bluuebunny/crossref_metadata_2025 huggingface dataset:
Uniform Inhibition of Dopamine Neurons in the Ventral Tegmental Area by Aversive Stimuli
Authors: Ungless Mark A. , Magill Peter J. , Bolam J. Paul
Published: March 2004

Dopamine neurons play a key role in reward-related behaviors. Reward coding theories predict that dopamine neurons will be inhibited by or will not respond to aversive stimuli. Paradoxically, between 3 and 49% of presumed dopamine neurons are excited by aversive stimuli. We found that, in the ventral tegmental area of anesthetized rats, the population of presumed dopamine neurons that are excited by aversive stimuli is actually not dopaminergic. The identified dopamine neurons were inhibited by the aversive stimulus. These findings suggest that dopamine neurons are specifically excited by reward and that a population of nondopamine neurons is excited by aversive stimuli.
AUGMENTATION OF SINGULARITIES OF SMOOTH MAPPINGS
Authors: HOUSTON KEVIN
Published: March 2004

Augmentation is a process which produces a new singular map from combining a singular map and a hypersurface singularity. This notion has important applications to the classification and topological study of singularities because the properties of an augmentation can be described by those of its constituent parts.

A short proof of an earlier result on a bound for the [Formula: see text]-codimension of an augmentation is given, but which is now also shown to hold for smooth real maps. For certain singularities a condition is given to detect when a map is an augmentation. This gives a process similar to that in the Splitting lemma for hypersurface singularities.
KÄHLER MANIFOLDS AND FUNDAMENTAL GROUPS OF NEGATIVELY δ-PINCHED MANIFOLDS
Authors: JOST JÜRGEN , YANG YI-HU
Published: March 2004

In this note, we will show that the fundamental group of any negatively δ-pinched [Formula: see text] manifold cannot be the fundamental group of a quasi-compact Kähler manifold. As a consequence of our proof, we also show that any nonuniform lattice in F4(-20) cannot be the fundamental group of a quasi-compact Kähler manifold. The corresponding result for uniform lattices was proved by Carlson and Hernández [3]. Finally, we follow Gromov and Thurston [6] to give some examples of negatively δ-pinched manifolds [Formula: see text] of finite volume which, as topological manifolds, admit no hyperbolic metric with finite volume under any smooth structure. This shows that our result for δ-pinched manifolds is a nontrivial generalization of the fact that no nonuniform lattice in SO(n,1)(n≥3) is the fundamental group of a quasi-compact Kähler manifold [21].
REAL OPTIONS: BATCH PROCESS AND MARKET ENTRY/EXIT DECISIONS UNDER UNCERTAINTY
Authors: LIN CHIN-TSAI , WU CHENG-RU
Published: March 2004

Under uncertainty of exchange rate, we extend the batch process production model of Lin et al. (2002) by considering an export-oriented manufacturer making decisions to switch freely between domestic and foreign locations. The export-oriented manufacturer is risk neutral and has rational expectations. We use dynamic programming and Lagrange multiplies for a stochastic optimization control problem to get the productive value of exporter produces in domestic and foreign locations. Next, the export-oriented manufacturer can make decision regarding the optimal entry (exit) trigger for transferable locations wherever the product locations are. It provides the supplier with another way to make decisions.
SOME PROPERTIES OF OPTIMAL MULTIFUNCTIONS IN PARAMETRIC MULTIOBJECTIVE OPTIMIZATION WITH SET-VALUED MAPS
Authors: LI MAO Q. , CRAVEN BRUCE D.
Published: March 2004

In this paper, we obtained results on the properties of Lipschitz, upper and lower semicontinuities of optimal multifunctions and optimal solution-set functions in parametric programming, where the objective and constrain functions are set-valued.
ON THE DENSITY OF HAUSDORFF DIMENSIONS OF BOUNDED TYPE CONTINUED FRACTION SETS: THE TEXAN CONJECTURE
Authors: JENKINSON OLIVER
Published: March 2004

Given a non-empty finite subset A of the natural numbers, let EA denote the set of irrationals x∈[0,1] whose continued fraction digits lie in A. In general, EA is a Cantor set whose Hausdorff dimension dim (EA) is between 0 and 1. It is shown that the set [Formula: see text] intersects [0,1/2] densely.

We then describe a method for accurately computing dimensions dim (EA), and employ it to investigate numerically the way in which [Formula: see text] intersects [1/2,1]. These computations tend to support the conjecture, first formulated independently by Hensley, and by Mauldin & Urbański, that [Formula: see text] is dense in [0,1].

In the important special case A={1,2}, we use our computational method to give an accurate approximation of dim (E{1,2}), improving on the one given in [18].
ANOMALOUS OUTCOMES IN PREFERENTIAL VOTING
Authors: QUAS ANTHONY
Published: March 2004

We consider the preferential voting system and investigate the frequency of non-monotonic allocations of votes, in which by getting more votes, a winning candidate can become a losing candidate.
STABILITY OF GYROSCOPIC SYSTEMS UNDER SMALL RANDOM EXCITATIONS
Authors: KHASMINSKII R. , MILSTEIN G. N.
Published: March 2004

Gyroscopic systems with two degrees of freedom under small random perturbations are investigated by use of the stochastic averaging principle. It is proved that the principal term of the Lyapunov exponent for the original system coincides with the Lyapunov exponent for the averaged system. An explicit formula for the averaged Lyapunov exponent is derived. The averaged moment Lyapunov exponent is also considered. An example is given in which an unstable gyroscopical system is stabilized by noise of the Stratonovich type.
APERIODICITY OF COCYCLES AND CONDITIONAL LOCAL LIMIT THEOREMS
Authors: AARONSON J. , DENKER M. , SARIG O. , ZWEIMÜLLER R.
Published: March 2004

