An Assessment of the Recent Past and Future Climate Change, Glacier Retreat, and Runoff in the Caucasus Region Using Dynamical and Statistical Downscaling and HBV-ETH Hydrological Model

The paper discusses the observed and projected warming in the Caucasus region and its implications for glacier melt and runoff. A strong positive trend in summer air temperatures of 0.05 degrees C a(-1) is observed in the high-altitude areas providing for a strong glacier melt and continuous decline in glacier mass balance. A warming of 4-7 degrees C and 3-5 degrees C is projected for the summer months in 2071-2100 under the A2 and B2 emission scenarios respectively, suggesting that enhanced glacier melt can be expected. The expected changes in winter precipitation will not compensate for the summer melt and glacier retreat is likely to continue. However, a projected small increase in both winter and summer precipitation combined with the enhanced glacier melt will result in increased summer runoff in the currently glaciated region of the Caucasus (independent of whether the region is glaciated at the end of the twenty-first century) by more than 50% compared with the baseline period.

Disease progression in heterosexual patients infected with closely related subtype B strains of HIV type 1 with differing coreceptor usage properties

Previously we described a heterosexual outbreak of HIV-1 subtype B in a town in the north of England (Doncaster) where 11 of 13 infections were shown to be linked by phylogenetic analysis of the env gp120 region. The 11 infections were related to a putative index case, Don1, and further divided into two groups based on the patients' disease status, their viral sequences, and other epidemiological information. Here we describe two further findings. First, we found that viral isolates and gp120 recombinant viruses derived from patients from one group used the CCR5 coreceptor, whereas viruses from the other group could use both the CCR5 and CXCR4 coreceptors. Patients with the X4/R5 dual tropic strains were symptomatic when diagnosed and progressed rapidly, in contrast to the other patient group that has remained asymptomatic, implying a link between the tropism of the strains and disease outcome. Second, we present additional sequence data derived from the index case, demonstrating the presence of sequences from both clades, with an average interclade distance of 9.56%, providing direct evidence of a genetic link between these two groups. This new study shows that Don1 harbored both strains, implying he was either dually infected or that over time intrahost diversification from the R5 to R5/X4 phenotype occurred. These events may account for/have led to the spread of two genetically related strains with different pathogenic properties within the same heterosexual community.

The influence of G protein subtype on agonist action at D-2 dopamine receptors

In previous studies, we have shown that agonists influence the ability of D-2 dopamine receptors to couple to G proteins and here we extend this work. The human D-2Short dopamine receptor and a natural polymorphism of this D-2Short(Ser(311)Cys), have been studied by co-expressing the receptors in insect cells with Gbeta(1)gamma(2) and either Galpha(o), Galpha(i1), Galpha(i2) or Galpha(i3) G protein subunits. These preparations have been used to study the G protein coupling profiles of the two receptors and the influence of agonists. Receptor/G protein coupling was analysed in dopamine/[H-3]spiperone competition binding experiments and through stimulation of [S-35]GTPgammaS binding. Although the Ser(311)Cys polymorphism itself had no appreciable effect on the G protein coupling specificity of the D-2 receptor, agonist stimulation of [S-35]GTPgammaS binding, revealed that both dopamine and (+)-3PPP showed a clear preference for Galpha(o) compared to the Galpha(i) subtypes, but quinpirole did not. These results indicate that agonists are able to stabilise different receptor conformations with different abilities to couple to G proteins. (C) 2004 Elsevier Ltd. All rights reserved.

Parenting by anxious mothers: effects of disorder subtype, context and child characteristics

Background:  There has been increasing research interest in parenting by anxious adults; however, little is known about anxiety-subtype effects, or effects of the context in which parenting is assessed. Methods:  Two groups of anxious mothers, social phobia (N = 50), generalised anxiety disorder (N = 38), and nonanxious controls (N = 62) were assessed with their 4.9-year-old children in three tasks: two presented threat specifically relevant to each maternal disorder, namely, a social threat task where the child had to give a speech, and a nonsocial threat task where the child had to explore potentially scary objects; the third was a nonthreat task (playing with play dough). Seven parenting dimensions were scored. Effects on parenting of maternal anxiety subgroup and task, and their interactions, were examined, as were effects of earlier child behavioural inhibition and currently manifest anxiety. Results:  There were no parenting differences between maternal groups in the nonthreat play-dough task; parenting difficulties in the two anxious groups were principally evident in the disorder-specific challenge. Parenting differences between nonanxious and anxious mothers occurred independently of child characteristics. There was little evidence for particular forms of parenting difficulty being unique to maternal disorder. Conclusions:  Anxious mothers’ parenting difficulties emerge when occurring under challenge, especially when this is disorder-specific. These effects should be considered in research and clinical practice.

