bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender and the historiography of science
Authors: Jordanova Ludmilla
Published: January 2009

The production of big pictures is arguably the most significant sign of the intellectual maturity of a field. It suggests both that the field's broad contours, refined over several generations of scholarship, enjoy the approval of practitioners, and that audiences exist with an interest in or need for overviews. The situation is somewhat more complicated in the history of science, since the existence of big historical pictures precedes that of a well-defined scholarly field by about two centuries. Broadly conceived histories of science and medicine were being written in the eighteenth century, when such an all-encompassing vision was central to the claims about the progress of knowledge upon which Enlightenment ideologues set such store. The Plato to Nato style histories, characteristic of the earlier twentieth century, were written largely by isolated pioneers, and while these were used in teaching as the field was becoming professionalized, recent scholars have preferred to concentrate on a monographic style of research. Despite the existence of the series started by Wiley, and now published by Cambridge University Press, it is only in the last ten years or so that more conscious attempts have been made to generate a big-picture literature informed by new scholarship. It is noteworthy that most of this is addressed to students and general readers, although there is no logical reason why it should not tackle major theoretical issues of concern to scholars. My point about maturity still holds, then, since as a designated discipline the history of science is rather new; it is still feeling out its relationship with cognate disciplines. Big-picture histories have an important role to play in these explorations since they make findings and ideas widely available and thereby offer material through which ambitious interpretations can be debated, modified and transformed.
Kepler's invention of the second planetary law
Authors: Donahue William H.
Published: January 2009

Kepler saw it as one of the chief advantages of the Copernican system that it put order into the planetary motions. Although Copernicus had indeed noted that the planetary periods increase with their distance from the sun, he did not, as far as we know, attempt to find a relationship between the two. Believing that God would not have failed to establish some mathematically precise ratio, Kepler sought from the very first to find it. Thus we see, in some of his earliest surviving letters, his attempts to relate planetary periods to the radii of their orbits using circular quadrants intersected by straight lines. Right from the beginning, Kepler gave the sun that dynamic role that was to characterize his ‘new astronomy based upon physics’. Immediately after describing the nested polyhedra that he believed determined the number and distances of the planets, he wrote:

Next, there is a moving soul and an infinite motion in the sun, and a double decrement of motion in the movables. In the first place, there is the inequality of their circuits, caused by the unequal amplitude of the orbs, which would occur even were the moving power the same in all orbs. But (2) actually this moving power (like light, in optics) is weaker the further it is from the source.
The calculating eye: Baily, Herschel, Babbage and the business of astronomy
Authors: Ashworth William J.
Published: January 2009

Astronomy does not often appear in the socio-political and economic history of nineteenthcentury Britain. Whereas contemporary literature, poetry and the visual arts made significant reference to the heavens, the more earthbound arena of finance seems an improbable place to encounter astronomical themes. This paper shows that astronomical practice was an important factor in the emergence of what can be described as an accountant's view of the world. I begin by exploring the senses of the term ‘calculation’ in Regency England, and then seek to reveal how the dramatic growth of vigilance in science, the organization and control of labour, and the monitoring of society and the economy drew upon and informed this disciplined numerical technique. Observations in all these areas could only be trusted if correctly reduced through a single system of calculation assisted by a group of standardized tables and division of mental labour. Within this setting the stellar economy provided an object that was seemingly ordered and law-like and therefore predictable through a powerful combination of techniques.
The show that never ends: perpetual motion in the early eighteenth century
Authors: Schaffer Simon
Published: January 2009

During high summer 1721, while rioters and bankrupts gathered outside Parliament, Robert Walpole's new ministry forced through a bill to clear up the wreckage left by the stock-market crash, the South Sea Bubble, and the visionary projects swept away when it burst. In early August the President of the Royal Society Isaac Newton, a major investor in South Sea stock, and the Society's projectors, learned of a new commercial scheme promising apparently automatic profits, a project for a perpetual motion. Their informants were a young Viennese courtier Joseph Emmanuel Fischer von Erlach, a contact of Desaguliers recently engaged in industrial espionage in northern England, and the Leiden physics professor Willem 'sGravesande, who had visited London five years earlier. They reported that they had been summoned to a remarkable series of demonstrations in the castle of Weissenstein, the seat of the Landgrave of Hesse-Kassel. In a carefully guarded room of the castle there was set up a hollow wooden wheel covered in oilcloth, about 12 feet in diameter and 18 inches thick on an axle 6 feet in length. Its designer, a Saxon engineer and clockmaker Johann Bessler, who travelled Germany under the name Orffyreus, had been in Kassel for four years, published schemes for perpetual motion and been appointed commercial councillor. The Landgrave, well-known as a patron of advanced engineering schemes, commissioned him to build a new machine and put it on show before expert witnesses (Figure 1).
The ‘culture’ of science and colonial culture, India 1820–1920
Authors: Kumar Deepak
Published: January 2009

The culture of science is deeply influenced and conditioned by the socio-political realities of both time and locale. Pre-colonial India, for example, was no tabula rasa. It had a vigorous tradition in at least the realms of mathematics, astronomy and medicine. But gradual colonization made a big dent. It brought forth a massive cultural collision which influenced profoundly the cognitive and material existence of both the colonizer and the colonized.
Invisible resource: William Crookes and his circle of support, 1871–81
Authors: Gay Hannah
Published: January 2009

In a 1976 paper, Robert DeKosky wrote ‘William Crookes is a puzzle to historians of latenineteenth century science. Despite his achievements we are forced to ask why he did not accomplish more.’ It is an interesting question; equally interesting is the question that prompts this paper – how did he accomplish so much?

