bluuebunny/crossref_metadata_2025 huggingface dataset:
The Initial-Value Problem for a Slab. I. Anisotropic Scattering
Authors: Mika Janusz
Published: May 2005

In this paper, the spectral properties of the Boltzmann operator describing the transport of mono-energetic neutrons with anisotropic scattering in a slab are considered. The Hille-Yosida theorem is applied to obtain the semi-group of operators solving the initial-value problem.
Optically Calibrated Infrared High Pressure Cell
Authors: Williamson Donald E. , Nichols Ivan A. , Schurin Bertram
Published: May 2005

A high pressure optical cell of large aperture has been constructed for use in pressure broadening studies of gases in the infrared region of the spectrum. The cell is tight at both vacuum and 1000 psi and is constructed of stainless steel with 3×1-in. calcium fluoride windows. A method of measuring short path length cell spacing to an accuracy of 1% using an optical “butterfly” is described. Data are presented on the pressure-induced distortion of the cell path length for calcium fluoride windows as well as optical glass windows.
Predicting mammalian target-specificity of the M-44 ejector in south-eastern Australia
Authors: Marks Clive A. , Wilson Rebecca
Published: May 2005

Meat-based baits are currently used for the control of the exotic red fox (Vulpes vulpes) in south-eastern Australia. Thirty-one quadrupedal endemic mammals are considered to be potentially bait consuming (PBC) and may be exposed to bait toxicants. Mechanical toxicant ejectors may be more selective if some PBC species cannot apply enough upward force to trigger them. A simple relationship between body mass and pulling force was sought to enable estimates of ejector specificity to be made. The pulling force applied to ejector baits was measured for the red fox and six endemic mammals. The relationship between body mass and pulling force was highly significant (P < 0.001) and the resulting regression equation was used to estimate the highest pulling forces for 31 quadrupedal mammals based upon the largest body mass recorded for each species. In a sample of 640 foxes, taken by a range of methods in south-eastern Australia, the lowest adult body mass detected from January to September was 3 kg and declined only when cubs were present in the population from October to December. An ejector trigger force of 26.46 N was estimated to allow foxes weighing >3 kg to trigger the device, while eliminating exposure of 26 of the 31 PBC mammals. Appropriate toxicant selection and dose rates may ensure that four out of five susceptible mammals are less likely to be affected by unwanted exposure.
Giant snakes in tropical forests: a field study of the Australian scrub python, Morelia kinghorni
Authors: Fearn S. , Schwarzkopf L. , Shine R.
Published: May 2005

Studies on species that attain very large body sizes provide a powerful opportunity to clarify the ecological correlates and consequences of body size, but logistical obstacles mean that most ‘giant’ species have attracted little field-based research. The Australian scrub python, Morelia kinghorni (= M. amethistina in earlier literature), is the largest Australian snake. Our three-year field study in the Tully River Gorge of tropical north-eastern Australia provides the first detailed ecological data on this species. Snakes aggregate in the gorge during the dry season for reproductive activities (combat, courtship and mating), and these aggregations consist primarily of large adult males. Wet-season samples from a nearby road contained more females, and more juvenile animals. Body temperatures of diurnally active pythons averaged 25.2°C, and were highly correlated with air and substrate temperatures. Larger snakes were cooler than smaller conspecifics, perhaps reflecting their slower heating rates. Recapture of marked individuals suggests that pythons of both sexes and all body sizes maintain fixed home ranges, as the distance from initial capture did not increase through time; most animals were recaptured <100 m from their initial capture point, but some dispersed at least 1.5 km. Adult male pythons spanned a massive range in body sizes (1.3–3.76 m in snout–vent length, 0.30–11 kg in mass), and larger males were more likely to engage in combat, exhibit combat-related injuries (bite wounds) and obtain matings. Presumably reflecting the reproductive advantage of larger body size, males attained much larger maximum sizes than did females within our study population.
The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity
Authors: Clouaire Thomas , Roussigne Myriam , Ecochard Vincent , Mathe Catherine , Amalric François , Girard Jean-Philippe
Published: April 2005