Fibroblast growth factor 2 maintains the neurogenic capacity of embryonic neural progenitor cells in vitro but changes their neuronal subtype specification

Many in vitro systems used to examine multipotential neural progenitor cells (NPCs) rely on mitogens including fibroblast growth factor 2 (FGF2) for their continued expansion. However, FGF2 has also been shown to alter the expression of transcription factors (TFs) that determine cell fate. Here, we report that NPCs from the embryonic telencephalon grown without FGF2 retain many of their in vivo characteristics, making them a good model for investigating molecular mechanisms involved in cell fate specification and differentiation. However, exposure of cortical NPCs to FGF2 results in a profound change in the types of neurons generated, switching them from a glutamatergic to a GABAergic phenotype. This change closely correlates with the dramatic upregulation of TFs more characteristic of ventral telencephalic NPCs. In addition, exposure of cortical NPCs to FGF2 maintains their neurogenic potential in vitro, and NPCs spontaneously undergo differentiation following FGF2 withdrawal. These results highlight the importance of TFs in determining the types of neurons generated by NPCs in vitro. In addition, they show that FGF2, as well as acting as a mitogen, changes the developmental capabilities of NPCs. These findings have implications for the cell fate specification of in vitro-expanded NPCs and their ability to generate specific cell types for therapeutic applications. Disclosure of potential conflicts of interest is found at the end of this article.

Subtype-selective GABAergic drugs facilitate extinction of mouse operant behaviour

Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.

Vehicle subtype, make and model classification from side profile video

This paper addresses the challenging domain of vehicle classification from pole-mounted roadway cameras, specifically from side-profile views. A new public vehicle dataset is made available consisting of over 10000 side profile images (86 make/model and 9 sub-type classes). 5 state-of-the-art classifiers are applied to the dataset, with the best achieving high classification rates of 98.7% for sub-type and 99.7- 99.9% for make and model recognition, confirming the assertion made that single vehicle side profile images can be used for robust classification.

Effects of neuropathy on high-voltage-activated Ca2+ current in sensory neurones

Voltage-dependent Ca2+ channels (VDCCs) have emerged as targets to treat neuropathic pain; however, amongst VDCCs, the precise role of the CaV2.3 subtype in nociception remains unproven. Here, we investigate the effects of partial sciatic nerve ligation (PSNL) on Ca2+ currents in small/medium diameter dorsal root ganglia (DRG) neurones isolated from CaV2.3(−/−) knock-out and wild-type (WT) mice. DRG neurones from CaV2.3(−/−) mice had significantly reduced sensitivity to SNX-482 versusWTmice. DRGs from CaV2.3(−/−) mice also had increased sensitivity to the CaV2.2 VDCC blocker -conotoxin. In WT mice, PSNL caused a significant increase in -conotoxin-sensitivity and a reduction in SNX-482-sensitivity. In CaV2.3(−/−) mice, PSNL caused a significant reduction in -conotoxin-sensitivity and an increase in nifedipine sensitivity. PSNL-induced changes in Ca2+ current were not accompanied by effects on voltagedependence of activation in either CaV2.3(−/−) or WT mice. These data suggest that CaV2.3 subunits contribute, but do not fully underlie, drug-resistant (R-type) Ca2+ current in these cells. In WT mice, PSNL caused adaptive changes in CaV2.2- and CaV2.3-mediated Ca2+ currents, supporting roles for these VDCCs in nociception during neuropathy. In CaV2.3(−/−) mice, PSNL-induced changes in CaV1 and CaV2.2 Ca2+ current, consistent with alternative adaptive mechanisms occurring in the absence of CaV2.3 subunits.