Why some scientists become prolific and successful is a question with both historical and ahistorical dimensions. Among the former are a number of cultural aspects rarely studied by historians. They include the nature of childhood experience, family attitudes, mentoring, and the existence of intellectual and practical support networks in adulthood. Ail are important, but how they contribute to individual success varies with time and place.
Fatty acid metabolism (desaturation, elongation and β-oxidation) in rainbow trout fed fish oil- or linseed oil-based diets
Authors: Turchini Giovanni M. , Francis David S.
Published: January 2009

In consideration of economical and environmental concerns, fish oil (FO) substitution in aquaculture is the focus of many fish nutritionists. The most stringent drawback of FO replacement in aquafeeds is the consequential modification to the final fatty acid (FA) make-up of the fish fillet. However, it is envisaged that a solution may be achieved through a better understanding of fish FA metabolism. Therefore, the present study investigated the fate of individual dietary FA in rainbow trout (Oncorhynchus mykiss) fed a FO-based diet (rich in 20 : 5n-3) or a linseed oil-based diet (LO; rich in 18 : 3n-3). The study demonstrated that much of the 18 : 3n-3 content from the LO diet was oxidised and, despite the significantly increased accretion of Δ-6 and Δ-5 desaturated FA, a 2- and 3-fold reduction in the fish body content of 20 : 5n-3 and 22 : 6n-3, respectively, compared with the FO-fed fish, was recorded. The accretion of longer-chain FA was unaffected by the dietary treatments, while there was a greater net disappearance of FA provided in dietary surplus. SFA and MUFA recorded a net accretion of FA producedex novo. In the fish fed the FO diet, the majority of dietary 20 : 5n-3 was accumulated (53·8 %), some was oxidised (14·7 %) and a large proportion (31·6 %) was elongated and desaturated up to 22 : 6n-3. In the fish fed the LO diet, the majority of dietary 18 : 3n-3 was accumulated (58·1 %), a large proportion was oxidised (29·5 %) and a limited amount (12·4 %) was bio-converted to longer and more unsaturated homologues.
Prevalence of pathogens in milk samples of dairy cows with clinical mastitis and in heifers at first parturition
Authors: Tenhagen Bernd-Alois , Hansen Inken , Reinecke Annette , Heuwieser Wolfgang
Published: January 2009

Prevalence of mastitis pathogens in milk samples from dairy cows and heifers was studied over a period of 1 year (Aug 2005–Aug 2006) in ten dairy herds in Germany. Milk samples (n=8240) were collected from heifers without clinical mastitis at parturition (n=6915), from primiparous cows with clinical mastitis (n=751) and from older cows with clinical mastitis (n=574). Coagulase negative staphylococci (CNS) were the predominant group of bacteria isolated (46·8% of samples) from clinically healthy quarters of primiparous cows around parturition, followed by streptococci (12·6%), coliforms (4·7%) and Staphylococcus aureus (4·0%). Thirty-three percent of samples were negative on culture (range on farm level, 12·0–46·4%). In cases of clinical mastitis in primiparous and older cows, streptococci were the predominant finding (32·1 and 39·2%) followed by CNS (27·4 and 16·4%), coliforms (10·3 and 13·1%) and Staph. aureus (10·0 and 11·7%). Negative results were obtained from 21·3% (range, 0·0–30·6%) and 19·5% (range, 0·0–32·6%) of these samples. Results indicated substantial differences in the prevalence of pathogens among herds. There was a positive within-herd correlation between the monthly prevalences for Streptococcus dysgalactiae between the three groups of samples. This correlation was also found between clinical samples of primiparous and older cows for Staph. aureus. These correlations were not found for the other pathogens. Besides herd, prevalence of pathogens was influenced by parity, type of sample and season.
What our left hand has been doing
Authors: Fowler John M. , West Richard
Published: January 2009

WHO ARE “NONSCIENCE STUDENTS” and what shall we teach them? These appear to be reasonable questions. The Commission on College Physics has asked these questions in various ways during its ten years of existence and has some products and by-products of the asking. The vagueness of the first part of the question has made the last part difficult to answer; it is not easy to decide what to teach students when you only know who they are not. In the instruction of our physics majors we can afford to rely heavily on intuition. These students are exposed to physics and physicists for a long enough period to learn from the left hand the subtle processes of physics along with the content that we teach with the right. But we do not have time for this approach to our nonscience students. We must do the choreography for the left as well as the right hand.
An on-farm evaluation of the capability of saline land for livestock production in southern Australia
Authors: Thomas D. T. , White C. L. , Hardy J. , Collins J.-P. , Ryder A. , Norman H. C.
Published: January 2009

