The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

When long-range zero-lag synchronization is feasible in cortical networks

Many studies have reported long-range synchronization of neuronal activity between brain areas, in particular in the beta and gamma bands with frequencies in the range of 14–30 and 40–80 Hz, respectively. Several studies have reported synchrony with zero phase lag, which is remarkable considering the synaptic and conduction delays inherent in the connections between distant brain areas. This result has led to many speculations about the possible functional role of zero-lag synchrony, such as for neuronal communication, attention, memory, and feature binding. However, recent studies using recordings of single-unit activity and local field potentials report that neuronal synchronization may occur with non-zero phase lags. This raises the questions whether zero-lag synchrony can occur in the brain and, if so, under which conditions. We used analytical methods and computer simulations to investigate which connectivity between neuronal populations allows or prohibits zero-lag synchrony. We did so for a model where two oscillators interact via a relay oscillator. Analytical results and computer simulations were obtained for both type I Mirollo–Strogatz neurons and type II Hodgkin–Huxley neurons. We have investigated the dynamics of the model for various types of synaptic coupling and importantly considered the potential impact of Spike-Timing Dependent Plasticity (STDP) and its learning window. We confirm previous results that zero-lag synchrony can be achieved in this configuration. This is much easier to achieve with Hodgkin–Huxley neurons, which have a biphasic phase response curve, than for type I neurons. STDP facilitates zero-lag synchrony as it adjusts the synaptic strengths such that zero-lag synchrony is feasible for a much larger range of parameters than without STDP.

On wave action and phase in the non-canonical Hamiltonian formulation

The long time–evolution of disturbances to slowly–varying solutions of partial differential equations is subject to the adiabatic invariance of the wave action. Generally, this approximate conservation law is obtained under the assumption that the partial differential equations are derived from a variational principle or have a canonical Hamiltonian structure. Here, the wave action conservation is examined for equations that possess a non–canonical (Poisson) Hamiltonian structure. The linear evolution of disturbances in the form of slowly varying wavetrains is studied using a WKB expansion. The properties of the original Hamiltonian system strongly constrain the linear equations that are derived, and this is shown to lead to the adiabatic invariance of a wave action. The connection between this (approximate) invariance and the (exact) conservation laws of pseudo–energy and pseudomomentum that exist when the basic solution is exactly time and space independent is discussed. An evolution equation for the slowly varying phase of the wavetrain is also derived and related to Berry's phase.

RNA interference suppression of genes in glycosyl transferase families 43 and 47 in wheat starchy endosperm causes large decreases in arabinoxylan content

The cell walls of wheat (Triticum aestivum) starchy endosperm are dominated by arabinoxylan (AX), accounting for 65% to 70% of the polysaccharide content. Genes within two glycosyl transferase (GT) families, GT43 (IRREGULAR XYLEM9 [IRX9] and IRX14) and GT47 (IRX10), have previously been shown to be involved in the synthesis of the xylan backbone in Arabidopsis, and close homologs of these have been implicated in the synthesis of xylan in other species. Here, homologs of IRX10 TaGT47_2 and IRX9 TaGT43_2, which are highly expressed in wheat starchy endosperm cells, were suppressed by RNA interference (RNAi) constructs driven by a starchy endosperm-specific promoter. The total amount of AX was decreased by 40% to 50% and the degree of arabinosylation was increased by 25% to 30% in transgenic lines carrying either of the transgenes. The cell walls of starchy endosperm in sections of grain from TaGT43_2 and TaGT47_2 RNAi transgenics showed decreased immunolabeling for xylan and arabinoxylan epitopes and approximately 50% decreased cell wall thickness compared with controls. The proportion of AX that was water soluble was not significantly affected, but average AX polymer chain length was decreased in both TaGT43_2 and TaGT47_2 RNAi transgenics. However, the long AX chains seen in controls were absent in TaGT43_2 RNAi transgenics but still present in TaGT47_2 RNAi transgenics. The results support an emerging picture of IRX9-like and IRX10-like proteins acting as key components in the xylan synthesis machinery in both dicots and grasses. Since AX is the main component of dietary fiber in wheat foods, the TaGT43_2 and TaGT47_2 genes are of major importance to human nutrition.

A comparison of tests of non-linear cointegration with an application to the predictability of US interest rates using the term structure

We test whether there are nonlinearities in the response of short- and long-term interest rates to the spread in interest rates, and assess the out-of-sample predictability of interest rates using linear and nonlinear models. We find strong evidence of nonlinearities in the response of interest rates to the spread. Nonlinearities are shown to result in more accurate short-horizon forecasts, especially of the spread.

