bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies
Authors: Mahadevan Daruka , List Alan F.
Published: June 2004

The multidrug resistance-1 (MDR1) gene product, P-glycoprotein (P-gp), and the multidrug resistance–related proteins (MRPs) are members of the adenosine triphosphate (ATP)–binding cassette (ABC) transporter gene superfamily that regulates the trafficking of drugs, peptides, ions, and xenobiotics across cell membrane barriers. Three-dimensional modeling of human MDR1/P-gp indicates that these glycoproteins function as efficient, ATP-dependent gate-keepers, which scan the plasma membrane and its inner leaflet to flip lipophilic substrates to the outer membrane leaflet. Delineation of the adverse prognostic power of MDR1 in adult acute myeloid leukemia (AML) raised hopes that pharmacologic blockade of P-gp would improve the outcome of conventional cytotoxic therapy, perhaps more so than in any other human malignancy. Phase 3 clinical trials investigating first- and second-generation P-gp antagonists have yielded conflicting results, emphasizing the importance of applying preclinical principals to realistically appraise expectations for clinical benefit. Structure-based design strategies and the delineation of transcriptional regulators of survival gene cassettes promise to yield novel, more-effective strategies to overcome drug resistance. Lessons learned from investigations of these and other mechanisms of cellular defense hold promise for a renaissance in the development of targeted therapeutics in acute leukemia.
Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene
Authors: Sabatino Denise E. , Armstrong Elina , Edmonson Shyrie , Liu Yi-Lin , Pleimes Marc , Schuettrumpf Joerg , Fitzgerald Julie , Herzog Roland W. , Arruda Valder R. , High Katherine A.
Published: June 2004

Animal models have been critical to the development of novel therapeutics in hemophilia. A deficiency of current murine models of hemophilia B is that they are all due to gene deletions, a type of mutation that is relatively rare in the human hemophilia population. We generated mice with a range of mutations in the Factor IX (F.IX) gene; these more faithfully reflect the types of mutations that cause disease in the human population. Transgenic mice expressing either wild-type human F.IX (hF.IX), or F.IX variants with premature translation termination codons, or missense mutations, under the control of the murine transthyretin promoter, were generated and crossed with mice carrying a large deletion of the murine F.IX gene. Gene copy number, F.IX transcript levels in the liver, intrahepatocyte protein expression, and circulating levels of F.IX protein in the mice were determined and compared with data generated by transient transfection assays using the same F.IX variants. Mice were injected with a viral vector expressing hF.IX and displayed a range of immune responses to the transgene product, depending on the underlying mutation. These new mouse models faithfully mimic the mutations causing human disease, and will prove useful for testing novel therapies for hemophilia. (Blood. 2004;104:2767-2774)
P-selectin binding to P-selectin glycoprotein ligand-1 induces an intermediate state of αMβ2 activation and acts cooperatively with extracellular stimuli to support maximal adhesion of human neutrophils
Authors: Ma Yan-Qing , Plow Edward F. , Geng Jian-Guo
Published: June 2004

P-selectin glycoprotein ligand 1 (PSGL-1, CD162) and integrin αMβ2 (Mac-1, CD11bCD18) are leukocyte adhesion molecules essential for innate immunity and inflammation. The interaction of PSGL-1 with P-selectin (CD62P) mediates tethering, rolling, and weak adhesion of leukocytes, during which they become sufficiently activated in situ by locally released or displayed cytokines and chemoattractants for integrin-mediated firm adhesion. However, communication between P-selectin and the integrin, whether P-selectin can trigger β2-integrin activation, remains controversial. We found that P-selectin immunoglobulin chimera and PSGL-1 monoclonal antibodies (mAbs) increased adhesion of human neutrophils to immobilized, but not soluble, fibrinogen. This intermediate state of neutrophil adhesion was defined by moderate clustering of integrin αMβ2, no increase in CBRM1/5 (a mAb specific for the activation epitope on the αM subunit) recognition, and no increase in surface expression of αMβ2, whereas phorbol myristate acetate (PMA) induced extensive changes in these 3 parameters. Furthermore, platelet-activating factor or interleukin 8 acted in concert with P-selectin for further enhancing the activation of αMβ2. We thus propose a model in which P-selectin induces an intermediate state of integrin activation and then cooperates with other extracellular stimuli to support maximal adhesion of human neutrophils.
Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications
Authors: Kojouri Kiarash , Vesely Sara K. , Terrell Deirdra R. , George James N.
Published: June 2004

