Continuous lines- Promotion, Discontinuous lines- Inhibition; * Effect exerted by probiotics in animal studies, # Effect exerted by probiotics in human studies; eNOS, Endothelial Nitric Oxide ...Synthase; ICAM-1, Intercellular Adhesion Molecule 1; IκBα, Nuclear Factor Kappa B Inhibitor Alpha; IL-6, Interleukin-6; LPS, Lipopolysaccharides; MAPK, Mitogen-Activated Protein Kinase; MyD88, Myeloid Differentiation Primary Response 88; NADPH, Nicotinamide Adenine Dinucleotide Phosphate; NF-κB, Nuclear Factor Kappa B; NO, Nitric Oxide; ROS, Reactive Oxygen Species; TLR4, Toll-like Receptor 4; VCAM-1, Vascular Cell Adhesion Molecule 1.
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•LPS, a component of gram-negative bacteria, exerts a hypertensive effect.•LPS directly initiates interrelated redox and kinase-dependent signalling pathways through endothelial TLR4 activation.•Endothelial dysfunction and vascular inflammation play a significant role in the pathophysiology of hypertension.•Probiotics exert antihypertensive effect in hypertensive individuals.
High blood pressure (BP) presents a significant public health challenge. Recent findings suggest that altered microbiota can exert a hypertensive effect on the host. One of the possible mechanisms involved is the chronic translocation of its components, mainly lipopolysaccharides (LPS) into systemic circulation leading to metabolic endotoxemia. In animal models, LPS has been commonly used to induce endothelial dysfunction and vascular inflammation. In human studies, plasma LPS concentration has been positively correlated with hypertension, however, the mechanistic link has not been fully elucidated. It is hypothesised here that the LPS-induced direct alterations to the vascular endothelium and resulting hypertension are possible targets for probiotic intervention.
The methodology of this review involved a systematic search of the literature with critical appraisal of papers. Three tranches of search were performed: 1) existing review papers; 2) primary mechanistic animal, in vitro and human studies; and 3) primary intervention studies. A total of 70 peer-reviewed papers were included across the three tranches and critically appraised using SIGN50 for human studies and the ARRIVE guidelines for animal studies. The extracted information was coded into key themes and summarized in a narrative analysis.
Results highlight the role of LPS in the activation of endothelial toll-like receptor 4 (TLR4) initiating a cascade of interrelated signalling pathways including: 1) Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/ Reactive oxygen species (ROS)/ Endothelial nitric oxide synthase (eNOS) pathway leading to endothelial dysfunction; and 2) Mitogen-Activated Protein Kinase (MAPK) and Nuclear factor kappa B (NF-κB) pathways leading to vascular inflammation. Findings from animal intervention studies suggest an improvement in vasorelaxation, vascular inflammation and hypertension following probiotic supplementation, which was mediated by downregulation of LPS-induced pathways. Randomised controlled trials (RCTs) and systematic reviews provided some evidence for the anti-inflammatory effect of probiotics with statistically significant antihypertensive effect in clinical samples and may offer a viable intervention for the management of hypertension.
There is growing global concern over the chemical, biological and ecological impact of plastics in the ocean. Remote sensing has the potential to provide long-term, global monitoring but for marine ...plastics it is still in its early stages. Some progress has been made in hyperspectral remote sensing of marine macroplastics in the visible (VIS) to short wave infrared (SWIR) spectrum. We present a reflectance model of sunlight interacting with a sea surface littered with macro plastics, based on geometrical optics and the spectral signatures of plastic and seawater. This is a first step towards the development of a remote sensing algorithm for marine plastic using light reflectance measurements in air. Our model takes the colour, transparency, reflectivity and shape of plastic litter into account. This concept model can aid the design of laboratory, field and Earth observation measurements in the VIS-SWIR spectrum and explain the results.
•A concept spectral model is derived for the calculation of sea surface plastic.•Marine plastic litter should be visible with spectral light reflectance measurements.•Light reflectance controls the remote sensing signal of marine plastic litter.
There is growing global awareness of the presence and negative impacts of waste plastic in the marine environment. Risks to wildlife include ingestion and entanglement for macro-plastic (larger than ...5 mm in length), alongside food chain transfer for micro-plastics (less than 5 mm in length). Plastics in the marine environment have also been shown to adsorb and accumulate contaminants from seawater, e.g., heavy metals and hydrophobic organic compounds. This means that plastics can additionally act as vectors for transport of contaminants, permitting ecotoxicological risks to be spatially extended. However, the ability of waste plastic to adsorb pollutants also offers potential opportunity, if they can be used for the decontamination of wastewater. Here, we provide an overview of marine plastic types and distribution, and then systematically assess their potential to be repurposed as novel adsorbents. Data published in recent years are interrogated to gain an overview of the interaction mechanisms between marine plastics and both organic and inorganic contaminants. In addition, factors that may be exploited to enhance their performance in removal of contaminants are also reviewed and prioritised, e.g., surface modification and activation. This paper highlights the novel potential of repurposing plastic waste for wastewater treatment applications and seeks to identify key knowledge gaps and future research priorities for scientists and engineers.