Tests of non-linearity using LIFFE futures transactions price data

This paper presents and implements a number of tests for non-linear dependence and a test for chaos using transactions prices on three LIFFE futures contracts: the Short Sterling interest rate contract, the Long Gilt government bond contract, and the FTSE 100 stock index futures contract. While previous studies of high frequency futures market data use only those transactions which involve a price change, we use all of the transaction prices on these contracts whether they involve a price change or not. Our results indicate irrefutable evidence of non-linearity in two of the three contracts, although we find no evidence of a chaotic process in any of the series. We are also able to provide some indications of the effect of the duration of the trading day on the degree of non-linearity of the underlying contract. The trading day for the Long Gilt contract was extended in August 1994, and prior to this date there is no evidence of any structure in the return series. However, after the extension of the trading day we do find evidence of a non-linear return structure.

Interaction among non-toxic phytoplankton, toxic phytoplankton and zooplankton: inferences from field observations

We explore the mutual dependencies and interactions among different groups of species of the plankton population, based on an analysis of the long-term field observations carried out by our group in the North–West coast of the Bay of Bengal. The plankton community is structured into three groups of species, namely, non-toxic phytoplankton (NTP), toxic phytoplankton (TPP) and zooplankton. To find the pair-wise dependencies among the three groups of plankton, Pearson and partial correlation coefficients are calculated. To explore the simultaneous interaction among all the three groups, a time series analysis is performed. Following an Expectation Maximization (E-M) algorithm, those data points which are missing due to irregularities in sampling are estimated, and with the completed data set a Vector Auto-Regressive (VAR) model is analyzed. The overall analysis demonstrates that toxin-producing phytoplankton play two distinct roles: the inhibition on consumption of toxic substances reduces the abundance of zooplankton, and the toxic materials released by TPP significantly compensate for the competitive disadvantages among phytoplankton species. Our study suggests that the presence of TPP might be a possible cause for the generation of a complex interaction among the large number of phytoplankton and zooplankton species that might be responsible for the prolonged coexistence of the plankton species in a fluctuating biomass.

Alterations in predicted regulatory and coding regions of the sterol 14α-demethylase gene (CYP51) confer decreased azole sensitivity in the oilseed rape pathogen Pyrenopeziza brassicae

The incidence and severity of light leaf spot epidemics caused by the ascomycete fungus Pyrenopeziza brassicae on UK oilseed rape crops is increasing. The disease is currently controlled by a combination of host resistance, cultural practices and fungicide applications. We report decreases in sensitivities of modern UK P. brassicae isolates to the azole (imidazole and triazole) class of fungicides. By cloning and sequencing the P. brassicae CYP51 (PbCYP51) gene, encoding the azole target sterol 14α-demethylase, we identified two non-synonymous mutations encoding substitutions G460S and S508T associated with reduced azole sensitivity. We confirmed the impact of the encoded PbCYP51 changes on azole sensitivity and protein activity by heterologous expression in a Saccharomyces cerevisiae mutant YUG37::erg11 carrying a controllable promoter of native CYP51 expression. In addition, we identified insertions in the predicted regulatory regions of PbCYP51 in isolates with reduced azole sensitivity. The presence of these insertions was associated with enhanced transcription of PbCYP51 in response to sub-inhibitory concentrations of the azole fungicide tebuconazole. Genetic analysis of in vitro crosses of sensitive and resistant isolates confirmed the impact of PbCYP51 alterations in coding and regulatory sequences on a reduced sensitivity phenotype, as well as identifying a second major gene at another locus contributing to resistance in some isolates. The least sensitive field isolates carry combinations of upstream insertions and non-synonymous mutations, suggesting PbCYP51 evolution is on-going and the progressive decline in azole sensitivity of UK P. brassicae populations will continue. The implications for the future control of light leaf spot are discussed.

