bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Structure-Based Prediction of the Toxicokinetics of Inhaled Vapors in Humans
Authors: Poulin Patrick , Krishnan Kannan
Published: July 2002

The objectives of the present study were: (1) to evaluate the adequacy of setting hepatic extraction ratio (E) equal to 0 or 1 in physiologically based toxicokinetic (PBTK) models to generate the theoretically plausible envelope of venous blood concentration (Cv) profiles, and (2) to couple this approach with molecular structure-based estimation of blood:air and tissue: blood partition coefficients (PCs) to predictthe Cv profiles of volatile organic chemicals (VOCs) in humans. Setting E= 0 or 1 in PBTK models provided simulations of Cv envelopes that contained the Cv values determined in humans exposed to low concentrations of dichloromethane(DCM), ethylbenzene (EBZ), toluene (TOL), m-xylene(XYL), trichloroethy-lene (TCE), and 1,1,1-trichloroethane(TRI). Following the validation of using E= 0 or 1 in conventional PBTK models to predict the theoretically plausible envelope of Cv, a quantitative structure-toxicokinetic relationship (QSTkR) model was constructed. The QSTkR model used molecular structure information as the sole input to predict the PCs and considered E= 0 or 1 to generate simulations of the envelope of Cv. The experimental data on Cv were in most cases within the envelopes simulated using QSTkR models for DCM, EBZ, TOL, and XYL, but were outside the envelopes for TCE and TRI. The discrepancy observed between the Cv envelopes obtained using PBTK and QSTkR models can be explained by the fact that blood:air PCs of some VOCs were under-predicted while using molecular structure information. The modeling framework presented in this article represents the first animal-replacement tool that can provide a priori predictions of the toxicokinetic profiles of VOCs prior to laboratory experiments.
Autocrine Transforming Growth Factor‐β Growth Pathway in MurineOsteosarcoma Cell Lines Associated with Inability to AffectPhosphorylation of Retinoblastoma Protein
Authors: Navid Fariba , Letterio John J. , Yeung Choh L. , Pegtel Michiel , Helman Lee J.
Published: July 2002

Purpose. Production of active transforming growth factor‐β (TGF‐β )
by human osteosarcoma may contribute to malignant progression through mechanisms
that include induction of angiogenesis, immune suppression and autocrine growth
stimulation of tumor cell growth.To study events associated with induction of cell proliferation
by TGF‐β , we have evaluated the TGF‐β pathway in two murine osteosarcoma cell lines, K7
and K12.

Results. Northern and immunohistochemical analyses show that each cell
line expressesTGF‐β1 and TGF‐β3 mRNA and protein. Both cell lines secrete activeTGF‐β 1
and display a 30–50% reduction in growth when cultured in the presence of a TGF‐β blocking
antibody. Expression of TGF‐β receptors TβRI, TβRII and TβRIII is demonstrated by affinity
labeling with  125I
‐TGF‐β 1, and the intermediates, Smads 2, 3 and 4, are uniformly expressed.
Smads 2 and 3 are phosphorylated in response toTGF‐β , while pRb phosphorylation in each
osteosarcoma cell line is not affected by either exogenousTGF‐β or TGF‐β antibody.

Conclusions. The data implicate events downstream of Smad activation,
including impaired regulation of pRb, in the lack of a growth inhibitory response toTGF‐β ,
and indicate that this murine model of osteosarcoma is valid for investigating the roles of
autocrineTGF‐β in vivo.
Functional Outcome in Limb‐Salvage Surgery for Soft Tissue Tumours of the Foot and Ankle
Authors: Colterjohn Nigel R. , Davis Aileen M. , O′Sullivan Brian , Catton Charles N. , Wunder Jay S. , Bell Robert S.
Published: July 2002

Discussion. Thirty of 36 patients (83%) presenting with foot and ankle STS or fibromatosis were candidates for limb
preservation. With excellent local control and good functional outcome demonstrated in this study, limb salvage should
be a primary goal in the management of selected patients with STS and fibromatosis of the foot and ankle.
The Location and Appearance of Second Malignancies in Patients With Bilateral Retinoblastoma
Authors: Rubin Carole Z. , Rosenfield Nancy S. , Abramson Sara J. , Abramson David H. , Dunkel Ira J.
Published: July 2002

Purpose. This paper describes the clinical history and radiographic appearance of second
malignancies in patients with bilateral retinoblastoma.

Subjects/methods. The imaging studies and clinical data of 14 patients with a history of
bilateral retinoblastoma who were treated for second malignancies were reviewed.

Results. A total of 17 tumors were identified in 14 patients during the period 1978–1996. The median age of occurrence
of the second malignancy was 17 years (range 10–32 years). Fourteen of the 17 malignancies occurred in the facial
structures and three developed in the lower extremities. The histologies included osteosarcoma (n = 5), malignant fibrous
histiocytoma (n = 3), high‐grade spindle cell sarcoma (n = 3), malignant mesenchymoma
(n = 1), leiomyosarcoma (n = 4) and angiosarcoma
(n = 1). The tumors were locally aggressive and had a similar appearance to those found
in nonretinoblastoma patients. Six of the 14 patients are alive and disease free.

