bluuebunny/crossref_metadata_2025 huggingface dataset:
Age- and ability-related differences in young readers' use of conjunctions
Authors: CAIN KATE , PATSON NIKOLE , ANDREWS LEANNE
Published: December 2005

Two studies investigating young readers' use of conjunctions are reported. In Study One, 145 eight- to ten-year-olds completed one of two narrative cloze tasks in which different types of conjunction were deleted. Performance for additive conjunctions was not affected by age in this study, but older children were more likely to select the target conjunction than were younger children for temporal, causal, and adversative terms. Performance was superior in the cloze task in which they were given a restricted choice of responses (three vs. seven). In Study Two, 35 eight- and nine-year-old good and poor comprehenders completed the three-choice cloze task. The poor comprehenders were less likely to select the target terms in general. Sentence-level comprehension skills did not account for their poor performance. The results indicate that understanding of the semantic relations expressed by conjunctions is still developing long after these terms are used correctly in children's speech. The findings are discussed in relation to the role of conjunctions in text comprehension.
Assessing early communicative ability: a cross-reporter cumulative score for the MacArthur CDI
Authors: HOUWER ANNICK DE , BORNSTEIN MARC H. , LEACH DIANE B.
Published: December 2005

Thirty middle- to upper middle-class monolingual Dutch speaking families consisting of at least a mother and a father completed the Infant Form ‘Words and Gestures’ of the Dutch adaptation of the MacArthur Communicative Development Inventory for the same child at 1;1. Considerable inter- and intrafamily variation emerged in how two (or three) different reporters who are all presumably close to the child assess a particular child's communicative abilities. The greater the child's communicative ability, as rated by any one reporter, the more differences tended to emerge between reporters. In order to take into account multiple reporters' assessments of the same child, we propose the use of a Cumulative CDI Score that credits the child with the best score for any item on the CDI as checked by any single reporter. We conclude that single reporter CDI reports may underestimate the child's communicative knowledge.
A crosslinguistic study of the relationship between grammar and lexical development
Authors: DEVESCOVI ANTONELLA , CASELLI MARIA CRISTINA , MARCHIONE DANIELA , PASQUALETTI PATRIZIO , REILLY JUDY , BATES ELIZABETH
Published: December 2005

The relationship between grammatical and lexical development was compared in 233 English and 233 Italian children aged between 1;6 and 2;6, matched for age, gender, and vocabulary size on the MacArthur Communicative Development Inventories (CDI). Four different measures of Mean Length of Utterance were applied to the three longest utterances reported by parents, and to corrected/expanded versions representing the ‘target’ for each utterance. Italians had longer MLUs on most measures, but the ratio of actual to target MLUs did not differ between languages. Age and vocabulary both contributed significant variance to MLU, but the contribution of vocabulary was much larger, suggesting that vocabulary size may provide a better basis for crosslinguistic comparisons of grammatical development. The relationship between MLU and vocabulary size was non-linear in English but linear in Italian, suggesting that grammar ‘gets off the ground’ earlier in a richly inflected language. A possible mechanism to account for this difference is discussed.
IT'S ALIVE! The Birth of LawBore and the Indispensability of the Law Librarian
Authors: Allbon Emily
Published: December 2005

As soon as I saw the theme of the Harrogate conference, ‘Gateways, Gatekeepers and Gatecrashers’, I wanted to contribute, although the thought of doing a session unnerved me. I was keen to talk about my gateway, LawBore, and how it had changed since I first wrote an article on it in Legal Information Management back in 2003, but I also wanted to convey how creating LawBore had changed things for me within my workplace.
From our Own Correspondent…Selection Criteria for the Purchase of Legal Sources: a Model from the Netherlands
Authors: Bartelings Paul , Bok Elizabeth
Published: December 2005

Paul Bartelings and Elizabeth Bok from the Het Overleg (Dutch Law Firm Librarians Foundation) explain the theories and practices they have developed in co-operation with the Holland Consulting Group to produce a tool which will help us to compare similar legal resources offered by competing legal publishers and other providers.
Wintertime circulation off southeast Australia: Strong forcing by the East Australian Current
Authors: Middleton John F. , Cirano Mauro
Published: December 2005

Numerical results and observations are used to examine the sub–weather band wintertime circulation off the eastern shelf slope region between Tasmania and Cape Howe. The numerical model is forced using wintertime‐averaged atmospheric fluxes of momentum, heat, and freshwater and using transports along open boundaries that are obtained from a global ocean model. The boundary to the north of Cape Howe has a prescribed transport of 17 Sv, which from available observations represents strong forcing by the East Australian Current (EAC). Nonetheless, the model results are in qualitative (and quantitative) agreement with several observational studies. In accord with observations, water within Bass Strait is found to be driven to the east and north with speeds of up to 30 cm s−1 off the southeast Victorian coast. The water is colder and denser than that found farther offshore, which is associated with the southward flowing (warm) EAC. In agreement with observations the density difference between the two water masses is about 0.6 kg m−3 and leads to a cascade of dense Bass Strait water to depths of 300 m and as a plume that extends 5–10 km in the cross‐shelf direction. Typical vertical velocities of the model cascade are 20 m d−1. Along‐isobath currents become bottom intensified with speeds of 20 cm s−1 or so at depths of 200 m. The EAC is found to flow along isobaths and to the south and then west past Tasmania with speeds of up to 20 cm s−1. Mesoscale eddies grow to diameters of 100 km (speeds <40 cm s−1), and in accord with observations a semipermanent anticyclonic eddy is found to the east of Cape Howe.
Tidal and near‐inertial peak variations around the diurnal critical latitude
Authors: van Haren Hans
Published: December 2005

