Stable colloids of magnetic nanoparticles and nanoparticle assemblies with controlled size and magnetic resonance properties

Suspensions of both dispersed and clustered iron oxide nanoparticles are of interest for biomedical applications as diagnostic and therapeutic agents due to their bio-compatibility and interesting magnetic and magnetic resonance properties. Their application is critically dependent on the fact that these properties are highly size-dependant. By developing NP synthesis and assembly methods, to provide improved size control at the two levels of organisation, NP suspensions with controlled emergent magnetic properties have been prepared. The first part of this thesis presents the size-controlled synthesis of magnetic nanoparticles whose surface is functionalised with a wide range of stabilising ligands. An investigation was undertaken to elucidate the effect of the stabilising ligands on the physical properties. The second part of the thesis presents a novel method for the reproducible assembly, in suspension, of NPs to form clusters. The method can be used to produce clusters of controlled size in large quantities; it is also shown that the kinetics of assembly can be easily controlled and that this influences the emergent magnetic properties. Arising from this observation a study was undertaken to determine the role of cluster architecture on the magnetic resonance properties of their aqueous suspensions

Microbial Phosphorus Mobilization Strategies Across a Natural Nutrient Limitation Gradient and Evidence for Linkage With Iron Solubilization Traits

Microorganisms have evolved several mechanisms to mobilize and mineralize occluded and insoluble phosphorus (P), thereby promoting plant growth in terrestrial ecosystems. However, the linkages between microbial P-solubilization traits and the preponderance of insoluble P in natural ecosystems are not well known. We tested the P solubilization traits of hundreds of culturable bacteria representative of the rhizosphere from a natural gradient where P concentration and bioavailability decline as soil becomes progressively more weathered. Aluminum, iron phosphate and organic P (phytate) were expected to dominate in more weathered soils. A defined cultivation medium with these chemical forms of P was used for isolation. A combination of soil chemical, spectroscopic analyses and 16S rRNA gene sequencing were used to understand the in situ ability for solubilization of these predominant forms of P. Locations with more occluded and organic P harbored the greatest abundance of P-mobilizing microorganisms, especially Burkholderiaceae (Caballeronia and Paraburkholderia spp.). Nearly all bacteria utilized aluminum phosphate, however fewer could subsist on iron phosphate (FePO4) or phytate. Microorganisms isolated from phytic acid were also most effective at solubilizing FePO4, suggesting that phytate solubilization may be linked to the ability to solubilize Fe. Significantly, we observed Fe to be co-located with P in organic patches in soil. Siderophore addition in lab experiments reinstated phytase mediated P-solubilization from Fe-phytate complexes. Taken together, these results indicate that metal-organic-P complex formation may limit enzymatic P solubilization from phytate in soil. Additionally, the linked traits of phytase and siderophore production were mostly restricted to specific clades within the Burkholderiaceae. We propose that Fe complexation of organic P (e.g., phytate) represents a major constraint on P turnover and availability in acidic soils, as only a limited subset of bacteria appear to possess the traits required to access this persistent pool of soil P

Liquid phase pulsed laser ablation: a route to fabricate different carbon nanostructures

Carbon nanostructures in various forms and sizes, and with different speciation properties have been prepared from graphite by Liquid Phase - Pulsed Laser Ablation (LP-PLA) using a high frequency Nd:YAG laser. High energy densities and pulse repetition frequencies of up to 10 kHz were used in this ablation process to produce carbon nanomaterials with unique chemical structures. Dynamic Light Scattering (DLS), micro-Raman and High-Resolution Transmission Electron Microscopy (HRTEM) were used to confirm the size distribution, morphology, chemical bonding, and crystallinity of these nanostructures. This article demonstrates how the fabrication process affects measured characteristics of the produced carbon nanomaterials. The obtained particle properties have potential use for various applications including biochemical speciation applications

Writing in Britain and Ireland, c. 400 to c. 800

No abstract available

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

One-Step Preservation of Phosphoproteins and Tissue Morphology at Room Temperature for Diagnostic and Research Specimens

BACKGROUND: There is an urgent need to measure phosphorylated cell signaling proteins in cancer tissue for the individualization of molecular targeted kinase inhibitor therapy. However, phosphoproteins fluctuate rapidly following tissue procurement. Snap-freezing preserves phosphoproteins, but is unavailable in most clinics and compromises diagnostic morphology. Formalin fixation preserves tissue histomorphology, but penetrates tissue slowly, and is unsuitable for stabilizing phosphoproteins. We originated and evaluated a novel one-step biomarker and histology preservative (BHP) chemistry that stabilizes signaling protein phosphorylation and retains formalin-like tissue histomorphology with equivalent immunohistochemistry in a single paraffin block. RESULTS: Total protein yield extracted from BHP-fixed, routine paraffin-embedded mouse liver was 100% compared to snap-frozen tissue. The abundance of 14 phosphorylated proteins was found to be stable over extended fixation times in BHP fixed paraffin embedded human colon mucosa. Compared to matched snap-frozen tissue, 8 phosphoproteins were equally preserved in mouse liver, while AMPKβ1 Ser108 was slightly elevated after BHP fixation. More than 25 tissues from mouse, cat and human specimens were evaluated for preservation of histomorphology. Selected tissues were evaluated in a multi-site, independent pathology review. Tissue fixed with BHP showed equivalent preservation of cytoplasmic and membrane cytomorphology, with significantly better nuclear chromatin preservation by BHP compared to formalin. Immunohistochemical staining of 13 non-phosphorylated proteins, including estrogen receptor alpha, progesterone receptor, Ki-67 and Her2, was equal to or stronger in BHP compared to formalin. BHP demonstrated significantly improved immunohistochemical detection of phosphorylated proteins ERK Thr202/Tyr204, GSK3-α/β Ser21/Ser9, p38-MAPK Thr180/Tyr182, eIF4G Ser1108 and Acetyl-CoA Carboxylase Ser79. CONCLUSION: In a single paraffin block BHP preserved the phosphorylation state of several signaling proteins at a level comparable to snap-freezing, while maintaining the full diagnostic immunohistochemical and histomorphologic detail of formalin fixation. This new tissue fixative has the potential to greatly facilitate personalized medicine, biobanking, and phospho-proteomic research

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention