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A review is presented of the manufacture and use of different types of plastic, and the effects of pollution by these materials on animal, human and environmental health, insofar as this is known. Since 2004, the world has made as much plastic as it did in the previous half century, and it has been reckoned that the total mass of virgin plastics ever made amounts to 8.3 billion tonnes, mainly derived from natural gas and crude oil, used as chemical feedstocks and fuel sources. Between 1950 and 2015, a total of 6.3 billion tonnes of primary and secondary (recycled) plastic waste was generated, of which around 9% has been recycled, and 12% incinerated, with the remaining 79% either being stored in landfills or having been released directly into the natural environment. In 2015, 407 million tonnes (Mt) of plastic was produced, of which 164 Mt was consumed by packaging (36% of the total). Although quoted values vary, packaging probably accounts for around one third of all plastics used, of which approximately 40% goes to landfill, while 32% escapes the collection system. It has been deduced that around 9 Mt of plastic entered the oceans in 2010, as a result of mismanaged waste, along with up to 0.5 Mt each of microplastics from washing synthetic textiles, and from the abrasion of tyres on road surfaces. However, the amount of plastics actually measured in the oceans represents less than 1% of the (at least) 150 Mt reckoned to have been released into the oceans over time. Plastic accounts for around 10% by mass of municipal waste, but up to 85% of marine debris items – most of which arrive from land-based sources. Geographically, the five heaviest plastic polluters are P.R. China, Indonesia, Philippines, Vietnam and Sri Lanka, which between them contribute 56% of global plastic waste. Larger, primary plastic items can undergo progressive fragmentation to yield a greater number of increasingly smaller 'secondary' microplastic particles, thus increasing the overall surface area of the plastic material, which enhances its ability to absorb, and concentrate, persistent organic pollutants (POPs) such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), with the potential to transfer them to the tissues of animals that ingest the microplastic particles, particularly in marine environments. Although fears that such microparticles and their toxins may be passed via food webs to humans are not as yet substantiated, the direct ingestion of microplastics by humans via drinking water is a distinct possibility – since 92% of samples taken in the USA and 72% in Europe showed their presence – although any consequent health effects are as yet unclear. Foodstuffs may also become contaminated by microplastics from the air, although any consequent health effects are also unknown. In regard to such airborne sources, it is noteworthy that small plastic particles have been found in human lung tissue, which might prove an adverse health issue under given circumstances. It is also very striking that microplastics have been detected in mountain soils in Switzerland, which are most likely windborne in origin. Arctic ice core samples too have revealed the presence of microplastics, which were most likely carried on ocean currents from the Pacific garbage patch, and from local pollution from shipping and fishing. Thus, sea ice traps large amounts of microplastics and transports them across the Arctic Ocean, but these particles will be released into the global environment when the ice melts, particularly under the influence of a rising mean global temperature. While there is a growing emphasis toward the substitution of petrochemically derived plastics by bioplastics, controversy has arisen in regard to how biodegradable the latter actually are in the open environment, and they presently only account for 0.5% of the total mass of plastics manufactured globally. Since the majority of bioplastics are made from sugar and starch materials, to expand their use significantly raises the prospect of competition between growing crops to supply food or plastics, similarly to the diversion of food crops for the manufacture of primary biofuels. The use of oxo-plastics, which contain additives that assist the material to degrade, is also a matter of concern, since it is claimed that they merely fragment and add to the environmental burden of microplastics; hence, the European Union has moved to restrict their use. Since 6% of the current global oil (including natural gas liquids, NGLs) production is used to manufacture plastic commodities – predicted to rise to 20% by 2050 – the current approaches for the manufacture and use of plastics (including their end-use) demand immediate revision. More extensive collection and recycling of plastic items at the end of their life, for re-use in new production, to offset the use of virgin plastic, is a critical aspect both for reducing the amount of plastic waste entering the environment, and in improving the efficiency of fossil resource use. This is central to the ideology underpinning the circular economy, which has common elements with permaculture, the latter being a regenerative design system based on 'nature as teacher', which could help optimise the use of resources in town and city environments, while minimising and repurposing 'waste'. Thus, food might be produced more on the local than the global scale, with smaller inputs of fuels (including transportation fuels for importing and distributing food), water and fertilisers, and with a marked reduction in the use of plastic packaging. Such an approach, adopted by billions of individuals, could prove of immense significance in ensuring future food security, and in reducing waste and pollution – of all kinds.

