bluuebunny/crossref_metadata_2025 huggingface dataset:
The Alternative Oxidase: in vivo Regulation and Function
Authors: Millenaar F. F. , Lambers H.
Published: March 2003

Abstract: This review focuses on the biochemical regulation and function of the alternative oxidase in vivo. About 10 years ago, two activation mechanisms were discovered in isolated mitochondria, namely activation by reducing sulfur bonds in the protein and activation by an allosteric effect of pyruvate. It was proposed that plants would have a regulatory mechanism to modify alternative oxidase activity in vivo. However, more recent studies have shown that these two activation mechanisms may not play such an important role in regulation of alternative oxidase activity in vivo after all. Pyruvate and reduction of the sulfide bonds in the protein are definitely required for alternative oxidase activity, but they do not appear to be regulating the activity in vivo.

Despite the energy wasting nature of the alternative oxidase, there was no obvious physiological function for the pathway for many years. It is now more clear that the alternative oxidase can prevent the production of excess reactive oxygen species radicals by stabilizing the redox state of the mitochondrial ubiquinone pool, while allowing continued activity of the citric acid cycle. This may be important under conditions when the NADH supply is relatively high (reductant overflow), or when the cytochrome pathway is restrained. The cytochrome pathway might be inhibited by naturally occurring cyanide, nitric oxide, sulfide, high concentrations of CO2, low temperatures, or by limited phosphate supply.
Chiral tubule self-assembly from an achiral diynoic lipid
Authors: Pakhomov Serhii , Hammer Robert P. , Mishra Bijaya K. , Thomas Britt N.
Published: March 2003

Tubules possessing μm-scale chiral substructure self-assemble from an achiral isomer of the tubule-forming diynoic phosphatidylcholine, 1,2-bis(10,12-tricosadiynoyl)
sn
-glycero-3-phosphocholine [DC(8,9)PC], showing that molecular chirality is not essential for tubule formation. CD spectroscopy shows that these structures' helical sense of handedness instead originates in a spontaneous cooperative chiral symmetry-breaking process. We conclude that the chiral symmetry-breaking must originate in the unusual feature common to the chiral and achiral tubule-forming molecules, the diynes centered in their hydrocarbon tails.
Regulated subset of G
1
growth-control genes in response to derepression by the Wnt pathway
Authors: Baek Sung Hee , Kioussi Chrissa , Briata Paola , Wang Degeng , Nguyen H. D. , Ohgi Kenneth A. , Glass Christopher K. , Wynshaw-Boris Anthony , Rose David W. , Rosenfeld Michael G.
Published: March 2003

Pitx2 is a bicoid-related homeodomain factor that is required for effective cell type-specific proliferation directly activating a specific growth-regulating gene
cyclin D2
. Here, we report that Pitx2, in response to the Wnt/β-catenin pathway and growth signals, also can regulate c
-Myc
and
cyclin D1.
Investigation of molecular mechanisms required for Pitx2-dependent proliferation, in these cases, further supports a nuclear role for β-catenin in preventing the histone deacetylase 1-dependent inhibitory functions of several DNA-binding transcriptional repressors, potentially including E2F4/p130 pocket protein inhibitory complex, as well as lymphoid enhancer factor 1 and Pitx2, by dismissal of histone deacetylase 1 and loss of its enzymatic activity. Thus, β-catenin plays a signal-integrating role in Wnt- and growth factor-dependent proliferation events in mammalian development by both derepressing several classes of repressors and by activating Pitx2, regulating the activity of several growth control genes.
An affibody in complex with a target protein: Structure and coupled folding
Authors: Wahlberg Elisabet , Lendel Christofer , Helgstrand Magnus , Allard Peter , Dincbas-Renqvist Vildan , Hedqvist Anders , Berglund Helena , Nygren Per-Åke , Härd Torleif
Published: March 2003

Combinatorial protein engineering provides powerful means for functional selection of novel binding proteins. One class of engineered binding proteins, denoted affibodies, is based on the three-helix scaffold of the Z domain derived from staphylococcal protein A. The Z
SPA-1
affibody has been selected from a phage-displayed library as a binder to protein A. Z
SPA-1
also binds with micromolar affinity to its own ancestor, the Z domain. We have characterized the Z
SPA-1
affibody in its uncomplexed state and determined the solution structure of a Z:Z
SPA-1
protein–protein complex. Uncomplexed Z
SPA-1
behaves as an aggregation-prone molten globule, but folding occurs on binding, and the original (Z) three-helix bundle scaffold is fully formed in the complex. The structural basis for selection and strong binding is a large interaction interface with tight steric and polar/nonpolar complementarity that directly involves 10 of 13 mutated amino acid residues on Z
SPA-1
. We also note similarities in how the surface of the Z domain responds by induced fit to binding of Z
SPA-1
and Ig Fc, respectively, suggesting that the Z
SPA-1
affibody is capable of mimicking the morphology of the natural binding partner for the Z domain.
X-inactivation patch size in human female tissue confounds the assessment of tumor clonality
Authors: Novelli Marco , Cossu Antonio , Oukrif Dahmane , Quaglia Alberto , Lakhani Sunil , Poulsom Richard , Sasieni Peter , Carta Piera , Contini Marcella , Pasca Anna , Palmieri Giuseppe , Bodmer Walter , Tanda Francesco , Wright Nick
Published: March 2003

