bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress, Protein (Mis)folding, and Signaling: The Redox Connection
Authors: Sitia Roberto , Molteni Silvia Nerini
Published: September 2004

Correct folding is essential to protein function, which has led to the evolution of sophisticated chaperone systems. Protein folding occurs primarily in the cytoplasm and in the endoplasmic reticulum (ER). The differing redox and ionic milieus inside these two compartments, and the different functions and destinations of the client proteins folded therein, have necessitated the existence of distinct chaperone networks. Both networks exploit the exquisite sensitivity of cysteines to redox state, but they respond in opposite directions, reflecting the different conditions in the cytosol (reducing) and in the ER (more oxidizing). Thus, the cytosolic chaperone Hsp33 forms active dimers in response to oxidation, linking the responses to thermal and oxidative stress, and allows the cell to "remember" the experience: Folded proteins are released upon Hsp33 reduction, whereas unfolded substrates are released only in the presence of additional chaperone complexes that are able to refold them. In contrast, the ER oxidoreductase protein disulphide isomerase (PDI) appears to function as a chaperone primarily when reduced. Owing to the reactivity of their thiol groups, cysteines provide molecular switches that can be used to control the folding and to reversibly modify the structure and function of a protein. Cysteine oxidation provides as versatile a system as protein phosphorylation for the modification of specific substrates and the propagation of signaling cascades. Moreover, it offers the important advantage that cysteines can undergo different modifications, thus providing a molecular code that rapidly reports and responds to redox changes in the environment.
The Domains of Apoptosis: A Genomics Perspective
Authors: Reed John C. , Doctor Kutbuddin S. , Godzik Adam
Published: September 2004

Apoptosis plays important roles in many facets of normal physiology in animal species, including programmed cell death associated with fetal development or metamorphosis, tissue homeostasis, immune cell education, and some aspects of aging. Defects in the regulation of apoptosis contribute to multiple diseases associated with either inappropriate cell loss or pathological cell accumulation. Host-pathogen interactions have additionally provided evolutionary pressure for apoptosis as a defense mechanism against viruses and microbes, sometimes linking apoptosis mechanisms with inflammatory responses. To a large extent, the apoptosis machinery can be viewed as a network, with different nodes connected by physical interactions of evolutionarily conserved domains. These domains can serve as signatures for identification of proteins involved in the network. In particular, the caspase recruitment domains (CARDs); death effector domains (DEDs); death domains (DDs); BIR (baculovirus IAP repeat) domains of inhibitor of apoptosis proteins (IAPs); Bcl-2 family proteins; caspase protease domains; and endonuclease-associated CIDE (cell death–inducing DFF45-like effector) domains are found in common in proteins involved in apoptosis. In the genomes of mammals, genes encoding proteins that carry one or more of these signature domains are often present in multiple copies, making up diverse gene families that permit tissue-specific and highly regulated control of cell life and death decisions through combinations of stimulus-specific gene expression and complex protein interaction networks. In this Review, we organize the repertoire of apoptosis proteins of humans into domain families, drawing comparisons with homologs in other vertebrate and invertebrate animal species, and discuss some of the functional implications of these findings.
Empowering Targeted Therapy: Lessons from Rituximab
Authors: Olszewski Adam J. , Grossbard Michael L.
Published: September 2004

Rituximab, a monoclonal antibody directed against the B cell–specific protein CD20, has revolutionized lymphoma treatment by providing a highly effective form of therapy with relatively mild toxic side effects. Effective as a single agent against some forms of B cell lymphoma, rituximab also has a chemosensitizing effect, enhancing the efficacy of chemotherapy against other forms of the disease. Although the mechanisms whereby rituximab achieves its effects remain incompletely understood, these seem to involve at least three distinct phenomena: (i) antibody-dependent cell-mediated cytotoxicity, (ii) complement-mediated cell lysis, and (iii) stimulation of apoptosis in target cells. The latter occurs through interaction of complexes of rituximab and CD20 in lipid rafts, with elements of a signaling pathway involving Src kinases. Effector molecules trigger various gene expression events, leading to sensitization of malignant cells to proapoptotic stimuli. Lessons learned from the research on rituximab may be applied to the rational development of antibody-based therapies against other forms of cancer.
Conformational Coupling: A Physiological Calcium Entry Mechanism
Authors: Berridge Michael
Published: September 2004

The entry of external Ca
2+
that is activated by inositol 1,4,5-trisphosphate (IP
3
)

may occur through a conformation coupling mechanism. IP
3
receptors in the endoplasmic reticulum located in a junctional zone make contact with entry channels in the plasma membrane. IP
3
may act directly to stimulate this coupling complex or IP
3
could act indirectly by stimulating uncoupled IP
3
Rs in the vicinity of the junctional zone to induce a localized depletion of the ER store to switch on a store-operated mechanism. At physiological agonist concentrations, the earliest Ca
2+
response to receptor activation may be the stimulation of entry, which is then responsible for charging up the internal store to prime the IP
3
Rs for the large-scale regenerative release of Ca
2+
that occurs during each spike.
Store-Operated Ca
2+
Entry Channels: Still Elusive!
Authors: Nilius Bernd
Published: September 2004

