In this study, the presence of ...microplastics and other anthropogenic debris in seawater and mussels (Mytilus edulis) from coastal waters of the U.K., as well as supermarket sources, was investigated. These were detected in all samples from all sites with spatial differences observed. Seawater samples taken from 6 locations (in triplicates) displayed 3.5 ± 2.0 debris items/L on average (range: 1.5–6.7 items/L). In wild mussels sampled from 8 locations around the U.K. coastal environment, the number of total debris items varied from 0.7 to 2.9 items/g of tissue and from 1.1 to 6.4 items/individual. For the supermarket bought mussels, the abundance of microplastics was significantly higher in pre-cooked mussels (1.4 items/g) compared with mussels supplied live (0.9 items/g). Micro-FT-IR spectroscopy was conducted on 136 randomly selected samples, with 94 items characterized. The spectra found that 50% of these debris items characterized were microplastic, with an additional 37% made up of rayon and cotton fibers. The microplastic levels detected in the supermarket bought mussels present a route for human exposure and suggests that their quantification be included as food safety management measures as well as for environmental monitoring health measures.
Display omitted
•Coastal mussels sampled from around the United Kingdom all contain microplastics.•Supermarket bought mussels for human consumption also all contain microplastics.•43%/57% of debris items from coastal/supermarket mussels were microplastics.•Predicted ingestion of 70 microplastic items in 100 g processed mussels by consumers.
Microplastics in seawater, coastal mussels and supermarket mussels.
Adverse drug reactions (ADRs) are a major cause of hospital admissions, but recent data on the incidence and clinical characteristics of ADRs which occur following hospital admission, are lacking. ...Patients admitted to twelve wards over a six-month period in 2005 were assessed for ADRs throughout their admission. Suspected ADRs were recorded and analysed for causality, severity and avoidability and whether they increased the length of stay. Multivariable analysis was undertaken to identify the risk factors for ADRs. The 5% significance level was used when assessing factors for inclusion in multivariable models. Out of the 3695 patient episodes assessed for ADRs, 545 (14.7%, 95% CI 13.6-15.9%) experienced one or more ADRs. Half of ADRs were definitely or possibly avoidable. The patients experiencing ADRs were more likely to be older, female, taking a larger number of medicines, and had a longer length of stay than those without ADRs. However, the only significant predictor of ADRs, from the multivariable analysis of a representative sample of patients, was the number of medicines taken by the patient with each additional medication multiplying the hazard of an ADR episode by 1.14 (95% CI 1.09, 1.20). ADRs directly increased length of stay in 147 (26.8%) patients. The drugs most frequently associated with ADRs were diuretics, opioid analgesics, and anticoagulants. In conclusion, approximately one in seven hospital in-patients experience an ADR, which is a significant cause of morbidity, increasing the length of stay of patients by an average of 0.25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden.
During the past two decades there has been a shift in the geography of Global Supply Chains (GSCs) from developed countries to China, and more recently from China to successor developing countries in ...South Asia, Africa and Latin America. The shift in GSC geography influences global greenhouse gas (GHG) emissions because of an energy efficiency and low-carbon technology gap between developed and developing economies. Our simulations indicate that changing GSC geography toward China positively contributed, on average (2001–2008), 919 Mt CO2 equivalents to global GHG emissions annually. In addition, there are potentially even larger indirect effects, including import-related and transportation-related emissions that are attributable to GSC shift-related improvements in developing world consumption and infrastructure. We then investigate the emission impact of a further GSCs shift toward South Asia, Africa and Latin America. Although the direct impact of such a shift is likely negative due to a lower dependency on coal as well as lower carbon intensities in South Asia, Africa and Latin America relative to China, it is likely that the direct effects are more than offset by the indirect shift-related effects associated with improvements in consumption and infrastructure. Our results have policy implications for future climate change mitigation.
•There have been shifts in the geography of Global Supply Chains (GSCs) in recent decades.•The shift of GSCs toward China directly increased global GHG emissions by 919 Mt. CO2 annually.•The indirect effects on global emissions attributable to the GSCs shift to China may be as large as to 1.6 Gt CO2/yr.•A likely further GSC shift from China to South Asia, Africa and Latin America would increase the global GHG emissions.
Peters et al (2015 Environ. Res. Lett. 10 105004) find that the INDCs submitted prior to the upcoming UNFCCC meetings in Paris are not nearly 'fair and ambitious' enough to achieve the goal of ...limiting global warming to <2 °C and that much greater attention needs to be paid to advanced energy technologies, without which climate goals are unattainable.