Spectra from historic long‐term open‐ocean moored current meter data between latitudes 0° < ∣ϕ∣ < 45° reveal a significant drop in semidiurnal tidal band (D2) energy by ∼50% at ∣ϕ∣ ≈ 25–27°, whilst the peak near the local inertial frequency f is increased by a factor of ∼10 up to the level of D2‐energy at ∣ϕ∣ ≈ 28–30°, where f coincides with diurnal frequencies. The increase in f‐energy is accompanied by a red‐shift of the peak frequency to 0.97 ± 0.01f, or a poleward spreading of enhanced energy. This contrasts with more common blue‐shift. The enhancement may be the result of sub‐harmonic instability, as supported by sparse significant bicoherence at half‐D2, although i) systematic enhancement of diurnal tidal frequencies, notably M1, was not observed, ii) the latitudes of low D2‐energy and high f‐energy do not coincide. This may be due to a mix of coupled and independent waves, whilst the poleward trapping of sub‐f energy suggests non‐traditional effects.
Impact of higher‐order ionospheric terms on GPS estimates
Authors: Fritsche M. , Dietrich R. , Knöfel C. , Rülke A. , Vey S. , Rothacher M. , Steigenberger P.
Published: December 2005

Dual frequency GPS observables only allow the elimination of the 1st–order ionospheric term. Although higher–order ionospheric terms may cause a range bias of several centimeters, accounting for such effects is not yet a common strategy for GPS data analysis. In comparison to previous investigations a rigorous application of 2nd and 3rd–order ionospheric corrections is examined for the estimation not only of receiver positions but of all included parameters. The results reveal a linear dependence of the frame's origin on the integrated electron density. Furthermore, satellite positions are affected at the centimeter level when applying the above–mentioned corrections. Since the ionospheric correction terms show a significant impact on various GPS estimates, their consideration becomes necessary for scientific applications. Hence, the modeling of 2nd and 3rd–order ionospheric correction terms is part of the optimized strategy in an ongoing reprocessing project dealing with a global GPS network and spanning the time period from 1994 up to present time.
Variability of the ocean‐induced magnetic field predicted at sea surface and at satellite altitudes
Authors: Glazman Roman E. , Golubev Yury N.
Published: December 2005

Spatial and temporal variability of the magnetic field component induced by ocean circulation is investigated on the basis of a standard thin‐shell approximation of electro‐ and magneto‐static equations. Well‐known difficulties of numerical solution of the governing equations are resolved by reducing the problem to an equation for the electric field potential, Φ, as opposed to a more conventional approach focused on the vertical jump, ψ, of the magnetic field potential across a combined ocean/marine‐sediment‐layer spherical shell. The present formulation permits using more realistic input data on ocean currents and ultimately yields much greater (by at least an order of magnitude) values of the magnetic field at sea surface than predicted in earlier studies. Such large values are comparable to, and in some cases exceed, magnetic field variations caused by lithospheric and ionospheric sources on monthly to interannual timescales. At the 400‐km altitude (of CHAMP satellite), the field attains 6 nT. The model predictions show favorable comparisons with some in situ measurements as well as with Challenging Minisatellite Payload (CHAMP) satellite magnetometer data.
Direct transport of midlatitude stratospheric ozone into the lower troposphere and marine boundary layer of the tropical Pacific Ocean
Authors: Cooper O. R. , Stohl A. , Hübler G. , Hsie E. Y. , Parrish D. D. , Tuck A. F. , Kiladis G. N. , Oltmans S. J. , Johnson B. J. , Shapiro M. , Moody J. L. , Lefohn A. S.
Published: December 2005

The detailed survey of midlatitude stratospheric intrusions penetrating into the Northern Hemisphere tropics was one goal of the Pacific Sub‐Tropical Jet Study 2004, conducted from Honolulu, Hawaii, during 19–29 January and 28 February to 15 March. Using the National Oceanic and Atmospheric Administration G‐IV jet aircraft, instrumented with dropsondes and a 1‐s resolution ozone instrument, we targeted an intrusion above Hawaii on 29 February. The data describe the strongest tropospheric ozone enhancements ever measured above Hawaii (in comparison to a 22 year ozonesonde record) and illustrate the mixing of stratospheric ozone into the midtroposphere as a result of convection triggered by the advection of relatively cold midlatitude air into the tropics. Measurements from the G‐IV and Mauna Loa Observatory (3.4 km) show enhanced ozone in the lower troposphere, indicating that the remnants of the intrusion reached these levels. This conclusion is supported by a study using a stratospheric ozone tracer generated by the FLEXPART Lagrangian particle dispersion model. This paper also describes a similar intrusion that enhanced ozone at Mauna Loa on 10 March, as well as Honolulu, which is located in the marine boundary layer. G‐IV flights in and out of Honolulu measured enhanced ozone associated with this event on several occasions. The 10 March event transported an estimated 1.75 Tg of ozone into the tropical troposphere, and we suggest that stratospheric intrusions that break away from the polar jet stream as they advect into the tropics are more effective at transporting ozone into the troposphere than intrusions that remain close to the polar jet stream in midlatitudes. Analysis of the dynamic conditions indicates that the frequency of stratospheric intrusions was not anomalous during January–March 2004. While the 10 March event was by itself an extreme event, strong stratospheric intrusions can be expected to influence the tropical lower troposphere in any year.
Simulating terrestrial carbon fluxes using the new biosphere model “biosphere model integrating eco‐physiological and mechanistic approaches using satellite data” (BEAMS)
Authors: Sasai Takahiro , Ichii Kazuhito , Yamaguchi Yasushi , Nemani Ramakrishna
Published: December 2005