Non-Refoulement between 'Common Article 1' and 'Common Article 3'

This article considers whether, in the context of armed conflicts, certain non-refoulement obligations of non-belligerent States can be derived from the 1949 Geneva Conventions. According to Common Article 1 (CA1) thereof, all High Contracting Parties (HCPs) undertake to ‘respect and to ensure respect’ for the four conventions ‘in all circumstances’. It is contended that CA1 applies both in international armed conflicts (IACs) and in non-international armed conflicts (NIACs). In turn, it is suggested that Common Article 3 (CA3) which regulates conduct in NIACs serves as a ‘minimum yardstick’ also applicable in IACs. It is widely (though not uniformly) acknowledged that the undertaking to ‘ensure respect’ in a given armed conflict extends to HCPs that are not parties to it; nevertheless, the precise scope of this undertaking is subject to scholarly debate. This article concerns situations where, in the course of an (international or non-international) armed conflict, persons ’taking no active part in hostilities’ flee from States where violations of CA3 are (likely to be) occurring to a non-belligerent State. Based on the undertaking in CA1, the central claim of this article is that, as long as risk of exposure to these violations persists, persons should not be refouled notwithstanding possible assessment of whether they qualify as refugees based on the 1951 Refugee Convention definition, or could be eligible for complementary or subsidiary forms of protection that are regulated in regional arrangements. The analysis does not affect the explicit protection from refoulement that the Fourth Geneva Convention accords to ‘protected persons’ (as defined in Article 4 thereof). It is submitted that CA1 should be read in tandem with other obligations of non-belligerent States under the 1949 Geneva Conventions. Most pertinently, all HCPs are required to take specific measures to repress ‘grave breaches’ and to take measures necessary for the suppression of all acts contrary to the 1949 Geneva Conventions other than the grave breaches. A HCP that is capable of protecting displaced persons from exposure to risks of violations of CA3 and nonetheless refoules them to face such risks is arguably failing to take lawful measures at its disposal in order to suppress acts contrary to the conventions and, consequently, fails to ‘ensure respect’ for the conventions. KEYWORDS Non-refoulement; International Armed Conflict; Non-International Armed Conflict; Common Article 1; Common Article 3

Molecular archaeology of Flaviviridae untranslated regions: duplicated RNA structures in the replication enhancer of flaviviruses and pestiviruses emerged via convergent evolution.

RNA secondary structures in the 3'untranslated regions (3'UTR) of the viruses of the family Flaviviridae, previously identified as essential (promoters) or beneficial (enhancers) for replication, have been analysed. Duplicated enhancer elements are revealed as a global feature in the evolution of the 3'UTR of distantly related viruses within the genera Flavivirus and Pestivirus. For the flaviviruses, duplicated structures occur in the 3'UTR of all four distantly related ecological virus subgroups (tick-borne, mosquito-borne, no known vector and insect-specific flaviviruses (ISFV). RNA structural differences distinguish tick-borne flaviviruses with discrete pathogenetic characteristics. For Aedes- and Culex-associated ISFV, secondary RNA structures with different conformations display numerous short ssRNA direct repeats, exposed as loops and bulges. Long quadruplicate regions comprise almost the entire 3'UTR of Culex-associated ISFV. Extended duplicated sequence and associated RNA structures were also discovered in the 3'UTR of pestiviruses. In both the Flavivirus and Pestivirus genera, duplicated RNA structures were localized to the enhancer regions of the 3'UTR suggesting an adaptive role predominantly in wild-type viruses. We propose sequence reiteration might act as a scaffold for dimerization of proteins involved in assembly of viral replicase complexes. Numerous nucleotide repeats exposed as loops/bulges might also interfere with host immune responses acting as a molecular sponge to sequester key host proteins or microRNAs.

Ventilation performance in a passage between two non-parallel buildings

A great number of studies on wind conditions in passages between slab-type buildings have been conducted in the past. However, wind conditions under different structure and configuration of buildings is still unclear and studies existed still can’t provide guidance on urban planning and design, due to the complexity of buildings and aerodynamics. The aim of this paper is to provide more insight in the mechanism of wind conditions in passages. In this paper, a simplified passage model with non-parallel buildings is developed on the basis of the wind tunnel experiments conducted by Blocken et al. (2008). Numerical simulation based on CFD is employed for a detailed investigation of the wind environment in passages between two long narrow buildings with different directions and model validation is performed by comparing numerical results with corresponding wind tunnel measurements.

Model predictions of the occurrence of non-Maxwellian plasmas, and analysis of their effects on EISCAT data

The recent identification of non-thermal plasmas using EISCAT data has been made possible by their occurrence during large, short-lived flow bursts. For steady, yet rapid, ion convection the only available signature is the shape of the spectrum, which is unreliable because it is open to distortion by noise and sampling uncertainty and can be mimicked by other phenomena. Nevertheless, spectral shape does give an indication of the presence of non-thermal plasma, and the characteristic shape has been observed for long periods (of the order of an hour or more) in some experiments. To evaluate this type of event properly one needs to compare it to what would be expected theoretically. Predictions have been made using the coupled thermosphere-ionosphere model developed at University College London and the University of Sheffield to show where and when non-Maxwellian plasmas would be expected in the auroral zone. Geometrical and other factors then govern whether these are detectable by radar. The results are applicable to any incoherent scatter radar in this area, but the work presented here concentrates on predictions with regard to experiments on the EISCAT facility.