We establish conditions for aperiodicity of cocycles (in the sense of [12]), obtaining, via a study of perturbations of transfer operators, conditional local limit theorems and exactness of skew-products. Our results apply to a large class of Markov and non-Markov interval maps, including beta transformations. This allows us to establish various stochastic properties of beta expansions.
Comparison of skin sympathetic nerve responses to isometric arm and leg exercise
Authors: Ray Chester A. , Wilson Thad E.
Published: March 2004

Measurement of skin sympathetic nerve activity (SSNA) during isometric exercise has been previously limited to handgrip. We hypothesized that isometric leg exercise due to the greater muscle mass of the leg would elicit greater SSNA responses than arm exercise because of presumably greater central command and muscle mechanoreceptor activation. To compare the effect of isometric arm and leg exercise on SSNA and cutaneous end-organ responses, 10 subjects performed 2 min of isometric knee extension (IKE) and handgrip (IHG) at 30% of maximal voluntary contraction followed by 2 min of postexercise muscle ischemia (PEMI) in a normothermic environment. SSNA was recorded from the peroneal nerve. Cutaneous vascular conductance (laser-Doppler flux/mean arterial pressure) and electrodermal activity were measured within the field of cutaneous afferent discharge. Heart rate and mean arterial pressure significantly increased by 16 ± 3 and 23 ± 3 beats/min and by 22 ± 2 and 27 ± 3 mmHg from baseline during IHG and IKE, respectively. Heart rate and mean arterial pressure responses were significantly greater during IKE compared with IHG. SSNA increased significantly and comparably during IHG and IKE (52 ± 20 and 50 ± 13%, respectively). During PEMI, SSNA and heart rate returned to baseline, whereas mean arterial pressure remained significantly elevated (Δ12 ± 2 and Δ13 ± 2 mmHg from baseline for IHG and IKE, respectively). Neither cutaneous vascular conductance nor electrodermal activity was significantly altered by either exercise or PEMI. These results indicate that, despite cardiovascular differences in response to IHG and IKE, SSNA responses are similar at the same exercise intensity. Therefore, the findings suggest that relative effort and not muscle mass is the main determinant of exercise-induced SSNA responses in humans.
Carbenoxolone Inhibition of Voltage-Gated Ca Channels and Synaptic Transmission in the Retina
Authors: Vessey John P. , Lalonde Melanie R. , Mizan Hossein A. , Welch Nicole C. , Kelly Melanie E. M. , Barnes Steven
Published: March 2004

We show that carbenoxolone, a drug used to block hemichannels in the retina to test the ephaptic model of horizontal cell inhibitory feedback, has strong inhibitory effects on voltage-gated Ca channels. Carbenoxolone (100 μM) reduced photoreceptor-to-horizontal cell synaptic transmission by 92%. Applied to patch-clamped, isolated cone photoreceptors, carbenoxolone inhibited Ca channels with an EC50 of 48 μM. At 100 μM, it reduced cone Ca channel current by 37%, reduced depolarization-evoked [Ca2+] signals in fluo-4 loaded retinal slices by 57% and inhibited Ca channels in Müller cells by 52%. A synaptic transfer model suggests that the degree of block of Ca channels accounts for the reduction in synaptic transmission. These results suggest broad inhibitory actions for carbenoxolone in the retina that must be considered when interpreting its effects on inhibitory feedback.
Role of Tau Protein in Both Physiological and Pathological Conditions
Authors: AVILA JESÚS , LUCAS JOSÉ J. , PÉREZ MAR , HERNÁNDEZ FÉLIX
Published: March 2004

Avila, Jesús, José J. Lucas, Mar Pérez, and Félix Hernández. Role of Tau Protein in Both Physiological and Pathological Conditions. Physiol Rev 84: 361–384, 2004; 10.1152/physrev.00024.2003.—The morphology of a neuron is determined by its cytoskeletal scaffolding. Thus proteins that associate with the principal cytoskeletal compo-nents such as the microtubules have a strong influence on both the morphology and physiology of neurons. Tau is a microtubule-associated protein that stabilizes neuronal microtubules under normal physiological conditions. However, in certain pathological situations, tau protein may undergo modifications, mainly through phosphorylation, that can result in the generation of aberrant aggregates that are toxic to neurons. This process occurs in a number of neurological disorders collectively known as tauopathies, the most commonly recognized of which is Alzheimer's disease. The purpose of this review is to define the role of tau protein under normal physiological conditions and to highlight the role of the protein in different tauopathies.
Pleural Mechanics and Fluid Exchange
Authors: LAI-FOOK STEPHEN J.
Published: March 2004