In this study we present a new biosphere model called the Biosphere model integrating Eco‐physiological And Mechanistic approaches using Satellite data (BEAMS). BEAMS provides a new method of calculating the environmental stress affecting plant growth (Stress). Stress is calculated eco‐physiologically using a photosynthesis model and stomatal conductance formulation, providing a more realistic result than previous models. Stress values are used to estimate Gross Primary Production (GPP) estimates via the light use efficiency concept. We used BEAMS, including our new Stress approach, to investigate global spatial and temporal patterns of net primary production (NPP) and net ecosystem production (NEP). BEAMS was run for the years 1982–2000 using global scale satellite and climate data. Comparison of model results with observational measurements at flux sites reveals that GPP values predicted by BEAMS agree with measured GPP. Obtained Stress values were compared with those of MOD17 and CASA; the three methods produce contrasting spatial patterns. Upon comparing predicted and observed NPP, the pattern of NPP for each plant functional type can be adequately estimated. In terms of trend analysis, NPP increased for the years 1982–2000 in most regions. Different NPP trends were observed in Europe, Russia, and northeast Canada than those proposed by Nemani et al. (2003); we attribute these differences to climate‐related processes. Simulated interannual variations in global NEP are similar to results from inverse modeling. A sensitivity study of obtained NEP shows that the interannual variability in NEP is strongly controlled by air temperature, precipitation, CO2, and the fraction of absorbed photosynthetically active radiation.
Relationship between spectral induced polarization and hydraulic properties of saturated and unsaturated sandstone
Authors: Binley Andrew , Slater Lee D. , Fukes Melanie , Cassiani Giorgio
Published: December 2005

There is growing interest in the use of geophysical methods for hydrological model parameterization. Empirical induced polarization (IP)–hydraulic conductivity (K) relationships have been developed, but these are only applicable to sediments in which the IP response shows limited variation with electrical current frequency. Here we examine the spectral IP response of samples taken from a UK sandstone aquifer and compare measured parameters with physical and hydraulic properties. We demonstrate the limited value of existing IP‐K models due to the inherent IP frequency dependence of these samples. Our results show how the mean relaxation time, τ, is a more appropriate measure of IP response for these sediments. A significant inverse correlation between the surface area to pore volume ratio and τ is observed, suggesting that τ is a measure of a characteristic hydraulic length scale. This is supported by a measured strong positive correlation between log τ and log K. Our measurements also reveal evidence of a relationship between τ and a dominant pore throat size, which leads to postulations about the parallelism between the spectral IP behavior and unsaturated hydraulic characteristics. Additional experiments show how the relaxation time is affected by degree of fluid saturation, indicating that saturation levels must be accounted for if our empirical relationships are applied to vadose zone studies. Our results show clear evidence of the potential value of frequency‐based IP measurements for parameterization of groundwater flow models.
From Home to ‘Home’: Situating Emotions within the Caregiving Experience
Authors: Milligan Christine
Published: December 2005

Emotions are an integral part of our daily lives, affecting who we are and how we react to the people and places around us. This emotiospatial hermeneutic has particular resonance for understanding informal carers' experiences of transitions in the place of care. Yet little work has explicitly addressed the link between emotions, care, and place. That which has focuses largely on community and the home, and largely ignores the transition of care from the home to care-home settings. Drawing on carer narratives from New Zealand, this paper examines how emotion and the affective entity of informal caregiving for frail older people is manifest and experienced as the site of care shifts from the private space of the home to the semipublic space of the residential care home. In doing so, the paper contributes, first, to conceptual debates around the geography of emotions, and, second, to a deeper understanding of how informal carers seek to create new identities for themselves as carers in the new place of care. Finally, drawing on debates around the meaning of home, I consider the extent to which informal carers can feel ‘at home’ caring for their spouse or close family member within care-home settings.
Volumetric tomography of fluorescent proteins through small animals
in vivo
Authors: Zacharakis Giannis , Kambara Hirokazu , Shih Helen , Ripoll Jorge , Grimm Jan , Saeki Yoshinaga , Weissleder Ralph , Ntziachristos Vasilis
Published: December 2005

Volumetric detection and accurate quantification of fluorescent proteins in entire animals would greatly enhance our ability to monitor biological processes
in vivo
. Here we present a quantitative tomographic technique for visualization of superficial and deep-seated (>2–3 mm) fluorescent protein activity
in vivo
. We demonstrate noninvasive imaging of lung tumor progression in a murine model, as well as imaging of gene delivery using a herpes virus vector. This technology can significantly improve imaging capacity over the current state of the art and should find wide
in vivo
imaging applications in drug discovery, immunology, and cancer research.
Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear
Authors: Zhao Hong-Bo , Yu Ning , Fleming Carrie R.
Published: December 2005

