Green plants convert CO(2) to sugar for energy storage via photosynthesis. We report a novel catalyst that uses CO(2) and hydrogen to store energy in formic acid. Using a homogeneous iridium catalyst ...with a proton-responsive ligand, we show the first reversible and recyclable hydrogen storage system that operates under mild conditions using CO(2), formate and formic acid. This system is energy-efficient and green because it operates near ambient conditions, uses water as a solvent, produces high-pressure CO-free hydrogen, and uses pH to control hydrogen production or consumption. The extraordinary and switchable catalytic activity is attributed to the multifunctional ligand, which acts as a proton-relay and strong π-donor, and is rationalized by theoretical and experimental studies.
While sustained-release buprenorphine (BSR) is used as a long-lasting opioid analgesic in common marmosets (Callithrix jacchus), there are no published studies on pharmaceutical-grade ...extended-release buprenorphine options such as Ethiqa XR (EXR) for this species. However, BSR is a compounded product and has been reported to cause injection site reactions in multiple species, including marmosets. Additionally, now with the availability of EXR, a pharmaceutical-grade veterinary product, the use of BSR in laboratory animals is not compliant with the Guide for the Care and Use of Laboratory Animals (Guide) unless scientifically justified and approved by the IACUC. We compared pharmacokinetic and safety profiles of BSR (0.15 mg/kg) and EXR (0.1-0.2 mg/kg) administered subcutaneously to adult marmosets. Blood was collected by venipuncture of the saphenous vein at multiple time points (0.25-72 h) and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). EXR between 0.1 and 0.2 mg/kg resulted in a dose-dependent increase in C
(1.43-2.51 ng/mL) and were not statistically different from BSR (1.82 ng/mL). T
, lambda
, and t
were not statistically different between formulations. Mean plasma buprenorphine concentrations for BSR and EXR exceeded the therapeutic threshold (0.1 ng/mL) within 0.25 h and lasted for > 72 h. Mild sedation, but neither respiratory depression nor ataxia, was observed for both formulations. BSR injection sites had significantly higher histopathological scores compared to EXR. Video recordings for monitoring drug-induced behavioral changes showed increased animal activity levels after BSR and EXR versus saline controls. Norbuprenorphine, a buprenorphine metabolite associated with respiratory depression, was detected in the plasma after BSR and EXR administration as well as by in vitro liver microsome assays. In conclusion, we recommend using EXR over BSR as a long-lasting buprenorphine analgesic in marmosets because EXR is a pharmaceutical-grade formulation that is compliant with FDA guidelines and the Guide as well as exhibits comparable PK and safety profiles as BSR.
PFAS mixtures in the environment are common and identifying PFAS constituents, bioaccumulation, and biological impacts of mixtures remains a challenge. Here, an omics-based ecosurveillance approach ...was taken to investigate the impacts of PFAS pollution in freshwater turtles (Emydura macquariimacquarii). Four turtles were collected from an impacted waterway downstream from an industrial source of PFAS contamination in Queensland, Australia and analysed for 49 different PFAS. One turtle was collected from a suitable control site. PFAS concentrations were quantified in turtle serum using an established targeted methodology. The serum PFAS concentration was ten-fold greater at the impacted site (Σ49 PFAS 1933 ± 481 ng/mL) relative to the control sample (Σ49 PFAS 140 ng/mL). Perfluorooctane sulfonate (PFOS; 889 ± 56 ng/mL) was 235 times higher in turtle serum than in the water that they were collected from (ΣPFAS 32.0 μg/L). Perfluorobutane sulfonamide (FBSA; 403 ± 83 ng/mL) and perfluorohexane sulfonamide (FHxSA; 550 ± 330 ng/mL) were also reported at substantial concentrations in the serum of impacted turtles. Biochemical profiles were analysed using a mixture of liquid chromatography triple quadrupole (QqQ) and quadrupole time-of-flight (QToF) mass spectrometry methodologies. These profiles demonstrated a positive correlation in the impacted turtles exposed to elevated PFAS with an enhanced purine metabolism, glycerophosphocholines and an innate immune response, which suggest an inflammation response, metabolic preservation and re-routing of central carbon metabolites. Conversely, lipid transport and binding activity were negatively correlated. Using these preliminary data, we were able to demonstrate the negative metabolic impact from PFAS mixtures on turtle metabolic health. With further research on a larger turtle cohort, omics-based data will contribute towards linking adverse outcome pathways for turtle populations exposed to PFAS mixtures. Moreover, expanding the use of ecosurveillance tools will inform mechanistic toxicological data for risk assessment and regulatory applications.