We have recently described an evolutionarily conserved protein motif, designated the THAP domain, which defines a previously uncharacterized family of cellular factors (THAP proteins). The THAP domain exhibits similarities to the site-specific DNA-binding domain of
Drosophila P
element transposase, including a putative metal-coordinating C2CH signature (CX
2–4
CX
35–53
CX
2
H). In this article, we report a comprehensive list of ≈100 distinct THAP proteins in model animal organisms, including human nuclear proapoptotic factors THAP1 and DAP4/THAP0, transcriptional repressor THAP7, zebrafish orthologue of cell cycle regulator E2F6, and
Caenorhabditis elegans
chromatin-associated protein HIM-17 and cell-cycle regulators LIN-36 and LIN-15B. In addition, we demonstrate the biochemical function of the THAP domain as a zinc-dependent sequence-specific DNA-binding domain belonging to the zinc-finger superfamily.
In vitro
binding-site selection allowed us to identify an 11-nucleotide consensus DNA-binding sequence specifically recognized by the THAP domain of human THAP1. Mutations of single nucleotide positions in this sequence abrogated THAP-domain binding. Experiments with the zinc chelator 1,10-
o
-phenanthroline revealed that the THAP domain is a zinc-dependent DNA-binding domain. Site-directed mutagenesis of single cysteine or histidine residues supported a role for the C2CH motif in zinc coordination and DNA-binding activity. The four other conserved residues (P, W, F, and P), which define the THAP consensus sequence, were also found to be required for DNA binding. Together with previous genetic data obtained in
C. elegans
, our results suggest that cellular THAP proteins may function as zinc-dependent sequence-specific DNA-binding factors with roles in proliferation, apoptosis, cell cycle, chromosome segregation, chromatin modification, and transcriptional regulation.
Ab initioquantum chemistry: Methodology and applications
Authors: Friesner Richard A.
Published: May 2005

This Perspective provides an overview of state-of-the-artab initioquantum chemical methodology and applications. The methods that are discussed include coupled cluster theory, localized second-order Moller–Plesset perturbation theory, multireference perturbation approaches, and density functional theory. The accuracy of each approach for key chemical properties is summarized, and the computational performance is analyzed, emphasizing significant advances in algorithms and implementation over the past decade. Incorporation of a condensed-phase environment by means of mixed quantum mechanical/molecular mechanics or self-consistent reaction field techniques, is presented. A wide range of illustrative applications, focusing on materials science and biology, are discussed briefly.
Potential energy functions for atomic-level simulations of water and organic and biomolecular systems
Authors: Jorgensen William L. , Tirado-Rives Julian
Published: May 2005

An overview is provided on the development and status of potential energy functions that are used in atomic-level statistical mechanics and molecular dynamics simulations of water and of organic and biomolecular systems. Some topics that are considered are the form of force fields, their parameterization and performance, simulations of organic liquids, computation of free energies of hydration, universal extension for organic molecules, and choice of atomic charges. The discussion of water models covers some history, performance issues, and special topics such as nuclear quantum effects.
Materials by numbers: Computations as tools of discovery
Authors: Landman Uzi
Published: May 2005

Current issues pertaining to theoretical simulations of materials, with a focus on systems of nanometer-scale dimensions, are discussed. The use of atomistic simulations as high-resolution numerical experiments, enabling and guiding formulation and testing of analytic theoretical descriptions, is demonstrated through studies of the generation and breakup of nanojets, which have led to the derivation of a stochastic hydrodynamic description. Subsequently, I illustrate the use of computations and simulations as tools of discovery, with examples that include the self-organized formation of nanowires, the surprising nanocatalytic activity of small aggregates of gold that, in the bulk form, is notorious for being chemically inert, and the emergence of rotating electron molecules in two-dimensional quantum dots. I conclude with a brief discussion of some key challenges in nanomaterials simulations.
Structural mechanism of the recovery stroke in the Myosin molecular motor
Authors: Fischer Stefan , Windshügel Björn , Horak Daniel , Holmes Kenneth C. , Smith Jeremy C.
Published: April 2005

The power stroke pulling myosin along actin filaments during muscle contraction is achieved by a large rotation (≈60°) of the myosin lever arm after ATP hydrolysis. Upon binding the next ATP, myosin dissociates from actin, but its ATPase site is still partially open and catalytically off. Myosin must then close and activate its ATPase site while returning the lever arm for the next power stroke. A mechanism for this coupling between the ATPase site and the distant lever arm is determined here by generating a continuous series of optimized intermediates between the crystallographic end-states of the recovery stroke. This yields a detailed structural model for communication between the catalytic and the force-generating regions that is consistent with experimental observations. The coupling is achieved by an amplifying cascade of conformational changes along the relay helix lying between the ATPase and the domain carrying the lever arm.
Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent
Authors: Bai Yun , Ann David K. , Shen Wei-Chiang
Published: May 2005