Connexin gap junctions play an important role in hearing function, but the mechanism by which this contribution occurs is unknown. Connexins in the cochlea are expressed only in supporting cells; no connexin expression occurs in auditory sensory hair cells. A gap junctional channel is formed by two hemichannels. Here, we show that connexin hemichannels in the cochlea can release ATP at levels that account for the submicromolar concentrations measured in the cochlear fluids
in vivo
. The release could be increased 3- to 5-fold by a reduction of extracellular Ca
2+
or an increase in membrane stress, and blocked by gap junctional blockers. We also demonstrated that extracellular ATP at submicromolar levels apparently affected outer hair cell (OHC) electromotility, which is an active cochlear amplifier determining cochlear sensitivity to sound stimulation in mammals. ATP reduced OHC electromotility and the slope factor of the voltage dependence and shifted the operating point to reduce the active amplifier gain. ATP also reduced the generation of distortion products. Immunofluorescent staining showed that purinergic receptors P2x2 and P2x7 were distributed on the OHC surface. Blockage of P2 receptors eliminated the effect of ATP on the OHC electromotility. The data revealed that there is a hemichannel-mediated, purinergic intercellular signaling pathway between supporting cells and hair cells in the cochlea to control hearing sensitivity. The data also demonstrated a potential source of ATP in the cochlea.
Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target
Authors: Ye Shiming , Huang Yadong , Müllendorff Karin , Dong Liming , Giedt Gretchen , Meng Elaine C. , Cohen Fred E. , Kuntz Irwin D. , Weisgraber Karl H. , Mahley Robert W.
Published: December 2005

Apolipoprotein (apo) E4 is a major risk factor for Alzheimer's disease, and many studies have suggested that apoE has isoform-specific effects on the deposition or clearance of amyloid β (Aβ) peptides. We examined the effects of apoE isoforms on the processing of amyloid precursor protein (APP) and on Aβ production in rat neuroblastoma B103 cells stably transfected with human wild-type APP695 (B103-APP). Lipid-poor apoE4 increased Aβ production in B103-APP cells to a greater extent than lipid-poor apoE3 (60% vs. 30%) due to more pronounced stimulation of APP recycling by apoE4 than apoE3. The difference in Aβ production was abolished by preincubating the cells with the receptor-associated protein (25 nM), which blocks the low-density lipoprotein receptor-related protein (LRP) pathway, or by reducing LRP expression by small interference RNA. The differences were also attenuated by replacing Arg-61 with threonine in apoE4 or pretreating apoE4 with small molecules, both of which abolish apoE4 intramolecular domain interaction. Thus, apoE4 appears to modulate APP processing and Aβ production through both the LRP pathway and domain interaction. These findings provide insights into why apoE4 is associated with increased risk for Alzheimer's disease and may represent a potential target for drug development.
Unexceptional sharpness of frequency tuning in the human cochlea
Authors: Ruggero Mario A. , Temchin Andrei N.
Published: December 2005

The responses to sound of auditory-nerve fibers are well known in many animals but are topics of conjecture for humans. Some investigators have claimed that the auditory-nerve fibers of humans are more sharply tuned than are those of various experimental animals. Here we invalidate such claims. First, we show that forward-masking psychophysical tuning curves, which were used as the principal support for those claims, greatly overestimate the sharpness of cochlear tuning in experimental animals and, hence, also probably in humans. Second, we calibrate compound action potential tuning curves against the tuning of auditory-nerve fibers in experimental animals and use compound action potential tuning curves recorded in humans to show that the sharpness of tuning in human cochleae is not exceptional and that it is actually similar to tuning in all mammals and birds for which comparisons are possible. Third, we note that the similarity of frequency of tuning across species with widely diverse cochlear lengths and auditory bandwidths implies that for any given stimulus frequency the “cochlear amplifier” is confined to a highly localized region of the cochlea.
Hyperpolarized krypton-83 as a contrast agent for magnetic resonance imaging
Authors: Pavlovskaya Galina E. , Cleveland Zackary I. , Stupic Karl F. , Basaraba Randall J. , Meersmann Thomas
Published: December 2005

For the first time, magnetic resonance imaging (MRI) with hyperpolarized (hp) krypton-83 (
83
Kr) has become available. The relaxation of the nuclear spin of
83
Kr atoms (
I
= 9/2) is driven by quadrupolar interactions during brief adsorption periods on surrounding material interfaces. Experiments in model systems reveal that the longitudinal relaxation of hp
83
Kr gas strongly depends on the chemical composition of the materials. The relaxation-weighted contrast in hp
83
Kr MRI allows for the distinction between hydrophobic and hydrophilic surfaces. The feasibility of hp
83
Kr MRI of airways is tested in canine lung tissue by using krypton gas with natural abundance isotopic distribution. Additionally, the influence of magnetic field strength and the presence of a breathable concentration of molecular oxygen on longitudinal relaxation are investigated.
TRUST, RESPONSIBILITY AND ENVIRONMENTAL POLICY
Authors: Pellizzoni Luigi
Published: December 2005

