The phase diagram of water at negative pressures: Virtual ices

The phase diagram of water at negative pressures as obtained from computer simulations for two models of water, TIP4P/2005 and TIP5P is presented. Several solid structures with lower densities than ice Ih, so-called virtual ices, were considered as possible candidates to occupy the negative pressure region of the phase diagram of water. In particular the empty hydrate structures sI, sII, and sH and another, recently proposed, low-density ice structure. The relative stabilities of these structures at 0 K was determined using empirical water potentials and density functional theory calculations. By performing free energy calculations and Gibbs-Duhem integration the phase diagram of TIP4P/2005 was determined at negative pressures. The empty hydrates sII and sH appear to be the stable solid phases of water at negative pressures. The phase boundary between ice Ih and sII clathrate occurs at moderate negative pressures, while at large negative pressures sH becomes the most stable phase. This behavior is in reasonable agreement with what is observed in density functional theory calculations.

Hydrogel-forming microneedle arrays exhibit antimicrobial properties:potential for enhanced patient safety

We describe, for the first time, the microbial characterisation of hydrogel-forming polymeric microneedle arrays and the potential for passage of microorganisms into skin following microneedle penetration. Uniquely, we also present insights into the storage stability of these hydroscopic formulations, from physical and microbiological viewpoints, and examine clinical performance and safety in human volunteers. Experiments employing excised porcine skin and radiolabelled microorganisms showed that microorganisms can penetrate skin beyond the stratum corneum following microneedle puncture. Indeed, the numbers of microorganisms crossing the stratum corneum following microneedle puncture were greater than 105 cfu in each case. However, no microorganisms crossed the epidermal skin. When using a 21G hypodermic needle, more than 104 microorganisms penetrated into the viable tissue and 106 cfu of Candida albicans and Staphylococcus epidermidis completely crossed the epidermal skin in 24 h. The hydrogel-forming materials contained no microorganisms following de-moulding and exhibited no microbial growth during storage, while also maintaining their mechanical strength, apart from when stored at relative humidities of 86%. No microbial penetration through the swelling microneedles was detectable, while human volunteer studies confirmed that skin or systemic infection is highly unlikely when polymeric microneedles are used for transdermal drug delivery. Since no pharmacopoeial standards currently exist for microneedle-based products, the exact requirements for a proprietary product based on hydrogel-forming microneedles are at present unclear. However, we are currently working towards a comprehensive specification set for this microneedle system that may inform future developments in this regard.

Solvent induced phase inversion-based in situ forming controlled release drug delivery implants

In situ forming (ISF) drug delivery implants have gained tremendous levels of interest over the last few decades. This is due to their wide range of biomedical applications such as in tissue engineering, cell encapsulation, microfluidics, bioengineering and drug delivery. Drug delivery implants forming upon injection has shown a range of advantages which include localized drug delivery, easy and less invasive application, sustained drug action, ability to tailor drug delivery, reduction in side effects associated with systemic delivery and also improved patient compliance and comfort. Different factors such as temperature, pH, ions, and exchange of solvents are involved in in situ implant formation. This review especially focuses on ISF implants that are formed through solvent induced phase inversion (SPI) technique. The article critically reviews and compares a wide range of polymers, solvents, and co-solvents that have been used in SPI implant preparation for control release of a range of drug molecules. Major drawback of SPI systems has been their high burst release. In this regard, the article exhaustively discusses factors that affect the burst release and different modification strategies that has been utilised to reduce the burst effect from these implants. Performance and controversial issues associated with the use of different biocompatible solvents in SPI systems is also discussed. Biodegradation, formulation stability, methods of characterisation and sterilisation techniques of SPI systems is comprehensively reviewed. Furthermore, the review also examines current SPI-based marketed products, their therapeutic application and associated clinical data. It also exemplifies the interest of multi-billion dollar pharma companies worldwide for further developments of SPI systems to a range of therapeutic applications. The authors believe that this will be the first review article that extensively investigate and discusses studies done to date on SPI systems. In so doing, this article will undoubtedly serve as an enlightening tool for the scientists working in the concerned area.

