Serotonin reuptake inhibitors and cardiovascular disease

Selective serotonin re-uptake inhibiting drugs (SSRIs) are widely used for endogenous depression. In addition to depleting the nerve terminals of serotonin they also lower blood platelet serotonin levels. Platelet aggregation is a major component of acute coronary syndromes, including sudden death, and also of limb ischaemia. Platelet-released serotonin causes constriction of diseased blood vessels. The recent literature has revealed a number of reports of association between the treatment of depression with SSRIs and reduced events caused by intra-arterial thrombosis. The effects of serotonin and serotonin depletion upon intracoronary thrombosis, diseased blood vessels, blood platelets and bleeding are discussed with recommendations for future research into the potential cardiovascular benefits of SSRIs and serotonin 5HT2A antagonists

Native Silk Feedstock as a Model Biopolymer: A Rheological Perspective.

Variability in silk's rheology is often regarded as an impediment to understanding or successfully copying the natural spinning process. We have previously reported such variability in unspun native silk extracted straight from the gland of the domesticated silkworm Bombyx mori and discounted classical explanations such as differences in molecular weight and concentration. We now report that variability in oscillatory measurements can be reduced onto a simple master-curve through normalizing with respect to the crossover. This remarkable result suggests that differences between silk feedstocks are rheologically simple and not as complex as originally thought. By comparison, solutions of poly(ethylene-oxide) and hydroxypropyl-methyl-cellulose showed similar normalization behavior; however, the resulting curves were broader than for silk, suggesting greater polydispersity in the (semi)synthetic materials. Thus, we conclude Nature may in fact produce polymer feedstocks that are more consistent than typical man-made counterparts as a model for future rheological investigations

The Rheology behind Stress-Induced Solidification in Native Silk Feedstocks.

The mechanism by which native silk feedstocks are converted to solid fibres in nature has attracted much interest. To address this question, the present work used rheology to investigate the gelation of Bombyx mori native silk feedstock. Exceeding a critical shear stress appeared to be more important than shear rate, during flow-induced initiation. Compositional changes (salts, pH etc.,) were not required, although their possible role in vivo is not excluded. Moreover, after successful initiation, gel strength continued to increase over a considerable time under effectively quiescent conditions, without requiring further application of the initial stimulus. Gelation by elevated temperature or freezing was also observed. Prior to gelation, literature suggests that silk protein adopts a random coil configuration, which argued against the conventional explanation of gelation, based on hydrophilic and hydrophobic interactions. Instead, a new hypothesis is presented, based on entropically-driven loss of hydration, which appears to explain the apparently diverse methods by which silk feedstocks can be gelled

Thermo-rheological behaviour of native silk feedstocks

The rheology of native silk protein feedstock specimens was characterised by shear and oscillatory measurements, over the temperature range from 2 to 55 �C, producing no evidence of thermally-driven phase change behaviour. All specimens exhibited flow characteristics typical of a concentrated polymer solution, with visco-elastic behaviour dominated by two main relaxation modes exhibiting time constants around 0.44 and 0.055 s at 25 �C. The specimens showed well-behaved temperature dependence following the Arrhenius equation, consistent with the kinetics being governed by an activation energy of flow, which ranged from 30.9 to 55.4 kJ mol�1 based on oscillatory data. Consequently, for the first time, it was possible to compile master-curves for native silk feedstock specimens following the principles of time-temperature superposition, using oscillatory data demonstrating visco-elastic behaviour typical of a polymer solution across a wide temperature range. Our work has highlighted the processing range of natural silks and furthered our stance on the molecular mechanisms governing the flow behaviour of these interesting and important material

The influence of metal ions on native silk rheology

Whilst flow is the basis for silk fibre formation, subtle changes in a silk feedstocks’ chemical environment may serve to increase both energetic efficiency and control hierarchical structure development during spinning. Despite the role of pH being largely understood, the influence of metal ions is not, only being inferred by correlative work and observations. Through a combination of rheology and microscopy, we provide a causative study of how the most abundant metal ions in the silk feedstock, Ca2+ and K+, affect its flow properties and structure. Our results show that Ca2+ ions increase viscosity and prevent molecular alignment and aggregation, providing ideal storage conditions for unspun silk. In contrast, the addition of K+ ions promotes molecular alignment and aggregation and therefore seems to transfer the silk feedstock into a spinning state which confirms recent ‘sticky reptation’ modelling hypotheses. Additionally, we characterised the influence of the ubiquitous kosmotropic agent Li+, used to prepare regenerated silk solutions, and find that it promotes molecular alignment and prevents aggregation which may permit a range of interesting artificial silk processing techniques to be developed. In summary, our results provide a clearer picture of how metal ions co-ordinate, control and thus contribute towards silk protein self-assembly which in turn can inspire structuring approaches in other biopolymer systems