Discussion. Most of the adolescent and young adult retinoblastoma survivors developed second malignancies in the
irradiated facial structures but some occurred in distal sites. Radiologically, these tumors do not differ in appearance from
those seen in non‐retinoblastoma patients with the exception of their location.
The Impact of Radiotherapy Dose on Local Control of Ewing′s Sarcoma of Bone
Authors: Burnet Neil G. , Bliss Judith M. , Harmer Clive L.
Published: July 2002

Purpose. Improvements in the systemic management of Ewing′s sarcoma of bone over the last 20 years have led to a
dramatic improvement in survival. The corollary is that treatment of the primary disease requires re‐evaluation, since a
significant number of patients still suffer local relapse.
Patients. The effect of radiation dose on local control was reviewed in a series of 96 patients treated between 1967 and
1986. Seventy‐four had no metastases at presentation (M0), 22 had metastases (M1). The 5‐year survival of all patients
was 28%, and of M0 patients alone 37%. Although these figures are poor by today′s standards, they are consistent with
published studies whose patients were enrolled during the same calendar period. Although most deaths occurred by 5
years, survival continued to fall beyond 10 years, which has implications for follow‐up in future studies.
Results. The local control (LC) rate at 5 years was 56% for all patients and for M0 patients analyzed separately. There
was no difference in either LC or survival between the first and second decades of the study. Primary site was a significant
determinant of survival and local control, with better outcome for limb tumours compared to pelvic primaries.
Chemotherapy also had a major effect on LC. Radiotherapy improved the probability of LC. Omission of radiotherapy,
or a dose <40 Gy, was ineffective. In the dose range 40–66 Gy, there was no evidence of a dose–response relationship.
Simultaneous Epstein Barr Virus and Cytomegalovirus Infection Accompanied by Leiomyomatous Change in a Well‐Differentiated Liposarcoma in a Patient With Long‐Term Corticosteroid Treatment
Authors: Sars Paul R. A. , Molenaar Willemina M. , Koudstaal Jan , Hoekstra Harald J.
Published: July 2002

Patient. A 59‐year‐old woman presented with a large tumour of the abdominal wall. She had been
taking corticosteroids for severe chronic obstructive pulmonary disease for 15 years. On CT scan the tumour had the characteristics of
lipomatous tissue with a dense core.

Results. Histology showed a well‐differentiated liposarcoma with a core of benign fibroleiomyomatous differentiation.
Within the core, a third component was observed, characterized by more pleomorphism and the presence of an
inflammatory infiltrate. In this component, immunoperoxidase stains and in situ hybridization demonstrated cytomegalovirus
(CMV) and Epstein Barr virus (EBV) infection in large and small cells, respectively.

Discussion. Long‐term corticosteroid use for pulmonary disease may extend the list of immunosuppressed states
associated with the development of leiomyomatous tumours with EBV infection, previously described in AIDS patients
and liver transplant recipients. The role of CMV is uncertain.
Zyxin, a Regulator of Actin Filament Assembly, Targets the Mitotic Apparatus by Interacting with H-Warts/Lats1 Tumor Suppressor
Authors: Hirota Toru , Morisaki Tetsuro , Nishiyama Yasuyuki , Marumoto Tomotoshi , Tada Kenji , Hara Toshihiro , Masuko Norio , Inagaki Masaki , Hatakeyama Katsuyoshi , Saya Hideyuki
Published: July 2002

The mitotic apparatus plays a pivotal role in dividing cells to ensure each daughter cell receives a full set of chromosomes and complement of cytoplasm during mitosis. A human homologue of the Drosophila warts tumor suppressor, h-warts/LATS1, is an evolutionarily conserved serine/threonine kinase and a dynamic component of the mitotic apparatus. We have identified an interaction of h-warts/LATS1 with zyxin, a regulator of actin filament assembly. Zyxin is a component of focal adhesion, however, during mitosis a fraction of cytoplasmic-dispersed zyxin becomes associated with h-warts/LATS1 on the mitotic apparatus. We found that zyxin is phosphorylated specifically during mitosis, most likely by Cdc2 kinase, and that the phosphorylation regulates association with h-warts/LATS1. Furthermore, microinjection of truncated h-warts/LATS1 protein, including the zyxin-binding portion, interfered with localization of zyxin to mitotic apparatus, and the duration of mitosis of these injected cells was significantly longer than that of control cells. These findings suggest that h-warts/LATS1 and zyxin play a crucial role in controlling mitosis progression by forming a regulatory complex on mitotic apparatus.
Connection of the Mitochondrial Outer and Inner Membranes by Fzo1 Is Critical for Organellar Fusion
Authors: Fritz Stefan , Rapaport Doron , Klanner Elisabeth , Neupert Walter , Westermann Benedikt
Published: July 2002