Lai-Fook, Stephen J. Pleural Mechanics and Fluid Exchange. Physiol Rev 84: 385–410, 2004; 10.1152/physrev.00026.2003.—The pleural space separating the lung and chest wall of mammals contains a small amount of liquid that lubricates the pleural surfaces during breathing. Recent studies have pointed to a conceptual understanding of the pleural space that is different from the one advocated some 30 years ago in this journal (Agostoni E. Physiol Rev 52: 57–128, 1972). The fundamental concept is that pleural surface pressure, the result of the opposing recoils of the lung and chest wall, is the major determinant of the pressure in the pleural liquid. Pleural liquid is not in hydrostatic equilibrium because the vertical gradient in pleural liquid pressure, determined by the vertical gradient in pleural surface pressure, does not equal the hydrostatic gradient. As a result, a viscous flow of pleural liquid occurs in the pleural space. Ventilatory and cardiogenic motions serve to redistribute pleural liquid and minimize contact between the pleural surfaces. Pleural liquid is a microvascular filtrate from parietal pleural capillaries in the chest wall. Homeostasis in pleural liquid volume is achieved by an adjustment of the pleural liquid thickness to the filtration rate that is matched by an outflow via lymphatic stomata.
Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading
Authors: KJÆR MICHAEL
Published: March 2004

Kjær, Michael. Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading. Physiol Rev 84: 649–698, 2004; 10.1152/physrev.00031.2003.—The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.
A Survey of Surgical Simulation: Applications, Technology, and Education
Authors: Liu Alan , Tendick Frank , Cleary Kevin , Kaufmann Christoph
Published: March 2004

Surgical simulation for medical education is increasingly perceived as a valuable addition to traditional teaching methods. Simulators provide a structured learning experience, permitting practice without danger to patients, and simulators facilitate the teaching of rare or unusual cases. Simulators can also be used to provide an objective assessment of skills. This paper is a survey of current surgical simulator systems. The components of a simulator are described, current research directions are discussed, and key research questions are identified.
Constructing a Gazebo: Supporting Teamwork in a Tightly Coupled, Distributed Task in Virtual Reality
Authors: Roberts David , Wolff Robin , Otto Oliver , Steed Anthony
Published: March 2004

Many tasks require teamwork. Team members may work concurrently, but there must be some occasions of coming together. Collaborative virtual environments (CVEs) allow distributed teams to come together across distance to share a task. Studies of CVE systems have tended to focus on the sense of presence or copresence with other people. They have avoided studying close interaction between us-ers, such as the shared manipulation of objects, because CVEs suffer from inherent network delays and often have cumbersome user interfaces. Little is known about the ef-fectiveness of collaboration in tasks requiring various forms of object sharing and, in particular, the concurrent manipu-lation of objects.

This paper investigates the effectiveness of supporting teamwork among a geographically distributed group in a task that requires the shared manipulation of objects. To complete the task, users must share objects through con-current manipulation of both the same and distinct at-tributes. The effectiveness of teamwork is measured in terms of time taken to achieve each step, as well as the impression of users. The effect of interface is examined by comparing various combinations of walk-in cubic immersive projection technology (IPT) displays and desktop devices.
The United States, Brazil, and the Cuban Missile Crisis, 1962 (Part 1)
Authors: Hershberg James G.
Published: March 2004

Though virtually ignored in the historiography, Brazil played an intriguing role in the politics and diplomacy of the Cuban missile crisis and in U.S. Cuban relations during the Kennedy administration. In the years after Fidel Castro took power, successive Brazilian governments tried secretly to mediate between the United States and Cuba as the two countries' mutual confrontation intensified. Newly available U.S., Brazilian, Cuban, and other sources reveal that this role climaxed during the missile crisis, as John F. Kennedy clandestinely sought to employ Brazil to transmit a message to Castro. In turn, Brazil, which was also promoting a Latin American denuclearization scheme at the United Nations as a possible method to resolve the crisis, sought to broker a formula for U.S. Cuban reconciliation that would heighten the prestige of its own “independent” policy in the Cold War. Ultimately, these efforts failed, but they shed light on previously hidden aspects of both the missile crisis and the triangular U.S. Cuban—Brazilian relationship. Thefirst part of this two—part article sets the scene for an in—depth look at the Cuban missile crisis, which will be covered in Part 2 of the article in the next issue of the journal.
PEA‐15 Modulates TNFα Intracellular Signaling in Astrocytes
Authors: SHARIF ARIANE , CANTON BRIGITTE , JUNIER MARIE‐PIERRE , CHNEIWEISS HERVÉ
Published: March 2004

Abstract: PEA‐15 is a small protein (15 kDa) that was first identified as an abundant phosphoprotein in brain astrocytes and subsequently shown to be widely expressed in different tissues and highly conserved among mammals. It is composed of an N‐terminal death effector domain (DED) and a C‐terminal tail of irregular structure. PEA‐15 is regulated by multiple calcium‐dependent phosphorylation pathways. PEA‐15 is ideally positioned to play a major role in signal integration. Accordingly, it has been demonstrated that PEA‐15 diverts astrocytes from TNFα‐triggered apoptosis and regulates the actions of the ERK MAP kinase cascade by binding to ERK and altering its subcellular localization. Expression of PEA‐15 directs TNFα outcomes toward survival, whereas its absence allows the development of the cytokine‐induced cell death.
Regulation of Drosophila MKP‐3 by Drosophila ERK
Authors: KIM SUNG‐EUN , KIM SUN‐HONG , CHOI KANG‐YELL
Published: March 2004