Depletion of intracellular Ca
2+
stores is believed to trigger Ca
2+
entry through a Ca
2+
- permeable channel in the plasma membrane called the store-operated Ca
2+
channel (SOC). This type of Ca
2+
entry is thought to play a pivotal role in a plethora of cell functions ranging from gene expression to sensory signal transduction. However, the molecular nature of these channels is still elusive. Many molecular candidates have been described as SOCs, but the candidacy of each has been countered by reports indicating that they are not SOCs. Most of the suggested candidates are members of the recently discovered superfamily of transient receptor potential cation channels (TRPCs). However, no TRP-family channel has yet been incontestably identified as an SOC. Even for the electrophysiologically best-described SOC, the highly Ca
2+
-permeable channel Ca
2+
release-activated Ca
2+
channel (CRAC), an acceptable candidate has yet to emerge. This perspective summarizes problems in identifying SOCs, suggests approaches to solving these problems, and discusses concerns over the current tendency to focus exclusively on the hypothesis that TRPCs comprise SOCs.
Store-Operated Calcium Channels: How Do We Measure Them, and Why Do We Care?
Authors: Putney James W.
Published: September 2004

A major mechanism whereby calcium entry into cells is regulated is the store-operated or capacitative calcium entry pathway. In this article, two basic issues are discussed: (i) the methods investigators use to measure store-operated entry, and (ii) the role played by the store-operated pathway in responses to hormones and neurotransmitters under physiological conditions. The two topics are considered together because they are closely interrelated; as we begin to ask questions about calcium movements at low concentrations of agonists, the technology to measure these movements becomes increasing challenging.
Toward a Consensus on the Operation of Receptor-Induced Calcium Entry Signals
Authors: Gill Donald L. , Patterson Randen L.
Published: September 2004

Receptor-induced Ca
2+
signals involve both Ca
2+
release from intracellular stores and extracellular Ca
2+
entry across the plasma membrane. The channels mediating Ca
2+
entry and the mechanisms controlling their function remain largely a mystery. Here we critically assess current views on the Ca
2+
entry process and consider certain modifications to the widely held hypothesis that Ca
2+
store emptying is the fundamental trigger for receptor-induced Ca
2+
entry channels. Under physiological conditions, receptor-induced store depletion may be quite limited. A number of distinct channel activities appear to mediate receptor-induced Ca
2+
entry, and their activation is observed to occur through quite diverse coupling processes.
AcK-knowledge Reversible Acetylation
Authors: Cohen Todd , Yao Tso-Pang
Published: September 2004

In 1966, the histone was identified as the first protein subject to reversible acetylation. The ensuing 30 years of research on histone acetylation has been critical for elucidating how gene transcription and chromatin remodeling are regulated at the molecular level. This central focus on histones, however, has also restricted our understanding of reversible acetylation, and therefore the enzymes that catalyze this reaction, to cellular processes predominantly associated with chromatin. The study of reversible acetylation has become more or less synonymous with histone acetylation. Recent developments—including increased ability to detect acetylated proteins, the characterization of novel acetyltransferases and deacetylases, and the identification of specific inhibitors for these enzymes—have revealed that this histone-central paradigm probably reflects only a fraction of the cellular processes regulated by reversible acetylation. New studies have uncovered unexpected roles for reversible acetylation in many diverse areas, thereby establishing protein acetylation as a highly versatile signaling modification that has functions beyond gene transcription and chromatin remodeling.
Human RAS Superfamily Proteins and Related GTPases
Authors: Colicelli John
Published: September 2004

The tumor oncoproteins HRAS, KRAS, and NRAS are the founding members of a larger family of at least 35 related human proteins. Using a somewhat broader definition of sequence similarity reveals a more extended superfamily of more than 170 RAS-related proteins. The RAS superfamily of GTP (guanosine triphosphate) hydrolysis–coupled signal transduction relay proteins can be subclassified into RAS, RHO, RAB, and ARF families, as well as the closely related Gα family. The members of each family can, in turn, be arranged into evolutionarily conserved branches. These groupings reflect structural, biochemical, and functional conservation. Recent findings have provided insights into the signaling characteristics of representative members of most RAS superfamily branches. The analysis presented here may serve as a guide for predicting the function of numerous uncharacterized superfamily members. Also described are guanosine triphosphatases (GTPases) distinct from members of the RAS superfamily. These related proteins employ GTP binding and GTPase domains in diverse structural contexts, expanding the scope of their function in humans.
Emerging Role for ERK as a Key Regulator of Neuronal Apoptosis
Authors: Cheung Eric C. C. , Slack Ruth S.
Published: September 2004

Extracellular signal–regulated kinases (ERKs) are traditionally viewed as a survival factor in the mitogen-activated protein kinase (MAPK) family. On the other hand, some recent reports have suggested that ERK can also be responsible for neuronal cell death in various neurodegeneration models. In-depth studies on the action of ERK in apoptosis, however, have not been done. A recent study has revealed that ERK is a key apoptotic factor in potassium deprivation–induced neuronal cell death by showing that ERK inhibitors protect neurons from low potassium conditions, whereas constitutively activated ERK activates cell death. Most important, this study shows how ERK can promote neuronal cell death by causing plasma membrane and DNA damage that is independent of caspase-3 activity. Further studies on the mechanism of ERK in neuronal cell death will shed light on the possibility of using ERK as a therapeutic target in treating neurodegeneration.
Mitochondrial Stop and Go: Signals That Regulate Organelle Movement
Authors: Reynolds Ian J. , Rintoul Gordon L.
Published: September 2004