Mitochondrial membrane fusion is a process essential for the maintenance of the structural integrity of the organelle. Since mitochondria are bounded by a double membrane, they face the challenge of fusing four membranes in a coordinated manner. We provide evidence that this is achieved by coupling of the mitochondrial outer and inner membranes by the mitochondrial fusion machinery. Fzo1, the first known mediator of mitochondrial fusion, spans the outer membrane twice, exposing a short loop to the intermembrane space. The presence of the intermembrane space segment is required for the localization of Fzo1 in sites of tight contact between the mitochondrial outer and inner membranes. Mutations in the intermembrane space domain of yeast Fzo1 relieve the association with the inner membrane. This results in a loss of function of the protein in vivo. We propose that the mitochondrial fusion machinery forms membrane contact sites that mediate mitochondrial fusion. A fusion machinery that is in contact with both mitochondrial membranes appears to be functionally important for coordinated fusion of four mitochondrial membranes.
Extending the Arp2/3 complex and its regulation beyond the leading edge
Authors: Miller Kathryn G.
Published: July 2002

Two studies characterizing Drosophila Arp2/3 complex and Scar mutants demonstrate that assembly of some actin structures in nonmotile cells of multicellular organisms utilizes the same proteins as are important for actin assembly in motile cells. These studies also show that assembly of other actin structures is independent of these proteins, suggesting that alternative mechanisms also exist.
Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) Interferes with Extracellular Signal-regulated Kinase (ERK) and Jun NH2-terminal Kinase (JNK) Activation, but Does Not Affect Phosphorylation of T Cell Receptor ζ and ZAP70
Authors: Calvo Concepcion Revilla , Amsen Derk , Kruisbeek Ada M.
Published: July 2002

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR-ζ chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.
A Small Molecule CXCR4 Inhibitor that Blocks T Cell Line–tropic HIV-1 Infection
Authors: Murakami Tsutomu , Nakajima Toshihiro , Koyanagi Yoshio , Tachibana Kazunobu , Fujii Nobutaka , Tamamura Hirokazu , Yoshida Nobuaki , Waki Michinori , Matsumoto Akiyoshi , Yoshie Osamu , Kishimoto Tadamitsu , Yamamoto Naoki , Nagasawa Takashi
Published: July 2002

Several members of the chemokine receptor family have been shown to function in association with CD4 to permit human immunodeficiency virus type 1 (HIV-1) entry and infection. The CXC chemokine receptor CXCR4/fusin is a receptor for pre–B cell growth stimulating factor (PBSF)/stromal cell–derived factor 1 (SDF-1) and serves as a coreceptor for the entry of T cell line–tropic HIV-1 strains. Thus, the development of CXCR4 antagonists or agonists may be useful in the treatment of HIV-1 infection. T22 ([Tyr5,12,Lys7]-polyphemusin II) is a synthesized peptide that consists of 18 amino acid residues and an analogue of polyphemusin II isolated from the hemocyte debris of American horseshoe crabs (Limulus polyphemus). T22 was found to specifically inhibit the ability of T cell line–tropic HIV-1 to induce cell fusion and infect the cell lines transfected with CXCR4 and CD4 or peripheral blood mononuclear cells. In addition, T22 inhibited Ca2+ mobilization induced by pre–B cell growth stimulating factor (PBSF)/SDF-1 stimulation through CXCR4. Thus, T22 is a small molecule CXCR4 inhibitor that blocks T cell line–tropic HIV-1 entry into target cells.
Acquisition of Ly49 Receptor Expression by Developing Natural Killer Cells
Authors: Dorfman Jeffrey R. , Raulet David H.
Published: July 2002

The formation of the repertoire of mouse natural killer (NK) cell receptors for major histocompatibility complex (MHC) class I molecules was investigated by determining the developmental pattern of Ly49 receptor expression. During the first days after birth, few or no splenic NK cells express Ly49A, Ly49C, Ly49G2, or Ly49I receptors. The proportion of Ly49+ splenic NK cells gradually rises to adult levels during the first 6–8 wk of life. The appearance of appreciable numbers of splenic Ly49+ NK cells coincides with the appearance of NK activity at 3–4 wk. After in vivo transfer, NK cells not expressing specific Ly49 receptors can give rise to NK cells that do, and cells expressing one of these four Ly49 receptors can give rise to cells expressing others. Once initiated, expression of a Ly49 receptor is stable for at least 10 d after in vivo transfer. Hence, initiation of Ly49 receptor expression occurs successively. Interestingly, expression of one of the receptors tested, Ly49A, did not occur after in vivo transfer of Ly49A− cells. One possible explanation for these data is that the order of Ly49 receptor expression by NK cells is nonrandom. The results provide a framework for evaluating models of NK cell repertoire formation, and how the repertoire is molded by host class I MHC molecules.
Mitogen-activated Protein Kinase Kinase Antagonized Fas-associated Death Domain Protein–mediated Apoptosis by Induced FLICE-inhibitory Protein Expression
Authors: Yeh Jung-Hua , Hsu Shu-Ching , Han Shou-Hwa , Lai Ming-Zong
Published: July 2002

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3– induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.
A Key Role for Cc Chemokine Receptor 4 in Lipopolysaccharide-Induced Endotoxic Shock
Authors: Chvatchko Yolande , Hoogewerf Arlene J. , Meyer Alexandra , Alouani Sami , Juillard Pierre , Buser Raphaele , Conquet Francois , Proudfoot Amanda E.I. , Wells Timothy N.C. , Power Christine A.
Published: July 2002