Most models of tumorigenesis assume that tumors are monoclonal in origin. This conclusion is based largely on studies using X chromosome-linked markers in females. One important factor, often ignored in such studies, is the distribution of X-inactivated cells in tissues. Because lyonization occurs early in development, many of the progeny of a single embryonic stem cell are grouped together in the adult, forming patches. As polyclonality can be demonstrated only at the borders of X-inactivation patches, the patch size is crucial in determining the chance of demonstrating polyclonality and hence the number of tumors that need to be examined to exclude polyclonality. Previously studies using X-linked genes such as glucose-6-phosphate dehydrogenase have been handicapped by the need to destroy the tissues to study the haplotypes of glucose-6-phosphate dehydrogenase [Fialkow, P.-J. (1976)
Biochim. Biophys. Acta
458, 283–321] or to determine the restriction fragment length polymorphisms of X chromosome-linked genes [Vogelstein, B., Fearon, E. R., Hamilton, S. R. & Feinberg, A. P. (1985)
Science
227, 642–645]. Here we visualize X-inactivation patches in human females directly. Results show that the patch size is relatively large in both the human colon and breast, confounding assessment of tumor clonality with traditional X-inactivation studies.
Altered properties of quantal neurotransmitter release at endplates of mice lacking P/Q-type Ca
2+
channels
Authors: Urbano Francisco J. , Piedras-Rentería Erika S. , Jun Kisun , Shin Hee-Sup , Uchitel Osvaldo D. , Tsien Richard W.
Published: March 2003

Transmission at the mouse neuromuscular junction normally relies on P/Q-type channels, but became jointly dependent on both N- and R-type Ca
2+
channels when the P/Q-type channel α
1A
subunit was deleted. R-type channels lay close to Ca
2+
sensors for exocytosis and I
K(Ca)
channel activation, like the P/Q-type channels they replaced. In contrast, N-type channels were less well localized, but abundant enough to influence secretion strongly, particularly when action potentials were prolonged. Our data suggested that active zone structures may select among multiple Ca
2+
channels in the hierarchy P/Q>R>N. The α
1A
−/− neuromuscular junction displayed several other differences from wild-type: lowered quantal content but greater ability to withstand reductions in the Ca
2+
/Mg
2+
ratio, and little or no paired-pulse facilitation, the latter findings possibly reflecting compensatory mechanisms at individual release sites. Changes in presynaptic function were also associated with a significant reduction in the size of postsynaptic acetylcholine receptor clusters.
Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction
Authors: Schmollinger Jan C. , Vonderheide Robert H. , Hoar Kara M. , Maecker Britta , Schultze Joachim L. , Hodi F. Stephen , Soiffer Robert J. , Jung Ken , Kuroda Marcelo J. , Letvin Norman L. , Greenfield Edward A. , Mihm Martin , Kutok Jeffery L. , Dranoff Glenn
Published: March 2003

The identification of antigens associated with tumor destruction is a major goal of cancer immunology. Vaccination with irradiated tumor cells engineered to secrete granulocyte–macrophage colony stimulating factor generates potent, specific, and long-lasting antitumor immunity through improved tumor antigen presentation by dendritic cells and macrophages. A phase I clinical trial of this immunization strategy in patients with disseminated melanoma revealed the consistent induction in distant metastases of dense T and B cell infiltrates that effectuated substantial tumor necrosis and fibrosis. To delineate the target antigens of this vaccine-stimulated tumor destruction, we screened a melanoma cDNA expression library with postimmunization sera from a long-term responding patient (K030). High-titer IgG antibodies recognized melanoma inhibitor of apoptosis protein (ML-IAP), a caspase antagonist containing a single baculoviral IAP repeat and a COOH-terminal RING domain. Although K030 harbored antibodies to ML-IAP at the time of study entry, multiple courses of vaccination over 4 years increased antibody titers and elicited isotype switching. Moreover, lymphocyte infiltrates in necrotic metastases included CD4+and CD8+T cells specific for ML-IAP, as revealed by proliferation, tetramer, enzyme-linked immunospot, and cytotoxicity analysis. Whereas melanoma cells in densely infiltrated lesions showed strong ML-IAP expression by immunohistochemistry, lethal disease progression was associated with the loss of ML-IAP staining and the absence of lymphocyte infiltrates. These findings demonstrate that ML-IAP can serve as a target for immune-mediated tumor destruction, but that antigen-loss variants can accomplish immune escape.
Discrimination of native protein structures using atom–atom contact scoring
Authors: McConkey Brendan J. , Sobolev Vladimir , Edelman Marvin
Published: March 2003

We introduce a method for discriminating correctly folded proteins from well designed decoy structures using atom–atom and atom–solvent contact surfaces. The measure used to quantify contact surfaces integrates the solvent accessible surface and interatomic contacts into one quantity, allowing solvent to be treated as an atom contact. A scoring function was derived from statistical contact preferences within known protein structures and validated by using established protein decoy sets, including the “Rosetta” decoys and data from the CASP4 structure predictions. The scoring function effectively distinguished native structures from all corresponding decoys in >90% of the cases, using isolated protein subunits as target structures. If contacts between subunits within quaternary structures are included, the accuracy increases to 97%. Interactions beyond atom–atom contact range were not required to distinguish native structures from the decoys using this method. The contact scoring performed as well or better than existing statistical and physicochemical potentials and may be applied as an independent means of evaluating putative structural models.
Displacement of the tyrosyl radical cofactor in ribonucleotide reductase obtained by single-crystal high-field EPR and 1.4-Å x-ray data
Authors: Högbom Martin , Galander Marcus , Andersson Martin , Kolberg Matthias , Hofbauer Wulf , Lassmann Günter , Nordlund Pär , Lendzian Friedhelm
Published: March 2003

The R2 protein of class I ribonucleotide reductase generates and stores a tyrosyl radical essential for ribonucleotide reduction and, thus, DNA synthesis. X-ray structures of the protein have enabled detailed mechanistic suggestions, but no structural information has been available for the active radical-containing state of the protein. Here we report on methods to generate the functional tyrosyl radical in single crystals of R2 from
Escherichia coli
(Y122
•
). We further report on subsequent high-field EPR experiments on the radical-containing crystals. A full rotational pattern of the spectra was collected and the orientation of the g-tensor axes were determined, which directly reflect the orientation of the radical in the crystal frame. The EPR data are discussed in comparison with a 1.42-Å x-ray structure of the met (oxidized) form of the protein, also presented in this paper. Comparison of the orientation of the radical Y122
•
obtained from high-field EPR with that of the reduced tyrosine Y122-OH reveals a significant rotation of the tyrosyl side chain, away from the diiron center, in the active radical state. Implications for the radical transfer connecting the diiron site in R2 with the substrate-binding site in R1 are discussed. In addition, the present study demonstrates that structural and functional information about active radical states can be obtained by combined x-ray and high-field EPR crystallography.
Persistence and brain circuitry
Authors: Gusnard Debra A. , Ollinger John M. , Shulman Gordon L. , Cloninger C. Robert , Price Joseph L. , Van Essen David C. , Raichle Marcus E.
Published: March 2003

The orbitofrontal and adjacent medial prefrontal cortex may play an important role in normal social functioning and affect modulation. Recent anatomical studies of this area of the prefrontal cortex have demonstrated a striking correspondence of fine-grained architectonic partitioning schemes in humans and nonhuman primates. This finding allows neurophysiological recording and anatomical connectivity data in animals to be considered together with functional imaging data and lesion studies in humans. In a functional MRI study, we show that individual differences in Persistence, a dimensional trait assessed with a seven-factor personality model, may be linked to specific areas in the lateral orbital and medial prefrontal cortex and the ventral striatum. These areas are part of an anatomical circuit that has been defined in nonhuman primates and has been implicated in functions related to behavioral persistence. These findings represent a fresh approach to linking normal individual differences in personality and behavior to specific neuronal structures and subsystems.
The CD8+cell noncytotoxic anti-HIV response can be blocked by protease inhibitors
Authors: Mackewicz Carl E. , Craik Charles S. , Levy Jay A.
Published: March 2003

CD8+cells from healthy HIV-infected individuals can suppress HIV replication in infected CD4+cells without killing the cells. This CD8+cell noncytotoxic antiviral response (CNAR), observed by coculture of CD8+cells with infected CD4+cells, is associated with secretion of a CD8+cell antiviral factor (CAF). In attempts to identify CAF, we discovered that certain protease inhibitors, particularly leupeptin, can block, by up to 95%, the anti-HIV activity in CD8+cell culture fluids as well as inhibit CNAR. The effect is dose-dependent and is observed in up to 70% of the CAF and CNAR assays by using fluids and cells from several different subjects. Pretreatment of CD8+cells with leupeptin reduces CNAR, further supporting an inhibitory effect on a CD8+cell product. This inhibitory activity of protease inhibitors does not affect cell growth, expression of activation antigens, or viability of either CD8+cells or the infected CD4+cells. The results suggest that a part of the CD8+cell noncytotoxic response involves the activity of a protease or a protein that interacts with protease inhibitors. Proteolysis of a CD8+cell product(s) may be involved. This observation offers a promising approach for identifying the mechanism of CNAR/CAF activity.
A high-throughput gene expression analysis technique using competitive PCR and matrix-assisted laser desorption ionization time-of-flight MS
Authors: Ding Chunming , Cantor Charles R.
Published: March 2003

We report here an approach for gene expression analysis by combining competitive PCR and matrix-assisted laser desorption ionization time-of-flight MS. A DNA standard is designed with an artificial single nucleotide polymorphism in the gene of interest. The standard is added to the reverse transcription product before PCR. Subsequently, a base extension reaction is carried out at the single nucleotide polymorphism position, and the products are quantified by matrix-assisted laser desorption ionization time-of-flight MS. The approach is capable of relative and absolute quantification of gene expression; it is extremely sensitive (as few as five copies of DNA were quantified) and highly reproducible. It is also capable of simultaneous quantification of both alleles for heterozygotes and alternatively spliced genes. We have incorporated this technique with the homogeneous Mass Extension system (Sequenom) to create a high-throughput, automated gene expression analysis platform where a few hundred genes from 20–500 different samples can be accurately quantified per day.
Discrete two-terminal single nanocluster quantum optoelectronic logic operations at room temperature
Authors: Lee Tae-Hee , Dickson Robert M.
Published: March 2003

Readily formed at nanoscale break junctions, arrays of individual spatially isolated, strongly electroluminescent Ag
2
–Ag
8
nanoclusters perform complex logic operations within individual two-terminal nanoscale optoelectronics devices. Simultaneous electrical excitation of discrete room-temperature nanocluster energy levels directly yields AND, OR, NOT, XOR, and even full addition logic operations with either individual nanoclusters or nanocluster pairs as the active medium between only two electrodes. Imaged in parallel, noncontact electroluminescent readout obviates the need for electrically isolating individual features. This gated, pulsed, two-terminal device operation will likely drive future nano and molecular electronics advances without complicated nanofabrication.
Kinetics of size changes of individual
Bacillus thuringiensis
spores in response to changes in relative humidity
Authors: Westphal Andrew J. , Price P. Buford , Leighton Terrance J. , Wheeler Katherine E.
Published: March 2003

Using an automated scanning microscope, we report the surprising result that individual dormant spores of
Bacillus thuringiensis
grow and shrink in response to increasing and decreasing relative humidity. We simultaneously monitored the size of inorganic calibration particles. We found that the spores consistently swell in response to increased relative humidity, and shrink to near their original size on reexposure to dry air. Although the dispersion of swelling amplitudes within an ensemble of spores is wide (≈30% of the average amplitude), amplitudes for individual spores are highly correlated between different swelling episodes, suggesting that individual spores respond consistently to changes in humidity. We find evidence for two distinct time scales for swelling: one with a time scale of no more than ≈50 s, and another with a time scale of ≈8 min. We speculate that these two mechanisms may be due to rapid diffusion of water into the spore coat + cortex, followed by slower diffusion of water into the spore core, respectively. Humidity-dependent swelling may account for the greater kill effectiveness of spores by gas-phase chlorine dioxide, formaldehyde, and ethylene oxide at very high relative humidity.
Is the olfactory receptor a metalloprotein?
Authors: Wang Jiangyun , Luthey-Schulten Zaida A. , Suslick Kenneth S.
Published: March 2003

The sense of smell is arguably our most primal faculty and also the least understood. Even our own olfactorily impaired species is capable of detecting ≈10,000 distinct scents [Buck, L. & Axel, R. (1991)Cell65, 175–187]. To achieve that amazing diversity, mammals have ≈1,000 olfactory genes, which accounts for ≈3% of their entire genome [Mombaerts, P. (1999)Science286, 707–711]. The olfactory receptors (ORs) are believed to be seven-helix transmembrane proteins, with an odorant-binding site on the periplasmic domain and a G protein-binding site on the cytoplasmic domain. Odorants first bind to an OR, which then undergoes some structural change that triggers the G protein activation and the following cascade of events leading to nerve cell activity. The structural details of ORs, however, remain to be determined. In this paper, we will describe a hypothesis in which metal ions play an important role for odorant recognition. We analyze the predicted structure and consensus sequence of the ORs and propose a metal-binding site in the loop between fourth and fifth helix (4–5 loop). We have prepared synthetically a pentapeptide that contains this putative binding site and find that it not only has high affinity for binding Cu(II) and Zn(II) ions, but that it also undergoes a dramatic transition to an α-helical structure upon metal ion binding. Based on these observations, we propose a “shuttlecock” mechanism for the possible structural change in ORs upon odorant binding. This mechanism involves membrane penetration of the 4–5 loop after residue charge neutralization by metal ion binding.
An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node
Authors: Maier Sebastian K. G. , Westenbroek Ruth E. , Yamanushi T. T. , Dobrzynski H. , Boyett Mark R. , Catterall William A. , Scheuer Todd
Published: March 2003

Voltage-gated Na
+
channels are composed of pore-forming α and auxiliary β subunits. The majority of Na
+
channels in the heart contain tetrodotoxin (TTX)-insensitive Na
v
1.5 α subunits, but TTX-sensitive brain-type Na
+
channel α subunits are present and functionally important in the transverse tubules of ventricular myocytes. Sinoatrial (SA) nodal cells were identified in cardiac tissue sections by staining for connexin 43 (which is expressed in atrial tissue but not in SA node), and Na
+
channel localization was analyzed by immunocytochemical staining with subtype-specific antibodies and confocal microscopy. Brain-type TTX-sensitive Na
v
1.1 and Na
v
1.3 α subunits and all four β subunits were present in mouse SA node, but Na
v
1.5 α subunits were not. Na
v
1.1 α subunits were also present in rat SA node. Isolated mouse hearts were retrogradely perfused in a Langendorff preparation, and electrocardiograms were recorded. Spontaneous heart rate and cycle length were constant, and heart rate variability was small under control conditions. In contrast, in the presence of 100 nM TTX to block TTX-sensitive Na
+
channels specifically, we observed a significant reduction in spontaneous heart rate and markedly greater heart rate variability, similar to sick-sinus syndrome in man. We hypothesize that brain-type Na
+
channels are required because their more positive voltage dependence of inactivation allows them to function at the depolarized membrane potential of SA nodal cells. Our results demonstrate an important contribution of TTX-sensitive brain-type Na
+
channels to SA nodal automaticity in mouse heart and suggest that they may also contribute to SA nodal function and dysfunction in human heart.
Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence
Authors: Krones-Herzig Anja , Adamson Eileen , Mercola Dan
Published: March 2003