In order to satisfy the metabolic and ion homeostasis demands of neurons, mitochondria must be transported to appropriate locations within cells. Although it is well established that much of this trafficking occurs on microtubules and, to a lesser extent, actin, the mechanisms by which the trafficking of mitochondria is controlled are poorly understood. A recent study by Chada and Hollenbeck shows that nerve growth factor halts the movement of mitochondria in axons by means of a mechanism that depends on activation of phosphatidylinositol 3-kinase. These studies provide important new insights into the mechanisms that regulate mitochondrial movement and control mitochondrial docking. These insights are critical to the understanding of the factors that control the distribution, location, and function of mitochondria in both healthy and injured neurons.
COUNTING RATIONAL MAPS ONTO SURFACES AND FUNDAMENTAL GROUPS
Authors: BANDMAN T. , LIBGOBER A.
Published: September 2004

We consider the class of quasiprojective varieties admitting a dominant morphism onto a curve with negative Euler characteristic. The existence of such a morphism is a property of the fundamental group. We show that for a variety in this class the number of maps onto a hyperbolic curve or surfaces can be estimated in terms of the numerical invariants of the fundamental group. We use this estimates to find the number of biholomorphic automorphisms of complements to some arrangements of lines.
INTERSECTIONS OF FINITE FAMILIES OF FINITE INDEX SUBFACTORS
Authors: JONES VAUGHAN F. R. , XU FENG
Published: September 2004

We prove that finiteness of the index of the intersection of a finite set of finite index subalgebras in a von Neumann algebra (with small centre) is equivalent to the finite dimensionality of the algebra generated by the conditional expectations onto the subalgebras.
ARE STOCK SPLITS CREDIBLE SIGNALS? EVIDENCE FROM THE SINGAPORE MARKET
Authors: ARIFF M. , KHAN WALAYET A. , BAKER H. KENT
Published: September 2004

This paper studies the effects of stock splits on returns using daily data from the Singapore Stock Exchange over the period 1983-2000. Specifically, it examines whether stock split announcements provide credible signals due to asymmetry of information. We find that the market, on average, responds positively and significantly to announcements of stock splits. We then partition the sample into sub-samples: one with dividends (earnings) increasing firms and another with dividends (earnings) decreasing firms the 12 month period after the stock split. Both groups respond positively to stock split announcements on the event period, which initially casts doubt on the signaling hypothesis. Additional tests show that the difference between the cumulative average returns of the two sub-samples is significantly positive during the post-event and/or full-test period. An implication of this finding is that the market can differentiate ex ante between the two sub-samples, which lends support to the hypothesis that stock split announcements generally provide credible signals of future prospects.
CHINA — CAN RAPID ECONOMIC GROWTH CONTINUE?
Authors: BOLTHO ANDREA
Published: September 2004

Between 1978 and 2000, Chinese GDP expanded more than seven-fold; present official projections suggest a further four-fold expansion to 2020. Is this feasible and, if so, what would be the consequences for the rest of the world? China has a huge catch-up potential and a vast resource of cheap labor. Policies are improving. The fiscal, employment and regional disparity problems, while serious, seem manageable. Hence, further rapid growth is possible. For the world economy this is bound to be beneficial thanks to resource reallocation, the growth of a large market and likely terms of trade gains. Developing countries, particularly in Asia, will, however feel a strong competitive challenge.
SECOND-ORDER INTERTWINING OPERATOR AND ISOSPECTRAL PARTNER OF COMPLEX PT INVARIANT POTENTIAL
Authors: ROY B. , ROYCHOUDHURY R.
Published: September 2004

A generalized second-order differential realization of intertwining operator is given and isospectral partners of complex PT invariant Scarf II potential are obtained.
STRUCTURAL AND DYNAMICAL PROPERTIES OF LIQUID PD–AG ALLOYS
Authors: KART H. H. , TOMAK M. , ULUDOĞAN M. , ÇAĞIN T.
Published: September 2004

Structural and dynamical properties of Pd, Ag pure liquid metals and especially PdxAg1-xalloys are studied by the molecular dynamics simulation. The effects of temperature and concentration on the liquid properties of PdxAg1-xare analyzed. Sutton–Chen (SC) and Quantum Sutton–Chen (Q–SC) many-body potentials are used as interatomic interactions. The calculated diffusion constants and viscosities are in good agreement with the available experimental data and theoretical calculations. The coefficients of Arrhenius equation are also presented to calculate the self-diffusion coefficient and shear viscosity of Pd–Ag alloys at the desired temperature and concentration. We have shown that Q–SC potential parameters are more reliable in determining physical properties of metals and their alloys studied in this work.
SOLVING THE INTENSITY DEPENDENT COUPLING HAMILTONIAN VIA MULTI-PHOTON INTERACTION IN A KERR MEDIUM BY VIRTUE OF SUPERSYMMETRIC TRANSFORMATION
Authors: FAN HONG-YI , GUI WEI-JUN
Published: September 2004

We reveal that the intensity dependent coupling Hamiltonian via multi-photon interaction in a Kerr medium possesses a supersymmetric structure and therefore can be solved with the supersymmetric transform method. By selecting suitable supersymmetric generators, we derive its energy eigenvalues and eigenvectors.
TUNNELING MAGNETORESISTANCE IN FERROMAGNETIC SEMICONDUCTOR TUNNEL JUNCTIONS
Authors: TAO Y. C. , HU J. G.
Published: September 2004