CC chemokine receptor (CCR)4, a high affinity receptor for the CC chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), is expressed in the thymus and spleen, and also by peripheral blood T cells, macrophages, platelets, and basophils. Recent studies have shown that CCR4 is the major chemokine receptor expressed by T helper type 2 (Th2) polarized cells. To study the in vivo role of CCR4, we have generated CCR4-deficient (CCR4−/−) mice by gene targeting. CCR4−/− mice developed normally. Splenocytes and thymocytes isolated from the CCR4−/− mice failed to respond to the CCR4 ligands TARC and MDC, as expected, but also surprisingly did not undergo chemotaxis in vitro in response to macrophage inflammatory protein (MIP)-1α. The CCR4 deletion had no effect on Th2 differentiation in vitro or in a Th2-dependent model of allergic airway inflammation. However, CCR4−/− mice exhibited significantly decreased mortality on administration of high or low dose bacterial lipopolysaccharide (LPS) compared with CCR4+/+ mice. After high dose LPS treatment, serum levels of tumor necrosis factor α, interleukin 1β, and MIP-1α were reduced in CCR4−/− mice, and decreased expression of MDC and MIP-2 mRNA was detected in peritoneal exudate cells. Analysis of peritoneal lavage cells from CCR4−/− mice by flow cytometry also revealed a significant decrease in the F4/80+ cell population. This may reflect a defect in the ability of the CCR4−/− macrophages to be retained in the peritoneal cavity. Taken together, our data reveal an unexpected role for CCR4 in the inflammatory response leading to LPS-induced lethality.
Rare Occurrence of Classical Hodgkin's Disease as a T Cell Lymphoma
Authors: Müschen Markus , Rajewsky Klaus , Bräuninger Andreas , Baur Audrey Sylvia , Oudejans Joost J. , Roers Axel , Hansmann Martin-Leo , Küppers Ralf
Published: July 2002

Recent work identified Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) as clonal progeny of mature B cells. Therefore, it is generally assumed that cHD homogenously represents a B cell lymphoma. In a subset of cHD, however, H/RS cells expressing T cell–associated proteins may be candidates for alternative lineage derivation. Single H/RS cells with cytotoxic T cell phenotype were micromanipulated from three cases of cHD and analyzed by single cell polymerase chain reaction for immunoglobulin heavy (IgH) and light chain (IgL) gene rearrangements, T cell receptor (TCR)-β gene rearrangements, and germline configuration of the IgH and TCR-β loci. H/RS cells from two cases of cHD harbored clonal, somatically mutated Ig gene rearrangements, whereas TCR-β loci were in germline configuration. In contrast, H/RS cells from an additional case harbored clonal TCR-β variable/diversity/joining (VDJ) and DJ gene rearrangements, whereas the IgH locus was in germline configuration on both alleles. Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell molecules, the tumor cells are derived from mature B cells that aberrantly express T cell markers. In a third case, however, H/RS cells were derived from a T cell, demonstrating that cHD can also occur as a T cell lymphoma.
bcl-2 Transgene Expression Inhibits Apoptosis in the Germinal Center and Reveals Differences in the Selection of Memory B Cells and Bone Marrow Antibody-Forming Cells
Authors: Smith Kenneth G.C. , Light Amanda , O'Reilly Lorraine A. , Ang Soon-Meng , Strasser Andreas , Tarlinton David
Published: July 2002

Immunization with T cell–dependent antigens generates long-lived memory B cells and antibody-forming cells (AFCs). Both populations originate in germinal centers and, predominantly, produce antibodies with high affinity for antigen. The means by which germinal center B cells are recruited into these populations remains unclear. We have examined affinity maturation of antigen-specific B cells in mice expressing the cell death inhibitor bcl-2 as a transgene. Such mice had reduced apoptosis in germinal centers and an excessive number of memory B cells with a low frequency of V gene somatic mutation, including those mutations encoding amino acid exchanges known to enhance affinity. Despite the frequency of AFCs being increased in bcl-2–transgenic mice, the fraction secreting high-affinity antibody in the bone marrow at day 42 remained unchanged compared with controls. The inability of BCL-2 to alter selection of bone marrow AFCs is consistent with these cells being selected within the germinal center on the basis of their affinity being above some threshold rather than their survival being due to a selective competition for an antigen-based signal. Continuous competition for antigen does, however, explain formation of the memory compartment.
Gene Dose–Dependent Maturation and Receptor Editing of B Cells Expressing Immunoglobulin (Ig)g1 or Igm/Igg1 Tail Antigen Receptors
Authors: Pogue Sarah L. , Goodnow Christopher C.
Published: July 2002