The proliferation of most primary cells in culture is limited by replicative senescence and crisis, p53-dependent events. However, the regulation of p53 itself has not been defined. We find that deletion of the early growth response 1 (EGR1) transcription factor leads to a striking phenotype, including complete bypass of senescence and apparent immortal growth consistent with loss of a suppressor gene. EGR1-null mouse embryo fibroblasts (MEFs) exhibit decreased expression of p53, p21
Cip1/Waf1
, and other p53 “marker” proteins. Precrisis WT but not EGR1-null cells exhibit irradiation-induced arrest. WT MEFs that emerge from crisis exhibit a mutated p53 (sequence confirmed), colony formation, and tumorigenicity. In contrast, high-passage EGR1-null MEFs retain the WT p53 sequence but with much reduced expression, remain untransformed, and grow continuously. An EGR1-expressing retrovirus restores p53 expression and sencescence to EGR1-null but not p53-null MEFs or postcrisis WT cells. Taken together, the results establish EGR1 as a major regulator of cell senescence and previously undescribed upstream “gatekeeper” of the p53 tumor suppressor pathway.
Complete Nucleotide Sequence of the Coturnix chinensis (Blue-Breasted Quail) Mitochondorial Genome and a Phylogenetic Analysis With Related Species
Authors: Nishibori M. , Tsudzuki M. , Hayashi T. , Yamamoto Y. , Yasue H.
Published: March 2003

Coturnix chinensis (blue-breasted quail) has been classically grouped in Galliformes Phasianidae Coturnix, based on morphologic features and biochemical evidence. Since the blue-breasted quail has the smallest body size among the species of Galliformes, in addition to a short generation time and an excellent reproductive performance, it is a possible model fowl for breeding and physiological studies of the Coturnix japonica (Japanese quail) and Gallus gallus domesticus (chicken), which are classified in the same family as blue-breasted quail. However, since its phylogenetic position in the family Phasianidae has not been determined conclusively, the sequence of the entire blue-breasted quail mitochondria (mt) genome was obtained to provide genetic information for phylogenetic analysis in the present study. The blue-breasted quail mtDNA was found to be a circular DNA of 16,687 base pairs (bp) with the same genomic structure as the mtDNAs of Japanese quail and chicken, though it is smaller than Japanese quail and chicken mtDNAs by 10 bp and 88 bp, respectively. The sequence identity of all mitochondrial genes, including those for 12S and 16S ribosomal RNAs, between blue-breasted quail and Japanese quail ranged from 84.5% to 93.5%; between blue-breasted quail and chicken, sequence identity ranged from 78.0% to 89.6%. In order to obtain information on the phylogenetic position of blue-breasted quail in Galliformes Phasianidae, the 2,184 bp sequence comprising NADH dehydrogenase subunit 2 and cytochrome b genes available for eight species in Galliformes [Japanese quail, chicken, Gallus varius (green junglefowl), Bambusicola thoracica (Chinese bamboo partridge), Pavo cristatus (Indian peafowl), Perdix perdix (gray partridge), Phasianus colchicus (ring-neck pheasant), and Tympanchus phasianellus (sharp-tailed grouse)] together with that of Aythya americana (redhead) were examined using a maximum likelihood (ML) method. The ML analyses on the first/second codon positions, the third codon positions, and amino acid sequence consistently demonstrated that blue-breasted quail and Japanese quail are in the same phylogenetic cluster.
A navigation system for wheelchairs
Authors: Kusuda Yoshihiro
Published: March 2003

A Tokyo based video and image processing equipment manufacturer, For‐A Ltd has been developing a new navigation system for wheelchairs. The new system not only provides navigation information to wheelchair users via cellular phone network but also receives “barrier‐free” information from wheelchairs to automatically create and update the “barrier‐free” map resident in the central computer. Prototypes have been developed and have undergone field‐test to prove their usefulness in the real world. Commercial models will become available next year after successful introduction to a new town project nearby Tokyo International Airport. In the future, this approach would also be useful for automatic navigation for mobile robots such as “seeing‐eye dog” robots, guide robots etc.
SETS OF PERIODS FOR PIECEWISE MONOTONE TREE MAPS
Authors: ALSEDÀ LL. , JUHER D. , MUMBRÚ P.
Published: March 2003