Splenectomy has been a standard treatment for adult patients with idiopathic thrombocytopenic purpura (ITP) for more than 50 years. However, the durability of responses, the ability to predict who will respond, and the frequency of surgical complications with splenectomy all remain uncertain. To better interpret current knowledge we systematically identified and reviewed all 135 case series, 1966 to 2004, that described 15 or more consecutive patients who had splenectomy for ITP and that had data for 1 of these 3 outcomes. Complete response was defined as a normal platelet count following splenectomy and for the duration of follow-up with no additional treatment. Forty-seven case series reported complete response in 1731 (66%) of 2623 adult patients with follow-up for 1 to 153 months; complete response rates did not correlate with duration of follow-up (r = -0.103, P = .49). None of 12 preoperative characteristics that have been reported consistently predicted response to splenectomy. Mortality was 1.0% (48 of 4955 patients) with laparotomy and 0.2% (3 of 1301 patients) with laparoscopy. Complication rates were 12.9% (318 of 2465) with laparotomy and 9.6% (88 of 921 patients) with laparoscopic splenectomy. Although the risk of surgery is an important consideration, splenectomy provides a high frequency of durable responses for adult patients with ITP. (Blood. 2004; 104:2623-2634)
VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis
Authors: Le Gouill Steven , Podar Klaus , Amiot Martine , Hideshima Teru , Chauhan Dharminder , Ishitsuka Kenji , Kumar Shaji , Raje Noopur , Richardson Paul G. , Harousseau Jean-Luc , Anderson Kenneth C.
Published: June 2004

Interleukin-6 (IL-6) triggers multiple myeloma (MM) cell proliferation and protects against apoptosis by up-regulating myeloid cell leukemia 1 (Mcl-1). Vascular endothelial growth factor (VEGF) induces modest proliferation of MM cells and induces IL-6 secretion in a paracrine loop involving MM cells and bone marrow stromal cells. Using murine embryonic fibroblast cell lines as a model (Mcl-1wt/wt and Mcl-1Δ/null MEFs), we here demonstrate that deletion of Mcl-1 reduces fetal bovine serum (FBS)-, VEGF-, and IL-6-induced proliferation. We also show that VEGF up-regulates Mcl-1 expression in a time- and dose-dependent manner in 3 human MM cell lines and MM patient cells. Importantly, we demonstrate that the pan-VEGF inhibitor, GW654652, inhibits VEGF-induced up-regulation of Mcl-1 and, as with Mcl-1 siRNA, is associated with decreased proliferation and induction of apoptosis. Finally, we show that VEGF protects MM patient cells against FBS starvation-induced apoptosis. Our studies therefore demonstrate that VEGF-induced MM cell proliferation and survival are mediated via Mcl-1, providing the preclinical framework for novel therapeutics targeting Mcl-1 and/or VEGF to improve patient outcome in MM.
Impact of modifications of heterocyclic bases in CpG dinucleotides on their immune-modulatory activity
Authors: Vollmer Jörg , Weeratna Risini D , Jurk Marion , Davis Heather L , Schetter Christian , Wüllner Meike , Wader Tanja , Liu Ming , Kritzler Andrea , Krieg Arthur M
Published: June 2004

Synthetic phosphorothioate oligodeoxynucleotides (ODN) bearing unmethylated CpG motifs can mimic the immune-stimulatory effects of bacterial DNA and are recognized by Toll-like receptor 9 (TLR9). Past studies have demonstrated that nucleotide modifications at positions at or near the CpG dinucleotides can severely affect immune modulation. However, the effect of nucleotide modifications to stimulate human leukocytes and the mechanism by which chemically modified CpG ODN induce this stimulation are not well understood. We investigated the effects of CpG deoxyguanosine substitutions on the signaling mediated by human TLR9 transfected into nonresponsive cells. ODN incorporating most of these substitutions stimulated detectable TLR9-dependent signaling, but this was markedly weaker than that induced by an unmodified CpG ODN. One of the most active ODN tested contained deoxyinosine for deoxyguanosine substitutions (CpI ODN), but its relative activity to induce cytokine secretion on mouse cells was much weaker than on human cells. The activity was dependent on TLR9, as splenocytes from mice genetically deficient in TLR9 did not respond to CpI ODN stimulation. It is surprising that CpI ODN were nearly as strong as CpG ODN for induction of human B cell stimulation but were inferior to CpG ODN in their ability to induce T helper cell type 1 effects. These data indicate that certain deoxyguanosine substitutions in CpG dinucleotides are tolerated to stimulate a TLR9-mediated immune response, but this response is insufficient to induce optimal interferon-α-mediated effects, which depend on the presence of an unmodified CpG dinucleotide. These studies provide a structure-activity relationship for TLR9 agonist compounds with diverse immune effects.
Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis
Authors: Ahmad Ali , Alvarez Fernando
Published: June 2004

Natural killer (NK) cells constitute the first line of host defense against invading pathogens. They usually become activated in an early phase of a viral infection. Liver is particularly enriched in NK cells, which are activated by hepatotropic viruses such as hepatitis C virus (HCV). The activated NK cells play an essential role in recruiting virus-specific T cells and in inducing antiviral immunity in liver. They also eliminate virus-infected hepatocytes directly by cytolytic mechanisms and indirectly by secreting cytokines, which induce an antiviral state in host cells. Therefore, optimally activated NK cells are important in limiting viral replication in this organ. This notion is supported by the observations that interferon treatment is effective in HCV-infected persons in whom it increases NK cell activity. Not surprisingly, HCV has evolved multiple strategies to counter host's NK cell response. Compromised NK cell functions have been reported in chronic HCV-infected individuals. It is ironic that activated NK cells may also contribute toward liver injury. Further studies are needed to understand the role of these cells in host defense and in liver pathology in HCV infections. Recent advances in understanding NK cell biology have opened new avenues for boosting innate and adaptive antiviral immune responses in HCV-infected individuals.
Eosinophils function as antigen-presenting cells
Authors: Shi Huan-Zhong
Published: June 2004