Geochemical records of palaeoenvironmental controls on peat forming processes in the Mfabeni peatland, Kwazulu Natal, South Africa since the Late Pleistocene

The Mfabeni peatland is the only known sub-tropical coastal fen that transcends the Last Glacial Maximum (LGM). This ca. 10m thick peat sequence provides a continuous sedimentation record spanning from the late Pleistocene to present (basal age c. 47kcalyr BP). We investigated the paleaeoenvironmental controls on peat formation and organic matter source input at the Mfabeni fen by: 1) exploring geochemical records (mass accumulation rate, total organic carbon, carbon accumulation rate, δC, δN and C/N ratio) to delineate primary production, organic matter source input, preservation and diagenetic processes, and 2) employ these geochemical signatures to reconstruct the palaeoenvironmental conditions and prevailing climate that drove carbon accumulation in the peatland. We established that the Mfabeni peat sediments have undergone minimal diagenetic alteration. The peat sequence was divided into 5 linear sedimentation rate (LSR) stages indicating distinct changes in climate and hydrological conditions: LSR stage 1 (c. 47 to c. 32.2kcalyr BP): predominantly cool and wet climate with C4 plant assemblages, interrupted by two short warming events. LSR stage 2 (c. 32.2 to c. 27.6kcalyr BP): dry and windy climate followed by a brief warm and wet period with increased C4 sedge swamp vegetation. LSR stage 3 (c. 27.6 to c. 20.3kcalyr BP): initial cool and wet period with prevailing C4 sedge plant assemblage until c. 23kcalyr BP; then an abrupt change to dry and cool glacial conditions and steady increases in C3 grasses. LSR stage 4 (c. 20.3 to c. 10.4kcalyr BP): continuation of cool and dry conditions and strong C3 grassland signature until c. 15kcalyr BP, after which precipitation increases. LSR stage 5 (c. 10.4kcalyr BP to present): characterised by extreme fluctuations between pervasive wet and warm to cool interglacial conditions with intermittent abrupt millennial-scale cooling/drying events and oscillations between C3 and C4 plant assemblages. In this study we reconstructed a high-resolution record of local hydrology, bulk plant assemblage and inferred climate since the Late Pleistocene, which suggest an anti-phase link between Southern African and the Northern Hemisphere, most notably during Heinrich (5 to 2) and Younger Dryas events. © 2013 Elsevier B.V.

Magma Evolution in the Primitive, Intra-oceanic Tonga Arc: Petrogenesis of Basaltic Andesites at Tofua Volcano

Tofua volcano is situated midway along the Tonga oceanic arc and has undergone two phases of ignimbrite-forming activity. The eruptive products are almost entirely basaltic andesites (52 center dot 5-57 wt % SiO2) with the exception of a volumetrically minor pre-caldera dacite. The suite displays a strong tholeiitic trend with K2O <1 wt %. Phenocryst assemblages typically comprise plagioclase + clinopyroxene +/- orthopyroxene with microlites of Ti-magnetite. Olivine (Fo(83-88)) is rare and believed to be dominantly antecrystic. An increase in the extent and frequency of reverse zoning in phenocrysts, sieve-textured plagioclase and the occurrence of antecrystic phases in post-caldera lavas record a shift to dynamic conditions, allowing the interaction of magma batches that were previously distinct. Pyroxene thermobarometry suggests crystallization at 950-1200 degrees C and 0 center dot 8-1 center dot 8 kbar. Volatile measurements of glassy melt inclusions indicate a maximum H2O content of 4 center dot 16 wt % H2O, and CO2-H2O saturation curves indicate that crystallization occurred at two levels, at depths of 4-5 center dot 5 km and 1 center dot 5-2 center dot 5 km. Major and trace element models suggest that the compositions of the majority of the samples represent a differentiation trend whereby the dacite was produced by 65% fractional crystallization of the most primitive basaltic andesite. Trace element models suggest that the sub-arc mantle source is the residuum of depleted Indian mid-ocean ridge basalt mantle (IDMM-1% melt), whereas radiogenic isotope data imply addition of 0 center dot 2% average Tongan sediment melt and a fluid component derived from the subducted altered Pacific oceanic crust. A horizontal array on the U-Th equiline diagram and Ra excesses of up to 500% suggest fluid addition to the mantle wedge within the last few thousand years. Time-integrated (Ra-226/Th-230) vs Sr/Th and Ba/Th fractionation models imply differentiation timescales of up to 4500 years for the dacitic magma compositions at Tofua.

