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Organosilanes are widely used to bond organic materials such as polymers to inorganic materials in polymer composites. However, the mechanism of adhesion is poorly understood. One postulated mechanism is the interdiffusion of the silane and polymer, along with condensation of the silane to form an interpenetrating polymer network (IPN). The techniques of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and Raman confocal microscopy have been used to study the diffusion, hydrolysis and condensation of three organosilanes in silicon / PVC / silane laminates. These processes are thought to contribute to the formation of the IPN, and hence to be vital for adhesion. The organosilanes studied were [3-(amino)propyl]trimethoxysilane, also known as A1110, [3-(phenylamino)propyl]trimethoxysilane, known as Y9669, and [3-(mercapto)propyl]triethoxysilane, known as A1891.ATR-FTIR was shown to be an excellent technique for studying the kinetics of silane diffusion through PVC films. It was shown that at room temperature, no diffusion through unplasticised PVC films occurred. At 70 °C, however, diffusion occurred readily for Y9669 and A1891. In plasticised PVC films, diffusion was observed for all three silanes at room temperature. It was shown that the diffusion occurred more quickly with higher plasticiser concentrations, and hence lower glass transition temperatures. The kinetics of diffusion was found to fit a dual mode sorption model. Hydrolysis of the silanes was also followed by infrared spectroscopy, and the kinetics of hydrolysis and condensation were shown to be highly dependent upon silane type, the concentration of water, and the presence of an acid catalyst. The hydrolysis of the silanes was found to slow their diffusion through both plasticised and unplasticised PVC films. It was shown that the presence of water in the films caused the hydrolysis of the silanes in situ. Raman depth profiles were measured of the films before, during and after diffusion. The spatial resolution was shown to be adversely affected by refraction at the air / PVC interface. It was shown that it is possible to deconvolve the confocal response of the microscope from the depth profiles, resulting in greater spatial resolution. Hydrolysis of the silanes was followed in solution by Raman spectroscopy, and it was found that each of the three silanes showed different rates of hydrolysis and condensation. It was shown that it was also possible to follow the kinetics of diffusion by Raman microscopy, and the results agreed well with those shown by ATR-FTIR spectroscopy.

AbstractObjectiveTo compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation.DesignSystematic review, network meta-analysis, and cost effectiveness analysis.Data sourcesMedline, PreMedline, Embase, and The Cochrane Library.Eligibility criteria for selecting studiesPublished randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation.Results23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin.ConclusionsThe network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis.Systematic review registrationPROSPERO CRD 42013005324.

Severe acute respiratory syndrome (SARS) emerged in 2002 to 2003 in southern China. The origin of its etiological agent, the SARS coronavirus (SARS-CoV), remains elusive. Here we report that species of bats are a natural host of coronaviruses closely related to those responsible for the SARS outbreak. These viruses, termed SARS-like coronaviruses (SL-CoVs), display greater genetic variation than SARS-CoV isolated from humans or from civets. The human and civet isolates of SARS-CoV nestle phylogenetically within the spectrum of SL-CoVs, indicating that the virus responsible for the SARS outbreak was a member of this coronavirus group.

Singlet molecular oxygen ( 1 O 2 ) has well-established roles in photosynthetic plants, bacteria and fungi 1 – 3 , but not in mammals. Chemically generated 1 O 2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N- formylkynurenine 4 , whereas enzymatic oxidation of tryptophan to N- formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1 5 . Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure 6 . However, whether indoleamine 2,3-dioxygenase 1 forms 1 O 2 and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of 1 O 2 . We observed that in the presence of hydrogen peroxide, the enzyme generates 1 O 2 and that this is associated with the stereoselective oxidation of l -tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1α. Our findings demonstrate a pathophysiological role for 1 O 2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. Singlet molecular oxygen, produced by indoleamine 2,3-dioxygenase 1 activity, gives rise to a signalling molecule that regulates arterial relaxation under inflammatory conditions.