AbstractObjectiveTo characterise the clinical features of patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United Kingdom during the growth phase of the first wave of ...this outbreak who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study, and to explore risk factors associated with mortality in hospital.DesignProspective observational cohort study with rapid data gathering and near real time analysis.Setting208 acute care hospitals in England, Wales, and Scotland between 6 February and 19 April 2020. A case report form developed by ISARIC and WHO was used to collect clinical data. A minimal follow-up time of two weeks (to 3 May 2020) allowed most patients to complete their hospital admission.Participants20 133 hospital inpatients with covid-19.Main outcome measuresAdmission to critical care (high dependency unit or intensive care unit) and mortality in hospital.ResultsThe median age of patients admitted to hospital with covid-19, or with a diagnosis of covid-19 made in hospital, was 73 years (interquartile range 58-82, range 0-104). More men were admitted than women (men 60%, n=12 068; women 40%, n=8065). The median duration of symptoms before admission was 4 days (interquartile range 1-8). The commonest comorbidities were chronic cardiac disease (31%, 5469/17 702), uncomplicated diabetes (21%, 3650/17 599), non-asthmatic chronic pulmonary disease (18%, 3128/17 634), and chronic kidney disease (16%, 2830/17 506); 23% (4161/18 525) had no reported major comorbidity. Overall, 41% (8199/20 133) of patients were discharged alive, 26% (5165/20 133) died, and 34% (6769/20 133) continued to receive care at the reporting date. 17% (3001/18 183) required admission to high dependency or intensive care units; of these, 28% (826/3001) were discharged alive, 32% (958/3001) died, and 41% (1217/3001) continued to receive care at the reporting date. Of those receiving mechanical ventilation, 17% (276/1658) were discharged alive, 37% (618/1658) died, and 46% (764/1658) remained in hospital. Increasing age, male sex, and comorbidities including chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease and obesity were associated with higher mortality in hospital.ConclusionsISARIC WHO CCP-UK is a large prospective cohort study of patients in hospital with covid-19. The study continues to enrol at the time of this report. In study participants, mortality was high, independent risk factors were increasing age, male sex, and chronic comorbidity, including obesity. This study has shown the importance of pandemic preparedness and the need to maintain readiness to launch research studies in response to outbreaks.Study registrationISRCTN66726260.
This article looks to the original meaning of the Fourteenth Amendment's provisions on equal citizenship to defend an approach to the free exercise of religion distinct both from Employment Division ...v. Smithand the Sherbert-Yoder regime it replaced. Members of all religious groups are equally citizens: in the first Justice Harlan's words in The Civil Rights Cases, a "component part of the people for whose welfare and happiness government is ordained." Such citizens are entitled to equal solicitude from their state regarding even indirect costs of that state's laws. Just as trustees must affirmatively promote the interests of their beneficiaries, not merely avoid purposely harming them, states must affirmatively promote the interests of their citizens, not merely avoid targeting them for ill treatment. This obligation applies to all citizens no maKer their religion or race. Contrary to Smith, therefore, the Fourteenth Amendment requires more than a no-religious-targeting rule. And contrary to Washington v. Davis, it requires more than a no-racial-targeting rule. The Court was right in both Smith and Washington, however, that strict scrutiny for any law significantly affecting racial or religious groups would threaten chaos. A refusal to countenance any impact on religious practices, no maKer how socially harmful, would allow religious citizens to be laws unto themselves. A refusal to countenance any disparate impact on racial groups would require racially discriminatory quotas that would themselves undermine equal citizenship. The Fourteenth Amendment requires a more nuanced assessment of the arbitrariness of the distinct
Over the past few decades, a large literature has emerged on the question of how one might unify all or most of psychology under a single, coherent, rigorous framework, in a manner similar to that ...which unified physics under Newton's Laws, or biology under Darwin's theory of natural selection. It is argued here that this is a highly unlikely scenario in psychology given the contingent and opportunistic character of the processes that brought its original topics together into a new discipline, and the nearly continuous institutional, social, and even political negotiating and horse-trading that has determined psychology's "boundaries" in the 14 decades since. Psychology, as the field currently stands, does not have the intellectual coherence to be brought together by any set of principles that would enable its phenomena to be captured and explained as rigorous products of those principles. If there is a kind of unification in psychology's future, it is more likely to be one that, paradoxically, sees it broken up into a number of large "super-subdisciplines," each of which exhibits more internal coherence than does the current sprawling and heterogeneous whole.
To bring real-world applications of DNA nanostructures to fruition, advanced microscopy techniques are needed to shed light on factors limiting the availability of addressable sites. Correlative ...microscopy, where two or more microscopies are combined to characterize the same sample, is an approach to overcome the limitations of individual techniques, yet it has seen limited use for DNA nanotechnology. We have developed an accessible strategy for high resolution, correlative DNA-based points accumulation for imaging in nanoscale topography (DNA-PAINT) super-resolution and atomic force microscopy (AFM) of DNA nanostructures, enabled by a simple and robust method to selectively bind DNA origami to cover glass. Using this technique, we examined addressable “docking” sites on DNA origami to distinguish between two defect scenarios–structurally incorporated but inactive docking sites, and unincorporated docking sites. We found that over 75% of defective docking sites were incorporated but inactive, suggesting unincorporated strands played a minor role in limiting the availability of addressable sites. We further explored the effects of strand purification, UV irradiation, and photooxidation on availability, providing insight on potential sources of defects and pathways toward improving the fidelity of DNA nanostructures.
Identifying drug-drug interactions (DDIs) is a major challenge in drug development. Previous attempts have established formal approaches for pharmacokinetic (PK) DDIs, but there is not a feasible ...solution for pharmacodynamic (PD) DDIs because the endpoint is often a serious adverse event rather than a measurable change in drug concentration. Here, we developed a metric "S-score" that measures the strength of network connection between drug targets to predict PD DDIs. Utilizing known PD DDIs as golden standard positives (GSPs), we observed a significant correlation between S-score and the likelihood a PD DDI occurs. Our prediction was robust and surpassed existing methods as validated by two independent GSPs. Analysis of clinical side effect data suggested that the drugs having predicted DDIs have similar side effects. We further incorporated this clinical side effects evidence with S-score to increase the prediction specificity and sensitivity through a Bayesian probabilistic model. We have predicted 9,626 potential PD DDIs at the accuracy of 82% and the recall of 62%. Importantly, our algorithm provided opportunities for better understanding the potential molecular mechanisms or physiological effects underlying DDIs, as illustrated by the case studies.
PDF