We study the set of periods of tree maps f : T → T which are monotone between any two consecutive points of a fixed periodic orbit P. This set is characterized in terms of some integers which depend only on the combinatorics of f|P and the topological structure of T. In particular, a typep ≥ 1 of P is defined as a generalization of the notion introduced by Baldwin in his characterization of the set of periods of star maps. It follows that there exists a divisor k of the period of P such that if the set of periods of f is not finite then it contains either all the multiples of kp or an initial segment of the kp≥ Baldwin's ordering, except for a finite set which is explicitly bounded. Conversely, examples are given where f has precisely these sets of periods.
CONTROLLING CHAOTIC SYSTEMS VIA PHASE SPACE RECONSTRUCTION TECHNIQUE
Authors: CAO Y. J. , ZHANG P. X. , CHENG S. J.
Published: March 2003

A novel approach to control chaotic systems has been developed. The approach employs the technique of phase space reconstruction in nonlinear dynamical systems theory to construct a linear part in the reconstructed system and design a feedback control law. The effectiveness of the proposed approach has been demonstrated through its applications to two well-known chaotic systems: Lorenz chaos and Rössler chaos.
ON STABILIZING N-DIMENSIONAL CHAOTIC SYSTEMS
Authors: LAVAL LAURENT , M'SIRDI NACER K.
Published: March 2003

This paper deals with the control of a class of n-dimensional chaotic systems. The proposed method consists in a Variable Structure Control approach based on system energy consideration for both controller design and system stabilization. First, we present some theoretical results related to the stabilization of global invariant sets included in a selected two-dimensional subspace of the state space. Then, we define some conditions, involving both system definition and control law design, under which the stabilized orbits can be maintained in a neighborhood of an invariant, nondegenerate, closed conic section (i.e. an ellipse or a circle). Finally, an example related to the chaotic circuit of Chua is given.
PATTERN DYNAMICS IN A NONLINEAR ELECTRICAL LATTICE
Authors: BINCZAK S. , BILBAULT J. M. , MARQUIÉ P.
Published: March 2003

In this paper, we present experiments using a nonlinear electrical line, modeling the FitzHugh–Nagumo equation, without recovery term. Different patterns are studied according to the parameters of this medium and initial conditions. We then propose to apply these results to the domain of signal processing. We show that erosion and dilation of a binary signal, two kinds of binarization — one depending on an amplitude threshold, the other on an energetical threshold — and nonlinear filtering allowing noise removal can be obtained in the same medium.
ON USING REMOTE USER DEFINED FUNCTIONS AS WRAPPERS FOR BIOLOGICAL DATABASE INTEROPERABILITY
Authors: CHEN LIANGYOU , JAMIL HASAN M.
Published: March 2003

Similar to most scientific studies, biological analyses demand a great deal of computations and simulations involving sophisticated tools that are often found geographically distributed over the Internet. A worldwide effort in genomics research has resulted in a powerful collection of publicly available sequence analysis tools. These tools often require specialized local services and domain knowledge to function correctly, rendering them unlikely candidates for integration into remote database applications. Thus, integration of heterogeneous "functions" still remains an open problem. Providing a reasonable framework for seamless integration of these tools with database query engines will enable application developers to exploit and harness the power of these effective analysis tools. In this paper, we present an integration framework for such tools by enabling access to them in a user transparent way as part of database queries. In our system, such online tools are abstracted as remote user defined functions (RUDF). An extended SQL DDL language, called the Internet Function Definition Language (IFDL), is presented for the specification and definition of RUDFs. The interface between database system and the Internet is implemented using a layer based on a language called the Hyper Text Query Language (HTQL). The separation of IFDL, DDL, HTQL and SQL DML offers several optimization opportunities and makes it possible to develop an architecture for interoperability of heterogeneous databases with RUDFs in more simple and efficient ways.
A CASE STUDY: DEVELOPMENT OF AN ORGANISM–SPECIFIC PROTEIN INTERACTION DATABASE AND ITS ASSOCIATED TOOLS
Authors: HWANG DOOSUNG , FOTOUHI FARSHAD , SON YOUNGJU
Published: March 2003

In this paper, we describe the architecture of a protein interaction database and tools for manipulating Drosophila protein interaction data. The proposed system not only maintains interaction data collected by an experiment, but also associates the interaction data with valuable data from various genomic databases. The system inherits a layered-modular architecture by introducing a wrapper-mediator approach in order to solve the syntactic and semantic heterogeneity among multiple data sources. The component modules for wrapping and integrating the relevant data, querying the database, and visualizing the interaction data among proteins are discussed. The system wrapped the relevant data for 14,000 Drosophila proteins from 5 publicly accessible sources. A web-based query interface is developed to browse the database and a query result can be viewed as in a protein interaction map depicting functional pathways, complexes or networks. Protein interaction maps aid in understanding or predicting potential functions for uncharacterized proteins and in describing their functional networks in a biological context. We show that the proposed approach supports data association and data interoperability in a protein interaction database.
A QUANTUM-CLASSICAL APPROACH TO MOLECULAR DYNAMICS
Authors: BILLING G. D.
Published: March 2003