Eosinophils release lipid mediators, including leukotriene C4, platelet-activating factor, and liposins, and contain four distinct granule cationic proteins, major basic protein, eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin, which may cause dysfunction and destruction of other cells. Eosinophils are primarily thought of as terminal effectors of allergic responses and of parasite elimination. Eosinophils are characteristically present within the airway lumina of asthmatics, and these airway eosinophils have been induced in vivo to express major histocompatibility complex II (MHC-II) complexes and costimulatory molecules, which are required for T lymphocytes to be functionally activated. In in vitro experiments, eosinophils can process antigen and express the costimulatory molecules, and after cytokine-elicited induction of MHC-II, expression can function as antigen-presenting cells in stimulating T lymphocyte responses. Airway luminal eosinophils can migrate into draining paratracheal lymph nodes, localized to T cell-rich paracortical areas, and stimulate antigen-specific T cell proliferation in vivo within paratracheal lymph nodes, which was CD80- and CD86-dependent and limited to CD4+ T cells. Furthermore, eosinophils within the lumina of airways promote expansion of T helpr cell type 2 (Th2) by presenting antigen, suggesting that eosinophils actively modulate immune responses by amplifying Th2 cell responses.
HIV-1 compartmentalization in diverse leukocyte populations during antiretroviral therapy
Authors: Potter Simon J , Lemey Philippe , Achaz Guillaume , Chew Choo Beng , Vandamme Anne-Mieke , Dwyer Dominic E , Saksena Nitin K
Published: June 2004

CD4+ T lymphocytes are the primary target of human immunodeficiency virus type 1 (HIV-1), but there is increasing evidence that other immune cells in the blood, including CD8+ T lymphocytes and monocytes, are also productively infected. The extent to which these additional cellular reservoirs contribute to ongoing immunodeficiency and viral persistence during therapy remains unclear. In this study, we conducted a detailed investigation of HIV-1 diversity and genetic structure in CD4+ T cells, CD8+ T cells, and monocytes of 13 patients receiving highly active antiretroviral therapy (HAART). Analysis of molecular variance and nonparametric tests performed on HIV-1 envelope sequences provided statistically significant evidence of viral compartmentalization in different leukocyte populations. Signature pattern analysis and predictions of coreceptor use provided no evidence that selection arising from viral tropism was responsible for the genetic structure observed. Analysis of viral genetic variation in different leukocyte populations demonstrated the action of founder effects as well as significant variation in the extent of genetic differentiation between subpopulations among patients. In the absence of evidence for leukocyte-specific selection, these features were supportive of a metapopulation model of HIV-1 replication as described previously among HIV-1 populations in the spleen. Compartmentalization of the virus in different leukocytes may have significant implications for current models of HIV-1 population genetics and contribute to the highly variable way in which drug resistance evolves in different individuals during HAART.
Functional plasticity of macrophages: reversible adaptation to changing microenvironments
Authors: Stout Robert D , Suttles Jill
Published: June 2004

There has been substantial research activity in the past decade directed at phenotyping macrophage lineages and defining macrophage functional subsets or patterns of activity. The emphasis over the past 2–3 years has been to divide macrophage functional patterns into type 1 (Th1-driven) or type 2 (Th2-driven) functions. However, a huge array of environmental factors (including cytokines, chemokines, pattern recognition receptors, hormones) differentially regulates macrophage response patterns, resulting in the display of numerous distinct, functional phenotypes. Upon stimulation, a macrophage does not display just a single set of functions but rather displays a progression of functional changes in response to the progressive changes in its microenvironment. The remarkable ability of monocytes and tissue macrophages to adapt to changes in their microenvironment challenges the thesis that macrophages displaying unique tissue-specific or response-specific, functional patterns represent distinct lineages. With the exception of mature osteoclasts and mature dendritic cells, evidence supporting stable differentiation as the basis for macrophage functionl heterogeneity is equivocal. The concept of whether macrophages develop into functional subsets as opposed to continuously adapting their functional pattern in response to the changing environment of a progressive inflammatory response is important to resolve from the perspectives of therapeutic targeting and understanding the role of macrophages in disease pathogenesis.
Role of endogenous IL-10 in LPS-induced STAT3 activation and IL-1 receptor antagonist gene expression
Authors: Carl Virginia S , Gautam Jitendra K , Comeau Laurey D , Smith Michael F
Published: June 2004