Grazing livestock on revegetated saline land is one of few profitable options to continue using this class of agricultural land. However, there has been little research conducted to assess the capability of saline land to support livestock production based on the soil and water characteristics at a particular site. In this study, data from 11 grazing studies collected from eight commercial farms across southern Australia were used to estimate metabolisable energy (ME) utilised/ha, as well as total ME produced/ha. All data were from the autumn (March–May) period, when feed is normally in short supply and of limited quality. Site characteristics indicative of the severity of salinisation varied across the sites. Topsoil electrical conductivity (ECe) ranged from 1 to 33 dS/m and groundwater EC from 14 to 60 dS/m (equivalent to sea water). Feed on offer before grazing varied from 700 kg dry matter/ha to 9000 kg dry matter/ha between sites. Thinopyrum ponticum and Puccinellia ciliata featured prominently in the less saline revegetated sites, with Atriplex spp. present on the more saline sites and some lucerne and rhodes grass on the less saline, well drained sites. Grazing days per ha for sheep (ME-adjusted dry sheep equivalent) on autumn pastures across the sites ranged from 41 to 3600, and liveweight gains ranged from –95 to 314 g/sheep.day. The grazing value of the highest producing saltland was at least as high as that expected on adjacent areas that were not salt affected.
The major advantage of establishing saltland pastures included an out-of-season feed supply high in crude protein and micronutrients that possessed the ability to capture summer and autumn rain. This should represent a substantial reduction in supplementary feed costs and increases the flexibility of methods for feeding livestock through periods of low annual pasture availability. The value of the ME produced on the highest yielding saltland pasture was estimated to be $360/ha based on substituting the best alternative strategy of purchasing lupin grain as a supplement. A quadratic relationship (R2 = 0.62, P = 0.024) was found between soil ECe and ME produced across the sites. Significant relationships were not found between other saline site characteristics and ME production, which partly reflects the complexity of these systems as well as limitations with site characterisation.
Influence of wheat hardness and xylanase supplementation on the performance, energy utilisation, digestive tract development and digesta parameters of broiler starters
Authors: Amerah A. M. , Ravindran V. , Lentle R. G.
Published: January 2009

The aim of this study was to examine the influence of wheat hardness and xylanase supplementation on the performance, energy utilisation, digestive tract development and digesta parameters of broilers fed wheat-based diets. The experimental design was a 2 × 2 factorial arrangement of treatments evaluating wheat hardness (soft or hard) with or without xylanase supplementation. Two diets based on soft or hard wheat were formulated. Whole wheat (200 g/kg) from the same wheat batch replaced ground wheat before cold-pelleting of each diet. Each diet was fed ad libitum to six pens of eight male broilers each from day 1 to 21 posthatch. The distribution of particle size differed between diets, with the hard wheat diet having 32.7% of particles greater than 1 mm in size compared with 18.7% in the soft wheat diet. Interactions (P < 0.05) were observed between wheat hardness and enzyme supplementation for weight gain, feed intake, feed per gain and nitrogen-corrected apparent metabolisable energy (AMEn). Enzyme supplementation increased (P < 0.05) weight gain in the soft wheat-based diet but not in the hard wheat diet. Enzyme supplementation also increased (P < 0.05) feed intake in the soft wheat-based diet, but reduced (P < 0.05) intake in the hard wheat diet. Feed per gain and AMEn were improved (P < 0.05) by enzyme supplementation in the hard wheat-based diet, while no enzyme effect was observed in the soft wheat diet. Feeding the hard wheat-based diet increased (P < 0.05) the relative gizzard weight, and this was associated with a general increase in finer particles in the proximal intestinal digesta when compared with those present in the diet. These results suggest that the response of broilers to xylanase supplementation is influenced by wheat hardness and that wheat hardness may be an important criterion to consider when choosing for whole wheat inclusion in broiler diets.
On the fate of anthropogenic nitrogen
Authors: Schlesinger William H.
Published: January 2009

This article provides a synthesis of literature values to trace the fate of 150 Tg/yr anthropogenic nitrogen applied by humans to the Earth's land surface. Approximately 9 TgN/yr may be accumulating in the terrestrial biosphere in pools with residence times of ten to several hundred years. Enhanced fluvial transport of nitrogen in rivers and percolation to groundwater accounts for ≈35 and 15 TgN/yr, respectively. Greater denitrification in terrestrial soils and wetlands may account for the loss of ≈17 TgN/yr from the land surface, calculated by a compilation of data on the fraction of N2O emitted to the atmosphere and the current global rise of this gas in the atmosphere. A recent estimate of atmospheric transport of reactive nitrogen from land to sea (NOxand NHx) accounts for 48 TgN/yr. The total of these enhanced sinks, 124 TgN/yr, is less than the human-enhanced inputs to the land surface, indicating areas of needed additional attention to global nitrogen biogeochemistry. Policy makers should focus on increasing nitrogen-use efficiency in fertilization, reducing transport of reactive N to rivers and groundwater, and maximizing denitrification to its N2endproduct.
Transmission of allostery through the lectin domain in selectin-mediated cell adhesion
Authors: Waldron Travis T. , Springer Timothy A.
Published: January 2009