Abstract: DMKP‐3 is a Drosophila dual‐specificity phosphatase, which has high substrate specificity for Drosophila extracellular signal‐regulated kinases (DERK). By in vitro reconstitution experiments, we found that DERK activates DMKP‐3. Moreover, DMKP‐3 was specifically activated by the addition of DERK but not by DJNK, Dp38, or Sevenmaker DERK D334N, a DMKP‐3‐ binding mutant. The phosphatase activity of DMKP‐3‐R56A/R57A, a DERK‐binding mutant, was not increased by DERK. Significantly, mammalian MKP‐3 was also found to be activated by DERK. This cross‐reactivity suggests a high level of conservation of the activation mechanism of ERK‐specific phosphatases in Drosophila and mammals. When DMKP‐3 was co‐expressed with DERK in Drosophila Schneider cells, DMKP‐3 protein levels increased, but this was not observed for the co‐expressions of DJNK or Dp38. The stabilizations of the DERK binding mutants (DMKP‐3‐RR and DMKP‐3‐CA‐RR) were not increased by DERK co‐expression. Our results suggest that DERK specifically regulates DMKP‐3 in terms of its enzyme activity and protein stability, and that direct protein‐protein interaction is an essential aspect of this regulation.
Activation of JNK in Sensory Neurons Protects against Sensory Neuron Cell Death in Diabetes and on Exposure to Glucose/Oxidative Stress in Vitro
Authors: PRICE SALLY A. , HOUNSOM LUKE , PURVES‐TYSON TERTIA D. , FERNYHOUGH PAUL , TOMLINSON DAVID R.
Published: March 2004

Abstract: Diabetes activates all three groups of MAP kinases in sensory ganglia. Inhibition of this activation for the ERK and p38 groups prevents nerve damage, and agents that improve neuronal function in diabetic rats—antioxidants and aldose reductase inhibitors—also inhibit activation of ERK and p38 in dorsal root ganglia (DRG). However, these same treatments consistently increase activation of JNK. Thus, in DRG from rats with streptozotocin (STZ)‐induced diabetes of 12‐week duration, the p54/56 isoforms of JNK were activated by 2.75 compared to controls (P < .05). In DRG from diabetic rats treated with a gamma‐linolenic acid and alpha‐lipoic acid diester (GLA⁁⁁LA), the activity of the p54/56 isoform was 3.75 that of controls and the p46 isoform was also increased to 1.75 that of controls (both P < .05 compared to both controls and untreated diabetics). We therefore tested the hypothesis that JNK activation is protective. Exposure of rats to diabetes increased activation of JNK in DRG, but treatment with GLA⁁⁁LA increased this effect (P < .05). Specific inhibition of JNK in primary cultures of DRG neurons using a peptide inhibitor of JNK (JNKi1, 159–600‐R100, 7.5 μM, Alexis Biochemicals) increased the release of LDH and reduced MTT staining; both findings indicate an increase in neuronal damage. Taken together these findings indicate that multiple isoforms of JNK were activated in sensory neurons of diabetic rats, probably by a combination of raised glucose and oxidative stress, and that this activation of JNK serves to protect the neurons from damage.
Study of PTPC Composition during Apoptosis for Identification of Viral Protein Target
Authors: VERRIER FLORENCE , MIGNOTTE BERNARD , JAN GWENAËL , BRENNER CATHERINE
Published: March 2004

Abstract: The permeability transition pore complex (PTPC), a mitochondrial polyprotein complex, has been previously described to be involved in the control of mitochondrial membrane permeabilization (MMP) during chemotherapy‐induced apoptosis. PTPC may contain proteins from both mitochondrial membranes [e.g., voltage‐dependent anion channel (VDAC), PRAX‐1, peripheral benzodiazepine receptor (PBR), adenine nucleotide translocator (ANT)], from cytosol (e.g., hexokinase II, glycerol kinase), from matrix [e.g., cyclophilin D (CypD)], and from intermembrane space (e.g., creatine kinase). PTPC may also interact with tumor suppressor proteins (i.e., Bax and Bid), oncoprotein homologues of Bcl‐2 and some viral proteins, which can regulate apoptosis induced by pore opening. ANT and VDAC are the target of numerous pro‐apoptotic MMP inducers. However, the precise composition of PTPC as well as the respective role of each PTPC component represent major issues in the understanding MMP process. Using several experimental strategiesthat combine co‐immunoprecipitation, proteomics, and functional tests with proteoliposomes, we and others have been able to characterize some of the intra/inter‐PTPC protein interactions leading to a better understanding of the process of MMP. In addition, this approach could identify new putative members and regulators of PTPC pro‐apoptotic function and new targets of viral protein involved in the modulation of apoptosis during infection.
Prodigiosin Induces Apoptosis by Acting on Mitochondria in Human Lung Cancer Cells
Authors: LLAGOSTERA ESTHER , SOTO‐CERRATO VANESSA , MONTANER BEATRIZ , PÉREZ‐TOMÁS RICARDO
Published: March 2004

Abstract: Prodigiosin (PG) is a secondary metabolite, isolated from a culture of Serratia marcescens, which has shown potent cytotoxicity against various human cancer cell lines as well as immunosuppressive activity. The purpose of this study was to evaluate the role of mitochondria in PG‐induced apoptosis. Therefore, we evaluated the apoptotic action of PG in GLC4 small cell lung cancer cell line by Hoechst 33342 staining. In these cells, we examined mitochondrial apoptosis‐inducing factor (AIF) and cytochrome c (cyt c) release to the cytosol in PG time‐response studies. These findings suggest that PG induces apoptosis in both caspase‐dependent and caspase‐independent pathways.
Molecular Interaction between Cyclophilin D and Adenine Nucleotide Translocase in Cytochrome c Release
Authors: MACHIDA KIYOTAKA , OSADA HIROYUKI
Published: March 2004