The regulation of secretory interleukin (IL)-1 receptor antagonist (sIL-1Ra) in response to IL-10 is unique. In contrast to most cytokines, the lipopolysaccharide (LPS)-induced expression of the sIL-1Ra gene is enhanced by concomitant treatment with IL-10. Cotreatment of RAW 264.7 cells with IL-10 + LPS resulted in at least a twofold increase in sIL-1Ra promoter activity and mRNA expression compared with LPS alone; IL-10 alone had no effect on promoter activity or mRNA expression. Examination of sIL-1Ra mRNA expression in bone marrow-derived macrophages (BMDM) resulted in identical results. Transfection of RAW 264.7 cells with the sIL-1Ra/luc reporter and a dominant-negative signal transducer and activator of transcripton (STAT)3 (Y705A) expression plasmid inhibited the enhanced response induced by exogenous IL-10 in the presence of LPS. The presence of a functional STAT3-bininding site within the proximal sIL-1Ra promoter was demonstrated. As IL-10 is produced by LPS-stimulated macrophages, a role for endogenously produced IL-10 in the response of the sIL-1Ra gene to LPS was suggested. This was confirmed in IL-10-deficient BMDM, which when compared with normal BMDM, had significantly decreased LPS-induced sIL-1Ra mRNA levels that could be restored by exogenously provided IL-10, which induced a fivefold increase of LPS-induced IL-1Ra mRNA in cells from IL-10−/− BMDM. Western blot analysis of phosphorylated STAT3 from wild-type and IL-10−/− BMDM and IL-10 neutralization experiments demonstrated a role for endogenously produced IL-10 in the LPS-induced STAT3 activity. Together, these results demonstrate that endogenously produced IL-10 plays a significant role in LPS-induced sIL-1Ra gene expression via the activation of STAT3.
Existence of Chaos Associated with Weak Ballistic Capture and Applications
Authors: BELBRUNO EDWARD
Published: June 2004

Abstract: New results are stated to prove that under certain conditions weak capture gives rise to complicated chaotic dynamics due to the existence of a so called hyperbolic invariant set. Included in the dynamics is the existence of permanent capture. Low energy transfers to the moon using weak capture were first operationally demonstrated in 1991.
Geometric Mechanics and the Dynamics of Asteroid Pairs
Authors: KOON WANG‐SANG , MARSDEN JERROLD E. , ROSS SHANE D. , LO MARTIN , SCHEERES DANIEL J.
Published: June 2004

Abstract:The purpose of this paper is to describe the general setting for the application of techniques from geometric mechanics and dynamical systems to the problem of asteroid pairs. The paper also gives some preliminary results on transport calculations and the associated problem of calculating binary asteroid escape rates. The dynamics of an asteroid pair, consisting of two irregularly shaped asteroids interacting through their gravitational potential is an example of afull‐body problemor FBP in which two or more extended bodies interact. One of the interesting features of the binary asteroid problem is that there is coupling between their translational and rotational degrees of freedom. General FBPs have a wide range of other interesting aspects as well, including the 6‐DOF guidance, control, and dynamics of vehicles, the dynamics of interacting or ionizing molecules, the evolution of small body, planetary, or stellar systems, and almost any other problem in which distributed bodies interact with each other or with an external field. This paper focuses on the specific case of asteroid pairs using techniques that are generally applicable to many other FBPs. This particular full two‐body problem (F2BP) concerns the dynamical evolution of two rigid bodies mutually interacting via a gravitational field. Motivation comes from planetary science, where these interactions play a key role in the evolution of asteroid rotation states and binary asteroid systems. The techniques that are applied to this problem fall into two main categories. The first is the use of geometric mechanics to obtain a description of the reduced phase space, which opens the door to a number of powerful techniques, such as the energy‐momentum method for determining the stability of equilibria and the use of variational integrators for greater accuracy in simulation. Second, techniques from computational dynamic systems are used to determine phase space structures that are important for transport phenomena and dynamic evolution.
Migration of Jupiter‐Family Comets and Resonant Asteroids to Near‐Earth Space
Authors: IPATOV S I , MATHER J C
Published: June 2004

Abstract: The orbital evolution of about 26,000 Jupiter‐crossing objects and 1,500 resonant asteroids under the gravitationa influence of planets was investigated. The rate of their collisions with terrestrial planets was estimated by computing the probabilities of collisions based on random‐phase approximations and the orbital elements sampled with a 500 yr step. The Bulirsh‐Stoer and a symplectic orbit integrator gave similar results for orbital evolution, but sometimes give different collision probabilities with the Sun. For orbits close to that of Comet 2P, the mean collision probabilities of Jupiter‐crossing objects with terrestrial planets were greater by two orders of magnitude than for some other comets. For initial orbital elements close to those of Comets 2P, 10P, 44P, and 113P, a few objects (about 0.1%) entered Earth‐crossing orbits with semi‐major axes a < 2 AU and aphelion distances Q < 4.2 AU, and moved in such orbits for more than 1 Myr (up to tens or even hundreds of Myr). Some of them even got inner‐Earth orbits (Q < 0.983 AU) and Aten orbits. A few comets achieve typical asteroidal orbits for hundreds of Myr. Most former trans‐Neptunian objects that have typical near‐Earth object orbits moved in such orbits for millions of years; thus, during most of this time they were extinct comet, if they did not disintegrate.
Formation Flying Design and Applications in Weak Stability Boundary Regions
Authors: FOLTA DAVID
Published: June 2004