An expression construct harboring granulocyte colony-stimulating factor (G-CSF)-transferrin (Tf) fusion protein (G-CSF-Tf) was engineered by fusing human cDNAs encoding G-CSF and Tf to explore the feasibility of using Tf as a carrier moiety for oral delivery of therapeutic proteins. The recombinant protein, G-CSF-Tf, was harvested from protein-free, conditioned medium of transfected HEK293 cells. The
in vitro
studies demonstrated that the purified G-CSF-Tf fusion protein possesses the activity of both Tf receptor (TfR) binding in Caco-2 cells and G-CSF-dependent stimulation of NFS-60 cell proliferation. Subcutaneous administration of G-CSF-Tf fusion protein to BDF1 mice demonstrated a pharmacological effect comparable to the commercial G-CSF on the increase of absolute neutrophil counts (ANC). However, the fusion protein elicited a significant increase in ANC upon oral administration to BDF1 mice, whereas G-CSF had no effect. This study also showed that orally administered G-CSF-Tf elicits a sustained myelopoietic effect up to 3 days, whereas the s.c. administered G-CSF or G-CSF-Tf lasts only 1 day. Furthermore, coadministration of free Tf abolished the increase of ANC by orally delivered G-CSF-Tf, suggesting that the recombinant protein is absorbed via a TfR-mediated process in the gastrointestinal tract. Taken together, we conclude that the Tf-based recombinant fusion protein technology represents a promising approach for future development of orally effective peptide and protein drugs.
Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease
Authors: Kirino Yohei , Goto Yu-ichi , Campos Yolanda , Arenas Joaquin , Suzuki Tsutomu
Published: May 2005

Mutations in mtDNA are responsible for a variety of mitochondrial diseases, where the mitochondrial tRNA
Leu(UUR)
gene has especially hot spots for pathogenic mutations. Clinical features often depend on the tRNA species and/or positions of the mutations; however, molecular pathogenesis elucidating the relation between the location of the mutations and their leading phenotype are not fully understood. We report here that mitochondrial tRNAs
Leu(UUR)
harboring one of five mutations found in tissues from patients with symptoms of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (A3243G, G3244A, T3258C, T3271C, and T3291C) lacked the normal taurine-containing modification (5-taurinomethyluridine) at the anticodon wobble position. In contrast, mitochondrial tRNAs
Leu(UUR)
with different mutations found in patients that have mitochondrial diseases but do not show the MELAS symptoms (G3242A, T3250C, C3254T, and A3280G) had the normal 5-taurinomethyluridine modifications. These observations were made by using a modified primer extension technique that can detect the modification deficiency in the extremely limited quantities of mutant tRNAs obtainable from patient tissues. These results strongly suggest deficient wobble modification could be a key molecular factor responsible for the phenotypic features of MELAS, which can explain why the different MELAS-associated mutations result in indistinguishable clinical features.
STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes
Authors: Zhang Qian , Wang Hong Y. , Marzec Michal , Raghunath Puthiyaveettil N. , Nagasawa Tomohiko , Wasik Mariusz A.
Published: May 2005

Expression of SHP-1 phosphatase, a key negative regulator of cell signaling, is lost in T cell lymphomas and other malignancies due to DNA methylation of the SHP-1 promoter by a currently undefined mechanism. We demonstrate that malignant T cells express DNA methyltransferase (DNMT) 1 and that constantly activated signal transducer and activator of transcription (STAT) 3 is capable of bindingin vitroto DNA oligonucleotides corresponding to four STAT3 SIE/GAS binding sites identified in the SHP-1 promoter. STAT3, DNMT1, and histone deacetylase 1 form complexes and bind to the SHP-1 promoterin vivo. Treatment with pharmacologic grade DNMT1 anti-sense oligonucleotides and STAT3 small-interfering RNA induces in the malignant T cells DNA demethylation and expression ofSHP-1gene. These data indicate that STAT3 may, in part, transform cells by inducing epigenetic silencing of SHP-1 in cooperation with DNMT1 and, apparently, histone deacetylase 1. Reversal of such gene silencing represents an attractive aim for novel anticancer therapies.
Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons
Authors: Lopez-Coviella Ignacio , Follettie Maximillian T. , Mellott Tiffany J. , Kovacheva Vesela P. , Slack Barbara E. , Diesl Veronica , Berse Brygida , Thies R. Scott , Blusztajn Jan Krzysztof
Published: May 2005

Basal forebrain cholinergic neurons (BFCN) participate in processes of learning, memory, and attention. Little is known about the genes expressed by BFCN and the extracellular signals that control their expression. Previous studies showed that bone morphogenetic protein (BMP) 9 induces and maintains the cholinergic phenotype of embryonic BFCN. We measured gene expression patterns in septal cultures of embryonic day 14 mice and rats grown in the presence or absence of BMP9 by using species-specific microarrays and validated the RNA expression data of selected genes by immunoblot and immunocytochemistry analysis of their protein products. BMP9 enhanced the expression of multiple genes in a time-dependent and, in most cases, reversible manner. The set of BMP9-responsive genes was concordant between mouse and rat and included genes encoding cell-cycle/growth control proteins, transcription factors, signal transduction molecules, extracellular matrix, and adhesion molecules, enzymes, transporters, and chaperonins. BMP9 induced the p75 neurotrophin receptor (NGFR), a marker of BFCN, and
Cntf
and
Serpinf1
, two trophic factors for cholinergic neurons, suggesting that BMP9 creates a trophic environment for BFCN. To determine whether the genes induced by BMP9 in culture were constituents of the BFCN transcriptome, we purified BFCN from embryonic day 18 mouse septum by using fluorescence-activated cell sorting of NGFR
+
cells and profiled mRNA expression of these and NGFR
–
cells. Approximately 30% of genes induced by BMP9
in vitro
were overexpressed in purified BFCN, indicating that they belong to the BFCN transcriptome
in situ
and suggesting that BMP signaling contributes to maturation of BFCN
in vivo
.
Human biliverdin reductase: A member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity
Authors: Lerner-Marmarosh Nicole , Shen Jenny , Torno Michael D. , Kravets Anatoliy , Hu Zhenbo , Maines Mahin D.
Published: May 2005