Conserved differences between the transmembrane and cytoplasmic domains of membrane immunoglobulin (Ig)M and IgG may alter the function of antigen receptors on naive versus memory B cells. Here, we compare the ability of these domains to signal B cell allelic exclusion and maturation in transgenic mice. A lysozyme-binding antibody was expressed in parallel sets of mice as IgM, IgG1, or a chimeric receptor with IgM extracellular domains and transmembrane/cytoplasmic domains of IgG1. Like IgM, the IgG1 or chimeric IgM/G receptors triggered heavy chain allelic exclusion and supported development of mature CD21+ B cells. Many of the IgG or IgM/G B cells became CD21high and downregulated their IgG and IgM/G receptors spontaneously, resembling memory B cells and B cells with mutations that exaggerate B cell antigen receptor signaling. Unlike IgM-transgenic mice, “edited” B cells that carry non–hen egg lysozyme binding receptors preferentially accumulated in IgG and IgM/G mice. This was most extreme in lines with the highest transgene copy number and diminished in variant offspring with fewer copies. The sensitivity of B cell maturation to transgene copy number conferred by the IgG transmembrane and cytoplasmic domains may explain the diverse phenotypes found in other IgG-transgenic mouse strains and may reflect exaggerated signaling.
Control of Von Willebrand Factor Multimer Size by Thrombospondin-1
Authors: Xie Lijuan , Chesterman Colin N. , Hogg Philip J.
Published: July 2002

Plasma von Willebrand factor (vWF) is a multimeric protein that mediates adhesion of platelets to sites of vascular injury. Only the very large vWF multimers are effective in promoting platelet adhesion in flowing blood. A protein disulfide bond reductase in plasma reduces the average multimer size of vWF secreted by endothelial cells. This activity has been isolated from human endothelial cell conditioned medium and shown to be the trimeric glycoprotein, thrombospondin-1 (TSP-1). Incubation of purified TSP-1 with vWF resulted in formation of thiol-dependent complexes of TSP-1 and vWF, generation of new thiols in vWF, and reduction in the average multimer size of vWF. The ratio of the concentrations of TSP-1 and vWF in plasma reflected with average multimer size of vWF. The higher the plasma TSP-1/vWF molar ratio, the smaller the average vWF multimer size. In addition, administration of TSP-1 to mice resulted in reduction in the average multimer size of plasma vWF. Interaction of TSP-1 with vWF is mediated by TSP-1 type 1 properdin domains and the vWF A3 domain. These results indicate that TSP-1 regulates the multimeric size and therefore hemostatic activity of vWF.
The Human Immunodeficiency Virus Type 1 Accessory Protein Vpu Induces Apoptosis by Suppressing the Nuclear Factor κB–dependent Expression of Antiapoptotic Factors
Authors: Akari Hirofumi , Bour Stephan , Kao Sandra , Adachi Akio , Strebel Klaus
Published: July 2002

Human immunodeficiency virus (HIV) type 1 Vpu is an integral membrane protein with a unique affinity for βTrCP (TrCP), a key member of the SkpI-Cullin-F-box E3 ubiquitin ligase complex that is involved in the regulated degradation of cellular proteins, including IκB. Remarkably, Vpu is resistant to TrCP-mediated degradation and competitively inhibits TrCP-dependent degradation of IκB, resulting in the suppression of nuclear factor (NF)-κB activity in Vpu-expressing cells. We now report that Vpu, through its interaction with TrCP, potently contributes to the induction of apoptosis in HIV-infected T cells. Vpu-induced apoptosis is specific and independent of other viral proteins. Mutation of a TrCP-binding motif in Vpu abolishes its apoptogenic property, demonstrating a close correlation between this property of Vpu and its ability to inhibit NF-κB activity. The involvement of NF-κB in Vpu-induced apoptosis is further supported by the finding that the levels of antiapoptotic factors Bcl-xL, A1/Bfl-1, and TNF receptor-associated factor (TRAF)1, all of which are expressed in an NF-κB–dependent manner, are reduced and, at the same time, levels of active caspase-3 are elevated. Thus, Vpu induces apoptosis through activation of the caspase pathway by way of inhibiting the NF-κB–dependent expression of antiapoptotic genes.
The Noncompetitive Inhibitor Ww781 Senses Changes in Erythrocyte Anion Exchanger (Ae1) Transport Site Conformation and Substrate Binding
Authors: Knauf Philip A. , Raha Nancy Mendoza , Spinelli Laurie J.
Published: July 2002

WW781 binds reversibly to red blood cell AE1 and inhibits anion exchange by a two-step mechanism, in which an initial complex (complex 1) is rapidly formed, and then there is a slower equilibration to form a second complex (complex 2) with a lower free energy. According to the ping-pong kinetic model, AE1 can exist in forms with the anion transport site facing either inward or outward, and the transition between these forms is greatly facilitated by binding of a transportable substrate such as Cl−. Both the rapid initial binding of WW781 and the formation of complex 2 are strongly affected by the conformation of AE1, such that the forms with the transport site facing outward have higher affinity than those with the transport site facing inward. In addition, binding of Cl− seems to raise the free energy of complex 2 relative to complex 1, thereby reducing the equilibrium binding affinity, but Cl− does not compete directly with WW781. The WW781 binding site, therefore, reveals a part of the AE1 structure that is sensitive to Cl− binding and to transport site orientation, in addition to the disulfonic stilbene binding site. The relationship of the inhibitory potency of WW781 under different conditions to the affinities for the different forms of AE1 provides information on the possible asymmetric distributions of unloaded and Cl−-loaded transport sites that are consistent with the ping-pong model, and supports the conclusion from flux and nuclear magnetic resonance data that both the unloaded and Cl−-loaded sites are very asymmetrically distributed, with far more sites facing the cytoplasm than the outside medium. This asymmetry, together with the ability of WW781 to recruit toward the forms with outward-facing sites, implies that WW781 may be useful for changing the conformation of AE1 in studies of structure–function relationships.
On the problem of linearization for state-dependent delay differential equations
Authors: Cooke Kenneth , Huang Wenzhang
Published: July 2002