Fat and fatty acid composition of cooked meat from UK retail chickens labelled as from organic and non-organic production systems

This study compared fat and fatty acids in cooked retail chicken meat from conventional and organic systems. Fat contents were 1.7, 5.2, 7.1 and 12.9 g/100 g cooked weight in skinless breast, breast with skin, skinless leg and leg with skin respectively, with organic meat containing less fat overall (P < 0.01). Meat was rich in cis-monounsaturated fatty acids, although organic meat contained less than did conventional meat (1850 vs. 2538 mg/100 g; P < 0.001). Organic meat was also lower (P < 0.001) in 18:3 n−3 (115 vs. 180 mg/100 g) and, whilst it contained more (P < 0.001) docosahexaenoic acid (30.9 vs. 13.7 mg/100 g), this was due to the large effect of one supermarket. This system by supermarket interaction suggests that poultry meat labelled as organic is not a guarantee of higher long chain n−3 fatty acids. Overall there were few major differences in fatty acid contents/profiles between organic and conventional meat that were consistent across all supermarkets.

Endothelial function and insulin sensitivity during acute non-esterified fatty acid elevation: effects of fat composition and gender

Background and Aims: We have reported that adverse effects on flow-mediated dilation of an acute elevation of non-esterified fatty acids rich in saturated fat (SFA) are reversed following addition of long-chain (LC) n-3 polyunsaturated fatty acids (PUFA), and hypothesised that these effects may be mediated through alterations in insulin signalling pathways. In a subgroup, we explored the effects of raised NEFA enriched with SFA, with or without LC n-3 PUFA, on whole body insulin sensitivity (SI) and responsiveness of the endothelium to insulin infusion. Methods and Results: Thirty adults (mean age 27.8 y, BMI 23.2 kg/m2) consumed oral fat loads on separate occasions with continuous heparin infusion to elevate NEFA between 60-390 min. For the final 150 min, a hyperinsulinaemic-euglycaemic clamp was performed, whilst FMD and circulating markers of endothelial function were measured at baseline, pre-clamp (240 min) and post-clamp (390 min). NEFA elevation during the SFA-rich drinks was associated with impaired FMD (P=0.027) whilst SFA+LC n-3 PUFA improved FMD at 240 min (P=0.003). In males, insulin infusion attenuated the increase in FMD with SFA+LC n-3 PUFA (P=0.049), with SI 10% greater with SFA+LC n-3 PUFA than SFA (P=0.041). Conclusion: This study provides evidence that NEFA composition during acute elevation influences both FMD and SI, with some indication of a difference by gender. However our findings are not consistent with the hypothesis that the effects of fatty acids on endothelial function and SI operate through a common pathway. Trial registered at clinicaltrials.gov, NCT01351324.

Long-term conditioning of soil by plantation eucalypts and pines does not affect growth of the native jarrah tree

Plant species can condition the physico-chemical and biological properties of soil in ways that modify plant growth via plant–soil feedback (PSF). Plant growth can be positively affected, negatively affected or neutrally affected by soil conditioning by the same or other plant species. Soil conditioning by other plant species has particular relevance to ecological restoration of historic ecosystems because sites set aside for restoration are often conditioned by other, potentially non-native, plant species. We investigated changes in properties of jarrah forest soils after long-term (35 years) conditioning by pines (Pinus radiata), Sydney blue gums (Eucalyptus saligna), both non-native, plantation trees, and jarrah (Eucalyptus marginata; dominant native tree). Then, we tested the influence of the conditioned soils on the growth of jarrah seedlings. Blue gums and pines similarly conditioned the physico-chemical properties of soils, which differed from soil conditioning caused by jarrah. Especially important were the differences in conditioning of the properties C:N ratio, pH, and available K. The two eucalypt species similarly conditioned the biological properties of soil (i.e. community level physiological profile, numbers of fungal-feeding nematodes, omnivorous nematodes, and nematode channel ratio), and these differed from conditioning caused by pines. Species-specific conditioning of soil did not translate into differences in the amounts of biomass produced by jarrah seedlings and a neutral PSF was observed. In summary, we found that decades of soil conditioning by non-native plantation trees did not influence the growth of jarrah seedlings and will therefore not limit restoration of jarrah following the removal of the plantation trees.