Abstract: We propose a model for the mechanism of permeability transition (PT) related cytochrome c release. It is likely that the Ca2+ requirement for the induction of the mitochondrial permeability transition pore (MPTP) opening might be due to the Ca2+‐dependent interaction between cyclophilin D and ANT. We show here that the modification of adenine nucleotide translocase (ANT), which is one of the components of MPTP, can induce two different types of the cytochrome c release. One is dependent on classical PT, resulting in mitochondrial swelling, and is inhibited by cyclosporin A. The other is PT‐independent, without swelling, and is insensitive to cyclosporin A.
Cisplatin‐Induced Apoptosis in Melanoma Cells
Authors: DEL BELLO BARBARA , VALENTINI MARTA A. , COMPORTI MARIO , MAELLARO EMILIA
Published: March 2004

Abstract: Apoptosis protease‐activating factor‐1 (Apaf‐1), which plays a central role in the formation of the apoptosome, is absent or poorly expressed (because of a transcriptional silencing by methylation) in a substantial percentage of metastatic melanomas and melanoma cell lines, which are unable to activate caspase‐9 and execute the mitochondrial pathway of apoptosis. We studied cisplatin‐induced apoptosis of the Apaf‐1‐positive human metastatic Me665/2/21 melanoma cells. Our results indicate that caspase‐7 is already processed in still‐adhering cells and such activation, contrary to the common view, precedes caspase‐3 processing. As expected by the cytochrome c release into the cytosol, caspase‐9 is processed to active forms (p37 and p35), along with a yet‐unidentified p28. Interestingly, we also demonstrate a remarkable loss of Apaf‐1 protein, along with the appearance of a related immunoreactive fragment of ≊ 26 kDa; such proteolytic degradation proves to be a caspase‐3/‐7‐mediated event. Our data also indicate that the inhibition afforded by ac‐DEVD‐CHO on several components (i.e., caspase‐3/‐7 and caspase‐9 activities), and Apaf‐1 proteolytic degradation, does not significantly abrogate either the apoptotic morphology or the cleavage of canonical targets, such as poly(ADP‐ribose) polymerase (PARP) and lamin B. These results suggest that caspase‐3 and caspase‐7 are dispensable for the execution of apoptosis and, in our cellular model, the point of no return could be out of the mitochondrial cascade.
Combination of Tumor Necrosis Factor‐α with Sulindac in Human Carcinoma Cells in Vivo
Authors: YASUI HIROSHI , ADACHI MASAAKI , IMAI KOHZOH
Published: March 2004

Abstract: Transcription factor NF‐κB plays a pivotal role in cancer cells in the resistance to apoptosis, since NF‐κB is frequently activated in many primary carcinoma cells. Indeed, several NF‐κB inhibitors are found to be promising anti‐cancer agents. However, some anti‐cancer agents activate NF‐κB signals and may reduce their potential, including tumor necrosis factor (TNF)‐α. Recently, the nonsteroidal anti‐inflammatory drug (NSAID) sulindac and its metabolites have been shown to inhibit the NF‐κB‐mediated survival signals through inhibition of IKK‐β by their direct interaction. We thus investigate whether sulindac and its metabolite can augment TNF‐α‐mediated apoptosis in human carcinoma cells and be applicable for in vivo clinical usage. We here demonstrate that sulindac inhibited TNF‐α‐mediated NF‐κB activation and greatly enhanced TNF‐α‐induced apoptosis in human gastric MKN45 and cervical HeLa carcinoma cell lines. The in vivo tumor growth of MKN45 cells was most strongly inhibited by a combination of TNF‐α with sulindac compared with TNF‐α or sulindac alone. Moreover, we demonstrate that sulindac sulfide further augmented TNF‐α‐mediated apoptosis. Our data strongly suggest that combination therapy of TNF‐α with sulindac and its metabolites may sensitize cancer cells to TNF‐α and augment its pro‐apoptotic potential. Therefore, in combination with sulindac or its metabolites, TNF‐α may become a potentially useful anti‐cancer agent to suppress tumor.
ICBP90 Expression Is Downregulated in Apoptosis‐Induced Jurkat Cells
Authors: ABBADY ABDUL‐QADER , BRONNER CHRISTIAN , TROTZIER MARIE‐ALINE , HOPFNER RAPHAEL , BATHAMI KAWTAR , MULLER CHRISTIAN D. , JEANBLANC MICHAEL , MOUSLI MARC
Published: March 2004

Abstract: Inhibition of apoptosis, resulting from an increase in anti‐apoptotic protein, plays a fundamental role in carcinogenesis. Because ICBP90 gene expression is deregulated in cancer cells, we studied its expression in Jurkat cells under apoptotic conditions to see whether ICBP90 is involved in the regulation of apoptosis. We found that ICBP90 expression and the percentage of living cells were dose‐dependently decreased in PHA and ionophore A23187‐stimulated Jurkat cells, but not in THP‐1 cells. These results suggest that apoptosis is dependent upon ICBP90 expression downregulation and that ICBP90 exhibits anti‐apoptotic properties.
Apoptosis Induced by the Alkaloid Sampangine in HL‐60 Leukemia Cells
Authors: KLUZA JÉRÔME , CLARK ALICE M. , BAILLY CHRISTIAN
Published: March 2004