Abstract: Weak stability regions serve as superior locations for interferomertric scientific investigations. These regions are often selected to minimize environmental disturbances and maximize observation efficiency. Designs of formations in these regions are becoming ever more challenging as more complex missions are envisioned. The development of algorithms to enable the capability for formation design must be further enabled to incorporate better understanding of weak stability boundary solution space. This development will improve the efficiency and expand the capabilities of current approaches. The Goddard Space Flight Center (GSFC) is currently supporting multiple formation missions in weak stability boundary regions. This end‐to‐end support consists of mission operations, trajectory design, and control. It also includes both algorithm and software development. The Constellation‐X, Maxim, and Stellar Imager missions are examples of the use of improved numeric methods to attain constrained formation geometries and control their dynamical evolution. This paper presents a survey of formation missions in the weak stability boundary regions and a brief description of formation design using numerical and dynamical techniques.
Accessibility, Stabilizability, and Feedback Control of Continuous Orbital Transfer
Authors: GURFIL PINI
Published: June 2004

Abstract: This paper investigates the problem of low‐thrust orbital transfer using orbital element feedback from a control‐theoretic standpoint, concepts of controllability, feedback stabilizability, and their interaction. The Gauss variational equations (GVEs) are used to model the state‐space dynamics. First, the notion of accessibility, a weaker form of controllability, is presented. It is then shown that the GVEs are globally accessible. Based on the accessibility result, a nonlinear feedback controller is derived that asymptotically steers a vehicle from an initial elliptic Keplerian orbit to any given elliptic Keplerian orbit. The performance of the new controller is illustrated by simulating an orbital transfer between two geosynchronous Earth orbits. It is shown that the low‐thrust controller requires less fuel than an impulsive maneuver for the same transfer time. Closed‐form, analytic expressions for the new orbital transfer controller are given. Finally, it is proved, based on a topological nonlinear stabilizability test, that there does not exist a continuous closed‐loop controller that can transfer a spacecraft to a parabolic escape trajectory.
Finite Burn Maneuver Modeling for a Generalized Spacecraft Trajectory Design and Optimization System
Authors: OCAMPO CESAR
Published: June 2004

Abstract: The modeling, design, and optimization of finite burn maneuvers for a generalized trajectory design and optimization system is presented. A generalized trajectory design and optimization system is a system that uses a single unified framework that facilitates the modeling and optimization of complex spacecraft trajectories that may operate in complex gravitational force fields, use multiple propulsion systems, and involve multiple spacecraft. The modeling and optimization issues associated with the use of controlled engine burn maneuvers of finite thrust magnitude and duration are presented in the context of designing and optimizing a wide class of finite thrust trajectories. Optimal control theory is used examine the optimization of these maneuvers in arbitrary force fields that are generally position, velocity, mass, and are time dependent. The associated numerical methods used to obtain these solutions involve either, the solution to a system of nonlinear equations, an explicit parameter optimization method, or a hybrid parameter optimization that combines certain aspects of both. The theoretical and numerical methods presented here have been implemented in copernicus, a prototype trajectory design and optimization system under development at the University of Texas at Austin.
A Systematic‐Heuristic Approach for Space Trajectory Design
Authors: VASILE MASSIMILIANO
Published: June 2004

Abstract: In this paper a novel algorithm is proposed for space trajectory design that combines a systematic and a heuristic method for global optimization. For the systematic part of the algorithm a branching technique is used, whereas a particular implementation of evolution programming forms the core of the heuristic part. The idea is to use a limited population evolving for a small number of generations, according to specific evolution rules, in subregions of the solution space defined by a branching procedure. On the other hand the branching rules are functions of the outcome from the evolution optimization. The proposed combined systematic‐heuristic global optimization performs quite well on the cases analyzed in this paper, suggesting the possibility of more complex applications.
Autonomous Low‐Thrust Guidance: Application to SMART‐1 and BepiColombo
Authors: GIL‐FERNÁNDEZ JESÚS , GRAZIANO MARIELLA , GÓMEZ‐TIERNO M A , MILIC E
Published: June 2004

Abstract: Several techniques have been developed to obtain optimum trajectories with low‐thrust propulsion. However, few low‐thrust guidance schemes have been investigated to fly the reference optimum trajectories. The guidance algorithm successfully employed in the DeepSpace1 mission was the first approximation through the presented guidance schemes, valid for various interplanetary low‐thrust trajectories, independently of the optimization technique they result from. A method is presented to transform any given thrust profile to a thrust law defined by a finite set of control variables. This law allows the definition of a control vector to be optimized for the guidance purposes. Simulations were carried out to compare the performances of the algorithms to very different missions, such as SMART‐1 and BepiColombo. The good performance of the enhanced guidance schemes prove the generic applicability of the algorithm. Parametric analysis allows the assessment of stability and robustness of the schemes and the sensitivity to certain parameters.
The Bering Small Vehicle Asteroid Mission Concept
Authors: MICHELSEN RENE , ANDERSEN ANJA , HAACK HENNING , JØRGENSEN JOHN L. , BETTO MAURIZIO , JØRGENSEN PETER S.
Published: June 2004

