•Heat exchange between piles and surrounding ground.•Contextualizes reported response thermally-activated piles in cohesive media.•Demonstrates influence of pile mobilisation under mechanical load on ...thermal response as function of: factor-of-safety on shaft resistance, pile spacing within groups.•Characterises impact of heat loss from building on: Thermo-mechanical response of pile foundation, Heat exchange between piles and surrounding ground
The thermal-activation of pile foundations for use within shallow geothermal energy systems has received much attention with a number of studies having reported full- and small-scale testing and/or numerical analysis. Various conditions in terms of pile type, ground profiles and thermal loading, have been considered in these studies, leading to a broad understanding of the thermo-mechanical behaviour of thermally-activated pile foundations. One area that requires further attention is the clarification of the foundation response under seasonal cyclic thermal loading. This study systematically assesses the impact of cyclic thermal loading in relation to the initial mechanical loading, for isolated floating piles and pile groups in a cohesive soil medium. For piles where the shaft resistance dominates the pile total resistance, it was found that irrecoverable movement will be small and thermal stress and pile head movements change in a cyclic and regular manner. It is shown that the effect of the coefficient of thermal expansion of the soil, is much reduced from that suggested in studies using constant thermal loads applied over long periods. The effect of the overlying building was explored and it is shown that thermal-activation of the pile foundation mitigates the effect of the imposition of a higher average temperature at the surface.
Positron emission tomography is a widely used imaging platform for studying physiological processes. Despite the proliferation of modern synthetic methodologies for radiolabeling, the optimization of ...these reactions still primarily relies on inefficient one-factor-at-a-time approaches. High-throughput experimentation (HTE) has proven to be a powerful approach for optimizing reactions in many areas of chemical synthesis. However, to date, HTE has rarely been applied to radiochemistry. This is largely because of the short lifetime of common radioisotopes, which presents major challenges for efficient parallel reaction setup and analysis using standard equipment and workflows. Herein, we demonstrate an effective HTE workflow and apply it to the optimization of copper-mediated radiofluorination of pharmaceutically relevant boronate ester substrates. The workflow utilizes commercial equipment and allows for rapid analysis of reactions for optimizing reactions, exploring chemical space using pharmaceutically relevant aryl boronates for radiofluorinations, and constructing large radiochemistry data sets.
Studies on hypoxia‐sensitive pathways have identified a series of Fe(II)‐dependent dioxygenases that regulate hypoxia‐inducible factor (HIF) by prolyl and asparaginyl hydroxylation. The asparaginyl ...hydroxylase factor inhibiting HIF (FIH) targets a conserved asparaginyl residue in the C‐terminal transactivation domain of HIF‐α. This modification suppresses HIF transcriptional activity by inhibiting co‐activator recruitment. Recent work has demonstrated that FIH targets an alternative class of substrate. Proteins containing a common interaction motif known as the ankyrin repeat domain (ARD) have been shown to be efficiently hydroxylated by FIH. This review aims to summarize what is currently known regarding ARD hydroxylation, including the kinetics and determinants of FIH‐mediated ARD hydroxylation, the structural and functional consequences of ARD hydroxylation, and the potential for cross‐talk between ARD proteins and HIF signaling.
This report describes the development of a Zn(OTf)2‐mediated method for converting α‐tertiary haloamides to the corresponding fluorine‐18 labelled α‐tertiary fluoroamides with no‐carrier‐added ...18Ftetramethylammonium fluoride. 1,5,7‐Triazabicyclo4.4.0dec‐5‐ene is an essential additive for achieving high radiochemical conversion. Under the optimised conditions, radiofluorination proceeds at sterically hindered tertiary sites in high radiochemical conversions, yields, and purities. This method has been successfully automated and applied to access >200 mCi (>7.4 GBq) of several model radiofluorides. Mechanistic studies led to the development of a new, nucleophilic C−H radiofluorination process using N‐sulphonyloxyamide substrates.