We present a new method for treating the dynamics of molecular systems. The method has been named "quantum dressed" classical mechanics and is based on an expansion of the wave function in a time-dependent basis-set, the Gauss–Hermite basis-set. From here it is possible to proceed in two ways, one is in principle exact and the other approximate. In the exact approach one constructs a discrete variable representation (DVR) in which the grid points are defined by the Hermite part of the Gauss–Hermite basis set. In the approximate method a second order expansion of the potential around the classical trajectories is introduced and the quantum dymamics solved in a second quantization rather than a wave-function representation.
USING WAVELETS TO EXTEND QUANTUM DYNAMICS CALCULATIONS TO TEN OR MORE DEGREES OF FREEDOM
Authors: POIRIER BILL
Published: March 2003

A customizable, orthonormal basis for solving the multidimensional Schrödinger equation is constructed using modified Wilson–Daubechies wavelets, and a simple phase space truncation scheme. Unprecedented numerical efficiency is achieved, enabling a ten-dimensional direct calculation of nearly 600 eigenvalues to be performed. Higher dimensionalities are possible using more sophisticated linear algebra techniques. The new approach is ideally suited to rovibrational spectroscopy applications, but can be used in any context where elliptic partial differential equations are involved.
Integrin α
IIb
β
3
and Its Antagonism
Authors: Quinn Martin J. , Byzova Tatiana V. , Qin Jun , Topol Eric J. , Plow Edward F.
Published: March 2003

α
IIb
β
3
, the major membrane protein on the surface of platelets, is a member of the integrin family of heterodimeric adhesion receptors. The α
IIb
and β
3
subunits are each composed of a short cytoplasmic tail, a single transmembrane domain, and a large, extracellular region that consists of a series of linked domains. Recent structural analyses have provided insights into the organization of this and other integrins and how a signal is initiated at its cytoplasmic tail to transform the extracellular domain of α
IIb
β
3
into a functional receptor for fibrinogen or von Willebrand factor to support platelet aggregation and thrombus formation. These functions of α
IIb
β
3
have been targeted for antithrombotic therapy, and intravenous α
IIb
β
3
antagonists have been remarkably effective in the setting of percutaneous coronary interventions, showing both short-term and long-term mortality benefits. However, the development of oral antagonists has been abandoned on the basis of excess of mortality in clinical trials, and the extension of therapy with existing α
IIb
β
3
antagonists to broadly treat acute coronary syndromes has not fully met expectations. An in-depth understanding of how antagonists engage and influence the function of α
IIb
β
3
and platelets in the context of the new structural insights may explain its salutary and potential deleterious effects.
Raised Sympathetic Nerve Activity in Heart Failure and Central Sleep Apnea Is Due to Heart Failure Severity
Authors: Mansfield Darren , Kaye David M. , Brunner La Rocca Hanspeter , Solin Peter , Esler Murray D. , Naughton Matthew T.
Published: March 2003

Background—

Congestive heart failure (CHF) patients with central sleep apnea (CHF-CSA) have elevated plasma norepinephrine (NE) compared with CHF patients without apnea (CHF-N). Patients with CHF-CSA also demonstrate higher mean pulmonary artery pressure (PAP), which is suggestive of worse cardiac function. Whether CSA contributes to chronic elevation of sympathetic nerve activity or is associated with more severe CHF remains unknown. We measured awake total body and cardiac NE spillover and related these to measurements of cardiac hemodynamics and apnea severity in CHF patients with CSA, with normal breathing, and with obstructive sleep apnea (CHF-OSA).

Methods and Results—

A total of 55 CHF patients underwent right heart catheterization and measurements of total body and cardiac NE spillover using NE radioisotope dilution methodology. After polysomnography, patients were grouped by apnea type: 19 were CHF-N, 15 were CHF-OSA, and 21 were CHF-CSA. Compared with the CHF-N and CHF-OSA groups, the CHF-CSA group had significantly higher total body NE spillover (4.62±0.56 versus 4.47±0.54 versus 6.95±0.89 nmol/min, respectively;
P
=0.03), cardiac NE spillover (0.25±0.05 versus 0.21±0.05 versus 0.42±0.06 nmol/min, respectively;
P
=0.02) and mean PAP (23.5±2.4 versus 21.2±0.8 versus 30.4±0.2 mm Hg, respectively;
P
<0.02). However, controlling for severity of CHF resulted in no significant differences in NE kinetics among the 3 groups. In a stepwise regression, only mean PAP independently correlated with total body (
r
=0.33,
P
=0.03) and cardiac NE spillover (
r
=0.44,
P
=0.002). Sleep apnea severity bore no relationship to markers of sympathetic nerve activity.

Conclusion—

Total body and cardiac sympathetic nerve activity are elevated in CHF-CSA compared with CHF-OSA and CHF-N patients and are related to heart failure not apnea severity.
Stem cell factor protects erythroid precursor cells from chemotherapeutic agents via up-regulation of BCL-2 family proteins
Authors: Zeuner Ann , Pedini Francesca , Signore Michele , Testa Ugo , Pelosi Elvira , Peschle Cesare , De Maria Ruggero
Published: March 2003