The selectins are cell adhesion proteins that must resist applied forces to mediate leukocyte tethering and rolling along the endothelium and have 2 conformational states. Selectin–ligand bond dissociation increases only modestly with applied force, and exhibits catch bond behavior in a low-force regime where bond lifetimes counterintuitively increase with increasing force. Both allosteric and sliding–rebinding models have emerged to explain catch bonds. Here, we introduce a large residue into a cleft that opens within the lectin domain to stabilize the more extended, high-affinity selectin conformation. This mutation stabilizes the high-affinity state, but surprisingly makes rolling less stable. The position of the mutation in the lectin domain provides evidence for an allosteric pathway through the lectin domain, connecting changes at the lectin–EGF interface to the distal binding interface.
Structural basis for selectin mechanochemistry
Authors: Springer Timothy A.
Published: January 2009

Selectins are adhesion molecules that resist large tensile forces applied by hydrodynamic forces to leukocytes binding to vessel walls. In crystals, the liganded (high-affinity) and unliganded (low-affinity) conformations differ in orientation between their tandem lectin and EGF domains. I examine how tensile force exerted on a selectin–ligand complex in vivo could favor the more extended, high-affinity conformation. Allostery is transmitted from the EGF–lectin domain interface to the ligand-binding interface on the lectin domain, 30 Å away. Trp-1 of the lectin domain and the long axis of the EGF domain form an L-shaped prybar that is welded together by hydrogen bonds to the Trp-1 α-amino group. Pivoting of the prybar induced by force demolishes an interface between the Trp-1 side chain and the lectin domain at a switch1 region. These changes are transmitted by rigid body movement of the switch2 region to rearrangements in the switch3 region at the ligand binding site. Another switch region corresponds to a single residue in the EGF domain with large effects on ligand binding and rolling adhesion. Allostery in selectins, and the alignment of tensile force on a selectin–ligand complex with the transition pathway for conformational change, explain much of the structural basis for selectin mechanochemistry.
Neuronal activity regulates phosphorylation-dependent surface delivery of G protein-activated inwardly rectifying potassium channels
Authors: Chung Hee Jung , Qian Xiang , Ehlers Melissa , Jan Yuh Nung , Jan Lily Yeh
Published: January 2009

G protein-activated inwardly rectifying K+(GIRK) channels regulate neuronal excitability by mediating inhibitory effects of G protein-coupled receptors for neurotransmitters and neuromodulators. Notwithstanding many studies reporting modulation of GIRK channel function, whether neuronal activity regulates GIRK channel trafficking remains an open question. Here we report that NMDA receptor activation in cultured dissociated hippocampal neurons elevates surface expression of the GIRK channel subunits GIRK1 and GIRK2 in the soma, dendrites, and dendritic spines within 15 min. This activity-induced increase in GIRK surface expression requires protein phosphatase-1-mediated dephosphorylation of a serine residue (Ser-9) preceding the GIRK2 Val-13/Leu-14 (VL) internalization motif, thereby promoting channel recycling. Because activation of GIRK channels hyperpolarizes neuronal membranes, the NMDA receptor-induced regulation of GIRK channel trafficking may represent a dynamic adjustment of neuronal excitability in response to inhibitory neurotransmitters and/or neuromodulators.
G protein-activated inwardly rectifying potassium channels mediate depotentiation of long-term potentiation
Authors: Chung Hee Jung , Ge Woo-Ping , Qian Xiang , Wiser Ofer , Jan Yuh Nung , Jan Lily Yeh
Published: January 2009

Excitatory synapses in the brain undergo activity-dependent changes in the strength of synaptic transmission. Such synaptic plasticity as exemplified by long-term potentiation (LTP) is considered a cellular correlate of learning and memory. The presence of G protein-activated inwardly rectifying K
+
(GIRK) channels near excitatory synapses on dendritic spines suggests their possible involvement in synaptic plasticity. However, whether activity-dependent regulation of GIRK channels affects excitatory synaptic plasticity is unknown. In a companion article we have reported activity-dependent regulation of GIRK channel density in cultured hippocampal neurons that requires activity of NMDA receptors (NMDAR) and protein phosphatase-1 (PP1) and takes place within 15 min. In this study, we performed whole-cell recordings of cultured hippocampal neurons and found that NMDAR activation increases basal GIRK current and GIRK channel activation mediated by adenosine A
1
receptors, but not GABA
B
receptors. Given the similar involvement of NMDARs, adenosine A
1
receptors, and PP1 in depotentiation of LTP caused by low-frequency stimulation that immediately follows LTP-inducing high-frequency stimulation, we wondered whether NMDAR-induced increase in GIRK channel surface density and current may contribute to the molecular mechanisms underlying this specific depotentiation. Remarkably, GIRK2 null mutation or GIRK channel blockade abolishes depotentiation of LTP, demonstrating that GIRK channels are critical for depotentiation, one form of excitatory synaptic plasticity.
The specificity of T cell regulation that enables self-nonself discrimination in the periphery
Authors: Wu Yilun , Zheng Zongyu , Jiang Yihua , Chess Leonard , Jiang Hong
Published: January 2009