We describe here the tyrosine kinase activity of human biliverdin reductase (BVR) and its potential role in the insulin-signaling pathway. BVR is both a substrate for insulin receptor (IR) tyrosine kinase (IRK) activity and a kinase for serine phosphorylation of IR substrate 1 (IRS-1). Our previous studies have revealed serine/threonine kinase activity of BVR. Y
198
, in the YMKM motif found in the C-terminal domain of BVR, is shown to be a substrate for insulin-activated IRK. This motif in IRS proteins provides a docking site for proteins that contain a Src homology 2 domain. Additionally, Y
228
in the YLSF sequence and Y
291
are IRK substrates; the former sequence provides optimum recognition motif in the tyrosine phosphatase, SHP-1, and for SHC (Src homology 2 domain containing transfroming protein 1). BVR autophosphorylates N-terminal tyrosines Y
72
and Y
83
. Serine residues in IRS-1 are targets for BVR phosphorylation, and point mutation of serine residues in the kinase domain of the reductase inhibits phosphotransferase activity. Because tyrosine phosphorylation of IRS-1 activates the insulin signaling pathway and serine phosphorylation of IRS-1 blocks insulin action, our findings that insulin increases BVR tyrosine phosphorylation and that there is an increase in glucose uptake in response to insulin when expression of BVR is “knocked down” by small interfering RNA suggest a potential role for BVR in the insulin signaling pathway.
Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations
Authors: Splawski Igor , Timothy Katherine W. , Decher Niels , Kumar Pradeep , Sachse Frank B. , Beggs Alan H. , Sanguinetti Michael C. , Keating Mark T.
Published: April 2005

Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent,
de novo
cardiac L-type calcium channel (Ca
V
1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified
de novo
missense mutations in exon 8 of Ca
V
1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of Ca
V
1.2 containing exon 8 is highly expressed in heart and brain, accounting for ≈80% of Ca
V
1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of Ca
V
1.2 exons 8 and 8A cause distinct forms of TS.
Selective anxiolysis produced by ocinaplon, a GABA
A
receptor modulator
Authors: Lippa A. , Czobor P. , Stark J. , Beer B. , Kostakis E. , Gravielle M. , Bandyopadhyay S. , Russek S. J. , Gibbs T. T. , Farb D. H. , Skolnick P.
Published: May 2005

Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses >25-fold higher than the minimum effective dose (3.1 mg/kg) in the Vogel “conflict” test. This anticonflict effect is blocked by flumazenil (Ro 15-1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABA
A
receptors. Nonetheless, in eight recombinant GABA
A
receptor isoforms expressed in
Xenopus
oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180-240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disorders.
Monoclonal antibodies reveal the potential of the tetragnathid spider Pachygnatha degeeri (Araneae: Tetragnathidae) as an aphid predator
Authors: Harwood J.D. , Sunderland K.D. , Symondson W.O.C.
Published: May 2005

The drive towards a more sustainable and integrated approach to pest management has engendered a renewed interest in conservation biological control, the role of natural enemy communities and their interactions with prey. Monoclonal antibodies have provided significant advances in enhancing our knowledge of trophic interactions and can be employed to help quantify predation on target species. The tetragnathid spider Pachygnatha degeeri Sundevall was collected from fields of winter wheat in the UK and assayed by ELISA for aphid proteins. It was demonstrated that this spider did not simply consume greater quantities of aphids because it was bigger. In addition, P. degeeri contained significantly greater concentrations of aphid in their guts than other spiders, showing that aphids comprised a greater proportion of their diet. Although P. degeeri constituted only 6% of the spider population numerically, females and males respectively contained 16% and 37% of total aphid proteins within all spiders screened, significantly more than their density would predict. These spiders also preyed upon aphids at a disproportionately high rate in June, during the aphid establishment phase, theoretically the best time for limiting growth in the aphid population. Although less abundant than other generalist predators, the capability of these hunting spiders to consume large numbers of aphids highlights them as a more significant component of the predator complex than had previously been realized. Limitation of aphid numbers early in the year by generalist predators provides more time for the specialist aphid predators and parasitoids to move in.
Impact of inulin and oligofructose on gastrointestinal peptides
Authors: Delzenne Nathalie M. , Cani Patrice D. , Daubioul Catherine , Neyrinck Audrey M.
Published: May 2005

In the present paper, we summarise the data supporting the following hypothesis: dietary inulin-type fructans extracted from chicory root may modulate the production of peptides, such as incretins, by endocrine cells present in the intestinal mucosa, this phenomenon being involved in the regulation of food intake and/or systemic effects. To test this hypothesis, male Wistar rats received for 3 weeks either a standard diet or the same diet supplemented with 10% inulin-type fructans with different degrees of polymerisation. All the effects were most pronounced with the diet containing oligofructose, and consisted of (i) a decrease in mean daily energy intake and in epididymal fat mass; (ii) a higher caecal pool of the anorexigenic glucagon-like peptide-1 (7–36) amide (GLP-1), and peptide YY (PYY), due to caecal tissue proliferation; (iii) an increase in GLP-1 and of its precursor – proglucagon mRNA – concentrations in the proximal colon; (iv) an increase in portal serum level of GLP-1 and PYY; (v) a decrease in serum orexigenic peptide ghrelin. Moreover, oligofructose supplementation improved glucose homeostasis (i.e. decreased glycaemia, increased pancreatic and serum insulin content) in diabetic rats previously treated with streptozotocin, a phenomenon that is partly linked to the reduction in food intake and that correlates with the increase in colic and portal GLP-1 content. Based on these results it appears justified to test, in human subjects, the hypothesis that dietary inulin-type fructans could play a role in the management of obesity and diabetes through their capacity to promote secretion of endogenous gastrointestinal peptides involved in appetite regulation.
Methodological considerations in measuring human calcium absorption: relevance to study the effects of inulin-type fructans
Authors: Griffin Ian J. , Abrams Steven A.
Published: May 2005

During the last 50 years, a variety of methods have been developed to estimate Ca absorption in man. Mass balances were initially used, but these were unable to accurately measure fractional Ca absorption because they cannot distinguish unabsorbed dietary Ca from endogenous faecal Ca excretion (excretion of previously absorbed Ca back into the gut). A number of isotopic methods have been developed that can measure true fractional Ca absorption, employing radioisotopes, stable isotopes, or both. Different methods involve collection of urine, faecal or plasma samples. Of the currently available methods, the dual isotope tracer method with a timed urine collection is probably the most precise and reliable. It is also relatively straightforward to carry out and avoids the need for a faecal collection. The purpose of the present paper is to discuss the general advantages and disadvantages of the different methods of Ca absorption. In addition, the limitations the different methods have in examining the possible effects of non-digestible oligosaccharides on Ca absorption will be discussed.
Mucosal bacteria in ulcerative colitis
Authors: Macfarlane S. , Furrie E. , Kennedy A. , Cummings J. H. , Macfarlane G. T.
Published: May 2005

Ulcerative colitis (UC) is an acute and chronic inflammatory bowel disease of unknown aetiology, although bacterial species belonging to the normal colonic microbiota are known to be involved in its initiation and maintenance. Several organisms have been linked to the disease; however, mucosa-associated bacteria are more likely to be involved than their luminal counterparts, due to their close proximity to the host epithelium. Comparative bacteriological analyses were done on rectal biopsies to investigate differences in mucosal bacteria in patients with UC and healthy controls. Complex bacterial communities were found in both groups, with significant reductions in bifidobacterial numbers in UC, which suggested that they might have a protective role in the disease. Accordingly, a therapy for treating UC was designed, with the aim of modifying the mucosal microbiota to increase bifidobacterial colonisation and reduce inflammation. Ranges of mucosal and faecal bifidobacteria were tested for their substrate preferences and their abilities to survive under a variety of environmental conditions. A synbiotic comprising a probiotic (Bifidobacterium longum) isolated from healthy rectal mucosa combined with a prebiotic (oligofructose-enriched inulin – Synergy 1TM) was developed. The treatment was used in a randomised controlled trial involving eighteen patients with active UC, for a period of 1 month. Rectal biopsies were collected at the beginning and end of the study. Bacteriological analysis and transcription levels of epithelium-related immune markers were assessed. Results demonstrated that short-term synbiotic treatment resulted in increased bifidobacterial colonisation of the rectal mucosa and induced significant reductions in the expression of molecules that control inflammation in active UC.
The SYNCAN project: goals, set-up, first results and settings of the human intervention study
Authors: Loo Jan Van , Clune Yvonne , Bennett Mary , Collins John Kevin
Published: May 2005

