Estuaries are at the interface of marine and terrestrial systems and as such, are subject to environmental change arising from multiple driving mechanisms, with the interplay between the dominant ...controls varying spatially and temporally. Relative sea-level (RSL) change and sediment supply can play a significant role in driving environmental change. This study examines the relative influence of these drivers during the Holocene. Biostratigraphic records and RSL data are presented from two locations in the inner portion and upper reaches of the macrotidal Humber Estuary, eastern England. The results provide a new terrestrial limiting point and six sea-level index points, two of which at c. 1500 cal years BP provide the youngest sea-level index points for the inner estuary. An early-mid Holocene tidal lagoon system, that lacks modern equivalent, is recorded at one site. The results indicate a shift in the dominance of RSL rise driving the early Holocene creation of wetlands, to sediment supply dominating changes in the mid-late Holocene against the backdrop of a reduced rate of RSL rise, with a submergence of wetlands evident after c. 4000 cal years BP. The persistence of fen carr evident between c. 6800 and 5500 cal years BP suggests stability and resilience of the peatland system to continuing RSL rise. As rates of contemporary RSL rise increase, combined with climate and human impacts on the landscape, the drivers of change in these type of estuary systems will shift, with the records providing analogues of potential system responses that can help inform coastal management strategies.
Hepatic steatosis, a reversible state of metabolic dysregulation, can promote the onset of nonalcoholic steatohepatitis (NASH), and its transition is thought to be critical in disease evolution. The ...association between endoplasmic reticulum (ER) stress response and hepatocyte metabolism disorders prompted us to characterize ER stress-induced hepatic metabolic dysfunction in human induced pluripotent stem cell-derived hepatocytes (hiPSC-Hep), to explore regulatory pathways and validate a phenotypic
model for progression of liver steatosis. We treated hiPSC-Hep with a ratio of unsaturated and saturated fatty acids in the presence of an inducer of ER stress to synergistically promote triglyceride accumulation and dysregulate lipid metabolism. We monitored lipid accumulation by high-content imaging and measured gene regulation by RNA sequencing and reverse transcription quantitative PCR analyses. Our results show that ER stress potentiated intracellular lipid accumulation by 5-fold in hiPSC-Hep in the absence of apoptosis. Transcriptome pathway analysis identified ER stress pathways as the most significantly dysregulated of all pathways affected. Obeticholic acid dose dependently inhibited lipid accumulation and modulated gene expression downstream of the farnesoid X receptor. We were able to identify modulation of hepatic markers and gene pathways known to be involved in steatosis and nonalcoholic fatty liver disease (NAFLD), in support of a hiPSC-Hep disease model that is relevant to clinical data for human NASH. Our results show that the model can serve as a translational discovery platform for the understanding of molecular pathways involved in NAFLD, and can facilitate the identification of novel therapeutic molecules based on high-throughput screening strategies.
The late-Quaternary relative sea-level (RSL) history of Ireland is complex, positioned at the margins of the former British-Irish Ice Sheet, and subject to the influence of ice unloading and ...forebulge collapse. Geophysical models of post-glacial isostatic adjustment (GIA) provide estimates of the pattern of RSL change since deglaciation which may be tested and validated with empirical data from proxy records. For the region of northwest Ireland, there is a paucity of high-quality RSL data and, therefore, equivocal evidence to support the GIA models that predict a mid to Late-Holocene RSL highstand of between +0.5 and +2 m above present. This study aims to investigate this model-data discrepancy by reconstructing RSL change from a near continuous salt-marsh sequence at Bracky Bridge, Donegal, spanning the last ca. 2500 years. We develop a transfer function model to reconstruct the vertical position of sea level using a regional diatom training set to quantify the indicative meaning and predict the palaeomarsh elevation of the core samples. A chronology is provided by a combination of 14C and 210Pb data, with sample specific ages derived from an age-depth model using a Bayesian framework. Our reconstruction shows ca. 2 m of relative sea-level rise in the past 2500 years. This is not compatible with some previously published sea-level index points from the region, which we re-interpret as freshwater/terrestrial limiting data. These results do not provide any evidence to support a Mid-Holocene RSL highstand above present sea level. Whilst none of the available GIA models replicate the timing and magnitude of the Late-Holocene RSL rise in our reconstruction, those which incorporate a thick and extensive British-Irish Sea Ice Sheet provide the best fit.
The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological ...properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.
Pollen diagrams covering the Bronze Age to Roman period from northeast Northumberland are scarce. We present a
14
C-dated pollen record from a peat-filled forest hollow in Chillingham Wild Cattle ...Park, northeast Northumberland, that spans the Iron Age. For the first time for this part of Northumberland, fungal spores are also analysed to investigate whether clearances took place in the context of crop cultivation or pastoralism. The pollen diagram shows significant woodland cover during the Late Bronze Age, with small-scale landscape openness potentially representing crop cultivation and animal grazing under a tree canopy. A local clearance event, with arboreal pollen falling to 13.2%, is radiocarbon dated to the late Early to Middle Iron Age, likely coinciding with the construction and occupancy of the nearby Ros Castle hillfort. A significant rise in dung fungal spores and the presence of
Plantago
and other open vegetation taxa indicate animal husbandry played an important role in this clearance phase. A subsequent large decrease in dung fungi and a small rise in arboreal pollen may reflect a degree of abandonment of the area after the climate cooled. Peat formation ceased in the late Middle to Late Iron Age as the hollow filled up. Limited renewed peat growth occurred in the last century or so, after peat shrinkage due to drying and consequent oxidation provided the possibility for renewed peat formation within the hollow.