Taking into account the basic physics of diluted ferromagnetic semiconductors (DMS), we use the tunneling Hamiltonian approach to studying the spin-polarized transport in GaMnAs / AlAs / GaMnAs DMS tunnel junctions. It is found that the splitting, Fermi energies, and the hole concentration for a fixed Mn impurity density vary with temperature, which exert a great influence on the spin-polarized transport of the DMS. We have also shown that there exists a spin-flip tunneling process arising from the impurity Mn scattering in the barrier, and the variation of normalized conductance difference ΔG with temperature is consistent with that of experiment.
THE EFFECT OF OFF-RAMP ON THE ONE-DIMENSIONAL CELLULAR AUTOMATON TRAFFIC FLOW WITH OPEN BOUNDARIES
Authors: EZ-ZAHRAOUY HAMID , BENRIHANE ZOUBIR , BENYOUSSEF ABDELILAH
Published: September 2004

The effect of the position of the off-ramp (way out), on the traffic flow phase transition is investigated using numerical simulations in the one-dimensional cellular automaton traffic flow model with open boundaries using parallel dynamics. When the off-ramp is located between two critical positions ic1 and ic2 the current increases with the extracting rate β0, for β0<β0c1, and exhibits a plateau (constant current) for β0c1<β0<β0c2 and decreases with β0 for β0>β0c2. However, the density undergoes two successive first order transitions: from high density to plateau current phase at β0=β0c1; and from average density to the low one at β0=β0c2. In the case of two off-ramps located respectively at i1 and i2, these transitions occur only when i2-i1 is smaller than a critical value. Phase diagrams in the (α,β0), (β,β0) and (i1,β0) planes are established. It is found that the transitions between free traffic (FT), congested traffic (CT) and plateau current (PC) phases are of first order. The first order line transition in (i1,β0)-phase diagram terminates by an end point above which the transition disappears.
SEEBECK COEFFICIENTS OF Mn-Si MATERIALS PREPARED BY SPARK PLASMA SINTERING
Authors: WANG ZHI MIN , WU YI DONG , HE YUAN JIN
Published: September 2004

MnSi 1.73 and MnSi samples were grown by spark plasma sintering (SPS) from different Si / Mn ratio powders, at different sintering temperatures, and for different sintering times. X-ray diffraction (XRD) measurements showed samples containing MnSi and MnSi 1.73 and Si phases, depending on the initial stoichiometries. Measurements of the Seebeck coefficient revealed p-type conductance for all samples. The Seebeck coefficients of the samples with MnSi pure phase were very low (about 10 μ V/K) and changed little at the temperature range measured. The Seebeck coefficients of the samples with MnSi 1.73, MnSi and Si phases were similar to that of the sample with near-pure MnSi 1.73 phase, which were larger than those of the samples with MnSi 1.73 and MnSi phases, but a little smaller than those of the samples with MnSi 1.73 and Si phases. It seems that, for the samples with the same phases, larger ratio of the strongest intensity peak of MnSi 1.73 to [Formula: see text], MnSi 1.73 to [Formula: see text] or both lead to larger Seebeck coeffiecients.
KNOTS THAT HAVE MORE THAN TWO ACCIDENTAL SLOPES
Authors: MIYAZAKI KATURA
Published: September 2004

An accidental surface in the exterior of a knot in the 3-sphere is a closed essential surface for which there is an annulus in the knot exterior X connecting a loop in the surface and a nontrivial loop in ∂X, the peripheral torus of the knot. The isotopy class of the loop in ∂X is called an accidental slope; each accidental surface has a unique accidental slope. It is known that accidental slopes are integral or 1/0, and there is a knot with two accidental slopes 0 and 1/0. We show that for any integer m≥0, there is a hyperbolic knot which has m+1 accidental surfaces with accidental slopes 0,1,…,m.
ON THE VASSILIEV INVARIANT OF TYPE 3 OF 2-BRIDGE KNOTS
Authors: MIZUMA YOKO
Published: September 2004

The purpose of this note is to give a formula for the Vassiliev invariant of type three for 2-bridge knots, calculating without using a continued fraction expansion.
Experimentally induced ulcers and gastric sensory-motor function in rats
Authors: Kang Y. M. , Lamb K. , Gebhart G. F. , Bielefeldt K.
Published: September 2004

Prior studies have demonstrated that inflammation can sensitize visceral afferent neurons, contributing to the development of hyperalgesia. We hypothesized that both afferent and efferent pathways are affected, resulting in changes in motor and sensory function. Kissing ulcers (KU) were induced in the distal stomach by injecting 60% acetic acid for 45 s into a clamped area of the stomach. In controls, saline was injected into the stomach. A balloon catheter was surgically placed into the stomach, and electromyographic responses to gastric distension were recorded from the acromiotrapezius muscle at various times after ulcer induction. The accommodation reflex was assessed by slowly infusing saline into the distally occluded stomach. Gastric pressure changes in response to vagal stimulation were measured in anesthetized rats. Contractile function of circular muscle strips was examined in vitro using force-displacement transducers. KU caused gastric hypersensitivity that persisted for at least 14 days. Fluid distension of the stomach led to a rapid pressure increase in KU but not in control animals, consistent with an impaired accommodation reflex. Gastric ulcers enhanced the contractile response to vagal stimulation, whereas the effect of cholinergic stimulation on smooth muscle in vitro was not changed. These data suggest that inflammation directly alters gastric sensory and motor function. Increased activation of afferents will trigger vagovagal reflexes, thereby further changing motility and indirectly activating sensory neurons. Thus afferent and efferent pathways both contribute to the development of dyspeptic symptoms.
Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development
Authors: Balasubramaniyan N. , Shahid Mohammad , Suchy Frederick J. , Ananthanarayanan M.
Published: September 2004