Experimental evidence on the anticancer properties of dietary prebiotics such as chicory inulin and oligofructose and dietary probiotics has accumulated in recent years. Various experimental models ranging from chemoprevention studies, tumour implantation models to genetically modified mice models, etc. have systematically shown the protective effects of these food ingredients. In some studies it appeared that synbiotics (combination of pre- and probiotics) exerted synergistic activity against processes of carcinogenesis. The logical next step in research was to find out if these observations also would be valid for human volunteers. This was the principal goal of the EU-sponsored SYNCAN project (QLK1-1999-346) which involved the integration of an in vitro study to select the most suitable synbiotic preparation, the application of this synbiotic in an in vivo rat model of chemically induced colon cancer, and, as the heart of the project, the investigation of the synbiotic effects in a human intervention study. The in vitro tests consisted of fermentation studies where the interaction of pre- and probiotics was studied. Cell-free supernatants were generated from various synbiotic combinations fermented by faecal slurry, which were then used to optimise a series of bioassays. In the rat study the anticarcinogenic effect of prebiotics and synbiotics but not of probiotics was demonstrated. Using tissue samples generated in this model, attempts were made to gain a better insight into the mechanisms underlying cancer development. The human intervention study consisted of two groups of volunteers. One group was composed of people at high risk (polypectomised subjects) for colon cancer and the other of volunteers (colon cancer subjects) who had previously undergone ‘curative resection‘ for colon cancer but were not currently receiving treatment. The present paper describes the experimental design of the SYNCAN study, and demonstrates a functional effect of the synbiotic preparation (probiotic survival during gastrointestinal transit and modification of the intestinal flora). Detailed experimental outcome of the human intervention study will be reported elsewhere.
The role of gut-associated lymphoid tissues and mucosal defence
Authors: Forchielli Maria Luisa , Walker W. Allan
Published: May 2005

The newborn infant leaves a germ-free intrauterine environment to enter a contaminated extrauterine world and must have adequate intestinal defences to prevent the expression of clinical gastrointestinal disease states. Although the intestinal mucosal immune system is fully developed after a full-term birth, the actual protective function of the gut requires the microbial stimulation of initial bacterial colonization. Breast milk contains prebiotic oligosaccharides, like inulin-type fructans, which are not digested in the small intestine but enter the colon as intact large carbohydrates that are then fermented by the resident bacteria to produce SCFA. The nature of this fermentation and the consequent pH of the intestinal contents dictate proliferation of specific resident bacteria. For example, breast milk-fed infants with prebiotics present in breast milk produce an increased proliferation of bifidobacteria and lactobacilli (probiotics), whereas formula-fed infants produce more enterococci and enterobacteria. Probiotics, stimulated by prebiotic fermentation, are important to the development and sustainment of intestinal defences. For example, probiotics can stimulate the synthesis and secretion of polymeric IgA, the antibody that coats and protects mucosal surfaces against harmful bacterial invasion. In addition, appropriate colonization with probiotics helps to produce a balanced T helper cell response (Th1 = Th2 = Th3/Tr1) and prevent an imbalance (Th1 > Th2 or Th2 > Th1) contributing in part to clinical disease (Th2 imbalance contributes to atopic disease and Th1 imbalance contributes to Crohn's disease andHelicobacter pylori-induced gastritis). Furthermore, a series of pattern recognition receptors, toll-like receptors on gut lymphoid and epithelial cells that interact with bacterial molecular patterns (e.g. endotoxin (lipopolysaccharide), flagellin, etc.), help modulate intestinal innate immunity and an appropriate adaptive immune response. Animal and clinical studies have shown that inulin-type fructans will stimulate an increase in probiotics (commensal bacteria) and these bacteria have been shown to modulate the development and persistence of appropriate mucosal immune responses. However, additional studies are needed to show that prebiotics can directly or indirectly stimulate intestinal host defences. If this can be demonstrated, then prebiotics can be used as a dietary supplement to stimulate a balanced and an appropriately effective mucosal immune system in newborns and infants.
Intake and sources of phylloquinone (vitamin K1) in 4-year-old British children: comparison between 1950 and the 1990s
Authors: Prynne CJ , Thane CW , Prentice A , Wadsworth MEJ
Published: May 2005

Objective

To compare dietary intake and sources of phylloquinone (vitamin K1) in 4-year-old British children between 1950 and the 1990s, and report their variation by sociodemographic factors.

Design

Nationally representative samples of 4-year-olds from the longitudinal Medical Research Council National Survey of Health and Development (NSHD) (1950) and the cross-sectional National Diet and Nutrition Surveys (NDNS, 1992/93 and 1997).

Setting

Great Britain.

Subjects

Subjects were 4599 children born on 3–9 March 1946 (NSHD) and 307 children in the 1990s (NDNS).