Restoration of oligodendrocyte pools in a mouse model of chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion, a sustained modest reduction in cerebral blood flow, is associated with damage to myelinated axons and cognitive decline with ageing. Oligodendrocytes (the myelin producing cells) and their precursor cells (OPCs) may be vulnerable to the effects of hypoperfusion and in some forms of injury OPCs have the potential to respond and repair damage by increased proliferation and differentiation. Using a mouse model of cerebral hypoperfusion we have characterised the acute and long term responses of oligodendrocytes and OPCs to hypoperfusion in the corpus callosum. Following 3 days of hypoperfusion, numbers of OPCs and mature oligodendrocytes were significantly decreased compared to controls. However following 1 month of hypoperfusion, the OPC pool was restored and increased numbers of oligodendrocytes were observed. Assessment of proliferation using PCNA showed no significant differences between groups at either time point but showed reduced numbers of proliferating oligodendroglia at 3 days consistent with the loss of OPCs. Cumulative BrdU labelling experiments revealed higher numbers of proliferating cells in hypoperfused animals compared to controls and showed a proportion of these newly generated cells had differentiated into oligodendrocytes in a subset of animals. Expression of GPR17, a receptor important for the regulation of OPC differentiation following injury, was decreased following short term hypoperfusion. Despite changes to oligodendrocyte numbers there were no changes to the myelin sheath as revealed by ultrastructural assessment and fluoromyelin however axon-glial integrity was disrupted after both 3 days and 1 month hypoperfusion. Taken together, our results demonstrate the initial vulnerability of oligodendroglial pools to modest reductions in blood flow and highlight the regenerative capacity of these cells

Strings, T-duality breaking, and nonlocality without the shortest distance

T-duality of string theory suggests nonlocality manifested as the shortest possible distance. As an alternative, we suggest a nonlocal formulation of string theory that breaks T-duality at the fundamental level and does not require the shortest possible distance. Instead, the string has an objective shape in spacetime at all length scales, but different parts of the string interact in a nonlocal Bohmian manner.Comment: 7 pages, revised, to appear in Eur. Phys. J.

Sea Ice-Driven Variability in the Pacific Subantarctic Mode Water Formation Regions

Well-mixed mode waters that form in the north of the Southern Ocean are particularly important to the ocean absorption of heat and CO2 from the atmosphere. Two types of mode water form in the Pacific sector of the Southern Ocean: a Central pool and a Southeast pool. Both have shown significant year-to-year variability in recent decades. Variability in the regions where these waters form is shown to be due to changes in air-sea fluxes, horizontal advection, and the upward transport of deeper water. Transport of freshwater into the mode water formation regions is shown to be correlated with year-to-year changes in sea ice area in the Ross Sea and in the Amundsen/Bellingshausen seas. The results suggest that it takes around 6 months for sea ice melt from the Amundsen/Bellingshausen seas to reach the southeast mode water region, and up to 2 years for freshwater from the Ross Sea to reach both mode water formation sites. In 2015, Amundsen/Bellingshausen sea ice was particularly high, leading to more freshwater being transported to the southeast mode water site the following spring/summer. A huge decrease in winter sea ice in 2016 then caused the opposite, and salinity at the formation site was unusually high.publishedVersio

The relative impacts of initialization and climate forcing in coupled ice sheet‐ocean modeling application to Pope, Smith and Kohler glaciers

Coupled ice sheet-ocean models are beginning to be used to study the response of ice sheets to ocean warming. Initialising an ice-ocean model is challenging and can introduce nonphysical transients, and the extent to which such transients can affect model projections is unclear. We use a synchronously-coupled ice-ocean model to investigate evolution of Pope, Smith and Kohler Glaciers, West Antarctica, over the next half-century. Two methods of initialisation are used: in one, the ice-sheet model is constrained with observed velocities in its initial state; in another, the model is constrained with both velocities and grounded thinning rates over a 4-year period. Each method is applied to two basal sliding laws. For each resulting initialisation, two climate scenarios are considered: one where ocean conditions during the initialisation period persist indefinitely, and one where the ocean is in a permanent “warm” state. At first, model runs initialised with thinning data exhibit volume loss rates much closer to observed values than those initialised with velocity only, but after 1-2 decades the forcing primarily determines rates of volume loss and grounding line retreat. Such behaviour is seen for both basal sliding laws, although volume loss rates differ quantitatively. Under the “warm” scenario, a grounding line retreat of ∼30 km is simulated for Smith and Kohler, although variation in total retreat due to initialisation is nearly as large as that due to forcing. Furthermore it is questionable whether retreat will continue due to narrowing of submarine troughs and limiting of heat transport by bathymetric obstacles

Seeking solvation: exploring the role of protein hydration in silk gelation

The mechanism by which arthropods (e.g., spiders and many insects) can produce silk fibres from an aqueous protein (fibroin) solution has remained elusive, despite much scientific investigation. In this work, we used several techniques to explore the role of a hydration shell bound to the fibroin in native silk feedstock (NSF) from Bombyx mori silkworms. Small angle X-ray and dynamic light scattering (SAXS and DLS) revealed a coil size (radius of gyration or hydrodynamic radius) around 12 nm, providing considerable scope for hydration. Aggregation in dilute aqueous solution was observed above 65 °C, matching the gelation temperature of more concentrated solutions and suggesting that the strength of interaction with the solvent (i.e., water) was the dominant factor. Infrared (IR) spectroscopy indicated decreasing hydration as the temperature was raised, with similar changes in hydration following gelation by freezing or heating. It was found that the solubility of fibroin in water or aqueous salt solutions could be described well by a relatively simple thermodynamic model for the stability of the protein hydration shell, which suggests that the affected water is enthalpically favoured but entropically penalised, due to its reduced (vibrational or translational) dynamics. Moreover, while the majority of this investigation used fibroin from B. mori, comparisons with published work on silk proteins from other silkworms and spiders, globular proteins and peptide model systems suggest that our findings may be of much wider significance