The In Vitro Susceptibility of Biofilm Forming Medical Device Related Pathogens to Conventional Antibiotics

Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum biofilm eradication concentration (MBEC) and kill kinetics were established for vancomycin, rifampicin, trimethoprim, gentamicin, and ciprofloxacin against the biofilm forming bacteria Staphylococcus epidermidis (ATCC 35984), Staphylococcus aureus (ATCC 29213), Methicillin Resistant Staphylococcus aureus (MRSA) (ATCC 43300), Pseudomonas aeruginosa (PAO1), and Escherichia coli (NCTC 8196). MICs and MBCs were determined via broth microdilution in 96-well plates. MBECs were studied using the Calgary Biofilm Device. Values obtained were used to investigate the kill kinetics of conventional antimicrobials against a range of planktonic and biofilm microorganisms over a period of 24 hours. Planktonic kill kinetics were determined at 4xMIC and biofilm kill kinetics at relative MBECs. Susceptibility of microorganisms varied depending on antibiotic selected and phenotypic form of bacteria. Gram-positive planktonic isolates were extremely susceptible to vancomycin (highest MBC: 7.81 mg L−1: methicillin sensitive and resistant S. aureus) but no MBEC value was obtained against all biofilm pathogens tested (up to 1000 mg L−1). Both gentamicin and ciprofloxacin displayed the broadest spectrum of activity with MIC and MBCs in the mg L−1 range against all planktonic isolates tested and MBEC values obtained against all but S. epidermidis (ATCC 35984) and MRSA (ATCC 43300).

Hydrogel-Forming Microneedles Increase in Volume During Swelling in Skin, but Skin Barrier Function Recovery is Unaffected

We describe, for the first time, quantification of in-skin swelling and fluid uptake by hydrogel-forming microneedle (MN) arrays and skin barrier recovery in human volunteers. Such MN arrays, prepared from aqueous blends of hydrolyzed poly(methylvinylether/maleic anhydride) (15%, w/w) and the cross-linker poly(ethyleneglycol) 10,000 Da (7.5%, w/w), were inserted into the skin of human volunteers (n = 15) to depths of approximately 300 μm by gentle hand pressure. The MN arrays swelled in skin, taking up skin interstitial fluid, such that their mass had increased by approximately 30% after 6 h in skin. Importantly, however, skin barrier function recovered within 24 h after MN removal, regardless of how long the MN had been in skin or how much their volume had increased with swelling. Further research on closure of MN-induced micropores is required because transepidermal water loss measurements suggested micropore closure, whereas optical coherence tomography indicated that MN-induced micropores had not closed over, even 24 h after MN had been removed. There were no complaints of skin reactions, adverse events, or strong views against MN use by any of the volunteers. Only some minor erythema was noted after patch removal, although this always resolved within 48 h, and no adverse events were present on follow-up.

Hydrogel-Forming Microneedle Arrays Can Be Effectively Inserted in Skin by Self-Application: A Pilot Study Centred on Pharmacist Intervention and a Patient Information Leaflet

Purpose: To investigate, for the first time, the influence of pharmacist intervention and the use of a patient information leaflet on self-application of hydrogel-forming microneedle arrays by human volunteers without the aid of an applicator device.
Methods: A patient information leaflet was drafted and pharmacist counselling strategy devised. Twenty human volunteers applied 11 × 11 arrays of 400 μm hydrogel-forming microneedle arrays to their own skin following the instructions provided. Skin barrier function disruption was assessed using transepidermal water loss measurements and optical coherence tomography and results compared to those obtained when more experienced researchers applied the microneedles to the volunteers or themselves.
Results: Volunteer self-application of the 400 μm microneedle design resulted in an approximately 30% increase in skin transepidermal water loss, which was not significantly different from that seen with self-application by the more experienced researchers or application to the volunteers. Use of optical coherence tomography showed that self-application of microneedles of the same density (400 μm, 600 μm and 900 μm) led to percentage penetration depths of approximately 75%, 70% and 60%, respectively, though the diameter of the micropores created remained quite constant at approximately 200 μm. Transepidermal water loss progressively increased with increasing height of the applied microneedles and this data, like that for penetration depth, was consistent, regardless of applicant.
Conclusion: We have shown that hydrogel-forming microneedle arrays can be successfully and reproducibly applied by human volunteers given appropriate instruction. If these outcomes were able to be extrapolated to the general patient population, then use of bespoke MN applicator devices may not be necessary, thus possibly enhancing patient compliance.

The Influence of Structural Modeshape Variability on Limit Cycle Oscillation Behaviour

Modal analysis is a popular approach used in structural dynamic and aeroelastic problems due to its efficiency. The response of a structure is compo
sed of the sum of orthogonal eigenvectors or modeshapes and corresponding modal frequencies. This paper investigates the importance of modeshapes on the aeroelastic response of the Goland wing subject to structural uncertainties. The wing undergoes limit cycle oscillations (LCO) as a result of the inclusion of polynomial stiffness nonlinearities. The LCO computations are performed using a Harmonic Balance approach for speed, the modal properties of the system are extracted from MSC NASTRAN. Variability in both the wing’s structure and the store centre of gravity location is investigated in two cases:- supercritical and subcritical type LCOs. Results show that the LCO behaviour is only sensitive to change in modeshapes when the nature of the modes are changing significantly.

A high resolution study of complex organic molecules in hot cores

We present the results of a line identification analysis using data from the IRAM Plateau de Bure Inferferometer, focusing on six massive star-forming hot cores: G31.41+0.31, G29.96-0.02, G19.61-0.23, G10.62-0.38, G24.78+0.08A1 and G24.78+0.08A2. We identify several transitions of vibrationally excited methyl formate (HCOOCH$_3$) for the first time in these objects as well as transitions of other complex molecules, including ethyl cyanide (C$_2$H$_5$CN), and isocyanic acid (HNCO). We also postulate a detection of one transition of glycolaldehyde (CH$_2$(OH)CHO) in two new hot cores. We find G29.96-0.02, G19.61-0.23, G24.78+0.08A1 and 24.78+0.08A2 to be chemically very similar. G31.41+0.31, however, is chemically different: it manifests a larger chemical inventory and has significantly larger column densities. We suggest that it may represent a different evolutionary stage to the other hot cores in the sample, or it may surround a star with a higher mass. We derive column densities for methyl formate in G31.41+0.31, using the rotation diagram method, of $\times$10$^{17}$ cm$^{-2}$ and a T$_{rot}$ of $\sim$170 K. For G29.96-0.02, G24.78+0.08A1 and G24.78+0.08A2, glycolaldehyde, methyl formate and methyl cyanide all seem to trace the same material and peak at roughly the same position towards the dust emission peak. For G31.41+0.31, however, glycolaldehyde shows a different distribution to methyl formate and methyl cyanide and seems to trace the densest, most compact inner part of hot cores.

Microbial community of the deep-sea brine Lake Kryos seawater-brine interface is active below the chaotropicity limit of life as revealed by recovery of mRNA

Within the complex of deep, hypersaline anoxic lakes (DHALs) of the Mediterranean Ridge, we identified a new, unexplored DHAL and named it ‘Lake Kryos’ after a nearby depression. This lake is filled with magnesium chloride (MgCl2)-rich, athalassohaline brine (salinity > 470 practical salinity units), presumably formed by the dissolution of Messinian bischofite. Compared with the DHAL Discovery, it contains elevated concentrations of kosmotropic sodium and sulfate ions, which are capable of reducing the net chaotropicily of MgCl2-rich solutions. The brine of Lake Kryos may therefore be biologically permissive at MgCl2 concentrations previously considered incompatible with life. We characterized the microbiology of the seawater–Kryos brine interface and managed to recover mRNA from the 2.27–3.03 MMgCl2 layer (equivalent to 0.747–0.631 water activity), thereby expanding the established chaotropicity window-for-life. The primary bacterial taxa present there were Kebrit Deep Bacteria 1 candidate division and DHAL-specific group of organisms, distantly related toDesulfohalobium. Two euryarchaeal candidate divisions, Mediterranean Sea Brine Lakes group 1 and halophilic cluster 1, accounted for > 85% of the rRNA-containing archaeal clones derived from the 2.27–3.03 M MgCl2 layer, but were minority community-members in the overlying interface-layers. These findings shed light on the plausibility of life in highly chaotropic environments, geochemical windows for microbial extremophiles, and have implications for habitability elsewhere in the Solar System.

Analysis of Transonic Limit Cycle Oscillations under Uncertainty

For the computation of limit cycle oscillations (LCO) at transonic speeds, CFD is required to capture the nonlinear flow features present. The Harmonic Balance method provides an effective means for the computation of LCOs and this paper exploits its efficiency to investigate the impact of variability (both structural a nd aerodynamic) on the aeroelastic behaviour of a 2 dof aerofoil. A Harmonic Balance inviscid CFD solver is coupled with the structural equations and is validated against time marching analyses. Polynomial chaos expansions are employed for the stochastic investiga tion as a faster alternative to Monte Carlo analysis. Adaptive sampling is employed when discontinuities are present. Uncertainties in aerodynamic parameters are looked at first followed by the inclusion of structural variability. Results show the nonlinear effect of Mach number and it’s interaction with the structural parameters on supercritical LCOs. The bifurcation boundaries are well captured by the polynomial chaos.