It was recently shown that perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to control autoimmune disease. This regulation is achieved by CD8
+
T cells that recognize a common surrogate target structure, Qa-1/Hsp60sp, preferentially expressed by activated T cells of intermediate but not high avidity. A truncated self-reactive repertoire, devoid of high-avidity T cells, generated by thymic negative selection, allows selective down-regulation of intermediate-avidity T cells to accomplish self-nonself discrimination in the periphery. Identification of the common surrogate target structure expressed on intermediate-avidity T cells opens up a conceptual theme to understand the relationship between the specificity of peripheral immune regulation and self-nonself discrimination. Here, we investigated peptide vaccination induced cross-protection mediated by CD8
+
T cells in two autoimmune disease models, experimental allergic encephalomyelitis (EAE) and type 1 diabetes (T1D). We show that Qa-1 restricted CD8
+
T cells cross-protect animals from either EAE or T1D without abrogating the immune response to foreign antigens. Cross-protection occurs because potentially pathogenic self-reactive T cells included in the pool of intermediate-avidity T cells are capable of preferentially expressing common surrogate target structures on their surface to render themselves subject to the down-regulation, independent of the specificity of the antigens that they are triggered by. Thus, like in the thymus, the immune system discriminates self from nonself, during adaptive immunity in the periphery, not by recognizing the structural differences between self and foreign antigens, but rather by perceiving the avidity of T cell activation.
Hippocampal and extrahippocampal systems compete for control of contextual fear: Role of ventral subiculum and amygdala
Authors: Biedenkapp Joseph C. , Rudy Jerry W.
Published: January 2009

Two neural systems, a hippocampal system and an extrahippocampal system compete for control over contextual fear, and the hippocampal system normally dominates. Our experiments reveal that output provided by the ventral subiculum is critical for the hippocampal system to win this competition. Bilateral electrolytic lesions of the ventral subiculum after conditioning, but not before conditioning, impaired contextual fear conditioning. Reversibly inactivating this region by bilateral injections of muscimol produced the same results—no impairment when the injection occurred prior to conditioning but a significant impairment when this region was inactivated after conditioning. Thus, the extrahippocampal system can support contextual fear conditioning if the ventral subiculum is disabled before conditioning but not if it is disabled after conditioning. Our experiments also reveal that the basolateral region of the amygdala (BLA) is where the two systems compete for associative control of the fear system. To test this hypothesis we reasoned that the extrahippocampal system would also acquire associative control over the fear system, even if the hippocampal system were functional, if the basal level of plasticity potential in the BLA could be increased. We did this by injecting the D1 dopamine agonist, SKF82958, into the BLA just prior to conditioning. This treatment resulted in a significant increase in freezing when the ventral subiculum was disabled prior to the test. These results are discussed in relationship to the idea that D1 agonists increase plasticity potential by increasing the pool of available extrasynaptic GluR1 receptors in the population of neurons supporting acquired fear.
Complementary roles for amygdala and periaqueductal gray in temporal-difference fear learning
Authors: Cole Sindy , McNally Gavan P.
Published: January 2009

Pavlovian fear conditioning is not a unitary process. At the neurobiological level multiple brain regions and neurotransmitters contribute to fear learning. At the behavioral level many variables contribute to fear learning including the physical salience of the events being learned about, the direction and magnitude of predictive error, and the rate at which these are learned about. These experiments used a serial compound conditioning design to determine the roles of basolateral amygdala (BLA) NMDA receptors and ventrolateral midbrain periaqueductal gray (vlPAG) μ-opioid receptors (MOR) in predictive fear learning. Rats received a three-stage design, which arranged for both positive and negative prediction errors producing bidirectional changes in fear learning within the same subjects during the test stage. Intra-BLA infusion of the NR2B receptor antagonist Ifenprodil prevented all learning. In contrast, intra-vlPAG infusion of the MOR antagonist CTAP enhanced learning in response to positive predictive error but impaired learning in response to negative predictive error—a pattern similar to Hebbian learning and an indication that fear learning had been divorced from predictive error. These findings identify complementary but dissociable roles for amygdala NMDA receptors and vlPAG MOR in temporal-difference predictive fear learning.
Circadian modulation of short-term memory in Drosophila
Authors: Lyons Lisa C. , Roman Gregg
Published: January 2009

Endogenous biological clocks are widespread regulators of behavior and physiology, allowing for a more efficient allocation of efforts and resources over the course of a day. The extent that different processes are regulated by circadian oscillators, however, is not fully understood. We investigated the role of the circadian clock on short-term associative memory formation using a negatively reinforced olfactory-learning paradigm in Drosophila melanogaster. We found that memory formation was regulated in a circadian manner. The peak performance in short-term memory (STM) occurred during the early subjective night with a twofold performance amplitude after a single pairing of conditioned and unconditioned stimuli. This rhythm in memory is eliminated in both timeless and period mutants and is absent during constant light conditions. Circadian gating of sensory perception does not appear to underlie the rhythm in short-term memory as evidenced by the nonrhythmic shock avoidance and olfactory avoidance behaviors. Moreover, central brain oscillators appear to be responsible for the modulation as cryptochrome mutants, in which the antennal circadian oscillators are nonfunctional, demonstrate robust circadian rhythms in short-term memory. Together these data suggest that central, rather than peripheral, circadian oscillators modulate the formation of short-term associative memory and not the perception of the stimuli.
Eternal Youth, the Fate of Developing Arabidopsis Leaves uponRhodococcus fasciansInfection
Authors: Depuydt Stephen , De Veylder Lieven , Holsters Marcelle , Vereecke Danny
Published: January 2009