One vision of a future artificial intelligence (AI) is where many separate units can learn independently over a lifetime and share their knowledge with each other. The synergy between lifelong learning and sharing has the potential to create a society of AI systems, as each individual unit can contribute to and benefit from the collective knowledge. Essential to this vision are the abilities to learn multiple skills incrementally during a lifetime, to exchange knowledge among units via a common language, to use both local data and communication to learn, and to rely on edge devices to host the necessary decentralized computation and data. The result is a network of agents that can quickly respond to and learn new tasks, that collectively hold more knowledge than a single agent and that can extend current knowledge in more diverse ways than a single agent. Open research questions include when and what knowledge should be shared to maximize both the rate of learning and the long-term learning performance. Here we review recent machine learning advances converging towards creating a collective machine-learned intelligence. We propose that the convergence of such scientific and technological advances will lead to the emergence of new types of scalable, resilient and sustainable AI systems. An emerging research area in AI is developing multi-agent capabilities with collections of interacting AI systems. Andrea Soltoggio and colleagues develop a vision for combining such approaches with current edge computing technology and lifelong learning advances. The envisioned network of AI agents could quickly learn new tasks in open-ended applications, with individual AI agents independently learning and contributing to and benefiting from collective knowledge.

We recently established a large animal model that recapitulates key clinical features of heart failure with preserved ejection fraction (HFpEF) and tested the effects of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA reversed and prevented the development of cardiopulmonary impairment. This study evaluated the effects of SAHA at the level of cardiomyocyte and contractile protein function to understand how it modulates cardiac function. Both isolated adult feline ventricular cardiomyocytes (AFVM) and left ventricle (LV) trabeculae isolated from non-failing donors were treated with SAHA or vehicle before recording functional data. Skinned myocytes were isolated from AFVM and human trabeculae to assess myofilament function. SAHA-treated AFVM had increased contractility and improved relaxation kinetics but no difference in peak calcium transients, with increased calcium sensitivity and decreased passive stiffness of myofilaments. Mass spectrometry analysis revealed increased acetylation of the myosin regulatory light chain with SAHA treatment. SAHA-treated human trabeculae had decreased diastolic tension and increased developed force. Myofilaments isolated from human trabeculae had increased calcium sensitivity and decreased passive stiffness. These findings suggest that SAHA has an important role in the direct control of cardiac function at the level of the cardiomyocyte and myofilament by increasing myofilament calcium sensitivity and reducing diastolic tension.

Background HIV remains the largest cause of disease burden among men and women of reproductive age in sub-Saharan Africa. Voluntary medical male circumcision (VMMC) reduces the risk of female-to-male transmission of HIV by 50–60%. The World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) identified 14 priority countries for VMMC campaigns and set a coverage goal of 80% for men ages 15–49. From 2008 to 2017, over 18 million VMMCs were reported in priority countries. Nonetheless, relatively little is known about local variation in male circumcision (MC) prevalence. Methods We analyzed geo-located MC prevalence data from 109 household surveys using a Bayesian geostatistical modeling framework to estimate adult MC prevalence and the number of circumcised and uncircumcised men aged 15–49 in 38 countries in sub-Saharan Africa at a 5 × 5-km resolution and among first administrative level (typically provinces or states) and second administrative level (typically districts or counties) units. Results We found striking within-country and between-country variation in MC prevalence; most (12 of 14) priority countries had more than a twofold difference between their first administrative level units with the highest and lowest estimated prevalence in 2017. Although estimated national MC prevalence increased in all priority countries with the onset of VMMC campaigns, seven priority countries contained both subnational areas where estimated MC prevalence increased and areas where estimated MC prevalence decreased after the initiation of VMMC campaigns. In 2017, only three priority countries (Ethiopia, Kenya, and Tanzania) were likely to have reached the MC coverage target of 80% at the national level, and no priority country was likely to have reached this goal in all subnational areas. Conclusions Despite MC prevalence increases in all priority countries since the onset of VMMC campaigns in 2008, MC prevalence remains below the 80% coverage target in most subnational areas and is highly variable. These mapped results provide an actionable tool for understanding local needs and informing VMMC interventions for maximum impact in the continued effort towards ending the HIV epidemic in sub-Saharan Africa.

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1-/-) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1-/- mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.

Issue: The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the increasing ageing population, and is confounded by the high failure rate of translation from rodent-derived therapeutics to clinically effective human neurological interventions. Improved translation is demonstrated using higher order mammals with more complex/comparable neuroanatomy. These animals effectually span this translational disparity and increase confidence in factors including routes of administration/dosing and ability to scale, such that potential therapeutics will have successful outcomes when moving to patients. Coupled with advancements in genetic engineering to produce genetically tailored models, livestock are increasingly being used to bridge this translational gap. Approach: In order to aid in standardising characterisation of such models, we provide comprehensive neurological assessment protocols designed to inform on neuroanatomical dysfunction and/or lesion(s) for large animal species. We also describe the applicability of these exams in different large animals to help provide a better understanding of the practicalities of cross species neurological disease modelling. Recommendation: We would encourage the use of these assessments as a reference framework to help standardise neurological clinical scoring of large animal models.