Nuclear receptors (NRs) play pivotal roles in the regulation of genes contributing to hepatobiliary cholesterol and bile acid homeostasis. We have previously shown that transporters involved in bile formation are developmentally regulated and are poorly developed during the fetal stage, but their expression reached gradual maturity during the postnatal period. To define the molecular mechanisms underlying this regulation and the role that class II NRs and associated members [liver receptor homolog-1 (LRH-1) and short heterodimer partner (SHP)] play, we have analyzed the ontogeny of NR expression during liver development. Real-time PCR analysis of hepatic NR expression from fetal day 17 through adult revealed that steady-state mRNA levels for all NRs were very low during the embryonic period. However, mRNA levels peaked close to that of adult rats (>6 wk-old rats) by 4 wk of age for farnesoid X receptor (FXR), pregnane X receptor (PXR), liver X receptor-α (LXRα), peroxisome proliferator-activated receptor-α (PPARα), retinoid acid receptor-α (RARα), LRH-1, and SHP, whereas RXRα mRNA lagged behind. FXR, PXR, LXRα, RARα, and PPARα functional activity in liver nuclear extracts assayed by gel EMSA demonstrated that the activity attained adult levels by 4 wk of age, exhibiting a strict correlation with mRNA levels. Surprisingly, PPARα activity was delayed as seen by EMSA assay. Protein levels for NRs also corresponded to the mRNA and functional activity except for RXRα. RXRα protein levels were higher than message levels, suggesting increased protein stability. We conclude that expression of NRs during rat liver development is primarily regulated by transcriptional mechanisms, which in turn, control the regulation of bile acid and cholesterol metabolic pathways.
Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury
Authors: Willis Monte S. , Carlson Deborah L. , DiMaio J. Michael , White Michael D. , White D. Jean , Adams Glenn A. , Horton Jureta W. , Giroir Brett P.
Published: September 2004

We have recently demonstrated that macrophage migration inhibitory factor (MIF) is a myocardial depressant protein and that MIF mediates late, prolonged cardiac dysfunction after endotoxin challenge in mice. Because many factors, including endotoxin, have been implicated in the pathogenesis of cardiac dysfunction after burn injury, we tested the hypothesis that MIF might also be the mediator of prolonged cardiac dysfunction in this model. At 4 h after 40% total body surface area burn in anesthetized mice, serum MIF levels increased significantly compared with baseline (2.2-fold). This increase was accompanied by a significant decrease in cardiac tissue MIF levels (2.1-fold decrease compared with controls). This pattern was consistent with MIF release from preformed cytoplasmic stores in the heart and other organs. To determine whether MIF mediates cardiac dysfunction after burn injury, mice were pretreated with anti-MIF neutralizing monoclonal antibodies or isotype control antibodies. Beginning 4 h after burn injury (and continuing through 48 h), burned mice demonstrated a significantly depressed left ventricular shortening fraction of 38.6 ± 1.8%, compared with the normal controls (56.0 ± 2.6%). Mice treated with anti-MIF displayed an initial depression of cardiac function similar to nontreated animals but then showed rapid restoration of cardiac function with complete recovery by 24 h, which persisted for the duration of the protocol. This study is the first to demonstrate that MIF mediates late, prolonged cardiac dysfunction after burn injury and suggests that MIF blockade should be considered a therapeutic target for the treatment of burn injury.
Acute alcohol intoxication enhances myocardial eIF4G phosphorylation despite reducing mTOR signaling
Authors: Vary Thomas C. , Deiter Gina , Goodman Stacy A.
Published: September 2004

Acute alcohol intoxication impairs myocardial protein synthesis in rats, secondary to a diminished mRNA translational efficiency. Decreased mRNA translational efficiency occurs through altered regulation of peptide chain initiation. The purpose of the present set of experiments was to determine whether acute alcohol intoxication alters the phosphorylation state of eukaryotic initiation factor (eIF) 4G, eIF4G·eIF4E complex formation, and the mammalian target of rapamycin (mTOR) signaling pathway in the heart. Acute alcohol intoxication was induced by injection of alcohol (75 mmol/kg body wt ip). Control animals received an equal volume of saline. Alcohol administration enhanced phosphorylation of eIF4G (Ser1108) approximately threefold. Alcohol administration lowered formation of the active eIF4G·eIF4E complex by >90%, whereas it increased the abundance of the inactive 4E-binding protein 1 (4E-BP1)·eIF4E complex by ∼160%. Phosphorylation of mTOR on Ser2448and Ser2481was decreased by 50%. Reduced mTOR phosphorylation did not result from decreased phosphorylation of PKB. Phosphorylation of 4E-BP1 and S6 kinase 1 (Thr389), downstream targets of mTOR, were also reduced after acute alcohol administration. These data suggest that acute alcohol-induced impairments in myocardial mRNA translation initiation result, in part, from marked decreases in eIF4G·eIF4E complex formation, which appear to be independent of changes in phosphorylation of eIF4G but dependent on mTOR.
Imaging remodeling of the actin cytoskeleton in vascular smooth muscle cells after mechanosensitive arteriolar constriction
Authors: Flavahan Nicholas A. , Bailey Simon R. , Flavahan William A. , Mitra Srabani , Flavahan Sheila
Published: September 2004