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The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ...ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-3.3.1azabicyclononane core. Our lead compound 81 is a potent (EC50 = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.
Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored ...as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) remains a high priority in the medical and scientific community. Drug discovery programs to identify potential therapeutic compounds have supported high throughput/high-content screening of in vitro human-relevant models of NAFLD to accelerate development of efficacious anti-steatotic medicines. Human induced pluripotent stem cell (hiPSC) technology is a powerful platform for disease modeling and therapeutic assessment for cell-based therapy and personalized medicine. In this study, we applied AstraZeneca's chemogenomic library, hiPSC technology and multiplexed high content screening to identify compounds that significantly reduced intracellular neutral lipid content. Among 13,000 compounds screened, we identified hits that protect against hiPSC-derived hepatic endoplasmic reticulum stress-induced steatosis by a mechanism of action including inhibition of the cyclin D3-cyclin-dependent kinase 2-4 (CDK2-4)/CCAAT-enhancer-binding proteins (C/EBPα)/diacylglycerol acyltransferase 2 (DGAT2) pathway, followed by alteration of the expression of downstream genes related to NAFLD. These findings demonstrate that our phenotypic platform provides a reliable approach in drug discovery, to identify novel drugs for treatment of fatty liver disease as well as to elucidate their underlying mechanisms.
Estuaries are unique and complex systems that are important for ecological, cultural and economic reasons. They provide valuable habitat for biodiversity and provide a wide range of regulating, ...cultural and provisioning ecosystem services.
Estuaries have a disproportionate importance to people in comparison to other habitats, which has resulted in high levels of utilization and environmental impact. Poor management, ineffective conservation approaches and global economic changes have resulted in many temperate estuaries becoming both economically and environmentally degraded.
We present an argument for the use of the Natural Capital approach as part of the wider green economic agenda in temperate estuaries to support both the environmental and economic recovery of these areas.
We make the case that in a habitat always likely to be subject to intense human pressure it provides a holistic decision‐making approach which considers ecological aspects alongside the ecosystem's anthropogenic importance and pressures. This allows for damage to be identified quickly and accelerates the process of designing and implementing solutions. It provides a framework for multiple partners with a material interest in maintaining a healthy estuarine environment providing multiple benefits to drive investment in natural capital and delivery of nature recovery.
We highlight some of the obstacles in implementing the Natural Capital approach in estuaries at scale, including collaboration and communication between stakeholders in various sectors, the existence of quality natural capital and environmental baselines and the need for partnership to create investment opportunities. We explore how these are being addressed and identify progress in the Natural Capital approach and how this can inform and advance the widespread implementation of the approach.
Temperate estuaries provide important ecosystem services to people but they are degraded. We suggest that Natural Capital approaches should be used in these areas. We explore possible barriers and solutions to these, as well as highlighting case studies.
The management of the remainder of Europe’s once extensive forests is hampered by a poor understanding of the character of the vegetation and drivers of change before the onset of clearance for ...farming. Pollen data indicate a closed-canopy, mixed-deciduous forest, contrasting with the assertion that large herbivores would have maintained a mosaic of open grassland, regenerating scrub and forested groves. Coprophilous fungal spores from sedimentary sequences are increasingly used as a proxy for past herbivore impact on vegetation, but the method faces methodological and taphonomical issues. Using pollen trap data from a long-running experiment in Chillingham Wild Cattle Park, UK, we investigate the first steps in the mechanisms connecting herbivore density to the incorporation of fungal spores in sediments and assess the effects of environmental variables on this relationship. Herbivore utilisation levels correlate with dung fungal spore abundance. Chillingham is densely populated by large herbivores, but dung fungal spore influx is low. Herbivores may thus be present on the landscape but go undetected. The absence of dung fungal spores is therefore less informative than their presence. Dung fungal spores likely enter the sediment record through a different pathway from wind-borne pollen and thus dung fungal abundance is better expressed as influx rates than as percentage of total pollen. Landscape openness, vegetation type and site wetness do not distort the impact of utilisation levels on dung fungal spore representation. However, dung fungal spore influx varies markedly between seasons and years. Spores travel, leading to a background level of spore deposition across the landscape, and at times a depletion of spores, especially under wet weather conditions. Animal behaviour, as well as husbandry practices, can lead to the accumulation of dung, and thus fungal spores, in specific locations on the landscape that do not directly reflect grazing pressure.
Spores from coprophilous fungi are emerging as an important palaeoecological indicator of the presence of large herbivores, but the methods by which they are recovered may have a significant impact ...on their preservation and recognition. Here, we test a number of chemical and mechanical techniques used in palynology. Spore occurrence, size and shape is affected by preparation technique and is particularly affected by acetolysis. This has important implications for recognition of past megafaunal populations.
•We investigate the impact of preparation techniques on coprophilous fungal spores.•Taxonomically significant change in size and shape with most preparation techniques•Acetolysis impacts on most taxa and is particularly damaging to hyaline spores.•We outline implications for using fungal spores to study ancient megafauna.
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