Abstract: Sampangine, a plant‐derived copyrine alkaloid extracted from the stem bark of Cananga odorata, primarily exhibits antifungal and antimycobacterial activities, but it also displays in vitro antimalarial activity against Plasmodium falciparum and is cytotoxic to human malignant melanoma cells. It inhibits cell aggregation, but no molecular target has yet been identified. We investigated the biochemical pathway involved in sampangine‐induced cytotoxicity toward HL‐60 cells. These leukemia cells are prone to enter apoptosis after treatment with various stimuli, including genotoxic compounds structurally close to sampangine, such as ascididemin.
Pro‐oxidant Activity of Low Doses of Resveratrol Inhibits Hydrogen Peroxide—Induced Apoptosis
Authors: AHMAD KASHIF ADIL , CLEMENT MARIE‐VERONIQUE , PERVAIZ SHAZIB
Published: March 2004

Abstract: We have recently shown that efficient apoptotic signaling is a function of a permissive intracellular milieu created by a decrease in the ratio of superoxide to hydrogen peroxide and cytosolic acidification. Resveratrol, a phytoalexin found in grapes and wines, triggers apoptosis in some systems and inhibits the death signal in others. In this regard, the reported inhibitory effect on hydrogen peroxide‐induced apoptosis has been attributed to its antioxidant property. Here, we provide evidence that exposure of human leukemia cells to low concentrations of resveratrol (4–8 μM) inhibits caspase activation and DNA fragmentation induced by incubation with hydrogen peroxide or upon triggering apoptosis with a novel compound that kills via intracellular hydrogen peroxide production. At these concentrations, resveratrol elicits pro‐oxidant properties as evidenced by an increase in intracellular superoxide concentration. This pro‐oxidant effect is further supported by our observations that the drop in intracellular superoxide and cytosolic acidification induced by hydrogen peroxide is completely blocked in cells preincubated with resveratrol. Thus, the inhibitory effect of resveratrol on hydrogen peroxide‐induced apoptosis is not due to its antioxidant activity, but contrarily via a pro‐oxidant effect that creates an intracellular environment nonconducive for apoptotic execution.
The Sesame Seed Oil Constituent, Sesamol, Induces Growth Arrest and Apoptosis of Cancer and Cardiovascular Cells
Authors: JACKLIN ALIX , RATLEDGE COLIN , WELHAM KEVIN , BILKO DENNIS , NEWTON CHRISTOPHER J.
Published: March 2004

Abstract: Sesamol is a potent inhibitor of fungal fatty acid biosynthesis. This effect is apparently due to inhibition of malic enzyme and the supply of NADPH that is required for this biosynthetic pathway. It is the ability of sesamol to reduce the synthesis of the coenzyme, NADPH, that makes it attractive for use in studying the effect of oxidants on tumor and vascular endothelial cells. By conducting preliminary studies on the effect of sesamol alone, it was clear that the compound demonstrated marked cytotoxicity. This paper describes the experiments performed.
Catha edulis (Khat) Induces Cell Death by Apoptosis in Leukemia Cell Lines
Authors: DIMBA E , GJERTSEN B T. , FRANCIS G W. , JOHANNESSEN A C. , VINTERMYR O K.
Published: March 2004

Abstract: Khat is the Celastraceus edulis plant, a flowering evergreen tree or large shrub, which grows in the Horn of Africa and southwestern Arabia. Khat use has been associated with development of oral cancer, but its molecular effects remain controversial. This study describes a novel cytotoxic effect of whole khat extract on three leukemia cell lines. Cells were exposed to khat extract and harvested for analysis by fluorescent and electron microscopy, trypan blue exclusion, as well as immunoblotting to characterize the mode of cell death. In a separate series, cells were pretreated with a panel of caspase inhibitors for possible inhibitory effects. Khat induced a rapid cell death effect in HL‐60, Jurkat, and NB4 cells that occurred within 2 h of exposure. The treated cells retained their ability to exclude trypan blue dye, a key feature in the apoptotic process. Exposed cells consistently developed morphological features of manifest apoptosis. Z‐VAD, a pan‐caspase inhibitor, completely inhibited toxic activity for up to 8 h, with partial inhibition by other caspase‐specific agents. Western blot analysis showed specific cleavage of caspase‐3 in khat‐exposed cells. This study shows that khat induces cell death by apoptosis in a process sensitive to inhibition by caspase inhibitors, suggesting that subcellular interactions could be of particular relevance for the biological effects of khat in the cell death process and possibly carcinogenesis.
Curcumin‐Induced Cell Death in Two Leukemia Cell Lines: K562 and Jurkat
Authors: DUVOIX A , MORCEAU F , SCHNEKENBURGER M , DELHALLE S , GALTEAU M M. , DICATO M , DIEDERICH M
Published: March 2004

Abstract: Curcumin presents strong antioxidant and anticancer properties. However, molecular mechanisms leading to curcumin‐induced cell death are poorly understood. The effect of curcumin was compared in two different leukemia cell lines: K562 and Jurkat. Cell death was induced in both cell lines, and apoptosis pathways were investigated by Western blot analysis. Decreases in pro‐caspase 8 and 9 levels were observed. BH3 interacting domain death agonist (Bid) was also cleaved. Jurkat cells appeared to be more sensitive to curcumin, and apoptosis takes place earlier.
CUGBP2 Plays a Critical Role in Apoptosis of Breast Cancer Cells in Response to Genotoxic Injury
Authors: MUKHOPADHYAY DEBNATH , JUNG JESSE , MURMU NABENDU , HOUCHEN COURTNEY W. , DIECKGRAEFE BRIAN K. , ANANT SHRIKANT
Published: March 2004