Suppression of red blood cell production is a common complication of chemotherapy, causing anemia in a significant number of cancer patients. We have evaluated the sensitivity of human hematopoietic progenitors and erythroid precursor cells to chemotherapeutic drugs and found that probasophilic erythroblasts represent the stage of erythroid differentiation more vulnerable to the cytotoxic effects of myelosuppressive agents. Stem cell factor (SCF) supports proliferation and survival of early hematopoietic cells by binding to the c-kit receptor. In unilineage erythropoietic culture of CD34 + progenitors, short-term pretreatment of immature erythroid precursors with SCF results in protection from apoptosis induced by chemotherapeutic agents and restores normal proliferation and differentiation after removal of the cytotoxic stimulus. The levels of drug-induced caspase processing are significantly reduced in erythroblasts treated with SCF, indicating that activation of the c-kit receptor generates antiapoptotic signals acting before amplification of the caspase cascade. Accordingly, we found that SCF up-regulates Bcl-2 and Bcl-X L in erythroid precursors and that exogenous expression of these proteins protects erythroblasts from caspase activation and death induced by chemotherapeutic agents. These results suggest a possible mechanism for SCF-mediated protection of erythroid precursor cells from apoptosis and may contribute to devise new strategies for prevention and treatment of chemotherapy-induced anemia. (Blood. 2003; 102:87-93)
IL-4 synergistically enhances both IL-2– and IL-12–induced IFN-γ expression in murine NK cells
Authors: Bream Jay H. , Curiel Rafael E. , Yu Cheng-Rong , Egwuagu Charles E. , Grusby Michael J. , Aune Thomas M. , Young Howard A.
Published: March 2003

Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)–type cytokines like interferon-γ (IFN-γ). While investigating IL-4 regulation of IFN-γ expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN-γ production and mRNA expression in spleen-derived, IL-2–cultured NK cells, as well as negatively sorted fresh DX5+/CD3- NK cells albeit at lower levels. The positive effect of IL-4 on IL-2–induced IFN-γ production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6-/- mice. Notably, though, IL-12 plus IL-4 synergy on IFN-γ expression was intact in Stat6-/- mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN-γ promoter that may be involved, NK cells from human IFN-γ promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN-γ promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN-γ expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations. (Blood. 2003;102:207-214)
Expression of the candidate MCT-1 oncogene in B- and T-cell lymphoid malignancies
Authors: Shi Bo , Hsu Hsin-Ling , Evens Andy M. , Gordon Leo I. , Gartenhaus Ronald B.
Published: March 2003

Our laboratory has recently discovered a novel candidate oncogene, MCT-1, amplified in human T-cell lymphoma and mapped to chromosome Xq22-24. This region is amplified in a subset of primary B-cell non-Hodgkin lymphoma (NHL), suggesting that increased copy number of a gene(s) located in this region confers a growth advantage to some primary human lymphomas. We examined a diverse panel of lymphoid malignancies for the expression of MCT-1. We demonstrated that there are significantly increased levels of MCT-1 protein in a panel of T-cell lymphoid cell lines and in non-Hodgkin lymphoma cell lines. Furthermore, we identified a subset of primary diffuse large B-cell lymphomas that exhibited elevated levels of MCT-1 protein. Interestingly, all transformed follicular lymphomas in our study demonstrated elevated protein levels of MCT-1. There was no detectable MCT-1 protein in leukemic cells from patients with chronic lymphocytic leukemia or in any healthy lymphoid tissue examined. Lymphoid cell lines overexpressing MCT-1 exhibited increased growth rates and displayed increased protection against apoptosis induced by serum starvation when compared with matched controls. We found that MCT-1—overexpressing cells show constitutively higher levels of phosphorylated PKB/Akt protein, especially under serum starvation. Activation of survival pathways may be an additional function of the MCT-1 gene. Our data suggest that high levels of MCT-1 protein may be associated with a high-risk subset of lymphoid neoplasms and may further support the potential role of MCT-1 in promoting human lymphoid tumor development. (Blood. 2003;102: 297-302)
ADAMTS13 activity in thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients
Authors: Vesely Sara K. , George James N. , Lämmle Bernhard , Studt Jan-Dirk , Alberio Lorenzo , El-Harake Mayez A. , Raskob Gary E.
Published: March 2003

Initial management of patients with thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTP-HUS) is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. Although severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency may be specific for TTP, the role of ADAMTS13 activity measurements for initial management decisions is unknown. ADAMTS13 was measured before beginning plasma exchange treatment in 142 (88%) of 161 consecutive patients with clinically diagnosed TTP-HUS with assignment to 1 of 4 categories: less than 5% (severe deficiency), 5% to 9%, 10% to 25%, and more than 25%. Eighteen (13%) of 142 patients had severe ADAMTS13 deficiency. Among 6 predefined clinical categories (stem cell transplantation, pregnant/postpartum, drug association, bloody diarrhea, additional/alternative disorder, idiopathic), severe deficiency occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. The presenting features and clinical outcomes of the 16 patients with idiopathic TTP-HUS who had severe ADAMTS13 deficiency were variable and not distinct from the 32 patients with idiopathic TTPHUS who did not have severe ADAMTS13 deficiency. Many patients in all ADAMTS13 activity categories apparently responded to plasma exchange treatment. Therefore, severe ADAMTS13 deficiency does not detect all patients who may be appropriately diagnosed with TTP-HUS and who may respond to plasma exchange treatment. (Blood. 2003;102:60-68)