Experiments were performed to determine whether remodeling of the actin cytoskeleton contributes to arteriolar constriction. Mouse tail arterioles were mounted on cannulae in a myograph and superfused with buffer solution. The α1-adrenergic agonist phenylephrine (0.1–1 μmol/l) caused constriction that was unaffected by cytochalasin D (300 nmol/l) or latrunculin A (100 nmol/l), inhibitors of actin polymerization. In contrast, each compound abolished the mechanosensitive constriction (myogenic response) evoked by elevation in transmural pressure (PTM; 10–60 or 90 mmHg). Arterioles were fixed, permeabilized, and stained with Alexa-568 phalloidin and Alexa-488 DNAse I to visualize F-actin and G-actin, respectively, using a Zeiss 510 laser scanning microscope. Elevation in PTM, but not phenylephrine (1 μmol/l), significantly increased the intensity of F-actin and significantly decreased the intensity of G-actin staining in arteriolar vascular smooth muscle cells (VSMCs). The increase in F-actin staining caused by an elevation in PTMwas inhibited by cytochalasin D. In VSMCs at 10 mmHg, prominent F-actin staining was restricted to the cell periphery, whereas after elevation in PTM, transcytoplasmic F-actin fibers were localized through the cell interior, running parallel to the long axis of the cells. Phenylephrine (1 μmol/l) did not alter the architecture of the actin cytoskeleton. In contrast to VSMCs, the actin cytoskeleton of endothelial or adventitial cells was not altered by an elevation in PTM. Therefore, the actin cytoskeleton of VSMCs undergoes dramatic alteration after elevation in PTMof arterioles and plays a selective and essential role in mechanosensitive myogenic constriction.
Influence of serum cholesterol on atherogenesis and intimal hyperplasia after angioplasty: inhibition by amlodipine
Authors: Kahn Mark B. , Boesze-Battaglia Kathleen , Stepp David W. , Petrov Artium , Huang Yong , Mason R. Preston , Tulenko Thomas N.
Published: September 2004

The objectives of the present study were to determine whether serum hypercholesterolemia (HC) promotes the development of spontaneous and angioplasty-induced lesions and whether amlodipine inhibits these lesions and cellular processes underlying their genesis. Rabbits were fed normal, 0.5%, or 2% cholesterol diets for 9 wk, which resulted in the development of increasing HC. After week one, balloon dilation of the abdominal aorta was performed while the thoracic aorta was not disturbed and monitored for the development of spontaneous lesions. Lesion size increased with the degree of HC and was accompanied by increased collagen synthesis and smooth muscle cell (SMC) proliferation at each site. Amlodipine (5 mg/kg po) inhibited lesion size by 50% ( P < 0.01) at both sites in cholesterol-fed animals but not at angioplasty sites in animals on a normal diet. Local collagen synthesis was inhibited at both sites by amlodipine in the diet animals. The increase in HC was accompanied by a 1.7-fold increase in basal Ca2+uptake in SMCs in the thoracic aorta, which was not altered by amlodipine, nifedipine, Ni2+, or La3+, revealing an uninhibitable calcium leak during atherogenesis. In culture, cholesterol enrichment increased SMC proliferation, collagen synthesis, and the secretion of a soluble SMC mitogen, which were inhibited by amlodipine (10−9M). Finally, in SMC membranes, amlodipine uniquely restored the cholesterol-expanded membrane bilayer width without any effect on membrane fluidity. This study establishes a causal role between serum HC and the development of spontaneous and angioplasty-induced lesions and the ability of amlodipine to disrupt this action by a novel remodelling action on the SMC membrane.
Influences of breathing patterns on respiratory sinus arrhythmia in humans during exercise
Authors: Blain Grégory , Meste Olivier , Bermon Stéphane
Published: September 2004

Persistence of respiratory sinus arrhythmia (RSA) has been described in humans during intense exercise and attributed to an increase in ventilation. However, the direct influence of ventilation on RSA has never been assessed. The dynamic evolution of RSA and its links to ventilation were investigated during exercise in 14 healthy men using an original modeling approach. An evolutive model was estimated from the detrended and high-pass-filtered heart period series. The instantaneous RSA frequency ( FRSA, in Hz) and amplitude ( ARSA, in ms) were then extracted from all recordings. ARSAwas calculated with short-time Fourier transform. First, measurements of FRSAand ARSAwere performed from data obtained during a graded and maximal exercise test. Influences of different ventilation regimens [changes in tidal volume (VT) and respiratory frequency ( FR)] on ARSAwere then tested during submaximal [70% peak O2consumption (V̇o2peak)] rectangular exercise bouts. Under graded and maximal exercise conditions, ARSAdecreased from the beginning of exercise to 61.9 ± 3.8% V̇o2peakand then increased up to peak exercise. During the paced breathing protocol, normoventilation (69.4 ± 8.8 l/min), hyperventilation (81.8 ± 8.3 l/min), and hypoventilation (56.4 ± 6.2 l/min) led to significantly ( P < 0.01) different ARSAvalues (3.8 ± 0.5, 4.6 ± 0.8, and 2.9 ± 0.5 ms, respectively). In addition, no statistical difference was found in ARSAwhen ventilation was kept constant, whatever the FR-VTcombinations. Those results indicate that RSA persists for all exercise intensities and increases during the highest intensities. Its persistence and increase are strongly linked to both the frequency and degree of lung inflation, suggesting a mechanical influence of breathing on RSA.
Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses
Authors: Zhang Junlong , Lewis Rohan M. , Wang Chunli , Hales Nicholas , Byrne Christopher D.
Published: September 2004