The article argues that the crisis of legitimacy of environmental policy is closely connected with its declining effectiveness and efficiency in front of the growing saliency of uncertainty. Trust and responsibility are relevant analytical dimensions for addressing this issue. Contrary to the former, the latter has been poorly explored in its applications to policy issues. To this purpose a typology is presented, which helps to understand the evolutionary logic and current weakness of environmental policy. Theoretical reflection is supported by a study on public views of food safety. Trust and responsibility confirm their relevance. Opinions about the different actors involved in the food chain and the regulatory and control systems are contradictory, while attempts to provide trust with solid grounds are confronted with attitudes of mistrust, suspicion and resignation. Overall, citizens’ concerns remain largely unanswered. This indicates that institutional and corporate unresponsiveness represents a major issue, negatively affecting the social legitimation of food policy.
Mutational analyses reveal a novel function of the nucleotide-binding domain of γ-tubulin in the regulation of basal body biogenesis
Authors: Shang Yuhua , Tsao Che-Chia , Gorovsky Martin A.
Published: December 2005

We have used in vitro mutagenesis and gene replacement to study the function of the nucleotide-binding domain (NBD) of γ-tubulin in Tetrahymena thermophila. In this study, we show that the NBD has an essential function and that point mutations in two conserved residues lead to over-production and mislocalization of basal body (BB) assembly. These results, coupled with previous studies (Dammermann, A., T. Muller-Reichert, L. Pelletier, B. Habermann, A. Desai, and K. Oegema. 2004. Dev. Cell. 7:815–829; La Terra, S., C.N. English, P. Hergert, B.F. McEwen, G. Sluder, and A. Khodjakov. 2005. J. Cell Biol. 168:713–722), suggest that to achieve the precise temporal and spatial regulation of BB/centriole assembly, the initiation activity of γ-tubulin is normally suppressed by a negative regulatory mechanism that acts through its NBD.
Carbon Monoxide as a Guardian against Hepatobiliary Dysfunction
Authors: Suematsu Makoto , Tsukada Kosuke , Tajima Toshihide , Yamamoto Takehiro , Ochiai Daigo , Watanabe Hiroshi , Yoshimura Yasunori , Goda Nobuhito
Published: December 2005

Abstract: Carbon monoxide (CO) generated through the reaction of heme oxygenase (HO) has attracted great interest in regulation of hepatobiliary homeostasis. The gas generated by HO‐2 in the hepatic parenchyma can modestly activate soluble guanylate cyclase (sGC) expressed in hepatic stellate cells in a paracrine manner and thereby constitutively relax sinusoids. Kupffer cells express HO‐1, the inducible isozyme, even under normal unstimulated conditions and constitutes approximately 30% of the total HO activity in this organ. Upon exposure to a variety of stressors such as cytokines, endotoxin, hypoxia and oxidative stress, the liver induces HO‐1 and overproduces CO. The stress‐inducible CO has been shown to guarantee ample blood supply during detoxification of heme and thus to play a protective role in the liver. However, molecular mechanisms by which CO serves as a protectant for hepatocytes, the cells expressing little sGC, remain to be solved. Previous observation suggested that CO modulates intracellular calcium mobilization through inhibiting cytochrome P‐450 activities and thereby maintain stroke volume of bile canalicular contraction in cultured hepatocytes. CO also stimulates mrp2‐dependent excretion of bilirubin‐IXα and helps heme catabolism. Although a direct molecular target responsible for the latter event remains unknown, such properties of CO could support xenobiotic metabolism through its actions on sinusoidal hemodynamics and hepatobiliary systems.
Adipogenic Phenotype of Hepatic Stellate Cells
Authors: Tsukamoto Hide
Published: December 2005

Abstract: Transdifferentiation of hepatic stellate cells (HSC) constitutes a major cellular event in the genesis of alcoholic liver fibrosis and cirrhosis and molecular mechanisms underlying this process is incompletely understood. Our laboratory proposed several years ago that HSC quiescence requires the transcriptional program known to be integral to preadipocyte to adipocyte differentiation. In support of the hypothesis, our research demonstrates the expression of adipogenic transcription factors (C/EBPs, PPARγ, SREBP‐1c, LXRα) and adipocyte‐specific genes (adipsin, resistin) are high in quiescent HSC and depleted in activated HSC. Three gain‐of‐function approaches have been taken to test this notion: the treatment of activated HSC with the adipocyte differentiation cocktail; ectopic expression of PPARγ or SREBP‐1c. All three treatments coordinately upregulate a panel of putative adipogenic transcrition factors and cause morphologic and biochemical reversal of activated HSC to quiescent cells. These findings establish a new conceptual framework for the treatment of liver fibrosis and propose an intriguing notion concerning the plasticity of HSC.
Modulation of Non‐Alcoholic Steatohepatitis by Pattern Recognition Receptors in Mice: The Role of Toll‐Like Receptors 2 and 4
Authors: Szabo Gyongyi , Velayudham Arumugam , Romics Laszlo , Mandrekar Pranoti
Published: December 2005