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•The global use of plastic has resulted in plastic waste becoming a major issue in the environment.•Marine plastic waste can act as a vector for pollutants in aquatic systems.•The mechanisms of pollutant adsorption are complex and require further exploration.•SEM-EDX, BET, FTIR and XRD can be used to explore mechanisms.•Future studies should consider the potential utilisation of plastic waste as an adsorbent.
From the American and British counter-insurgency in Iraq to the bombing of Dresden and the Amristar Massacre in India, civilians are often abused and killed when they are caught in the cross-fire of ...wars and other conflicts. In Democracy's Blameless Leaders, Neil Mitchell examines how leaders in democracies manage the blame for the abuse and the killing of civilians, arguing that politicians are likely to react in a self-interested and opportunistic way and seek to deny and evade accountability. Using empirical evidence from well-known cases of abuse and atrocity committed by the security forces of established, liberal democracies, Mitchell shows that self-interested political leaders will attempt to evade accountability for abuse and atrocity, using a range of well-known techniques including denial, delay, diversion, and delegation to pass blame for abuse and atrocities to the lowest plausible level. Mitchell argues that, despite the conventional wisdom that accountability is a 'central feature' of democracies, it is only a rare and courageous leader who acts differently, exposing the limits of accountability in democratic societies. As democracies remain embroiled in armed conflicts, and continue to try to come to grips with past atrocities, Democracy's Blameless Leaders provides a timely analysis of why these events occur, why leaders behave as they do, and how a more accountable system might be developed.
Marine plastic pollution is an increasing, and global, environmental issue. Numerous marine species are affected by plastic debris through entanglement, nest incorporation, and ingestion, which can ...lead to lethal and sub-lethal impacts. However, in the northeastern Atlantic Ocean, an area of international importance for seabirds, there has been little effort to date to assess information from studies of wildlife and plastic to better understand the spatiotemporal variation of how marine plastic affects different seabird species. To improve our understanding of seabirds and marine plastic in this region, we completed a synthesis of the published and grey literature to obtain information on all known documented cases of plastic ingestion and nest incorporation by this group. We found that of 69 seabird species that commonly occur in the northeastern Atlantic, 25 had evidence of ingesting plastic. However, data on plastic ingestion was available for only 49% of all species, with 74% of investigated species recorded ingesting plastic. We found only three published studies on nest incorporation, for the Northern Gannet (Morus bassanus) and Black-legged Kittiwake (Rissa tridactyla). For many species, sample sizes were small or not reported, and only 39% of studies were from the 21st century, whilst information from multiple countries and years was only available for 11 species. This indicates that we actually know very little about the current prevalence of plastic ingestion and nest incorporation for many species, several of them globally threatened. Furthermore, in the majority of studies, the metrics reported were inadequate to carry out robust comparisons among locations and species or perform meta-analyses. We recommend multi-jurisdictional collaboration to obtain a more comprehensive and current understanding of how marine plastic is affecting seabirds in the northeastern Atlantic Ocean.
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•Among the 34 studied species, 74% were recorded to ingest plastic.•Only 16% of species had data on plastic ingestion for multiple countries and years.•In this region, 51% of species have not been investigated for plastic ingestion.•Published data on nest incorporation of plastic was available for just two species.•We recommend multi-jurisdictional collaboration in future monitoring.
Only 49% of commonly occurring northeastern Atlantic seabird species have been investigated for active interactions with marine plastic pollution, with 74% of these found to ingest plastic or incorporate it into their nests.
UNHCR, the world's largest humanitarian organization charged with assisting displaced people globally, estimates over 60 per cent of refugees now live in urban areas. This book explores how UNHCR's ...approach to urban displacement has changed since the 1990s through an in-depth study of how UNHCR works and conceives its role in global politics today.
Vascular endothelial growth factor (VEGF) signaling is key to tumor angiogenesis and is an important target in the development of anticancer drugs. However, VEGF receptor (VEGFR) expression in human ...cancers, particularly the relative expression of VEGFR-2 and VEGFR-3 in tumor vasculature versus tumor cells, is poorly defined.
VEGFR-2- and VEGFR-3-specific antibodies were identified and used in the immunohistochemical analysis of human primary cancers and normal tissue. The relative vascular localization of both receptors in colorectal and breast cancers was determined by coimmunofluorescence with vascular markers.
VEGFR-2 and VEGFR-3 were expressed on vascular endothelium but not on malignant cells in 13 common human solid tumor types (n > 400, bladder, breast, colorectal, head and neck, liver, lung, skin, ovarian, pancreatic, prostate, renal, stomach, and thyroid). The signal intensity of both receptors was significantly greater in vessels associated with malignant colorectal, lung, and breast than adjacent nontumor tissue. In colorectal cancers, VEGFR-2 was expressed on both intratumoral blood and lymphatic vessels, whereas VEGFR-3 was found predominantly on lymphatic vessels. In breast cancers, both receptors were localized to and upregulated on blood vessels.
VEGFR-2 and VEGFR-3 are primarily localized to, and significantly upregulated on, tumor vasculature (blood and/or lymphatic) supporting the majority of solid cancers. The primary clinical mechanism of action of VEGF signaling inhibitors is likely to be through the targeting of tumor vessels rather than tumor cells. The upregulation of VEGFR-3 on tumor blood vessels indicates a potential additional antiangiogenic effect for dual VEGFR-2/VEGFR-3-targeted therapy.
DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA ...double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.
The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and ...traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.
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