Abstract: The study of asteroids is traditionally performed by means of large Earth based telescopes, by means of which orbital elements and spectral properties are acquired. Space borne research, has so far been limited to a few occasional flybys and a couple of dedicated flights to a single selected target. Although the telescope based research offers precise orbital information, it is limited to the brighter, larger objects, and taxonomy as well as morphology resolution is limited. Conversely, dedicated missions offer detailed surface mapping in radar, visual, and prompt gamma, but only for a few selected targets. The dilemma obviously being the resolution versus distance and the statistics versus ΔV requirements. Using advanced instrumentation and onboard autonomy, we have developed a space mission concept whose goal is to map the flux, size, and taxonomy distributions of asteroids. The main focus is on main belt objects, but the mission profile will enable mapping of objects inside the Earth orbit as well.
Assessing NEO Hazard Mitigation in Terms of Astrodynamics and Propulsion Systems Requirements
Authors: REMO JOHN L.
Published: June 2004

Abstract:Uncertainties associated with assessing valid near‐Earth object (NEO) threats and carrying out interception missions place unique and stringent burdens on designing mission architecture, astrodynamics, and spacecraft propulsion systems. A prime uncertainty is associated with the meaning of NEO orbit predictability regarding Earth impact. Analyses of past NEO orbits and impact probabilities indicate uncertainties in determining if a projected NEO threat will actually materialize within a given time frame. Other uncertainties regard estimated mass, composition, and structural integrity of the NEO body. At issue is if one can reliably estimate a NEO threat and its magnitude. Parameters that determine NEO deflection requirements within various time frames, including the terminal orbital pass before impact, and necessary energy payloads, are quantitatively discussed. Propulsion system requirements for extending space capabilities to rapidly interact with NEOs at ranges of up to about 1 AU (astronomical unit) from Earth are outlined. Such missions, without gravitational boosts, are deemed critical for a practical and effective response to mitigation. If an impact threat is confirmed on an immediate orbital pass, the option for interactive reconnaissance, and interception, and subsequent NEO orbit deflection must be promptly carried out. There also must be an option to abort the mitigation mission if the NEO is subsequently found not to be Earth threatening. These options require optimal decision latitude and operational possibilities for NEO threat removal while minimizing alarm. Acting too far in advance of the projected impact could induce perturbations that ultimately exacerbate the threat. Given the dilemmas, uncertainties, and limited options associated with timely NEO mitigation within a decision making framework, currently available propulsion technologies that appear most viable to carry out a NEO interception/mitigation mission within the greatest margin of control and reliability are those based on a combined (bimodal) nuclear thermal/nuclear electric propulsion platform. Elements of required and currently available performance characteristics for nuclear and electric propulsion systems are also discussed.
Optimal Trajectories from the Earth‐Moon L1 and L3 Points to Deflect Hazardous Asteroids and Comets
Authors: MACCONE CLAUDIO
Published: June 2004

Abstract: Software code named asteroff was recently created by the author to simulate the deflection of hazardous asteroids off of their collision course with the Earth. This code was both copyrighted and patented to avoid unauthorized use of ideas that could possibly be vital to construct a planetary defense system in the vicinity of the Earth. Having so said, the basic ideas and equations underlying the asteroff simulation code are openly described in this paper. A system of two space bases housing missiles is proposed to achieve the planetary defense of the Earth against dangerous asteroids and comets, collectively called impactors herein. We show that the layout of the Earth‐Moon system with the five relevant Lagrangian (or libration) points in space leads naturally to only one, unmistakable location of these two space bases within the sphere of influence of the Earth. These locations are at the two Lagrangian points L1 (between the Earth and the Moon) and L3 (in the direction opposite to the Moon from the Earth). We show that placing missile bases at L1 and L3 would enable those missiles to deflect the trajectory of impactors by hitting them orthogonally to their impact trajectory toward the Earth, so as to maximize their deflection. We show that confocal conics are the best class of trajectories fulfilling this orthogonal deflection requirement. One additional remark is that the theory developed in this paper is just a beginning for a wider set of future research. In fact, we only develop the Keplerian analytical theory for the optimal planetary defense achievable from the Earth‐Moon Lagrangian points L1 and L3. Much more sophisticated analytical refinements would be needed to: (1) take into account many perturbation forces of all kinds acting on both the impactors and missiles shot from L1 and L3; (2) add more (non‐optimal) trajectories of missiles shot from either the Lagrangian points L4 and L5 of the Earth‐Moon System or from the surface of the Moon itself; and (3) encompass the full range of missiles currently available to the US (and possibly other countries) so as to really see which impactors could be diverted by which missiles, even in the very simplified scheme outlined here. Published for the first time in February 2002, our Keplerian planetary defense theory has proved, in just one year, to be simple enough to catch the attention of scholars, in addition to popular writers, and even of someone from the US Military. These recent developments might possibly mark the beginning of an all embracing vision in planetary defense beyond all learned congressional activities, dramatic movies, and unknown military plans covered by secrecy.
A Dynamic Metric for NEO Hazard Mitigation
Authors: REMO JOHN L.
Published: June 2004