Abstract: Posttranscriptional control of gene expression plays a key role in regulating gene expression in cells undergoing apoptosis. Cyclooxygenase‐2 (COX‐2) is a crucial enzyme in the conversion of arachidonic acid to prostaglandin E2 (PGE2) and is significantly upregulated in many types of adenocarcinomas. COX‐2 overexpression leads to increased PGE2 production, resulting in increased cellular proliferation. PGE2 enhances the resistance of cells to ionizing radiation. Accordingly, understanding mechanisms regulating COX‐2 expression may lead to important therapeutic advances. Besides transcriptional control, COX‐2 expression is significantly regulated by mRNA stability and translation. We have previously demonstrated that RNA binding protein CUGBP2 binds AU‐rich sequences to regulate COX‐2 mRNA translation. In the current study, we have determined that expression of both COX‐2 mRNA and CUGBP2 mRNA are induced in MCF‐7 cells, a breast cancer cell line, following exposure to 12 Gy γ‐irradiation. However, only CUGBP2 protein is induced, but COX‐2 protein levels were not altered. Silencer RNA (siRNA)‐mediated inhibition of CUGBP2 reversed the block in COX‐2 protein expression. Furthermore, MCF‐7 cells underwent apoptosis in response to radiation injury, which was also reversed by CUGBP2 siRNAs. These data suggest that CUGBP2 is a critical regulator of the apoptotic response to genotoxic injury in breast cancer cells.
Vaccinia Virus Complement Control Protein Modulates Inflammation Following Spinal Cord Injury
Authors: REYNOLDS D N. , SMITH S A. , ZHANG Y‐P , LAHIRI D K. , MORASSUTTI D J. , SHIELDS C B. , KOTWAL G J.
Published: March 2004

Abstract: The vaccinia virus complement control protein (VCP) possesses multiple modulatory functions. Functioning as a complement inhibitory protein, VCP reduces production of proinflammatory chemotactic factors produced during complement activation. Additionally, VCP binds heparin and heparan sulfate proteoglycans, resulting in added functions shown to block monocyte chemotaxis in vitro. Using an in vivo spinal cord contusive injury model in rats, the inflammation‐modulating abilities of VCP were evaluated. The results of both myeloperoxidase assaying and H&E stained section counts of spinal tissue reveal that neutrophil infiltration to the area of the lesion was reduced in animals that received VCP as compared to saline‐injected controls.
Characterization of Antiapoptotic Activities of Chlamydia pneumoniae in Infected Cells
Authors: Fischer S F. , Häcker G
Published: March 2004

Abstract: C. pneumoniae has the capacity to inhibit apoptosis. Here we provide further insight into how infection with C. pneumoniae affects the apoptotic signal transduction in infected human epitheloid cells. For assessing changes in the apoptotic response, intact cells and cell extracts were used. These results show that C. pneumoniae is able to interfere with the host cell's apoptotic apparatus at least at two steps in the signal transduction.
Role of Phospholipomannan in Candida albicans Escape from Macrophages and Induction of Cell Apoptosis through Regulation of Bad Phosphorylation
Authors: IBATA‐OMBETTA STELLA , IDZIOREK THIERRY , TRINEL PIERRE‐ANDRÉ , POULAIN DANIEL , JOUAULT THIERRY
Published: March 2004

Abstract: Candida albicans, the most common opportunistic fungal pathogen of humans is a part of the normal microbial flora. To investigate host‐parasite interaction related to the commensal‐pathogen switch of this yeast we compared the response of macrophages to C. albicans and to the non‐pathogenic yeast Saccharomyces cerevisiae. In contrast to S. cerevisiae, C. albicans survived within macrophages. This escape from macrophages was associated with qualitative differences in the sequential phosphorylation of MEK, ERK1/2, and p90RSK during phagocytosis. Decreased activation of this pathway was observed with C. albicans and was associated with a species‐specific overexpression of the MEK phosphatase, MKP‐1. Dysregulation of the ERK1/2/p90RSK signal transduction pathway by C. albicans was associated downstream with reduction in Bad phosphorylation, specifically at Ser‐112, and disappearance of free Bcl‐2. This ended at apoptosis of cells that have ingested C. albicans, as revealed by staining of phosphatidylserine exposure in the macrophage outer membrane. The role of phospholipomannan (PLM), a phylogenetically unique glycolipid with a phytoceramide moiety expressed at the surface of and shed by C. albicans, was examined. Addition of PLM to macrophages led to dysregulation similar to that observed with live C. albicans and promoted the survival of the sensitive S. cerevisiae within the cells. Evidence of externalization of membranous phosphatidylserine, loss of mitochondrial integrity, and DNA fragmentation after incubation of macrophages with PLM suggest that this molecule supported the activities observed with C. albicans yeast cells.
Inhibition of Apoptosis by Human T‐Lymphotropic Virus Type‐1 Tax Protein
Authors: SAGGIORO DANIELA , ACQUASALIENTE LIDIA , DAPRAI LAURA , CHIECO‐BIANCHI LUIGI
Published: March 2004