The phytopathogenic actinomycete Rhodococcus fascians induces neoplastic shooty outgrowths on infected hosts. Upon R. fascians infection of Arabidopsis (Arabidopsis thaliana), leaves are formed with small narrow lamina and serrated margins. These symptomatic leaves exhibit reduced tissue differentiation, display more but smaller cells that do not endoreduplicate, and accumulate in the G1 phase of the cell cycle. Together, these features imply that leaf growth occurs primarily through mitotic cell division and not via cell expansion. Molecular analysis revealed that cell cycle gene expression is activated continuously throughout symptomatic leaf development, ensuring persistent mitotic cycling and inhibition of cell cycle exit. The transition at the two major cell cycle checkpoints is stimulated as a direct consequence of the R. fascians signals. The extremely reduced phenotypical response of a cyclind3;1-3 triple knockout mutant indicates that the D-type cyclin/retinoblastoma/E2F transcription factor pathway, as a major mediator of cell growth and cell cycle progression, plays a key role in symptom development and is instrumental for the sustained G1-to-S and G2-to-M transitions during symptomatic leaf growth.
Efficacy and safety of 5‐grass pollen sublingual immunotherapy tablets in patients with different clinical profiles of allergic rhinoconjunctivitis
Authors: Malling H‐J. , Montagut A. , Melac M. , Patriarca G. , Panzner P. , Seberova E. , Didier A.
Published: January 2009

Background
The optimal dose of grass pollen tablets for sublingual immunotherapy (SLIT) in allergic rhinoconjunctivitis patients was previously established in a multinational, randomized, double‐blind, placebo‐controlled study in 628 adults. Patients were randomized to receive once‐daily 5‐grass pollen sublingual tablets of 100 IR (index of reactivity), 300 IR or 500 IR, or placebo starting 4 months before the pollen season.

Objective
The aim of this complementary analysis was to determine whether 300 IR 5‐grass pollen SLIT‐tablets is effective in different subtypes of patients who are allergic to grass pollen.

Methods
Different subgroups could be identified regarding comorbidities (with or without asthma during the grass‐pollen season), sensitization (mono/polysensitization) and symptom severity. An additional exploratory analysis was performed within four subgroups based on pre‐treatment assessment: Group 1=high specific IgE; Group 2=high symptom scores; Group 3=high skin sensitivity; Group 4=any of Group 1, 2 or 3.

Results
Asthma and sensitization status were not significant covariates as the average Rhinoconjunctivitis Total Symptom Score (RTSS) was identical for patients with and without grass‐pollen asthma, as well as for mono‐ and polysensitized patients. Across the four subgroups, average RTSSs (± SD) for the optimal dosage (300 IR) were 3.91 ± 3.16, 3.83 ± 3.14, 2.55 ± 2.13 and 3.61 ± 2.97, for subgroups 1, 2, 3 and 4, respectively. ancova showed that in Group 1 average RTSS did not differ significantly with different doses of SLIT. In Groups 2, 3 and 4, doses of 300 IR and 500 IR were significantly more effective than 100 IR and placebo (P0.035). All doses of SLIT administered in this study can be considered safe in the patients investigated.

Conclusions
The risk–benefit ratio validates the use of 300 IR tablets in clinical practice in all of these patient subgroups, regardless of severity profile, sensitization status and presence of asthma.
CD200R surface expression as a marker of murine basophil activation
Authors: Torrero M. N. , Larson D. , Hübner M. P. , Mitre E.
Published: January 2009

Background
Basophils are increasingly recognized as playing important roles in the immune responses of allergic diseases and helminth infections. One of the main obstacles to studying basophils has been the lack of a simple and rapid assay to measure basophil activation in mice.

Objective
The purpose of this study was to develop an assay to measure murine basophil activation.

Methods
Mouse blood cells were stained with various combinations of positive and negative markers for basophils – sorted and then assessed for basophil purity by May‐Grünwald staining of cytospins. Once a flow cytometric strategy for staining basophils was determined, basophil surface expression of CD200R was assessed by multi‐colour flow cytometry after stimulation of whole blood with anti‐IgE, ionomycin or N‐formyl MetLeuPhe (fMLP). Confirmation of basophil activation was assessed by concomitant staining of cells for intracellular IL‐4. To test the ability of flow cytometric basophil CD200R measurements to assess for antigen‐specific IgE‐mediated activation of basophils, surface CD200R expression in response to in vitro stimulation with media alone, helminth antigen or ovalbumin was measured on basophils obtained from control mice, mice infected with helminths and mice sensitized to ovalbumin.

Results
Using anti‐IgE‐FITC as a positive marker and a combination of anti‐CD4‐PERCP and anti‐B220‐PERCP as negative markers resulted in a well‐separated basophil population. Additional staining with anti‐CD200R‐PE demonstrated that (1) basophil CD200R expression increases in response to anti‐IgE, ionomycin and fMLP, (2) most CD200R‐positive basophils also stain positively for IL‐4 and (3) CD200R expression increases after antigen‐specific activation of basophils in murine models of helminth disease and allergy.