Abstract:A dynamic metric for near‐Earth object (NEO) hazard mitigation quantifies threats from potential NEO impacts with Earth in terms of energy required to perturb threatening NEO orbits to avoid collision. The required energy is based on NEO mass, anticipated velocity change to avoid collision, and the momentum coupling coefficient.
Classification of Periodic Orbits in the Four‐ and Five‐Body Problems
Authors: BROUCKE ROGER A.
Published: June 2004

Abstract: The research described in this paper was motivated by the new types of periodic solutions that were recently discovered by Moore, Chenciner, Montgomery, and Simo in the three‐body and the N‐body problem (with large N). We attempt to classify the various types of periodic orbits, in the inertial frame, on the basis of an extensive numerical exploration. We have started an exploration of the four‐body problem, where the classification of types of periodic orbits is more involved. We immediately found those orbits with symmetry with respect to the x‐axis, the y‐axis, or both. Complete quadruple interplay, or a triple system around a single mass is possible. Finally, what seems to be the most frequent, two binary systems in orbit around the general center of mass. However, the last group can be separated into several subgroups. We have, for instance, the case of two masses on one orbit and the two other masses on another orbit. This is again a partial choreography. We then have the case of double binary choreographies: two binary systems in which all four masses travel on one single curve. To realize this situation, a certain commensurability is needed between the overall period and the period of each binary system. The binary system makes an odd integer number, q, of revolutions during a general period. We computed many cases from q= 5 to 97. This indicates that we have a discrete infinity of choreographies. The choreography q= 5 is an especially remarkable star‐shaped curve. Actually, we have two such infinite families, one with corotational and the other with contrarotational motions. We show that they can be justified by simple Keplerian approximations. Finally, we mention that our work depends heavily on the existence of symmetries. They simplify the algorithms for finding periodic orbits and they play an important role in the classification. In the four‐body problem with equal masses, we have five different types of symmetries. In addition to the well‐known collinear symmetry, we also found what we call double isosceles and trapezoidal symmetries. All our four‐body choreographies satisfy these two symmetry conditions. In the five‐body problem, we limit our work to two symmetry cases. We show that in Gerver's super‐eight choreography, we are allowed to place a fifth mass at the center and we may speak about a larger sun with four smaller but equal planets that are in a choreography.
Analytical Theory of an Artificial Satellite of the Moon
Authors: DE SAEDELEER BERNARD , HENRARD JACQUES
Published: June 2004

Abstract: The dynamics of an artificial satellite of the moon is quite different from the dynamics of an artificial satellite of the Earth. Indeed, the C22 term is only 1/10 of the J2 term, and the effect of the Earth on the lunar satellite is much larger than the effect of the Moon on a terrestrial satellite. The method used here is the Lie method for averaging the Hamiltonian of the problem, in canonical variables. The solution is developed in powers of the small factors linked to J2 and C22. Short period terms (linked to l, the mean anomaly) are eliminated first, and then the long period terms (linked to g, the mean argument of the periaster, and to h, the longitude of the ascending node), which finally gives the secular motion. The results are obtained in a closed form, without any series developments in eccentricity or inclination. Thus, the solution applies for a wide range of values, except for few isolated critical values. The results are only very preliminary. As a side result, we were able to check the solution given by Kozai for the effect of the J2 term on an artificial satellite.
The Solar Photon Thruster as a Terrestrial Pole Sitter
Authors: MATLOFF GREGORY L.
Published: June 2004

Abstract: Geosynchronous satellites are invisible at high latitudes. A pole‐sitting spacecraft would have communication, climate‐studies, and near‐polar Earth observation applications. We present a pole‐sitter based on the solar photon thruster (SPT), a two‐sail variant of the solar sail using a large curved collector sail (always normal to the Sun) to direct sunlight against a much smaller thruster. Thrust decreases slower for an SPT than for a conventional sail arrangement as the angle between sunlight and the collector normal increases. An SPT pole‐sitter is offset from the terrestrial pole so that a component of Earth gravity balances the solar radiation‐pressure component pushing the SPT off station. The component of gravitational attraction of the Earth pulling the spacecraft towards Earth is also balanced by a solar radiation‐pressure component. Results are presented for 80‐100% collector/thruster reflectivities. For a spacecraft areal mass thickness of 0.002 kg/m2, collector and thruster reflectivities of 0.9, the SPT can be situated above latitude 45° at a distance of approximately 60 Earth radii. An SPT pole sitter would be affected by lunar perturbation, which can be compensated for by an on‐board rocket thruster producing 2 × 10−6g acceleration, a second SPT thruster sail thrusting against the influence of the Moon, or by directing a microwave beam against the spacecraft. Since an SPT pole sitter is in a position rather than an orbit, the effect of terrestrial gravitation limits the size and design of the payload package, which limits terrestrial target resolution.
Structural Characterization of Three Novel Rat OKL38 Transcripts, Their Tissue Distributions, and Their Regulation by Human Chorionic Gonadotropin
Authors: Ong Choon Kiat , Ng Chuan Young , Leong Caine , Ng Chee Pang , Ong Chye Sun , Nguyen Thi Thanh Tuyen , Huynh Hung
Published: June 2004