The local stability of the equilibrium for a general class of state-dependent delay equations of the form
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="ModifyingAbove x With dot left-parenthesis t right-parenthesis equals f left-parenthesis x Subscript t Baseline comma integral Subscript minus r 0 Superscript 0 Baseline d eta left-parenthesis s right-parenthesis g left-parenthesis x Subscript t Baseline left-parenthesis minus tau left-parenthesis x Subscript t Baseline right-parenthesis plus s right-parenthesis right-parenthesis right-parenthesis">

x
˙

(
t
)
=
f

(

x
t

,

∫

−

r
0

0

d
η
(
s
)
g
(

x
t

(
−
τ
(

x
t

)
+
s
)
)
)

\dot x(t)=f\left (x_t, \int ^0_{-r_0}\,d\eta (s)g(x_t(-\tau (x_t)+s))\right )

\]
has been studied under natural and minimal hypotheses. In particular, it has been shown that generically the behavior of the state-dependent delay

τ
\tau

(except the value of

τ
)

\tau )

near an equilibrium has no effect on the stability, and that the local linearization method can be applied by treating the delay

τ
\tau

as a constant value at the equilibrium.
Geometry and topology of ℝ-covered foliations
Authors: Calegari Danny
Published: July 2002

An

R

\mathbb {R}

-covered foliation is a special type of taut foliation on a

3
3

-manifold: one for which holonomy is defined for all transversals and all time. The universal cover of a manifold

M
M

with such a foliation can be partially compactified by a cylinder at infinity, somewhat analogous to the sphere at infinity of a hyperbolic manifold. The action of

π
1

(
M
)

\pi _1(M)

on this cylinder decomposes into a product by elements of

Homeo
(

S
1

)
×
Homeo
(

R

)

\text {Homeo}(S^1)\times \text {Homeo}(\mathbb {R})

. The action on the

S
1

S^1

factor of this cylinder is rigid under deformations of the foliation through

R

\mathbb {R}

-covered foliations. Such a foliation admits a pair of transverse genuine laminations whose complementary regions are solid tori with finitely many boundary leaves, which can be blown down to give a transverse regulating pseudo-Anosov flow. These results all fit in an essential way into Thurston’s program to geometrize manifolds admitting taut foliations.
Unsupervised classification of noisy chromosomes
Authors: Chan Tony Y. T.
Published: July 2002

Motivation: Almost all methods of chromosome recognition assume supervised training; i.e. we are given correctly classified chromosomes to start the training phase. Noise, if any, is confined only in the representation of the chromosomes and not in the classification of the chromosomes. During the recognition phase, the problem is simply to calculate the string edit distance of the unknowns to the representatives chosen from the training phase and classify the unknowns accordingly.

Results: In this paper, a general method to tackle the difficult unsupervised induction problem is described. The success of the method is demonstrated by showing how the inductive agent learns weights in a dynamic manner that allows it to distinguish between noisy median and telocentric chromosomes without knowing their proper labels. The process of learning is characterized as the process of finding the right distance function, i.e. the distance function that can nicely separate the classes.

Contact: t-chan@u-aizu.ac.jp
Chromatin remodeling enzymes: taming the machines
Authors: Peterson Craig L
Published: July 2002

Members of the ATP‐dependent family of chromatin remodeling enzymes play key roles in the regulation of transcription, development, DNA repair and cell cycle. Each of these enzymes are multi‐subunit assemblies that hydrolyze thousands of molecules of ATP in order to change nucleosome positions, disrupt DNA–histone interactions and perhaps destabilize chromatin folding. Here I review recent studies that suggest these potent machines can be ‘tamed’ by one of several mechanisms: targeting their activity to localized regions, blocking their chromatin binding activity or inhibiting their remodeling activity.
Nonlinear PCA: characterizing interactions between modes of brain activity
Authors: Friston Karl , Phillips Jacquie , Chawla Dave , Buchel Christian
Published: July 2002

This paper presents a nonlinear principal component analysis (PCA) that identifies underlying sources causing the expression of spatial modes or patterns of activity in neuroimaging time–series. The critical aspect of this technique is that, in relation to conventional PCA, the sources can interact to produce (second–order) spatial modes that represent the modulation of one (first–order) spatial mode by another. This nonlinear PCA uses a simple neural network architecture that embodies a specific form for the nonlinear mixing of sources that cause observed data. This form is motivated by a second–order approximation to any general nonlinear mixing and emphasizes interactions among pairs of sources. By introducing these nonlinearities principal components obtain with a unique rotation and scaling that does not depend on the biologically implausible constraints adopted by conventional PCA. The technique is illustrated by application to functional (positron emission tomography and functional magnetic resonance imaging) imaging data where the ensuing first– and second–order modes can be interpreted in terms of distributed brain systems. The interactions among sources render the expression of any one mode context–sensitive, where that context is established by the expression of other modes. The examples considered include interactions between cognitive states and time (i.e. adaptation or plasticity in PETdata) and among functionally specialized brain systems (using a fMRI study of colour and motion processing).
Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α
Authors: Elson David A. , Thurston Gavin , Huang L. Eric , Ginzinger David G. , McDonald Donald M. , Johnson Randall S. , Arbeit Jeffrey M.
Published: July 2002