Modeling the Stream Water Nitrate Dynamics in 60,000-km(2) European Catchment, the Garonne, Southwest France

The spatial and temporal dynamics in the stream water NO3-N concentrations in a major European river-system, the Garonne (62,700 km(2)), are described and related to variations in climate, land management, and effluent point-sources using multivariate statistics. Building on this, the Hydrologiska Byrans Vattenbalansavdelning (HBV) rainfall-runoff model and the Integrated Catchment Model of Nitrogen (INCA-N) are applied to simulate the observed flow and N dynamics. This is done to help us to understand which factors and processes control the flow and N dynamics in different climate zones and to assess the relative inputs from diffuse and point sources across the catchment. This is the first application of the linked HBV and INCA-N models to a major European river system commensurate with the largest basins to be managed tinder the Water Framework Directive. The simulations suggest that in the lowlands, seasonal patterns in the stream water NO3-N concentrations emerge and are dominated by diffuse agricultural inputs, with an estimated 75% of the river load in the lowlands derived from arable farming. The results confirm earlier European catchment studies. Namely, current semi-distrubuted catchment-scale dynamic models, which integrate variations in land cover, climate, and a simple representation of the terrestrial and in-stream N cycle, are able to simulate seasonal NO3-N patterns at large spatial (> 300 km(2)) and temporal (>= monthly) scales using available national datasets.

Modeling the Stream Water Nitrate Dynamics in 60,000-km(2) European Catchment, the Garonne, Southwest France

The spatial and temporal dynamics in the stream water NO3-N concentrations in a major European river-system, the Garonne (62,700 km(2)), are described and related to variations in climate, land management, and effluent point-sources using multivariate statistics. Building on this, the Hydrologiska Byrans Vattenbalansavdelning (HBV) rainfall-runoff model and the Integrated Catchment Model of Nitrogen (INCA-N) are applied to simulate the observed flow and N dynamics. This is done to help us to understand which factors and processes control the flow and N dynamics in different climate zones and to assess the relative inputs from diffuse and point sources across the catchment. This is the first application of the linked HBV and INCA-N models to a major European river system commensurate with the largest basins to be managed tinder the Water Framework Directive. The simulations suggest that in the lowlands, seasonal patterns in the stream water NO3-N concentrations emerge and are dominated by diffuse agricultural inputs, with an estimated 75% of the river load in the lowlands derived from arable farming. The results confirm earlier European catchment studies. Namely, current semi-distrubuted catchment-scale dynamic models, which integrate variations in land cover, climate, and a simple representation of the terrestrial and in-stream N cycle, are able to simulate seasonal NO3-N patterns at large spatial (> 300 km(2)) and temporal (>= monthly) scales using available national datasets.

Restrictions to the adaptation of influenza A virus H5 hemagglutinin to the human host

The binding specificities of a panel of avian influenza virus subtype H5 hemagglutinin (RA) proteins bearing mutations at key residues in the receptor binding site were investigated. The results demonstrate that two simultaneous mutations in the receptor binding site resulted in H5 RA binding in a pattern similar to that shown by human viruses. Coexpression of the ion channel protein, M2, from most avian and human strains tested protected H5 RA conformation during trafficking, indicating that no genetic barrier to the reassortment of the H5 surface antigen gene with internal genes of human viruses existed at this level.

Pharmacological characterisation of the agonist radioligand binding site of 5-HT2A, 5-HT2B and 5-HT2C receptors

In the present study we compared the affinity of various drugs for the high affinity "agonist-preferring" binding site of human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors stably expressed in monoclonal mammalian cell lines. To ensure that the "agonist-preferring" conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([H-3]-ketanserin for 5-HT2A receptor and [H-3]-mesulergine for 5-HT2B and 5-HT2C receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([I-125]-DOI for 5-HT2A receptor binding and [H-3]-5-HT for 5-HT2B and 5-HT2C receptor binding). Competition experiments were subsequently conducted against appropriate concentrations of the agonist radiolabels bound to the "agonist-preferring" subset of receptors in each preparation. These studies confirmed that there are a number of highly selective antagonists available to investigate 5-HT2 receptor subtype function (for example, MDL 100907, RS-127445 and RS-102221 for 5-HT2A, 5-HT2B and 5-HT2C receptors respectively). There remains, however, a lack of highly selective agonists. (-)DOI is potent and moderately selective for 5-HT2A receptors, BW723C86 has poor selectivity for human 5-HT2B receptors, while Org 37684 and VER-3323 display some selectivity for the 5-HT2C receptor. We report for the first time in a single study, the selectivity of numerous serotonergic drugs for 5-HT2 receptors from the same species, in mammalian cell lines and using, exclusively, agonist radiolabels. The results indicate the importance of defining the selectivity of pharmacological tools, which may have been over-estimated in the past, and highlights the need to find more selective agonists to investigate 5-HT2 receptor pharmacology.