A high‐yielding radiofluorination of unprotected α‐tertiary haloamides is described. This method provides a new strategy for radiochemists to install fluorine‐18 into sterically protected environments for positron emission tomography imaging. Preliminary mechanistic studies were leveraged to develop a novel C−H radiofluorination reaction of N‐sulphonyloxyamides.
Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA ...(endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (−11±1%) and low-density lipoprotein–associated (−20±3%) cholesterol, lipoprotein (a) (−16±2%) and triglycerides (−20±4%); high-density lipoprotein–associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (−19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT00810732.
Conventional oral drug formulations for colonic diseases require the administration of high doses of drug to achieve effective drug concentrations at the target site. However, this exposes patients ...to serious systemic toxicity in order to achieve efficacy. To overcome this problem, an oral drug delivery system was developed by loading a large amount (ca. 34% w/w) of prednisolone into 3-aminopropyl-functionalized mesoporous silica nanoparticles (MCM-NH2) and targeting prednisolone release to the colon by coating the nanoparticle with succinylated ε-polylysine (SPL). We demonstrate for the first time the pH-responsive ability of SPL as a “nanogate” to selectively release prednisolone in the pH conditions of the colon (pH 5.5–7.4) but not in the more acidic conditions of the stomach (pH 1.9) or small intestine (pH 5.0). In addition to targeting drug delivery to the colon, we explored whether the nanoparticles could deliver cargo intracellularly to immune cells (RAW 264.7 macrophages) and intestinal epithelial cells (LS 174T and Caco-2 adenocarcinoma cell lines). To trace uptake, MCM-NH2 were loaded with a cell membrane-impermeable dye, sulforhodamine B. The SPL-coated nanoparticles were able to deliver the dye intracellularly to RAW 264.7 macrophages and the intestinal epithelial cancer cells, which offers a highly promising and novel drug delivery system for diseases of the colon such as inflammatory bowel disease and colorectal cancer.
Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no ...therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6C
monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6C
monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C
monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.
Plasmodium falciparum,
the causative agent of malaria, remains a global health threat as parasites continue to develop resistance to antimalarial drugs used throughout the world. Accordingly, drugs ...with novel modes of action are desperately required to combat malaria.
P. falciparum
parasites infect human red blood cells where they digest the host’s main protein constituent, hemoglobin. Leucine aminopeptidase
Pf
A-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here, we use both reverse genetics and a compound specifically designed to inhibit the activity of
Pf
A-M17 to show that
Pf
A-M17 is essential for
P. falciparum
survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that loss of
Pf
A-M17 results in parasites exhibiting multiple digestive vacuoles at the trophozoite stage. In contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate
Pf
A-M17 as a potential novel drug target.
Malaria is a disease spread by mosquitoes. When infected insects bite the skin, they inject parasites called
Plasmodium
into the host. The symptoms of the disease then develop when
Plasmodium
infect host red blood cells. These parasites cannot make the raw materials to build their own proteins, so instead, they digest haemoglobin – the protein used by red blood cells to carry oxygen – and use its building blocks to produce proteins.
Blocking the digestion of haemoglobin can stop malaria infections in their tracks, but it is unclear how exactly
Plasmodium
parasites break down the protein. Researchers think that a group of four enzymes called aminopeptidases are responsible for the final stage in this digestion, releasing the amino acids that make up haemoglobin. However, the individual roles of each of these aminopeptidases are not yet known.
To start filling this gap, Edgar et al. set out to study one of these aminopeptidases, called PfA-M17. First, they genetically modified
Plasmodium falciparum
parasites so that the levels of this aminopeptidase were reduced during infection. Without the enzyme, the parasites were unable to grow. The next step was to confirm that this was because PfA-M17 breaks down haemoglobin, and not for another reason. To test this, Edgar et al. designed a new molecule that could stop PfA-M17 from releasing amino acids. This molecule, which they called ‘compound 3’, had the same effect as reducing the levels of PfA-M17. Further analysis showed that the amino acids that PfA- M17 releases match the amino acids found in haemoglobin.