Hypoxia-inducible factor-1α (HIF-1α) transactivates genes required for energy metabolism and tissue perfusion and is necessary for embryonic development and tumor explant growth. HIF-1α is overexpressed during carcinogenesis, myocardial infarction, and wound healing; however, the biological consequences of HIF-1α overexpression are unknown. Here, transgenic mice expressing constitutively active HIF-1α in epidermis displayed a 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six- to ninefold induction of each VEGF isoform. Despite marked induction of hypervascularity, HIF-1α did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin. Remarkably, blood vessel leakage resistance induced by HIF-1α overexpression was not caused by up-regulation of angiopoietin-1 or angiopoietin-2. Hypervascularity induced by HIF-1α could improve therapy of tissue ischemia.
Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis
Authors: Dasen Jeremy S. , Barbera Juan-Pedro Martinez , Herman Thomas S. , Connell Shawn O' , Olson Lorin , Ju BongGun , Tollkuhn Jessica , Baek Sung Hee , Rose David W. , Rosenfeld Michael G.
Published: July 2002

Understanding the functional significance of the coordinate expression of specific corepressors and DNA-binding transcription factors remains a critical question in mammalian development. During the development of the pituitary gland, two highly relatedpaired-like homeodomain factors, a repressor,Hesx1/Rpx and an activator, Prop-1, are expressed in sequential, overlapping temporal patterns. Here we show that while the repressive actions of Hesx1/Rpx may be required for initial pituitary organ commitment, progression beyond the appearance of the first pituitary (POMC) lineage requires both loss of Hesx1 expression and the actions of Prop-1. Although Hesx1 recruits both the Groucho-related corepressor TLE1 and the N-CoR/Sin3/HDAC complex on distinct domains, the repressor functions of Hesx1 in vivo prove to require the specific recruitment of TLE1, which exhibits a spatial and temporal pattern of coexpression during pituitary organogenesis. Furthermore, Hesx1-mediated repression coordinates a negative feedback loop with FGF8/FGF10 signaling in the ventral diencephalon, required to prevent induction of multiple pituitary glands from oral ectoderm. Our data suggest that the opposing actions of two structurally-related DNA-binding paired-like homeodomain transcription factors, binding to similar cognate elements, coordinate pituitary organogenesis by reciprocally repressing and activating target genes in a temporally specific fashion, on the basis of the actions of a critical, coexpressed TLE corepressor.
Estimating Coarse Gene Network Structure from Large-Scale Gene Perturbation Data
Authors: Wagner Andreas
Published: July 2002

Large scale gene perturbation experiments generate information about the number of genes whose activity is directly or indirectly affected by a gene perturbation. From this information, one can numerically estimate coarse structural network features such as the total number of direct regulatory interactions and the number of isolated subnetworks in a transcriptional regulation network. Applied to the results of a large-scale gene knockout experiment in the yeast Saccharomyces cerevisiae, the results suggest that the yeast transcriptional regulatory network is very sparse, containing no more direct regulatory interactions than genes. The network comprises >100 independent subnetworks.
Magnetic fields with photon beams: Use of circular current loops
Authors: Jette David
Published: July 2002

Strong transverse magnetic fields can produce very large dose enhancements and reductions in localized regions of a patient under irradiation by a photon beam. Through EGS4 Monte Carlo simulations, we have examined the effects of applying a magnetic field produced by a pair of circular current loops to a photon beam penetrating a water phantom of finite thickness. We have indeed found very substantial localized dose enhancements, albeit with no corresponding dose reduction just distal to the region of dose enhancement. (However, dose reduction does occur near the distal end of the phantom.) We have also observed two phenomena to be concerned with, for this configuration: significant broadening of the penumbra close to the current loop, and narrowness of the enhanced dose region in a plane parallel to the planes of the loops. We have also examined the use of a single current loop to produce the magnetic field, and have found great asymmetry in the dose distribution; this asymmetry appears to make it impossible to treat with a single circular magnet a tumor of large dimension extending below the application surface.
Experimental developments in dedicated scanners for positron emission tomography (in English)
Authors: Damiani Chiara
Published: July 2002