Attenuating mutations in the influenza virus genome which may increase the safety of vaccine production

Influenza virus epidemics occur on an annual basis and cause severe disease in the very young and old. The vaccine administered to high-risk groups is generated by amplifying reassortant viruses, with chronologically relevant viral surface antigens, in eggs. Every 20 years or so, influenza pandemics occur causing widespread fatality in all age groups. These viruses display novel viral surface antigens acquired from a zoonotic source, and vaccination against them poses new issues since production of large amounts of a respiratory virus containing novel surface antigens could be dangerous for those involved in manufacture. To minimise risks, it is advisable to use a virus whose genetic backbone is highly attenuated in man. Traditionally, the A/PR/8/34 strain of virus is used, however, the genetic basis of its attenuation is unclear. Cold-adapted (CA) strains of the influenza virus are all based on the H2N2 subtype, itself a virus with pandemic potential, and again the genetic basis of temperature sensitivity is not yet established. Reverse genetics technology allows us to engineer designer influenza viruses to order. Using this technology, we have been investigating mutations in several different gene segments to effectively attenuate potential vaccine strains allowing the safe production of vaccine to protect against the next pandemic. (C) 2003 Elsevier B.V. All rights reserved.

Neurokinin B is a paracrine vasodilator in the human fetal placental circulation

Neurokinin (NK) B is a member of the tachykinin family of neurotransmitters, exerting hypotensive or hypertensive effects in the mammalian vasculature through synaptic release from peripheral neurons, according to either NK1 and NK2 or NK3 receptor subtype expression, respectively. There is recent evidence that NKB is expressed by the syncytiotrophoblast of the human placenta, an organ that is not innervated. We hypothesized that NKB is a paracrine modulator of tone in the fetal placental circulation. We tested this hypothesis using the in vitro perfused human placental cotyledon. Our data show that NKB is a dilator of the fetal vasculature, causing a maximal 25.1+/-4.5% (mean+/-SEM; n=5) decrease in fetal-side arterial hydrostatic pressure (5-muM NKB bolus; effective concentration in the circulation, 1.89 nM) after preconstriction with U-46619. RT-PCR demonstrated the presence of mRNA for NK1 and NK2 tachykinin receptors in the placenta. Using selective receptor antagonists, we found that NKB-induced vasodilation is through the NK1 receptor subtype. We found no evidence for the involvement of either nitric oxide or prostacyclin in this response. This study demonstrates a paracrine role for NKB in the regulation of fetal placental vascular tone.

Educational value of different types of exhibits in an interactive science and technology center

This study analyzes the short-term consequences of visitors' use of different types of exhibits (i.e., "exemplars of phenomena" and "analogy based") together with the factors affecting visitors' understanding of and their evaluation of the use of such exhibits. One hundred and twenty five visitors (either alone or in groups) were observed during their interaction and interviewed immediately afterwards. Findings suggest that the type of exhibit constrains the nature of the understanding achieved. The use of analogical reasoning may lead to an intended causal explanation of an exhibit that is an exemplar of a phenomenon, but visitors often express misconceptions as a consequence of using this type of exhibit. Analogy-based exhibits are often not used as intended by the designer. This may be because visitors do not access the source domain intended; are unaware of the use of analogy per se (in particular, when the exhibit is of the subtype "only showing similarities between relationships"); only acquire fragmentary knowledge about the target; or fail to use analogical reasoning of which they were capable. Furthermore, exhibits related to everyday world situations are recognized to have an immediate educative value for visitors. Suggestions for enhancing the educative value of exhibits are proposed.