Exposure of benthic invertebrates to sediment vibration: From laboratory experiments to outdoor simulated pile-driving

Activities directly interacting with the seabed, such as pile-driving, can produce vibrations that have the potential to impact benthic invertebrates within their vicinity. This stimuli may interfere with crucial behaviors such as foraging and predator avoidance, and the sensitivity to vibration is largely unknown. Here, the responsiveness of benthic invertebrates to sediment vibration is discussed in relation to laboratory and semi-field trials with two marine species: the mussel (Mytilus edulis) and hermit crab (Pagurus bernhardus). Sensory threshold curves were produced for both species in controlled laboratory conditions, followed by small-scale pile-driving exposures in the field. The merits of behavioral indicators are discussed, in addition to using physiological measures, as a method of determining reception and measuring responses. The measurement and sensors required for sediment vibration quantification are also discussed. Response and threshold data were related to measurements taken in the vicinity of anthropogenic sources, allowing a link between responsiveness and actual operations. The impact of pile-driving on sediment-dwelling invertebrates has received relatively little research, yet the data here suggest that such activities are likely to impact key coastal species which play important roles within the marine environment

3D printed fluidics with embedded analytic functionality for automated reaction optimisation

Additive manufacturing or ‘3D printing’ is being developed as a novel manufacturing process for the production of bespoke micro- and milliscale fluidic devices. When coupled with online monitoring and optimisation software, this offers an advanced, customised method for performing automated chemical synthesis. This paper reports the use of two additive manufacturing processes, stereolithography and selective laser melting, to create multifunctional fluidic devices with embedded reaction monitoring capability. The selectively laser melted parts are the first published examples of multifunctional 3D printed metal fluidic devices. These devices allow high temperature and pressure chemistry to be performed in solvent systems destructive to the majority of devices manufactured via stereolithography, polymer jetting and fused deposition modelling processes previously utilised for this application. These devices were integrated with commercially available flow chemistry, chromatographic and spectroscopic analysis equipment, allowing automated online and inline optimisation of the reaction medium. This set-up allowed the optimisation of two reactions, a ketone functional group interconversion and a fused polycyclic heterocycle formation, via spectroscopic and chromatographic analysis

Domesticating Urban Theory? US Concepts, British Cities and the Limits of Cross-national Applications

The efficacy of the urban regime and growth machine concepts beyond the US remains a matter of considerable debate. Some argue that these frameworks retain considerable value so long as they are 'properly' applied and that recent concerns about the limits to these frameworks result from no more than their 'misapplication'. I critically examine this argument through a review of recent work on the mobilisation of business interests in British cities. The central claim is that, even when focused on the 'right' issues and questions, US frameworks quickly exhaust their explanatory capacity. In the context of a widening diversity of alternative approaches, I suggest that it is time to move squarely beyond growth coalition and regime accounts. The paper makes a number of suggestions for ways in which this new phase of theory building might proceed.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

The calcilytic agent NPS 2143 rectifies hypocalcemia in a mouse model with an activating calcium-sensing-receptor (CaSR) mutation:relevance to autosomal dominant hypocalcemia type 1 (ADH1)

Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum parathyroid hormone (PTH) concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalise the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells and the effect of NPS 2143 on their intracellular calcium responses determined by flow cytometry. NPS 2143 was also administered as a single intraperitoneal bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1, and improve the hypocalcemia associated with this disorder

Effect of ω-3 fatty acid supplementation on endothelial function, endogenous fibrinolysis and platelet activation in patients with a previous myocardial infarction:a randomised controlled trial