Maternal dietary Fe restriction reduced fasting plasma cholesterol and triglyceride (TG) concentrations in the fetuses, as well as decreased plasma TG levels in the adult offspring. To investigate how maternal Fe restriction was affecting fetal lipid metabolism, we investigated whether there were changes in liver lipid metabolism in the full-term fetuses. There was a ∼27% ( P < 0.05) increase in cholesterol but ∼29% reduction ( P = 0.01) in TG concentrations in the liver of the Fe-restricted fetuses. Hepatic mRNA levels of cholesterol 7α hydroxylase and liver X receptor-α (LXRα) were reduced by ∼50% ( P < 0.01) and ∼34% ( P < 0.01), respectively. As LXRα regulates expression of sterol response element binding protein-1c (SREBP-1c) expression, we measured SREBP-1c expression. There was an ∼43% ( P < 0.001) reduction in mRNA levels of SREBP-1c and its response genes, including acetyl-CoA carboxylase by ∼35% ( P = 0.01), fatty acid synthase by ∼18% ( P = 0.05), and diacylglycerol acyltransferase by ∼19% ( P = 0.03). Furthermore, protein levels of CD36 were reduced by ∼27% ( P = 0.02) in Fe-restricted fetuses. In conclusion, changes in liver cholesterol and TG concentrations in Fe-restricted fetuses may be coordinated through reduced expression of heme-containing cholesterol 7α hydroxylase and its regulator LXRα, mainly via downregulation of expression of genes in bile acid synthesis and fatty acid synthesis pathways.
Relaxin-induced changes in renal sodium excretion in the anesthetized male rat
Authors: Bogzil Alsadek H. , Eardley Rachel , Ashton Nick
Published: September 2004

Pregnancy is associated with profound changes in renal hemodynamics and electrolyte handling. Relaxin, a hormone secreted by the corpus luteum, has been shown to induce pregnancy-like increases in renal blood flow and glomerular filtration rate (GFR) and alter osmoregulation in nonpregnant female and male rats. However, its effects on renal electrolyte handling are unknown. Accordingly, the influence of short (2 h)- and long-term (7 day) infusion of relaxin on renal function was determined in the male rat. Short term infusion of recombinant human relaxin (rhRLX) at 4 μg·h−1·100 g body wt−1 induced a significant increase in effective renal blood flow (ERBF) within 45 min, which peaked at 2 h of infusion (vehicle, n = 6, 2.1 ± 0.4 vs. rhRLX, n = 7, 8.1 ± 1.1 ml·min−1·100 g body wt−1, P < 0.01). GFR and urinary excretion of electrolytes were unaffected. After a 7-day infusion of rhRLX at 4 μg/h, ERBF (1.4 ± 0.2 vs. 2.5 ± 0.4 ml·min−1·100 g body wt−1, P < 0.05), urine flow rate (3.1 ± 0.3 vs. 4.3 ± 0.4 μl·min−1·100 g body wt−1, P < 0.05) and urinary sodium excretion (0.8 ± 0.1 vs. 1.2 ± 0.1 μmol·min−1·100 g body wt−1, P < 0.05) were significantly higher; plasma osmolality and sodium concentrations were lower in rhRLX-treated rats. These data show that long-term relaxin infusion induces a natriuresis and diuresis in the male rat. The mechanisms involved are unclear, but they do not involve changes in plasma aldosterone or atrial natriuretic peptide concentrations.
Peptide YY(3–36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys
Authors: Moran Timothy H. , Smedh Ulrika , Kinzig Kimberly P. , Scott Karen A. , Knipp Susan , Ladenheim Ellen E.
Published: September 2004

Peptide YY3–36 [PYY(3–36)], a gastrointestinal peptide that is released into the circulation in response to ingesting a meal, has recently been suggested to play a role in controlling food intake. PYY(3–36) has been reported to inhibit food intake following peripheral administration in rodents and in human subjects. To more fully characterize the potential feeding actions of PYY(3–36), we examined the ability of a dose range of PYY(3–36) (0.3–3.0 nmol/kg) to affect liquid gastric emptying and daily 6-h food intake in male rhesus monkeys. Intramuscular PYY(3–36) produced a dose-related inhibition of saline gastric emptying that was maximal at a dose of 3 nmol/kg. Intramuscular PYY(3–36) administered before daily 6-h food access produced significant feeding reductions at doses of 1 and 3 nmol/kg. Analyses of the patterns of food intake across the 6-h period of food access revealed that PYY(3–36) increased the latency to the first meal and reduced average meal size without altering meal number. Although single doses of PYY(3–36) reduced intake, a suppressive effect on food intake was not sustained over multiple administrations across successive days. Together, these data suggest that PYY(3–36) has the ability to reduce food intake in acute test situations in nonhuman primates. Whether this is a physiological action of the endogenous peptide remains to be determined.
Left ventricular adaptations following short-term endurance training
Authors: Goodman Jack M. , Liu Peter P. , Green Howard J.
Published: September 2004