Plastic packaging accounts for 36% of all plastics made, but amounts to 47% of all plastic waste; 90% of all plastic items are used once and then discarded, which corresponds to around 50% of the total mass of plastics manufactured. Evidence for the ubiquity of microplastic pollution is accumulating rapidly, and wherever such material is sought, it seems to be found. Thus, microplastics have been identified in Arctic ice, the air, food and drinking water, soils, rivers, aquifers, remote maintain regions, glaciers, the oceans and ocean sediments, including waters and deep sea sediments around Antarctica, and within the deepest marine trenches of the Earth. They have also been detected in the bodies of animals, including humans, and as being passed along the hierarchy of food chains, up to marine top predators. Evidence has also been presented that microplastics are able to cross different life stages of mosquito that use different habitats – larva (feeding) to pupa (non-feeding) to adult terrestrial (flying) – and therefore can be spread from aquatic systems by flying insects. The so-called 'missing plastic problem' appears to be, in part, due to limitations in sampling methods, that is, many of the very small microplastic particles may simply escape capture in the trawl nets that are typically employed to collect them, but have been evidenced in grab-sampling experiments. Moreover, it is simply not possible to measure entirely through the vast, oceanic volumes of the oceans. It can, however, be concluded with some confidence that the majority of the plastic is not located at the sea surface, and indeed, several different sinks have been proposed for microplastics, including the sea floor and sediments, the ocean column itself, ice sheets, glaciers and soils. The treatment of land with sewage sludge is also thought to make a significant contribution of microplastics to soil. A substantial amount of airborne microparticulate pollution is created by the abrasion of tyres on road surfaces (and other 'non-exhaust' sources), meaning that even electric vehicles are not 'clean' in this regard, despite their elimination of tailpipe PM2.5 and PM10 emissions. The emergence of nanoplastics in the environment poses a new set of potential threats, although any impacts on human health are not yet known, save, as indicated from model studies. While improved design, manufacture, collection, reuse, repurposing and reprocessing/recycling of plastic items are necessary, overwhelmingly, a curbing in the use of plastic materials in the first place is demanded, particularly from single-use packaging. However, plastic pollution is just one element in the overall matrix of a changing climate ('the world's woes') and must be addressed as part of an integrated consideration of how we use all resources, fossil and otherwise, and the need to change our expectations, goals and lifestyles. In this effort, the role of deglobalisation/relocalisation may prove critical: thus, food and other necessities might be produced more on the local than the global scale, with smaller inputs of fossil fuels for transportation and other purposes, water and fertilisers, along with a marked reduction in the need for plastic packaging.

A review is made of the current state of agriculture, emphasising issues of soil erosion and dependence on fossil fuels, in regard to achieving food security for a relentlessly enlarging global population. Soil has been described as \"the fragile, living skin of the Earth\", and yet both its aliveness and fragility have all too often been ignored in the expansion of agriculture across the face of the globe. Since it is a pivotal component in a global nexus of soil-water-air-energy, how we treat the soil can impact massively on climate change – with either beneficial or detrimental consequences, depending on whether the soil is preserved or degraded. Regenerative agriculture has at its core the intention to improve the health of soil or to restore highly degraded soil, which symbiotically enhances the quality of water, vegetation and land-productivity. By using methods of regenerative agriculture, it is possible not only to increase the amount of soil organic carbon (SOC) in existing soils, but to build new soil. This has the effect of drawing down carbon from the atmosphere, while simultaneously improving soil structure and soil health, soil fertility and crop yields, water retention and aquifer recharge – thus ameliorating both flooding and drought, and also the erosion of further soil, since runoff is reduced. Since food production on a more local scale is found to preserve the soil and its quality, urban food production should be seen as a significant potential contributor to regenerative agriculture in the future, so long as the methods employed are themselves 'regenerative'. If localisation is to become a dominant strategy for dealing with a vastly reduced use of fossil fuels, and preserving soil quality – with increased food production in towns and cities – it will be necessary to incorporate integrated ('systems') design approaches such as permaculture and the circular economy (which minimise and repurpose 'waste') within the existing urban infrastructure. In addition to growing food in urban space, such actions as draught-proofing and thermally insulating existing building stock, and living/working on a more local scale, would serve well to cut our overall energy consumption. In order to curb our use of fossil fuels, methods for reducing overall energy use must be considered at least equally important to expanding low-carbon energy production. In synopsis, it is clear that only by moving from the current linear, 'take, make, dispose(waste-creation)' model for resource-consumption, to the systemic, circular alternative of 'reduce, reuse, recycle, regenerate', are we likely to meet demands for future generations.

Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. Homoeostatic effects of flow-activated transcription factor Krüppel-like factor 2 (KLF2) are compromised in PAH. Here, we show that KLF2-induced exosomal microRNAs, miR-181a-5p and miR-324-5p act together to attenuate pulmonary vascular remodelling and that their actions are mediated by Notch4 and ETS1 and other key regulators of vascular homoeostasis. Expressions of KLF2, miR-181a-5p and miR-324-5p are reduced, while levels of their target genes are elevated in pre-clinical PAH, idiopathic PAH and heritable PAH with missense p.H288Y KLF2 mutation. Therapeutic supplementation of miR-181a-5p and miR-324-5p reduces proliferative and angiogenic responses in patient-derived cells and attenuates disease progression in PAH mice. This study shows that reduced KLF2 signalling is a common feature of human PAH and highlights the potential therapeutic role of KLF2-regulated exosomal miRNAs in PAH and other diseases associated with vascular remodelling. Pulmonary arterial hypertension is a severe lung disease characterised by progressive vascular remodelling. Here, the authors show that reduced signalling of flow-activated transcription factor KLF2 is a common feature of human PAH and that KLF2-regulated exosomal miRNAs have a therapeutic effect.

Calcitonin receptor ( Calcr )-expressing neurons of the nucleus tractus solitarius (NTS; Calcr NTS cells) contribute to the long-term control of food intake and body weight. Here, we show that Prlh -expressing NTS (Prlh NTS ) neurons represent a subset of Calcr NTS cells and that Prlh expression in these cells restrains body weight gain in the face of high fat diet challenge in mice. To understand the relationship of Prlh NTS cells to hypothalamic feeding circuits, we determined the ability of Prlh NTS -mediated signals to overcome enforced activation of AgRP neurons. We found that Prlh NTS neuron activation and Prlh overexpression in Prlh NTS cells abrogates AgRP neuron-driven hyperphagia and ameliorates the obesity of mice deficient in melanocortin signaling or leptin. Thus, enhancing Prlh -mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity, demonstrating that NTS-mediated signals can override the effects of orexigenic hypothalamic signals on long-term energy balance. Calcitonin receptor-expressing neurons of the nucleus tractus solitarius contribute to long-term control of food intake and body weight. The authors show that a subset of these cells expresses Prlh and that enhancing Prlh-mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity in mice.

The brainstem dorsal vagal complex (DVC) is known to regulate energy balance and is the target of appetite-suppressing hormones, such as glucagon-like peptide 1 (GLP-1). Here we provide a comprehensive genetic map of the DVC and identify neuronal populations that control feeding. Combining bulk and single-nucleus gene expression and chromatin profiling of DVC cells, we reveal 25 neuronal populations with unique transcriptional and chromatin accessibility landscapes and peptide receptor expression profiles. GLP-1 receptor (GLP-1R) agonist administration induces gene expression alterations specific to two distinct sets of Glp1r neurons—one population in the area postrema and one in the nucleus of the solitary tract that also expresses calcitonin receptor ( Calcr ). Transcripts and regions of accessible chromatin near obesity-associated genetic variants are enriched in the area postrema and the nucleus of the solitary tract neurons that express Glp1r and/or Calcr , and activating several of these neuronal populations decreases feeding in rodents. Thus, DVC neuronal populations associated with obesity predisposition suppress feeding and may represent therapeutic targets for obesity. Ludwig et al. map transcription and chromatin accessibility in single cells across the brainstem dorsal vagal complex, thereby identifying neuronal populations, including some that control feeding.

Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a glucagon-like protein-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist, was shown to reduce blood glycaemia, body weight and hepatic steatosis in people with type 2 diabetes mellitus. Here, we demonstrate that the effects of cotadutide in reducing body weight and food intake and improving glucose control are predominantly mediated through Glp-1 signalling, whereas its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signalling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism enzymes in liver of mice treated with cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, consistent with a unique therapeutic contribution of GCGR agonism by cotadutide in vivo. Notably, cotadutide also alleviated fibrosis to a greater extent than liraglutide or obeticholic acid, despite dose adjustment to achieve similar weight loss in two preclinical mouse models of NASH. Thus, cotadutide, via direct hepatic (GcgR) and extrahepatic (Glp-1R) effects, exerts multifactorial improvement in liver function and is a promising therapeutic option for the treatment of steatohepatitis. Currently, there is no approved treatment for NAFLD and NASH. Here, Boland et al. show that the GLP-1R and GCGR dual-agonist cotadutide reduces hepatic steatosis, inflammation and fibrosis via GCGR agonism, and glucose homeostasis and weight gain by activating GLP-1 signalling.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy characterized by extensive pre-capillary arterial remodeling, instigating increased pulmonary vascular resistance and eventual right heart failure. Rare mutations in the SOX17 gene and common variants in the enhancer region are thought to predispose to PAH. Central to the PAH pathobiology is lung immune cell recruitment, orchestrated by the overproduction of chemokines (e.g. CXCL10) via the induction of NF-κB. Emerging evidence from murine models of SOX17 impairment suggests perivascular leukocyte accumulation in the lung, likely due to disordered inflammatory mediator expression. Therefore, in the current study we assessed the role of SOX17 deficiency in human pulmonary artery endothelial cells (HPAECs) on selected inflammatory mediator release. Following a semi-quantitative array of 100 cytokines and chemokines, we identified markedly elevated CXCL10 and CXCL11 mRNA and soluble protein release in SOX17 -silenced HPAECs (versus control siRNA-treated cells), driven by excessive NF-κB p65 activity. Further, we show that plasma CXCL10 levels are raised in a small cohort ( n  = 3) of carriers of pathogenic SOX17 rare variants versus healthy controls. Finally, SOX17 knockdown HPAEC supernatants mediated the in vitro migration of transfectants expressing CXCR3. Therefore, enhanced lymphocyte migration may be a pathomechanism of PAH due to SOX17 loss, driven by a CXCL10/CXCL11/CXCR3 axis.

An early driver of Type 2 diabetes mellitus (T2D) is ectopic fat accumulation, especially in the liver, that impairs insulin sensitivity. In T2D, GLP-1R/GCGR dual-agonists reduce glycaemia, body weight and hepatic steatosis. Here, we utilize cotadutide, a well characterized GLP-1R/GCGR dual-agonist, and demonstrate improvement of insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese (DIO) mice. Phosphoproteomic analyses of insulin stimulated liver from cotadutide-treated mice identifies previously unknown and known phosphorylation sites on key insulin signaling proteins associated with improved insulin sensitivity. Cotadutide or GCGR mono-agonist treatment also increases brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R mono-agonist shows a weak effect. BAT from cotadutide-treated mice have induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Finally, the cotadutide-induced improvement in insulin sensitivity is associated with reduction of insulin secretion from isolated pancreatic islets indicating reduced insulin secretory demand. Here we show, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a potentially effective T2D treatment. Early drivers of T2D include ectopic fat accumulation that impairs insulin sensitivity. Here, the authors show that GLP1/GCGR dual agonism provides multimodal benefits in obese male mice by reducing liver fat and improving insulin sensitivity resulting in endogenous β-cell recovery.