We previously identified a novel pregnancy-induced growth inhibitory gene, OKL38. To develop a rat model for further characterization of OKL38’s role in the initiation and progression of breast and ovarian cancer, we now report the cloning and characterization of three novel rat OKL38 cDNAs that are derived through alternative splicing and differential promoter usage. These three transcripts differ in their 5′ untranslated regions but share a common open reading frame that encoded for a 52-kDa protein. OKL38 is mapped to chromosome 19, spanning a region of approximately 15 kb, and contains eight exons. Differential expression of these three rat OKL38 transcripts was observed in liver, kidney, ovary, mammary gland, and uterus. In situ hybridization localized the rat OKL38 transcripts to the luminal epithelial cells of the rat mammary gland and to the granulosa cells in the rat ovary. In vivo studies showed that the RtOKL38-2.0 transcript and protein were regulated by human chorionic gonadotropin in the rat mammary gland and ovary. Importantly, overexpression of RtOKL38-enhanced green florescence protein fusion protein in Buffalo rat liver cells resulted in growth inhibition and cell death. Our present findings suggest that OKL38 may function as an effector for human chorionic gonadotropin protection against mammary carcinogenesis, and the availability of the three rat OKL38 cDNAs may help to elucidate the possible role of OKL38 in cellular growth, differentiation, and carcinogenesis.
Modeling Multiple Sources of State Dependence in Random Utility Models: A Distributed Lag Approach
Authors: Seetharaman P. B.
Published: June 2004

We propose a utility-theoretic brand-choice model that accounts for four different sources of state dependence: 1. effects of lagged choices (structural state dependence), 2. effects of serially correlated error terms in the random utility function (habit persistence type 1), 3. effects of serial correlations between utility-maximizing alternatives on successive purchase occasions of a household (habit persistence type 2), and 4. effects of lagged marketing variables (carryover effects). Our proposed model also allows habit persistence to be a function of lagged marketing variables, while accommodating the effects of unobserved heterogeneity in household choice parameters. This model is more flexible than existing state-dependence models in marketing and labor econometrics. Using scanner panel data, we find structural state dependence to be the most important source of state dependence. Marketing-mix elasticities are systematically understated if state-dependence effects are incompletely accounted for. The Seetharaman and Chintagunta (1998) model is shown to recover spurious variety-seeking effects while overstating habit-persistence effects. Ignoring habit persistence type 1 leads to an underestimation, while ignoring habit persistence type 2 leads to an overestimation of structural state-dependence effects. We find lagged promotions to have carryover effects on habit persistence. Ignoring one or more sources of state dependence underestimates the total incremental impact of a sales promotion. We draw implications for manufacturer pricing.
“Let Me Talk to My Manager”: Haggling in a Competitive Environment
Authors: Desai Preyas S. , Purohit Devavrat
Published: June 2004

Although negotiating over prices with sellers is common in many markets such as automobiles, furniture, services, consumer electronics, etc., it is not clear how a haggling price policy can help a firm gain a strategic advantage or whether it is even sustainable in a competitive market. In this paper, we explore the implications of haggling and fixed prices as pricing policies in a competitive market. We develop a model in which two competing retailers choose between offering either a fixed price or haggling over prices with customers. There are two consumer segments in our analysis. One segment, the hagglers, has a lower opportunity cost of time and a lower haggling cost than the other segment, the nonhagglers. When both retailers follow the same pricing policy, then a haggling policy is more profitable than a fixed-price policy only when the proportion of nonhagglers is sufficiently high. We find two kinds of prisoners' dilemma: under some conditions, a more profitable haggling policy can be broken by a fixed-price policy, and under other conditions, a fixed-price policy can be broken by a haggling policy. Surprisingly, we show that under some conditions, an asymmetric outcome with one retailer haggling and the other offering a fixed price is also an equilibrium.
Product Strategy for Innovators in Markets with Network Effects
Authors: Sun Baohong , Xie Jinhong , Cao H. Henry
Published: June 2004

This paper examines four alternative product strategies available to an innovating firm in markets with network effects: single-product monopoly, technology licensing, product-line extension, and a combination of licensing and product-line extension. We address three questions. First, what factors affect the attractiveness of each of the four product strategies? Second, under what conditions will any particular strategy dominate the others? Third, what is the impact of licensing fees on the profitability of a licensing strategy? We show that offering a product line utilizes consumer heterogeneity to increase the total user base and is superior to free licensing when the innovator's cost of producing a low-quality product is low and network effects are weak. However, because of the advantage of licensing in generating a larger installed base, free licensing can dominate line extension when network effects are strong, even if the innovator suffers no cost disadvantage compared to the competitor. We also show that paid licensing trumps free licensing when the clone product has a high quality or a low cost, regardless of network effect. Finally, strong network effects make a lump-sum fee more profitable than a royalty fee (or a combination of both) because a royalty fee reduces the licensee's production.