Conclusion
We developed a multi‐colour flow cytometry assay that measures murine basophil activation by utilizing CD200R as an activation marker. This assay is straightforward and rapid, taking approximately half a day for obtaining blood, in vitro stimulation and flow cytometric analysis.
BSACI guidelines for the management of drug allergy
Authors: Mirakian R. , Ewan P. W. , Durham S. R. , Youlten L. J. F. , Dugué P. , Friedmann P. S. , English J. S. , Huber P. A. J. , Nasser S. M.
Published: January 2009

These guidelines have been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and are intended for allergists and others with a special interest in allergy. As routine or validated tests are not available for the majority of drugs, considerable experience is required for the investigation of allergic drug reactions and to undertake specific drug challenge. A missed or incorrect diagnosis of drug allergy can have serious consequences. Therefore, investigation and management of drug allergy is best carried out in specialist centres with large patient numbers and adequate competence and resources to manage complex cases. The recommendations are evidence‐based but where evidence was lacking consensus was reached by the panel of specialists on the committee. The document encompasses epidemiology, risk factors, clinical patterns of drug allergy, diagnosis and treatment procedures. In order to achieve a correct diagnosis we have placed particular emphasis on obtaining an accurate clinical history and on the physical examination, as these are critical to the choice of skin tests and subsequent drug provocation. After the diagnosis of drug allergy has been established, communication of results and patient education are vital components of overall patient management.
Efficacy and safety of high‐doses sublingual immunotherapy in ultra‐rush scheme in children allergic to grass pollen
Authors: Stelmach I. , Kaczmarek‐Woźniak J. , Majak P. , Olszowiec‐Chlebna M. , Jerzynska J.
Published: January 2009

Background
Although sublingual immunotherapy (SLIT) has been used with increasing frequency, the data on the efficacy of SLIT in pediatric asthma are limited.

Aim
The aim of our study was to evaluate the efficacy and the safety of high‐dose SLIT given pre‐seasonally and co‐seasonally in an ultra‐rush scheme in children with bronchial asthma allergic to grass pollen.

Methods
Fifty children with asthma, aged 6–17, sensitive to grass pollen, participated in the 2‐year prospective, randomized, double‐blind, placebo‐controlled trial, to investigate the efficacy and safety of SLIT (Staloral 300 IR, Stallergenes SA, 25 μg major allergens) as a standardized extract of five grass pollen with ultra‐rush induction.

Results
SLIT significantly improved asthma symptom scores (41% vs. placebo group), reduced nasal symptoms (25% vs. placebo group) and the use of rescue medications (10% vs. placebo group), improved forced expiratory volume in 1 s, but had no effect on ocular symptoms, nasal hyper‐reactivity, peak expiratory flow and forced expiratory volume between 25% and 75% of vital capacity. Serum levels of immunoglobulin E and IgG4 did not change after SLIT. After the second season of SLIT, an improvement in bronchial hyperresponsiveness was observed; however, compared with placebo, this effect was not significant. Among all subjects in SLIT group, predominantly local reactions have been recorded in 59% of subjects in the first year of treatment and in 35% in the second.

Conclusions
Our study indicated that high‐dose ultra‐rush, co‐seasonal SLIT given for 2 years, was safe and reduced a multiple symptom–medication score.
Role of Ca2+mobilization and Ca2+sensitization in 8‐iso‐PGF2α‐induced contraction in airway smooth muscle
Authors: Shiraki A. , Kume H. , Oguma T. , Makino Y. , Ito S. , Shimokata K. , Honjo H. , Kamiya K.
Published: January 2009

BackgroundIsoprostanes are prostaglandin (PG)‐like compounds synthesized by oxidative stress, not by cyclooxygenase, and increase in bronchoalveolar lavage fluid of patients with asthma. The airway inflammation implicated in this disease may be amplified by oxidants. Although isoprostanes are useful biomarkers for oxidative stress, the action of these agents on airways has not been fully elucidated.

ObjectiveThis study was designed to determine the intracellular mechanisms underlying the effects of oxidative stress on airway smooth muscle, focused on Ca2+signalling pathways involved in the effect of 8‐iso‐PGF2α.

MethodsUsing simultaneous recording of isometric tension and F340/F380(an indicator of intracellular concentrations of Ca2+, [Ca2+]i), we examined the correlation between tension and [Ca2+]iin response to 8‐iso‐PGF2αin the fura‐2 loaded tracheal smooth muscle.

ResultsAugmented tension and F340/F380by 8‐iso‐PGF2αwere attenuated by ICI‐192605, an antagonist of thromboxane A2receptors (TP receptors). Moreover, D609, an antagonist of phosphatidylcholine‐specific phospholipase C, markedly reduced both the tension and F340/F380induced by 8‐iso‐PGF2α, whereas U73122, an antagonist of phosphatidylinositol‐specific phospholipase C, modestly inhibited them by 8‐iso‐PGF2α. SKF96365, a non‐selective antagonist of Ca2+channels, markedly reduced both tension and F340/F380by 8‐iso‐PGF2α. However, diltiazem and verapamil, voltage‐dependent Ca2+channel inhibitors, modestly attenuated tension although their reduction of F340/F380was not different from that by SKF96365. Y‐27632, an inhibitor of Rho‐kinase, significantly attenuated contraction induced by 8‐iso‐PGF2αwithout reducing F340/F380, whereas GF109203X and Go6983, protein kinase C inhibitors, did not markedly antagonize them although reducing F340/F380with a potency similar to Y‐27632.