OBJECTIVE: The mechanisms through which ω-3 fatty acids reduce adverse cardiac events remain uncertain. We aimed to investigate the effect of ω-3 fatty acid supplementation on endothelial vasomotor function, endogenous fibrinolysis, and platelet and monocyte activation in patients with coronary heart disease. DESIGN: Randomised, double-blind, placebo-controlled, cross-over trial. SETTING: Academic cardiac centre. PARTICIPANTS: 20 male patients with a previous myocardial infarction. INTERVENTION: ω-3 Fatty acid supplementation (2 g/day for 6 weeks) versus olive oil placebo. OUTCOME MEASURES: Peripheral blood was taken for analysis of platelet and monocyte activation, and forearm blood flow (FBF) was assessed in a subset of 12 patients during intrabrachial infusions of acetylcholine, substance P and sodium nitroprusside. Stimulated plasma tissue plasminogen activator (t-PA) concentrations were measured during substance P infusion. RESULTS: All vasodilators caused dose-dependent increases in FBF (p<0.0001). ω-3 Fatty acid supplementation did not affect endothelium-dependent vasodilation with acetylcholine and substance P compared with placebo (p=0.5 and 0.9). Substance P caused a dose-dependent increase in plasma t-PA concentrations (p<0.0001), which was not affected by ω-3 fatty acid supplementation (p=0.9). ω-3 Fatty acids did not affect platelet–monocyte aggregation, platelet P-selectin or CD40L, or monocyte CD40. CONCLUSIONS: We have demonstrated that dietary supplementation with ω-3 fatty acids does not affect endothelial vasomotor function, endothelial t-PA release, or platelet and monocyte activation in patients with coronary heart disease. Cardiac benefits conferred by ω-3 fatty acids in coronary heart disease are unlikely to be mediated through effects on these systems

Cosmic-Ray Positrons: Are There Primary Sources?

Cosmic rays at the Earth include a secondary component originating in collisions of primary particles with the diffuse interstellar gas. The secondary cosmic rays are relatively rare but carry important information on the Galactic propagation of the primary particles. The secondary component includes a small fraction of antimatter particles, positrons and antiprotons. In addition, positrons and antiprotons may also come from unusual sources and possibly provide insight into new physics. For instance, the annihilation of heavy supersymmetric dark matter particles within the Galactic halo could lead to positrons or antiprotons with distinctive energy signatures. With the High-Energy Antimatter Telescope (HEAT) balloon-borne instrument, we have measured the abundances of positrons and electrons at energies between 1 and 50 GeV. The data suggest that indeed a small additional antimatter component may be present that cannot be explained by a purely secondary production mechanism. Here we describe the signature of the effect and discuss its possible origin.Comment: 15 pages, Latex, epsfig and aasms4 macros required, to appear in Astroparticle Physics (1999

In vitro significance of SOCS-3 and SOCS-4 and potential mechanistic links to wound healing

Wound healing and the management of chronic wounds represent a significant burden on the NHS. Members of the suppressor of cytokine signalling (SOCS) family have been implicated in the regulation of a range of cellular processes. The current study aims to explore the importance of SOCS-3 and SOCS-4 in regulating cellular traits associated with wound healing. SOCS-3 over-expression and SOCS-4 knockdown mutant lines were generated and verified using q-PCR and western blotting in human keratinocytes (HaCaT) and endothelial cells (HECV). Over-expression of SOCS-3 resulted in a significantly reduced proliferative rate in HaCaT keratinocytes and also enhanced the tubule formation capacity of HECV cells. SOCS-4 knockdown significantly reduced HaCaT migration and HECV cell tubule formation. Suppression of SOCS-4 influenced the responsiveness of HaCaT and HECV cells to EGF and TGFβ and resulted in a dysregulation of phospho-protein expression in HaCaT cells. SOCS-3 and SOCS-4 appear to play regulatory roles in a number of keratinocyte and endothelial cellular traits associated with the wound healing process and may also be able to regulate the responsiveness of these cells to EGF and TGFβ. This implies a potential regulatory role in the wound healing process and, thus highlights their potential as novel therapies

Exposure of benthic invertebrates to sediment vibration:From laboratory experiments to outdoor simulated pile-driving

Activities directly interacting with the seabed, such as pile-driving, can produce vibrations that have the potential to impact benthic invertebrates within their vicinity. This stimuli may interfere with crucial behaviors such as foraging and predator avoidance, and the sensitivity to vibration is largely unknown. Here, the responsiveness of benthic invertebrates to sediment vibration is discussed in relation to laboratory and semi-field trials with two marine species: the mussel (Mytilus edulis) and hermit crab (Pagurus bernhardus). Sensory threshold curves were produced for both species in controlled laboratory conditions, followed by small-scale pile-driving exposures in the field. The merits of behavioral indicators are discussed, in addition to using physiological measures, as a method of determining reception and measuring responses. The measurement and sensors required for sediment vibration quantification are also discussed. Response and threshold data were related to measurements taken in the vicinity of anthropogenic sources, allowing a link between responsiveness and actual operations. The impact of pile-driving on sediment-dwelling invertebrates has received relatively little research, yet the data here suggest that such activities are likely to impact key coastal species which play important roles within the marine environment.</p

Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations