Bile salt composition is secondary to bile salt concentration in determining hydrocortisone and progesterone solubility in intestinal mimetic fluids.

Simulated intestinal fluids (SIFs) used to assay the solubility of orally administered drugs are typically based on a single bile salt; sodium taurocholate (STC). The aim of this study was to develop mimetic intestinal fluids with a closer similarity to physiological fluids than those reported to date by developing a mixed bile salt (MBS) system (STC, sodium glycodeoxycholate, sodium deoxycholate; 60:39:1) with different concentrations of lecithin, the preponderant intestinal phospholipid. Hydrocortisone and progesterone were used as model drugs to evaluate systematically the influence of SIF composition on solubility. Increasing total bile salt concentration from 0 to 30 mM increased hydrocortisone and progesterone solubility by 2- and ∼25-fold, respectively. Accordingly, higher solubilities were measured in the fed-state compared to the fasted-state SIFs. Progesterone showed the greatest increases in solubility in STC and MBS systems (2-7-fold) compared to hydrocortisone (no significant change; P>0.05) as lecithin concentration was increased. Overall, MBS systems gave similar solubility profiles to STC. In conclusion, the addenda of MBS and lecithin were found to be secondary to the influence of BS concentration. These data provide a foundation for the design of more bio-similar media for pivotal decision-guiding assays in drug development and quality control settings.

Salt forms of Amides: protonation and polymorphism of Carbamazepine and Cytenamide

In situ generation of HCl or HBr in alcohol leads to O-protonation of the amide group of carbamazepine. Six salt phases have been produced using this method and their crystal structures determined by single crystal diffraction. A new polymorph of carbamazepine hydrochloride is described as are two polymorphs of carbamazepine hydrobromide. All are protonated at the amide O atom to give RC(OH)NH2 cations. Prolonged exposure to air results in addition of water to the solid salt forms. Such hydration of carbamazepine hydrobromide simply gives a monohydrated phase, but similar treatment of the equivalent hydrochloride results in partial loss of HCl and the transfer of the remaining proton from the amide group to water to give [carbamazepine][H3O]0.5[Cl]0.5·H2O. A similar hydronium chloride species is the only product isolated after reaction of the carbamazepine analogue cytenamide with HCl generated in methanol.

IMF control of cusp proton emission intensity and dayside convection: implications for component and anti-parallel reconnection

We study a brightening of the Lyman-alpha emission in the cusp which occurred in response to a short-lived southward turning of the interplanetary magnetic field (IMF) during a period of strongly enhanced solar wind plasma concentration. The cusp proton emission is detected using the SI-12 channel of the FUV imager on the IMAGE spacecraft. Analysis of the IMF observations recorded by the ACE and Wind spacecraft reveals that the assumption of a constant propagation lag from the upstream spacecraft to the Earth is not adequate for these high time-resolution studies. The variations of the southward IMF component observed by ACE and Wind allow for the calculation of the ACE-to-Earth lag as a function of time. Application of the derived propagation delays reveals that the intensity of the cusp emission varied systematically with the IMF clock angle, the relationship being particularly striking when the intensity is normalised to allow for the variation in the upstream solar wind proton concentration. The latitude of the cusp migrated equatorward while the lagged IMF pointed southward, confirming the lag calculation and indicating ongoing magnetopause reconnection. Dayside convection, as monitored by the SuperDARN network of radars, responded rapidly to the IMF changes but lagged behind the cusp proton emission response: this is shown to be as predicted by the model of flow excitation by Cowley and Lockwood (1992). We use the numerical cusp ion precipitation model of Lockwood and Davis (1996), along with modelled Lyman-_ emission efficiency and the SI-12 instrument response, to investigate the effect of the sheath field clock angle on the acceleration of ions on crossing the dayside magnetopause. This modelling reveals that the emission commences on each reconnected field line 2–2.5min after it is opened and peaks 3–5 min after it is opened. We discuss how comparison of the Lyman-alpha intensities with oxygen emissions observed simultaneously by the SI-13 channel of the FUV instrument offers an opportunity to test whether or not the clock angle dependence is consistent with the “component” or the “anti-parallel” reconnection hypothesis.

Effect of feeding intensity and milking system on nutritionally relevant milk components in dairy farming systems in the North East of England

There is increasing concern that the intensification of dairy production reduces the concentrations of nutritionally desirable compounds in milk. This study therefore compared important quality parameters (protein and fatty acid profiles; α-tocopherol and carotenoid concentrations) in milk from four dairy systems with contrasting production intensities (in terms of feeding regimens and milking systems). The concentrations of several nutritionally desirable compounds (β-lactoglobulin, omega-3 fatty acids, omega-3/omega-6 ratio, conjugated linoleic acid c9t11, and/or carotenoids) decreased with increasing feeding intensity (organic outdoor ≥ conventional outdoor ≥ conventional indoors). Milking system intensification (use of robotic milking parlors) had a more limited effect on milk composition, but increased mastitis incidence. Multivariate analyses indicated that differences in milk quality were mainly linked to contrasting feeding regimens and that milking system and breed choice also contributed to differences in milk composition between production systems.

Global patterns of plant root colonization intensity by mycorrhizal fungi explained by climate and soil chemistry

Aim Most vascular plants on Earth form mycorrhizae, a symbiotic relationship between plants and fungi. Despite the broad recognition of the importance of mycorrhizae for global carbon and nutrient cycling, we do not know how soil and climate variables relate to the intensity of colonization of plant roots by mycorrhizal fungi. Here we quantify the global patterns of these relationships. Location Global. Methods Data on plant root colonization intensities by the two dominant types of mycorrhizal fungi world-wide, arbuscular (4887 plant species in 233 sites) and ectomycorrhizal fungi (125 plant species in 92 sites), were compiled from published studies. Data for climatic and soil factors were extracted from global datasets. For a given mycorrhizal type, we calculated at each site the mean root colonization intensity by mycorrhizal fungi across all potentially mycorrhizal plant species found at the site, and subjected these data to generalized additive model regression analysis with environmental factors as predictor variables. Results We show for the first time that at the global scale the intensity of plant root colonization by arbuscular mycorrhizal fungi strongly relates to warm-season temperature, frost periods and soil carbon-to-nitrogen ratio, and is highest at sites featuring continental climates with mild summers and a high availability of soil nitrogen. In contrast, the intensity of ectomycorrhizal infection in plant roots is related to soil acidity, soil carbon-to-nitrogen ratio and seasonality of precipitation, and is highest at sites with acidic soils and relatively constant precipitation levels. Main conclusions We provide the first quantitative global maps of intensity of mycorrhizal colonization based on environmental drivers, and suggest that environmental changes will affect distinct types of mycorrhizae differently. Future analyses of the potential effects of environmental change on global carbon and nutrient cycling via mycorrhizal pathways will need to take into account the relationships discovered in this study.

Just add water and salt: the optimisation of petrogenic hydrocarbon biodegradation in soils from semi-arid Barrow Island, Western Australia

We investigated the potential of soil moisture and nutrient amendments to enhance the biodegradation of oil in the soils from an ecologically unique semi-arid island. This was achieved using a series of controlled laboratory incubations where moisture or nutrient levels were experimentally manipulated. Respired CO2 increased sharply with moisture amendment reflecting the severe moisture limitation of these porous and semi-arid soils. The greatest levels of CO2 respiration were generally obtained with a soil pore water saturation of 50–70%. Biodegradation in these nutrient poor soils was also promoted by the moderate addition of a nitrogen fertiliser. Increased biodegradation was greater at the lowest amendment rate (100 mg N kg−1 soil) than the higher levels (500 or 1,000 mg N kg−1 soil), suggesting the higher application rates may introduce N toxicity. Addition of phosphorous alone had little effect, but a combined 500 mg N and 200 mg P kg−1 soil amendment led to a synergistic increase in CO2 respiration (3.0×), suggesting P can limit the biodegradation of hydrocarbons following exogenous N amendment.

Salt and ionic cocrystalline forms of amides: protonation of carbamazepine in aqueous media

The products of reactions of the pharmaceutical amide carbamazepine (CBZ) with strong acids under aqueous conditions were investigated by both powder and single crystal X-ray diffraction. Despite previous claims to the contrary, it was found that salt forms with CBZ protonated at the amide O atom could be isolated from reactions with both HCl and HBr. These forms include the newly identified hydrate phase [CBZ(H)][Cl]·H O. Reactions with other mineral acids (HI and HBF ) gave ionic cocrystalline (ICC) forms (CBZ· [acridinium][I ]·2.5I and CBZ·[H O ] [BF ] ·H O) as well as the salt form CBZ·[CBZ(H)][BF ]·0.5H O. Reaction 2 4 3 2 5 2 0.25 4 0.25 2 4 2 of CBZ with a series of sulfonic acids also gave salt forms, namely, [CBZ(H)][O SC H ], [CBZ(H)][O SC H (OH)]· 3 6 5 3 6 4 0.5H O, [CBZ(H)] [O SCH CH SO ], and [CBZ(H)][O SC H (OH) (COOH)]·H O. CBZ and protonated CBZ(H) 2 2 3 2 2 3 3 6 3 2 moieties can be differentiated in the solid state both by changes to molecular geometry and by differing packing preferences

A low mortality, high morbidity reduced intensity status epilepticus (RISE) model of epilepsy and epileptogenesis in the rat

Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles.

Neural signals of “Intensity” but not “Wanting” or “Liking” of rewards may be trait markers for depression

We have shown previously that particpants “at risk” of depression have decreased neural processing of reward suggesting this might be a neural biomarker for depression. However, how the neural signal related to subjective experiences of reward (wanting, liking, intensity) might differ as trait markers for depression, is as yet unknown. Using SPM8 parametric modulation analysis the neural signal related to the subjective report of wanting, liking and intensity was compared between 25 young people with a biological parent with depression (FH) and 25 age/gender matched controls. In a second study the neural signal related to the subjective report of wanting, liking and intensity was compared between 13 unmedicated recovered depressed (RD) patients and 14 healthy age/gender matched controls. The analysis revealed differences in the neural signal for wanting, liking and intensity ratings in the ventral striatum, dmPFC and caudate respectively in the RD group compared to controls . Despite no differences in the FH groups neural signal for wanting and liking there was a difference in the neural signal for intensity ratings in the dACC and anterior insula compared to controls. These results suggest that the neural substrates tracking the intensity but not the wanting or liking for rewards and punishers might be a trait marker for depression.