Abstract: Toll‐like receptors (TLR) recognize pathogen‐derived molecules and induce downstream activation of inflammatory pathways. Fatty liver has been shown to result in increased sensitivity to lipopolysaccharide (LPS), a TLR4 ligand. In this study, we investigated the roles of TLR2 and TLR4 in liver damage and on cytokine induction in a methionine‐choline deficient (MCD) diet‐induced model of nonalcoholic steatohepatitis. We found that mice with nonalcoholic fatty liver had increased liver injury and inflammatory cytokine induction after challenge with a TLR4 but not with a TLR2 ligand. TLR2 deficient mice were not protected against the development of steatohepatitis after MCD diet feeding. On the contrary, TLR2−/− mice had significantly higher levels of serum ALT and greater TNF‐α levels after LPS challenge suggesting increased liver injury. This was associated with reduced production of IL‐6, a cytokine with hepatoprotective effects in fatty liver. Increased liver injury in the MCD diet‐fed TLR2−/− mice was associated with reduced baseline and LPS‐induced NF‐kB and PPRE binding compared to MCS controls. These results demonstrate that TLR2 deficiency results in increased liver injury in association with nonalcoholic steatohepatitis and may suggest a protective role for TLR2‐mediated signals in liver injury.
The Oryza bacterial artificial chromosome library resource: Construction and analysis of 12 deep-coverage large-insert BAC libraries that represent the 10 genome types of the genus Oryza
Authors: Ammiraju Jetty S.S. , Luo Meizhong , Goicoechea José L. , Wang Wenming , Kudrna Dave , Mueller Christopher , Talag Jayson , Kim HyeRan , Sisneros Nicholas B. , Blackmon Barbara , Fang Eric , Tomkins Jeffery B. , Brar Darshan , MacKill David , McCouch Susan , Kurata Nori , Lambert Georgina , Galbraith David W. , Arumuganathan K. , Rao Kiran , Walling Jason G. , Gill Navdeep , Yu Yeisoo , SanMiguel Phillip , Soderlund Carol , Jackson Scott , Wing Rod A.
Published: December 2005

Rice (Oryza sativa L.) is the most important food crop in the world and a model system for plant biology. With the completion of a finished genome sequence we must now functionally characterize the rice genome by a variety of methods, including comparative genomic analysis between cereal species and within the genus Oryza. Oryza contains two cultivated and 22 wild species that represent 10 distinct genome types. The wild species contain an essentially untapped reservoir of agriculturally important genes that must be harnessed if we are to maintain a safe and secure food supply for the 21st century. As a first step to functionally characterize the rice genome from a comparative standpoint, we report the construction and analysis of a comprehensive set of 12 BAC libraries that represent the 10 genome types of Oryza. To estimate the number of clones required to generate 10 genome equivalent BAC libraries we determined the genome sizes of nine of the 12 species using flow cytometry. Each library represents a minimum of 10 genome equivalents, has an average insert size range between 123 and 161 kb, an average organellar content of 0.4%–4.1% and nonrecombinant content between 0% and 5%. Genome coverage was estimated mathematically and empirically by hybridization and extensive contig and BAC end sequence analysis. A preliminary analysis of BAC end sequences of clones from these libraries indicated that LTR retrotransposons are the predominant class of repeat elements in Oryza and a roughly linear relationship of these elements with genome size was observed.
The evolutionary dynamics of α-satellite
Authors: Rudd M. Katharine , Wray Gregory A. , Willard Huntington F.
Published: December 2005

α-Satellite is a family of tandemly repeated sequences found at all normal human centromeres. In addition to its significance for understanding centromere function, α-satellite is also a model for concerted evolution, as α-satellite repeats are more similar within a species than between species. There are two types of α-satellite in the human genome; while both are made up of ∼171-bp monomers, they can be distinguished by whether monomers are arranged in extremely homogeneous higher-order, multimeric repeat units or exist as more divergent monomeric α-satellite that lacks any multimeric periodicity. In this study, as a model to examine the genomic and evolutionary relationships between these two types, we have focused on the chromosome 17 centromeric region that has reached both higher-order and monomeric α-satellite in the human genome assembly. Monomeric and higher-order α-satellites on chromosome 17 are phylogenetically distinct, consistent with a model in which higher-order evolved independently of monomeric α-satellite. Comparative analysis between human chromosome 17 and the orthologous chimpanzee chromosome indicates that monomeric α-satellite is evolving at approximately the same rate as the adjacent non-α-satellite DNA. However, higher-order α-satellite is less conserved, suggesting different evolutionary rates for the two types of α-satellite.
Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes
Authors: Kimura Kouichi , Wakamatsu Ai , Suzuki Yutaka , Ota Toshio , Nishikawa Tetsuo , Yamashita Riu , Yamamoto Jun-ichi , Sekine Mitsuo , Tsuritani Katsuki , Wakaguri Hiroyuki , Ishii Shizuko , Sugiyama Tomoyasu , Saito Kaoru , Isono Yuko , Irie Ryotaro , Kushida Norihiro , Yoneyama Takahiro , Otsuka Rie , Kanda Katsuhiro , Yokoi Takahide , Kondo Hiroshi , Wagatsuma Masako , Murakawa Katsuji , Ishida Shinichi , Ishibashi Tadashi , Takahashi-Fujii Asako , Tanase Tomoo , Nagai Keiichi , Kikuchi Hisashi , Nakai Kenta , Isogai Takao , Sugano Sumio
Published: December 2005