Display omitted
•First ecosurveillance assessment of PFAS mixtures on freshwater turtles.•First report of FBSA and FHxSA in Australian freshwater turtles.•Bioaccumulation of PFOS in turtle serum 235 times higher than water concentrations.•Positive PFAS correlation with purine/lipid metabolism related to immune responses.•Negative PFAS correlation with lipid transport and binding activity.
The properties of van der Waals (vdW) materials often vary dramatically with the atomic stacking order between layers, but this order can be difficult to control. Trilayer graphene (TLG) stacks in ...either a semimetallic ABA or a semiconducting ABC configuration with a gate-tunable band gap, but the latter has only been produced by exfoliation. Here we present a chemical vapor deposition approach to TLG growth that yields greatly enhanced fraction and size of ABC domains. The key insight is that substrate curvature can stabilize ABC domains. Controllable ABC yields ~59% were achieved by tailoring substrate curvature levels. ABC fractions remained high after transfer to device substrates, as confirmed by transport measurements revealing the expected tunable ABC band gap. Substrate topography engineering provides a path to large-scale synthesis of epitaxial ABC-TLG and other vdW materials.
Fitting the reproduction number from UK coronavirus case data and why it is close to 1 Ackland, Graeme J.; Ackland, James A.; Antonioletti, Mario ...
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
10/2022, Letnik:
380, Številka:
2233
Journal Article
Recenzirano
Odprti dostop
We present a method for rapid calculation of coronavirus growth rates and
R
-numbers tailored to publicly available UK data. We assume that the case data comprise a smooth, underlying trend which is ...differentiable, plus systematic errors and a non-differentiable noise term, and use bespoke data processing to remove systematic errors and noise. The approach is designed to prioritize up-to-date estimates. Our method is validated against published consensus
R
-numbers from the UK government and is shown to produce comparable results two weeks earlier. The case-driven approach is combined with weight–shift–scale methods to monitor trends in the epidemic and for medium-term predictions. Using case-fatality ratios, we create a narrative for trends in the UK epidemic: increased infectiousness of the B1.117 (Alpha) variant, and the effectiveness of vaccination in reducing severity of infection. For longer-term future scenarios, we base future
R
(
t
)
on insight from localized spread models, which show
R
(
t
)
going asymptotically to 1 after a transient, regardless of how large the
R
transient is. This accords with short-lived peaks observed in case data. These cannot be explained by a well-mixed model and are suggestive of spread on a localized network.
This article is part of the theme issue ‘Technical challenges of modelling real-life epidemics and examples of overcoming these’.
Corporate social responsibility (CSR) is increasingly ubiquitous, but firms differ in their emphasis on conforming to industry CSR norms versus using CSR strategically to differentiate from ...competitors. Research explains that managers attempt to balance conformity and differentiation regarding CSR but does not explain what shifts this balance. We draw from optimal distinctiveness research to explain how different types of uncertainty created by industry task environments shift the balance between conforming to industry CSR norms and pursuing differentiated CSR activities. Using variance decomposition on a 9-year panel of 3,184 firms from 357 industries in the United States, we find that managers emphasize normative (strategic) CSR to a greater (lesser) extent in low-munificence and high-complexity task environments, where uncertainty drives managers toward the security of established industry CSR norms, and to a lesser (greater) extent in high-dynamism task environments, where following uncertain CSR norms is less attractive. We also find that the influence of uncertainty created by industry task environments has, on balance, remained constant as business norms shifted from shareholder to stakeholder primacy. Our theoretical framework reveals task environmental uncertainty as an antecedent to how managers attempt to achieve optimal distinctiveness regarding CSR and explains how different sources of uncertainty shape these attempts.
Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. ...This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r
values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.
Recent studies reveal that Seneca Valley Virus (SVV) exploits tumor endothelial marker 8 (TEM8) for cellular entry, the same surface receptor pirated by bacterial-derived anthrax toxin. This ...observation is particularly significant as SVV is a known oncolytic virus which selectively infects and kills tumor cells, particularly those of neuroendocrine origin. TEM8 is a transmembrane glycoprotein that is preferentially upregulated in some tumor cell and tumor-associated stromal cell populations. Both TEM8 and SVV have been evaluated for targeting of tumors of multiple origins, but the connection between the two was previously unknown. Here, we review currently understood interactions between TEM8 and SVV, anthrax protective antigen (PA), and collagen VI, a native binding partner of TEM8, with an emphasis on potential therapeutic directions moving forward.
Abstract Neuroinflammation is recognized as one of the obligatory pathogenic features of neurodegenerative diseases including Alzheimer’s, Parkinson’s or prion diseases. In prion diseases, space and ...time correlations between deposition of disease-associated, pathogenic form of the prion protein or PrP Sc and microglial-mediated neuroinflammation has been established. Yet, it remains unclear whether activation of microglia is triggered directly by a contact with PrP Sc , and what molecular features of PrP Sc microglia sense and respond to that drive microglia to inflammatory states. The current study asked the questions whether PrP Sc can directly trigger activation of microglia and whether the degree of microglia response depends on the nature of terminal carbohydrate groups on the surface of PrP Sc particles. PrP Sc was purified from brains of mice infected with mouse-adapted prion strain 22L or neuroblastoma N2a cells stably infected with 22L. BV2 microglial cells or primary microglia were cultured in the presence of purified 22L. We found that exposure of BV2 cells or primary microglia to purified PrP Sc triggered proinflammatory responses characterized by an increase in the levels of TNFα, IL6, nitric oxide (NO) and expression of inducible Nitric Oxide Synthase (iNOS). Very similar patterns of inflammatory response were induced by PrP Sc purified from mouse brains and neuroblastoma cells arguing that microglia response is independent of the source of PrP Sc . To test whether the microglial response is mediated by carbohydrate epitopes on PrP Sc surface, the levels of sialylation of PrP Sc N-linked glycans was altered by treatment of purified PrP Sc with neuraminidase. Partial cleavage of sialic acid residues was found to boost the inflammatory response of microglia to PrP Sc . Moreover, transient degradation of Iκβα observed upon treatment with partially desialylated PrP Sc suggests that canonical NFκB activation pathway is involved in inflammatory response. The current study is the first to demonstrate that PrP Sc can directly trigger inflammatory response in microglia. In addition, this work provides direct evidence that the chemical nature of the carbohydrate groups on PrP Sc surface is important for microglial activation.
Macrolide antibiotics for bronchiectasis Kelly, Carol; Chalmers, James D; Crossingham, Iain ...
Cochrane database of systematic reviews,
03/2018, Letnik:
2018, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Background
Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways ...leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long‐term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance.
Objectives
To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis.
Search methods
We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018.
Selection criteria
We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long‐term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high‐resolution computed tomography. We excluded studies in which participants had received continuous or high‐dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events.
Data collection and analysis
Two review authors independently screened the titles and s of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane.
Main results
We included 14 parallel‐group RCTs and one cross‐over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.
We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.
In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate‐quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate‐quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD ‐8.90, 95% CI ‐13.13 to ‐4.67; 68 participants; one study; moderate‐quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low‐quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non‐respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low‐quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo.
In children, exacerbation frequency was reduced more with macrolides than with placebo (IRR 0.50, 95% CI 0.35 to 0.71; 89 children; one study; low‐quality evidence). However there was no significant difference in this age group with regard to: hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low‐quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low‐quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide‐resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children.
Authors' conclusions
Long‐term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.
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