Results

Geometric mean dietary phylloquinone intake was significantly higher in 1950 (39 μg day−1, 95% confidence interval (CI) 37, 40) compared with the 1990s (24 μg day−1, 95% CI 22, 25) (P< 0.001). This difference remained when intake was expressed per MJ energy intake and per kilogram body weight, and after accounting for sex, region and occupational social class of the family. In 1950, phylloquinone intake in Scotland was significantly lower than in the rest of Britain. By the 1990s these regional differences had disappeared. Food sources of phylloquinone intake changed significantly between 1950 and the 1990s, with fats and oils contributing more and vegetables less, although vegetables contributed most (60% and 48%, respectively) to phylloquinone intake in both surveys.

Conclusions

Phylloquinone intakes of children have decreased significantly since 1950. With the suggested need for adequate phylloquinone intake for optimal development and maintenance of bone and the cardiovascular system, the substantially lower phylloquinone intakes reported in children of the 1990s, compared with 1950, may have implications for the health of these two systems in later adulthood.
Constructing Colonial Dharma in Calcutta
Authors: Pennington Brian K.
Published: April 2005

This chapter examines a one year run of the Bengali paper Samācār Candrikā to sketch the contours of an elite Bengali Hindu response to missionaries and Orientalists. Among the very earliest Hindu newspapers to survive today, the Samācār Candrikā was published in Calcutta by Bhabānīcaran Bandyopādhyāya and associated with the orthodox Hindu organization the Dharma Sabhā. First formed to protest elements of colonialism, especially the government’s proposed ban on satī, the Dharma Sabhā produced a biweekly, vernacular newspaper in an effort to galvanize broad Hindu support among disparate castes and classes. In so doing, it proffered a version of a homogenous Hinduism with a centralized authority similar to that emerging among reforming organizations such as the Rammohan Roy’s Brahmo Samaj, but with an explicitly traditionalist, Brahmanical agenda. Exchanges with Christian missionaries conducted in the paper also make it an early surviving form of Hindu-Christian dialogue.
Transgenerational body size effects caused by early developmental stress in zebra finches
Authors: Naguib Marc , Gil Diego
Published: May 2005

The nutritional and social conditions that individuals experience during early development can have profound effects on their morphology, physiology, behaviour and life history. Experimental increases in brood size in birds can result in reduced offspring condition and survival, indicating that developmental deficits in enlarged broods have negative fitness consequences within the affected generation. To study long-term effects (i.e. transgenerational effects of developmental stress), we conducted a two-step breeding experiment in which we manipulated early developmental conditions in zebra finches
Taeniopygia guttata
. We raised zebra finches by manipulating brood sizes and controlled for maternal and genetic effects by cross-fostering. In a previous study, we showed that offspring condition and body size decreased with increasing brood size. Here we show that this effect was carried over to the next generation. Body size in nestlings and at nutritional independence was affected by the brood size in which the mothers were raised. Female offspring did significantly worse than male offspring when the mother had been raised in large broods, suggesting sex-specific influences of maternal effects. These findings directly link early developmental stress in females via maternal effects to the phenotype of the next generation.
Non-self-adjoint difference operators and their spectrum
Authors: Wilson Robert Howard
Published: May 2005

Initially, this paper is a discrete analogue of the work of Brown
et al.
(1999
Proc. R. Soc. A
455
, 1235–1257) on second-order differential equations with complex coefficients. That is, we investigate the general non-self-adjoint second-order difference expression

where the coefficients
p

n

and
q

n

are complex and Δ is the forward difference operator, i.e. Δ
x

n

=
x

n
+1

−
x

n

. Properties of the so-called Hellinger–Nevanlinna
m
-function for the recurrence relation
Mx

n

=
λ
w

n

x

n

, where the
w

n

are real and positive, are examined, and relationships between the properties of the
m
-function and the spectrum of the associated operator are explored. However, an essential difference between the continuous and the discrete case arises in the way in which we define the operator natural to the problem. Nevertheless, analogous results regarding the spectrum of this operator are obtained.
Wave energy and swimming performance shape coral reef fish assemblages
Authors: Fulton C.J , Bellwood D.R , Wainwright P.C
Published: May 2005

Physical factors often have an overriding influence on the distribution patterns of organisms, and can ultimately shape the long-term structure of communities. Although distribution patterns in sessile marine organisms have frequently been attributed to functional characteristics interacting with wave-induced water motion, similar evidence for mobile organisms is lacking. Links between fin morphology and swimming performance were examined in three diverse coral reef fish families from two major evolutionary lineages. Among-habitat variation in morphology and performance was directly compared with quantitative values of wave-induced water motion from seven coral reef habitats of different depth and wave exposure on the Great Barrier Reef. Fin morphology was strongly correlated with both field and experimental swimming speeds in all three families. The range of observed swimming speeds coincided closely with the magnitude of water velocities commonly found on coral reefs. Distribution patterns in all three families displayed highly congruent relationships between fin morphology and wave-induced water motion. Our findings indicate a general functional relationship between fin morphology and swimming performance in labriform-swimming fishes, and provide quantitative evidence that wave energy may directly influence the assemblage structure of coral reef fishes through interactions with morphology and swimming performance.
Transient feedback and global instability in non-homogeneous systems
Authors: Timoshin S.N , Linkins J.M
Published: May 2005