By analyzing 1,780,295 5′-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.
Organization of the Caenorhabditis elegans small non-coding transcriptome: Genomic features, biogenesis, and expression
Authors: Deng Wei , Zhu Xiaopeng , Skogerbø Geir , Zhao Yi , Fu Zhuo , Wang Yudong , He Housheng , Cai Lun , Sun Hong , Liu Changning , Li Biao , Bai Baoyan , Wang Jie , Jia Dong , Sun Shiwei , He Hang , Cui Yan , Wang Yu , Bu Dongbo , Chen Runsheng
Published: December 2005

Recent evidence points to considerable transcription occurring in non-protein-coding regions of eukaryote genomes. However, their lack of conservation and demonstrated function have created controversy over whether these transcripts are functional. Applying a novel cloning strategy, we have cloned 100 novel and 61 known or predicted Caenorhabditis elegans full-length ncRNAs. Studying the genomic environment and transcriptional characteristics have shown that two-thirds of all ncRNAs, including many intronic snoRNAs, are independently transcribed under the control of ncRNA-specific upstream promoter elements. Furthermore, the transcription levels of at least 60% of the ncRNAs vary with developmental stages. We identified two new classes of ncRNAs, stem-bulge RNAs (sbRNAs) and snRNA-like RNAs (snlRNAs), both featuring distinct internal motifs, secondary structures, upstream elements, and high and developmentally variable expression. Most of the novel ncRNAs are conserved in Caenorhabditis briggsae, but only one homolog was found outside the nematodes. Preliminary estimates indicate that the C. elegans transcriptome contains ∼2700 small non-coding RNAs, potentially acting as regulatory elements in nematode development.
Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome
Authors: Ravasi Timothy , Suzuki Harukazu , Pang Ken C. , Katayama Shintaro , Furuno Masaaki , Okunishi Rie , Fukuda Shiro , Ru Kelin , Frith Martin C. , Gongora M. Milena , Grimmond Sean M. , Hume David A. , Hayashizaki Yoshihide , Mattick John S.
Published: December 2005

Recent large-scale analyses of mainly full-length cDNA libraries generated from a variety of mouse tissues indicated that almost half of all representative cloned sequences did not contain an apparent protein-coding sequence, and were putatively derived from non-protein-coding RNA (ncRNA) genes. However, many of these clones were singletons and the majority were unspliced, raising the possibility that they may be derived from genomic DNA or unprocessed pre-mRNA contamination during library construction, or alternatively represent nonspecific “transcriptional noise.” Here we show, using reverse transcriptase-dependent PCR, microarray, and Northern blot analyses, that many of these clones were derived from genuine transcripts of unknown function whose expression appears to be regulated. The ncRNA transcripts have larger exons and fewer introns than protein-coding transcripts. Analysis of the genomic landscape around these sequences indicates that some cDNA clones were produced not from terminal poly(A) tracts but internal priming sites within longer transcripts, only a minority of which is encompassed by known genes. A significant proportion of these transcripts exhibit tissue-specific expression patterns, as well as dynamic changes in their expression in macrophages following lipopolysaccharide stimulation. Taken together, the data provide strong support for the conclusion that ncRNAs are an important, regulated component of the mammalian transcriptome.
Development of a microscopic platform for real-time monitoring of biomolecular interactions
Authors: Sasuga Yasuhiro , Tani Tomomi , Hayashi Masahito , Yamakawa Hisashi , Ohara Osamu , Harada Yoshie
Published: December 2005

We developed a new microscopic platform for the real-time analysis of molecular interactions by combining microbead-tagging techniques with total internal reflection fluorescent microscopy (TIRFM). The optical manipulation of probe microbeads, followed by photo immobilization on a solid surface, enabled us to generate arrays with extremely high density (>100 microbeads in a 25 μm × 25 μm area), and TIRFM made it possible to monitor the binding reactions of fluorescently labeled targets onto probe microbeads without removal of free targets. We demonstrated the high performance of this platform through analyses of interactions between antigen and antibody and between small compounds and proteins. Then, recombinant protein levels in total cellular lysates of Escherichia coli were quantified from the association kinetics using antibody-immobilized microbead arrays, which served as a model for a protein-profiling array. Furthermore, in combination with in vitro synthesis-coupled protein labeling, we could kinematically analyze the interaction of nuclear factor κB (p50) with DNA. These results demonstrated that this platform enabled us to: (1) monitor binding processes of fluorescently labeled targets to multiple probes in real-time without removal of free targets, (2) determine concentrations of free targets only from the association kinetics at an early phase, and (3) greatly reduce the required volume of the target solution, in principle to subnanoliter, for molecular interaction analysis. The unique features of this microbead-based microarray system open the way to explore molecular interactions with a wide range of affinities in extremely small volumes of target solutions, such as extracts from single cells.
Expression of Bcl‐x in normal skin and benign cutaneous adnexal tumors*
Authors: Thamboo Thomas P. , Tan Leonard H.‐C. , Tan Soo‐Yong
Published: December 2005

Background:  Bcl‐x appears to have an antiapoptotic role in the epidermis. Little is known about the expression of Bcl‐x in cutaneous adnexal structures and benign cutaneous adnexal tumors.

Methods:  Tissues from 31 cases of benign cutaneous adnexal tumors (five trichofolliculomas, five trichoepitheliomas, two sebaceous adenomas, five apocrine hidradenomas, five eccrine poromas, five eccrine spiradenomas, and four syringomas) were immunostained for Bcl‐x.