Conclusion8‐iso‐PGF2αcauses airway smooth muscle contraction via activation of TP receptors. Ca2+mobilization by SKF96365‐ and D609‐sensitive Ca2+influx and Ca2+sensitization by Rho‐kinase contribute to the intracellular mechanisms underlying the action of 8‐iso‐PGF2α. Rho‐kinase may be a therapeutic target for the physiologic abnormalities induced by oxidative stress in airways.
Functional analysis of a polymorphism in the promoter region of the IL‐12/23p40 gene
Authors: Shimokawa N. , Nishiyama C. , Hirota T. , Tamari M. , Hara M. , Ikeda S. , Okumura K. , Ogawa H.
Published: January 2009

Background
Human IL‐12B gene on chromosome 5q31 encodes the common p40 subunit of IL‐12 and IL‐23. IL‐12 is known to play critical roles in the generation of T‐helper type 1 (TH1) cells, whereas IL‐23 is involved in maintenance and/or population expansion of TH17 cells. Although several reports suggested an association between a polymorphism (−6415CTCTAA/GC) in IL‐12B and asthma, the molecular mechanism how this polymorphism is involved in allergic inflammation is still unclear.

Methods
The transcription activity was analysed by reporter assay. A transcription factor binding to −6415 polymorphic site was identified by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. The amount of cytokines produced from peripheral monocytes were determined by ELISA.

Results
Reporter assay showed that the transcription activity of the GC allele was higher than that of the CTCTAA allele. A transcription factor Sp1 bound to the region including the GC allele with a higher affinity than that of the CTCTAA allele in EMSA. In vivo binding of Sp1 to IL‐12B gene carrying −6415GC was confirmed by ChIP assay. Overexpression of Sp1 up‐regulated transcription activity of promoter carrying GC allele sequence, whereas the CTCTAA promoter was not affected by Sp1. We examined the correlation between −6415CTCTA/GC polymorphism and production of cytokine IL‐12/23p40, IL‐12p70, and IL‐23 on peripheral blood monocytes, and monocytes with the GC/GC allele exhibited significantly higher expression of IL‐12p70 protein than those with the CTCTAA/CTCTAA allele (P=0.009).

Conclusions
The −6415 polymorphism is involved in cytokine production potential by affecting Sp1‐mediated transcription activity.
Faces of ghrelin – research for the 21st century
Authors: Hellström P. M.
Published: January 2009

Abstract  In this issue of Neurogastroenterology and Motility we find three new articles on different aspects of ghrelin, dealing with physiological and pathophysiological actions of the peptide. For the reader this is food for thoughts: Does this peptide do everything? Ghrelin is a gut peptide hormone well established to stimulate motility throughout most parts of the gastrointestinal (GI) tract and appetite. Ghrelin has been linked to various GI regulatory mechanisms, the most evident being hunger, over‐eating and obesity. In this setting ghrelin has been studied under physiological conditions converging on obesity as a pathophysiological process where the peptide has been employed as an interesting tool for studying the development of obesity. With a widespread distribution of ghrelin receptors on various immune cells, it has been assumed that ghrelin also possesses immunoregulatory properties, thus also being of interest in intestinal inflammation research. Anti‐inflammatory effects of exogenous ghrelin have been claimed in experimental colitis in mice. Further studies on this concept using ghrelin gene knock‐out mice, however, show an increased inflammatory activity in experimental colitis in wild‐type mice pointing to ghrelin as an enhancer of the inflammatory course of the disease. Taken together, recent studies on ghrelin indicate that the peptide is not only a regulatory agent in pathophysiological processes, but also participates in pathological disease conditions with actions that seem to even involve genetic mechanisms.
The vagus nerve as a modulator of intestinal inflammation
Authors: Van Der Zanden E. P. , Boeckxstaens G. E. , De Jonge W. J.
Published: January 2009

Abstract The cholinergic nervous system attenuates the production of pro‐inflammatory cytokines and inhibits inflammatory processes. Hence, in animal models of intestinal inflammation, such as postoperative ileus and dextran sulfate sodium‐induced colitis, vagus nerve stimulation ameliorates disease activity. On the other hand, in infectious models of microbial peritonitis, vagus nerve activation seemingly acts counteractive; it impairs bacterial clearance and increases mortality. It is originally indicated that the key mediator of the cholinergic anti‐inflammatory pathway, acetylcholine (ACh), inhibits cytokine release directly via the α7 nicotinic ACh receptor (nAChR) expressed on macrophages. However, more recent data also point towards the vagus nerve as an indirect modulator of innate inflammatory processes, exerting its anti‐inflammatory effects via postganglionic modulation of immune cells in primary immune organs. This review discusses advances in the possible mechanisms by which the vagus nerve can mediate the immune response, and the role of nAChR activation and signalling on macrophages and other immune cells.