Model examples of linear wave systems are considered to illustrate the origin of feedback instability in situations involving strong transients. Two mechanisms of transient growth are addressed. The first is a spatial amplification of resonant waves propagating in the same direction. The second form of transient growth is purely temporal. It is found that under certain conditions, both forms of transients can trigger global instability in a non-homogeneous system.
Rings, bracelet or snaps: fashionable alternatives for Smc complexes
Authors: Huang Catherine E , Milutinovich Mark , Koshland Douglas
Published: May 2005

The mechanism of higher order chromosome organization has eluded researchers for over 100 years. A breakthrough occurred with the discovery of multi-subunit protein complexes that contain a core of two molecules from the structural maintenance of chromosome (Smc) family. Smc complexes are important structural components of chromosome organization in diverse aspects of DNA metabolism, including sister chromatid cohesion, condensation, global gene repression, DNA repair and homologous recombination. In these different processes, Smc complexes may facilitate chromosome organization by tethering together two parts of the same or different chromatin strands. The mechanism of tethering by Smc complexes remains to be elucidated, but a number of intriguing topological alternatives are suggested by the unusual structural features of Smc complexes, including their large coiled-coil domains and ATPase activities. Distinguishing between these possibilities will require innovative new approaches.
The role of heterochromatin in centromere function
Authors: Pidoux Alison L , Allshire Robin C
Published: May 2005

Chromatin at centromeres is distinct from the chromatin in which the remainder of the genome is assembled. Two features consistently distinguish centromeres: the presence of the histone H3 variant CENP-A and, in most organisms, the presence of heterochromatin. In fission yeast, domains of silent ‘heterochromatin’ flank the CENP-A chromatin domain that forms a platform upon which the kinetochore is assembled. Thus, fission yeast centromeres resemble their metazoan counterparts where the kinetochore is embedded in centromeric heterochromatin. The centromeric outer repeat chromatin is underacetylated on histones H3 and H4, and methylated on lysine 9 of histone H3, which provides a binding site for the chromodomain protein Swi6 (orthologue of Heterochromatin Protein 1, HP1). The remarkable demonstration that the assembly of repressive heterochromatin is dependent on the RNA interference machinery provokes many questions about the mechanisms of this process that may be tractable in fission yeast. Heterochromatin ensures that a high density of cohesin is recruited to centromeric regions, but it could have additional roles in centromere architecture and the prevention of merotely, and it might also act as a trigger for kinetochore assembly. In addition, we discuss an epigenetic model for ensuring that CENP-A is targeted and replenished at the kinetochore domain.
Basic mechanism of eukaryotic chromosome segregation
Authors: Yanagida Mitsuhiro
Published: May 2005

We now have firm evidence that the basic mechanism of chromosome segregation is similar among diverse eukaryotes as the same genes are employed. Even in prokaryotes, the very basic feature of chromosome segregation has similarities to that of eukaryotes. Many aspects of chromosome segregation are closely related to a cell cycle control that includes stage-specific protein modification and proteolysis. Destruction of mitotic cyclin and securin leads to mitotic exit and separase activation, respectively. Key players in chromosome segregation are SMC-containing cohesin and condensin, DNA topoisomerase II, APC/C ubiquitin ligase, securin–separase complex, aurora passengers, and kinetochore microtubule destabilizers or regulators. In addition, the formation of mitotic kinetochore and spindle apparatus is absolutely essential. The roles of principal players in basic chromosome segregation are discussed: most players have interphase as well as mitotic functions. A view on how the centromere/kinetochore is formed is described.
Mechanism and function of poleward flux in
Xenopus
extract meiotic spindles
Authors: Mitchison T.J
Published: May 2005

In
Xenopus
extract meiotic spindles, microtubules slide continuously towards their minus ends, a process called poleward flux. This article discusses recent progress in determining the mechanism of poleward flux, and its functions in spindle organization and generating force on chromosomes. Bipolar organization is required for flux and inhibition of the mitotic kinesin Eg5 inhibits flux, suggesting the sliding force for flux is generated by Eg5 pushing anti-parallel microtubules apart. An important function of flux in spindle organization may be to transport minus ends nucleated at chromatin towards the pole. By pulling microtubules through attachment sites at kinetochores, flux may generate poleward force on metaphase chromosomes.
PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints
Authors: Lu Xiongbin , Nannenga Bonnie , Donehower Lawrence A.
Published: May 2005

The ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) kinases respond to DNA damage by phosphorylating cellular target proteins that activate DNA repair pathways and cell cycle checkpoints in order to maintain genomic integrity. Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. These homeostatic functions may be partially responsible for the oncogenic effects of PPM1D when it is amplified and overexpressed in human tumors.