Malaria causes hundreds of thousands of deaths per year. Although there are treatments available, the
Plasmodium
parasites are starting to develop resistance. Confirming the role of PfA-M17 provides a starting point for new studies by parasitologists, biologists, and drug developers. This could lead to the development of chemicals that block this enzyme, forming the basis for new treatments.
Micropiles are small-diameter foundation elements that are widely used in building refurbishment to reinforce existing foundations or provide new foundations where access for construction is ...difficult. Thermally-activated (TA) micropiles could be useful as an efficient means of providing cost-effective ground-coupling when shallow geothermal energy systems are considered in building rehabilitation. It is well-established that thermal activation of pile foundations results in thermo-mechanical interactions between the pile and the surrounding soil. These thermally-induced effects need to be examined to ensure that they do not adversely impact the load transfer function of the micropile. Numerical analysis is able to produce reliable predictions of thermo-mechanical behavior of TA piles, and this study applied this technique to examine the cyclic thermal behavior of micropiles, isolated and in groups. For the situations considered in this study, it is shown that during cyclic thermal activation, irrecoverable movements are unlikely to be significant in design terms, if the initial mobilization of the shaft resistance is low. Though stable, cyclic thermal movement amplitudes are large enough that they should be considered in design. The study highlights that large changes in thermal stress can develop and be locked-in to the response of long flexible piles, and that these should be verified in design. Further, as pile spacing reduces, thermal interference results in a loss of heat exchange capacity per pile, which has to be considered in the design of large groups of TA micropiles. Therefore, TA micropiles can offer an efficient and secure means of providing ground coupling in shallow geothermal energy systems.
Each year, an average of 45 tropical cyclones affect coastal areas and potentially impact forests. The proportion of the most intense cyclones has increased over the past four decades and is ...predicted to continue to do so. Yet, it remains uncertain how topographical exposure and tree characteristics can mediate the damage caused by increasing wind speed. Here, we compiled empirical data on the damage caused by 11 cyclones occurring over the past 40 years, from 74 forest plots representing tropical regions worldwide, encompassing field data for 22,176 trees and 815 species. We reconstructed the wind structure of those tropical cyclones to estimate the maximum sustained wind speed (MSW) and wind direction at the studied plots. Then, we used a causal inference framework combined with Bayesian generalised linear mixed models to understand and quantify the causal effects of MSW, topographical exposure to wind (EXP), tree size (DBH) and species wood density (ρ) on the proportion of damaged trees at the community level, and on the probability of snapping or uprooting at the tree level. The probability of snapping or uprooting at the tree level and, hence, the proportion of damaged trees at the community level, increased with increasing MSW, and with increasing EXP accentuating the damaging effects of cyclones, in particular at higher wind speeds. Higher ρ decreased the probability of snapping and to a lesser extent of uprooting. Larger trees tended to have lower probabilities of snapping but increased probabilities of uprooting. Importantly, the effect of ρ decreasing the probabilities of snapping was more marked for smaller than larger trees and was further accentuated at higher MSW. Our work emphasises how local topography, tree size and species wood density together mediate cyclone damage to tropical forests, facilitating better predictions of the impacts of such disturbances in an increasingly windier world.
The global proportion of the most intense cyclones is increasing and it remains uncertain how damage to tropical forests will change with increasing wind speed. We compiled empirical data on the damage caused by cyclones from forests representing tropical regions worldwide to better understand the effects of wind speed, topographical exposure to wind, and tree characteristics on the proportion of damaged trees and on the probability of snapping or uprooting. Our work emphasises how local topography, tree size and species wood density together mediate cyclone damage to tropical forests, facilitating better predictions of the impacts of such disturbances.
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