Results:  Strong staining for Bcl‐x was seen in cells of the epidermal granular layer and inner root sheath of hair follicles. Sebaceous gland cells showed strong staining. Apocrine gland cells showed weak to moderate staining. No staining was seen in eccrine gland cells. The basaloid cells of trichofolliculomas and trichoepitheliomas showed no staining. In sebaceous adenomas, the sebaceous cells showed strong staining while the basaloid cells were negative. The cells of apocrine hidradenomas showed patchy weak staining. No staining was seen in eccrine poromas, eccrine spiradenomas, and syringomas.

Conclusions:  The degree of Bcl‐x expression in cutaneous adnexal glandular structures appears to be related to their mode of secretion, being strongest in cells with apoptotic degradation of the entire cell (sebocytes). This pattern is recapitulated in the corresponding benign cutaneous adnexal tumors. Bcl‐x may be useful in identifying cells with sebaceous differentiation in poorly differentiated adnexal tumors.
Review article: proton pump inhibitors and bacterial overgrowth
Authors: WILLIAMS C. , McCOLL K. E. L.
Published: December 2005

Proton pump inhibitors are potent drugs producing profound suppression of gastric acid secretion. Consequently, they are highly effective at treating acid‐related disorders.

There have been concerns that the suppression of gastric acid will alter the bacterial flora of the upper gastrointestinal tract and lead to complications such as cancer, enteric or other infections and malabsorption.

Studies have confirmed that proton pump inhibitors do alter the bacterial population but present evidence indicates that this only rarely leads to clinical disease.

As with all drugs, proton pump inhibitors should only be used for disorders shown clearly to benefit from the therapy and where the benefits will outweigh the small risks associated with them. Further research to more fully quantify the risk associated with PPI therapy is required.
Risk of schizophrenia in people with coeliac disease, ulcerative colitis and Crohn's disease: a general population‐based study
Authors: WEST J. , LOGAN R. F. , HUBBARD R. B. , CARD T. R.
Published: December 2005

Background

Recently, interest has been revived in whether people with coeliac disease, in contrast to other inflammatory gastrointestinal diseases, have an increased risk of schizophrenia.

Aim

To compare the risk of schizophrenia in people diagnosed with coeliac disease, ulcerative colitis and Crohn's disease with the general population.

Methods

We used data from the UK General Practice Research Database. People with coeliac disease, Crohn's disease and ulcerative colitis were matched individually with five age‐, sex‐ and general practice‐matched controls. The prevalence of schizophrenia was calculated and compared between disease groups and their respective controls. We calculated odds ratios for schizophrenia using conditional logistic regression adjusting for smoking status.

Results

In people with coeliac disease, Crohn's disease and ulcerative colitis the prevalence of schizophrenia was 0.25%, 0.27% and 0.24%, respectively, compared with a general population prevalence of 0.37%. The adjusted odds ratios showed no association between schizophrenia and gastrointestinal disease (coeliac disease vs. controls 0.76, 95% CI: 0.41–1.4; Crohn's disease vs. controls 0.74, 95% CI: 0.44–1.3; ulcerative colitis 0.71, 95% CI: 0.44–1.1).

Conclusions Contrary to recent findings we found no evidence of an increased risk of schizophrenia in people with coeliac disease compared with the general population.
A partially overlapping treatment course with lamivudine and interferon in hepatitis B e antigen‐negative chronic hepatitis B
Authors: MANESIS E. K. , PAPATHEODORIDIS G. V. , HADZIYANNIS S. J.
Published: December 2005

Background

Treatment of patients with hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHBe‐) with interferon or lamivudine alone is inefficient and reports of combination treatment with both drugs, equivocal so far.

Aim

To investigate the efficacy of a lamivudine–interferon combination therapy in 36 patients HBeAg‐negative CHBe−.

Methods

Lamivudine was administered from 1 to 12 months and interferon‐α2b from 7 to 18 months. A historical control group of 36 CHBe− patients, matched for age and sex and treated with the same dosage of interferon‐α2b was used. All patients were followed up for ≥12‐month post‐treatment.

Results

The biochemical response rate at the end of treatment was 78% in lamivudine–interferon and 52.8% in interferon–control group (P = 0.026) and at 12‐month post‐treatment 38.9% and 22.2%, respectively (P = 0.125). Alanine aminotransferase normalization and serum HBV‐DNA levels ≤30 000 cp/mL were observed in 50.0% of lamivudine–interferon‐treated and 30.6% of interferon‐treated patients at the end of treatment (P =0.093) and in 22.2% and 13.9% of patients, respectively, at 12‐month post‐treatment (P = 0.358). Moreover, alanine aminotransferase normalization and undetectable serum HBV‐DNA (<400 cp/mL) was observed in 30.6% of lamivudine–interferon‐treated and 8.3% of interferon‐treated patients at the end of treatment (P = 0.017) and in 8.3% and 0% of patients, respectively, at 12‐month post‐treatment (P = 0.076).

Conclusions

In CHBe−, 12 months after ending a lamivudine–interferon partially overlapping 18‐month combination course, 22% of patients still maintain normal alanine aminotransferase and HBV‐DNA levels ≤30 000 cp/mL. However, a 12‐month interferon monotherapy course may achieve similar responses.