This study examined the effects of short-term endurance training (ET) on the left ventricular (LV) adaptation and functional response to a series of exercise challenges with increasing intensity. Eight untrained men, with a mean age of 19.4 ± 0.5 (SE) yr, were studied before and after 6 days of ET consisting of cycling 2 h/day at 65% peak aerobic power (V̇o2max). LV ejection fraction and LV volumes were assessed by radionuclide angiography at rest and during exercise at three uninterrupted successive work rates corresponding to 53, 68, and 83% of V̇o2max, each lasting 20 min. ET produced a calculated plasma volume expansion of 11.4 ± 2.2% ( P < 0.05). The increase in plasma volume was accompanied by an increase in V̇o2max from 45.9 ± 1.9 to 49.0 ± 1.0 ml·kg−1·min−1 ( P < 0.01) and a decrease in maximal heart rate (197 ± 2.3 to 188 ± 1.0 beats/min; P < 0.01). Resting LV function was not changed, although there was a trend for higher stroke volumes (SVs) and improvement in the rapid filling phase of diastole ( P = 0.08). Training induced an increase in exercise SV by 10.4, 10.2, and 7% at 53, 68, and 83% V̇o2max, respectively ( P < 0.01). These changes were secondary to increases in end-diastolic volume, which increased significantly at each exercise work rate following training (139 ± 6 to 154 ± 6 ml at 53% V̇o2max, and from 136 ± 5 to 156 ± 5 ml at 83% V̇o2max; P < 0.01). End-systolic volumes were unchanged after ET. A significant bradycardia was observed both at rest (decreasing 7%) and exercise (decreasing 10.4%). LV ejection fraction during exercise was increased slightly by training, reaching significance at the highest work rate, after 60 min of exercise. ( P < 0.05). Cardiac output was higher following training at the highest workload (20.8 ± 2.2 vs. 22.9 ± 3.1 l/min; P < 0.01). These data indicate that short-term training elicits rapid adaptation to the LV functional response exercise, with increases in SV being secondary to a Frank-Starling effect with minor changes in contractile performance. This produced a volume-induced bradycardia and increase in LV filling, which may be of benefit during prolonged exercise.
Afferent and Efferent Vessels of Premalignant and Overt Hepatocellular Carcinoma: Observation by Color Doppler Imaging
Authors: Tochio Hitoshi , Kudo Masatoshi
Published: September 2004

Afferent and efferent vessels of premalignant and overt hepatocellular carcinoma (HCC) were analyzed using color Doppler imaging. With afferent blood flow, constant waveform signals reflecting portal inflow are a characteristic finding in dysplastic nodules and early well-differentiated HCC. Among advanced HCCs lacking portal blood flow, inflow of arterial pulsatile blood flow signals is characteristic for advanced HCC with increased arterial vascularity. Efferent blood flow enters the hepatic vein of the lowest pressure system in dysplastic nodules and early well-differentiated HCC with afferent portal blood flow. Analysis of waveforms of efferent blood flow signals in advanced HCC detects in the opposite direction adjacent to an accompanying afferent arterial pulsatile blood flow signal. In conclusion, during multistep human hepatocarcinogenesis hemodynamics show characteristic changes; the state of afferent portal blood with low arterial vascularity loses the portal blood flow, and arterial vascularity gradually increases. The efferent blood flow pathway also changes with the pathological multistep developement process.
Contrast-Enhanced Sonography for Hepatocellular Carcinoma
Authors: Choi Byung Ihn , Lee Jae Young , Han Joon Koo , Lee Jeong Min , Kim Se Hyung
Published: September 2004

It is well known that contrast-enhanced sonography is valuable for the evaluation of tumoral vascularity in hepatocellular carcinoma (HCC). The knowledge of tumoral vascularity is important to diagnose HCC, to decide treatment method, and to assess therapeutic response after various treatments. Until now, various techniques of contrast-enhanced sonography have been investigated with HCCs. The purpose of this review is to describe various contrast-enhanced sonographic techniques for HCC in sequence of their development and to outline the advantages and limitation of each technique.
‘Nodule-in-Nodule’ Appearance in Hepatocellular Carcinoma: Its Significance as a Morphologic Marker of Dedifferentiation
Authors: Kojiro Masamichi
Published: September 2004

Small hepatocellular carcinoma (HCC) of the early stage can be divided into 2 types: small nodular HCC with distinct margins and small HCC with indistinct margins. The latter consists uniformly of well-differentiated cancerous tissue with a replacing growth at the boundary, and many portal tracts are retained in the tumor. When such tumors reach around 1.5–2.0 cm in diameter, moderately or poorly differentiated cancer tissues develop within the well-differentiated cancer tissue, and well-differentiated cancerous tissues are replaced by less differentiated cancerous tissues. Such a dedifferentiation seems to be closely related to tumor proliferation. When less differentiated cancerous tissues within the well-differentiated cancer nodules proliferate in an expansive fashion, a ‘nodule-in-nodule’ appearance is frequently seen. Thus, a ‘nodule-in-nodule’ appearance in early-stage HCC could be interpreted as a morphologic marker of dedifferentiation of early HCC.
Hepatocellular Carcinoma with Nodule-in-Nodule Appearance: Demonstration by Contrast-Enhanced Coded Phase Inversion Harmonic Imaging
Authors: Zheng Rong Qin , Zhou Pei , Kudo Masatoshi
Published: September 2004

Objective: A nodule-in-nodule hemodynamic pattern, namely a vascular spot in a hypovascular nodule, is specific for the diagnosis of early-stage hepatocellular carcinoma (HCC). The purpose of this study was to assess whether this unique hemodynamic pattern can be detected by contrast-enhanced coded phase inversion harmonic imaging (PIHI). Methods:159 consecutive patients with HCC who underwent contrast-enhanced coded PIHI were retrospectively reviewed. Cases with nodule-in-nodule patterns were selected, and findings were compared with those on computed tomography (CT) angiography (CTA) and intraarterial contrast-enhanced ultrasonography (US angiography). Results: Contrast-enhanced coded PIHI successfully displayed the nodule-in-nodule hemodynamic pattern in two cases of histologically proven HCC and the hemodynamic transition in one of the two cases, which corresponded well with findings on CTA and US angiography. Conclusions: Contrast-enhanced coded PIHI can demonstrate the special nodule-in-nodule hemodynamic pattern. It is useful in the diagnosis and follow-up of early-stage HCC or suspected nodules because of its noninvasiveness and easy performance.