Abstract: Deregulation of the apoptotic process can lead to pathophysiological changes that result in either degenerative diseases or cancer. Although the transactivator Tax has been established as an essential effector of human T‐lymphotropic virus type‐1 (HTLV‐1)‐mediated diseases, which include both a neurodegenerative pathology and leukemia/lymphoma, its exact role(s) in the pathogenesis remains to be clarified. Because the apoptotic potential of Tax is still being debated, we addressed this question by testing the susceptibility of Tax(‐) and Tax(+) cells to apoptosis under conditions of growth factor withdrawal and Bax overexpression. Results showed that Tax(+) cells are protected from apoptosis triggered by depletion of growth factors. This protective effect seems to be the result of a block in the apoptotic program regulated by mitochondria. Furthermore, in an attempt to elucidate which transcriptional pathway activated by Tax is important in the observed Tax‐induced resistance, we found that CREB/ATF activity plays a relevant role in protecting cells from apoptosis induced by Bax overexpression. All together, these data might suggest that the ability of Tax to inhibit certain apoptotic stimuli could be important in its role as a viral transforming protein.
Molecular Mechanisms for Cardiovascular Stem Cell Apoptosis and Growth in the Hearts with Atherosclerotic Coronary Disease and Ischemic Heart Failure
Authors: GENG YONG‐JIAN
Published: March 2004

Abstract: In the heart with atherosclerotic coronary disease, chronic ischemia causes progressive loss of cardiovascular cells and ultimately triggers myocardial dysfunctions or heart failure. Various types of stem cells from embryonic and adult tissues have potentials for regenerating functional cardiovascular cells in the heart undergoing ischemic injury. However, native or exogenous stem cells in the ischemic hearts are exposed to various proapoptotic or cytotoxic factors. Furthermore, during repopulation and differentiation, certain numbers of newly produced cells may die by apoptosis during neocardiovascular tissue remodeling and morphogenesis. Embryonic and adult stem cells may have different life spans, as being programmed genetically to apoptosis. The endogenous and environmental factors play important roles in regulation of stem cells, including inflammatory cytokines, growth factors, surface receptors, proteolytic enzymes, mitochondrial respiration, nuclear proteins, telomerase activities, hypoxia‐responding proteins, and stem cell‐host cell interaction. Clarification of the molecular mechanisms may help us understand and design stem cell therapies.
Assessment of In Vivo Chemotherapy‐Induced DNA Damage in a p53‐Mutated Rat Tumor by Micronuclei Assay
Authors: DRIESSENS GREGORY , HARSAN LAURA , BROWAEYS PATRICK , GIANNAKOPOULOS XENOFON , VELU THIERRY , BRUYNS CATHERINE
Published: March 2004

Abstract: Production of DNA damage is the basis of cancer treatments such as chemo‐ and radiotherapy. Such treatments induce mitotic catastrophe, a form of cell death resulting from abnormal mitosis and leading to the formation of interphase cells with multiple micronuclei. In this study, we compared apoptosis induction and micronuclei formation to assess the DNA damage provoked in vivo by cytotoxic agents in established 9L rat gliosarcoma tumors expressing a mutated p53 gene. Results from TUNEL assays revealed the efficiency of local γ‐irradiation at the tumor site to induce apoptosis within 9L tumor mass. However, little or no apoptosis was detected after systemic (ip) injection of cisplatin (1 mg/kg). Interestingly, the micronuclei assays showed that not only γ‐irradiation but also cisplatin treatment led to an increase in the emergence of binucleated cells with micronuclei. Apoptosis induction and micronuclei emergence are thus not absolutely correlated. However, micronuclei assays, rarely performed on solid tumors, appear more sensitive than apoptosis assays in evaluating DNA damage linked to chemotherapy.
A mission synthesis algorithm For fatigue damage analysis
Authors: Abdullah S , Giacomin J A , Yates J R
Published: March 2004

This paper presents a signal processing based algorithm, the Mildly Nonstationary Mission Synthesis (MNMS), which produces a short mission signal from long records of experimental data. The algorithm uses the discrete Fourier transform, orthogonal wavelet transform and bump reinsertion procedures. In order to observe the algorithm effectiveness a fatigue damage case study was performed for a vehicle lower suspension arm using signals containing tensile and compressive preloading. The mission synthesis results were compared to the original road data in terms of both the global signal statistics and the fatigue damage variation as a function of compression ratio. Three bump reinsertion methods were used and evaluated. The methods differed in the manner in which bumps (shock events) from different wavelet groups (frequency bands) were synchronized during the reinsertion process. One method, based on time-synchronized section reinsertion, produced the best results in terms of mission signal kurtosis, crest factor, root-mean-square level and power spectral density. For improved algorithm performance, bump selection was identified as the main control parameter requiring optimization.
Evaluation of energy-absorbing materials as a means to reduce foot/ankle axial load injury risk
Authors: Rudd R W , Kitagawa Y , Crandall J R , Poteau F C
Published: March 2004

Current restraint systems, such as seatbelts and airbags, have been developed mostly to protect the head and thorax during frontal crashes. They do not necessarily have equivalent effciency for lower extremities because of other loading factors such as the interaction between the foot and toepan or pedals. A relatively high frequency of foot and ankle injuries in combination with high morbidity warrants research into injury countermeasures. An energy-absorbing aluminium honeycomb was investigated as a means of load reduction during a simulated frontal impact with toepan intrusion. Test surrogates included human cadavers, a 50th percentile male Hybrid III leg with 45° dorsiflexion ankle and soft joint stop and a 50th percentile male Thor-Lx/HIIIr. Inclusion of an energy absorber between the cadaver heel and intruding footplate reduced tibia axial loads by as much as 39 per cent compared to cases without an energy absorber. Dummy results were compared to the human response and the Thor-Lx appeared to be more biofidelic than the Hybrid III.