The thesis describes a prototype of a new read out electronics developed for the YAPPET small animal PET tomograph at the Physics Laboratory of the University of Ferrara. The purpose of the new electronics was to make the YAPPET scanner easier to use and more suitable for duplication at other research institutes. The results of tests of the new electronics over a 3 year period are presented. The new electronics prototype attained the same performance as the present YAPPET electronics in energy, position, and time measurements. In addition, a significant improvement in count rate capability is now being studied. The second major component of this thesis is a description of the development of a new scanner prototype incorporating a PET detection system based on YAP:Ce scintillator matrix crystals and wave length shifting (WLS) fibers. Two ribbons of WLS fibers are mounted on the opposite sides of the scintillator matrix in order to read out the columns and the rows of the matrix and recognize the interaction point XY position. The thesis describes the investigation of the materials and methods to be used in this new design. The first tests with the new prototype detector are described in detail: the main result of these preliminary measurements is the evaluation of the light yield of the system which is a signal of about 10 photoelectrons on the detector for 511 keV photoelectric interactions. The new scanner design uses the YAPPET basic principles, but it should have improved performance with applicability to other fields such as scinti‐mammography. Copies of this thesis can be obtained from the Department of Physics of the University of Pisa or the author.
Electron dosimetry based on the absorbed dose to water concept: A comparison of the AAPM TG‐51 and DIN 6800‐2 protocols
Authors: Dohm Oliver S. , Christ Gunter , Nüsslin Fridtjof , Schüle Edmund , Bruggmoser Gregor
Published: July 2002

The dosimetry protocols DIN 6800‐2 and AAPM TG‐51, both based on the absorbed dose to water concept, are compared in their theoretical background and in their application to electron dosimetry. The agreement and disagreement in correction factors and energy parameters used in both protocols will be shown and discussed. Measurements with three different types of ionization chambers were performed and evaluated according to both protocols. As a result the perturbation correction factor for the Roos chamber was determined to 1.024 0.5%.
Effect of respiratory gating on reducing lung motion artifacts in PET imaging of lung cancer
Authors: Nehmeh S. A. , Erdi Y. E. , Ling C. C. , Rosenzweig K. E. , Squire O. D. , Braban L. E. , Ford E. , Sidhu K. , Mageras G. S. , Larson S. M. , Humm J. L.
Published: July 2002

Positron emission tomography (PET) has shown an increase in both sensitivity and specificity over computed tomography (CT) in lung cancer. However, motion artifacts in the fluorodioxydoglucose (FDG) PET images caused by respiration persists to be an important factor in degrading PET image quality and quantification. Motion artifacts lead to two major effects: First, it affects the accuracy of quantitation, producing a reduction of the measured standard uptake value (SUV). Second, the apparent lesion volume is overestimated. Both impact upon the usage of PET images for radiation treatment planning. The first affects the visibility, or contrast, of the lesion. The second results in an increase in the planning target volume, and consequently a greater radiation dose to the normal tissues. One way to compensate for this effect is by applying a multiple‐frame capture technique. The PET data are then acquired in synchronization with the respiratory motion. Reduction in smearing due to gating was investigated in both phantoms and patient studies. Phantom studies showed a dependence of the reduction in smearing on the lesion size, the motion amplitude, and the number of bins used for data acquisition. These studies also showed an improvement in the target‐to‐background ratio, and a more accurate measurement of the SUV. When applied to one patient, respiratory gating showed a 28% reduction in the total lesion volume, and a 56.5% increase in the SUV. This study was conducted as a proof of principle that a gating technique can effectively reduce motion artifacts in PET image acquisition.
A method for geometrical verification of dynamic intensity modulated radiotherapy using a scanning electronic portal imaging device
Authors: Ploeger Lennert S. , Smitsmans Monique H. P. , Gilhuijs Kenneth G. A. , van Herk Marcel
Published: July 2002

In order to guarantee the safe delivery of dynamic intensity modulated radiotherapy (IMRT), verification of the leaf trajectories during the treatment is necessary. Our aim in this study is to develop a method for on‐line verification of leaf trajectories using an electronic portal imaging device with scanning read‐out, independent of the multileaf collimator. Examples of such scanning imagers are electronic portal imaging devices (EPIDs) based on liquid‐filled ionization chambers and those based on amorphous silicon. Portal images were acquired continuously with a liquid‐filled ionization chamber EPID during the delivery, together with the signal of treatment progress that is generated by the accelerator. For each portal image, the prescribed leaf and diaphragm positions were computed from the dynamic prescription and the progress information. Motion distortion effects of the leaves are corrected based on the treatment progress that is recorded for each image row. The aperture formed by the prescribed leaves and diaphragms is used as the reference field edge, while the actual field edge is found using a maximum‐gradient edge detector. The errors in leaf and diaphragm position are found from the deviations between the reference field edge and the detected field edge. Earlier measurements of the dynamic EPID response show that the accuracy of the detected field edge is better than 1 mm. To ensure that the verification is independent of inaccuracies in the acquired progress signal, the signal was checked with diode measurements beforehand. The method was tested on three different dynamic prescriptions. Using the described method, we correctly reproduced the distorted field edges. Verifying a single portal image took 0.1 s on an 866 MHz personal computer. Two flaws in the control system of our experimental dynamic multileaf collimator were correctly revealed with our method. First, the errors in leaf position increase with leaf speed, indicating a delay of approximately 0.8 s in the control system. Second, the accuracy of the leaves and diaphragms depends on the direction of motion. In conclusion, the described verification method is suitable for detailed verification of leaf trajectories during dynamic IMRT.
Exceptional increases in electron cone output as the backup diaphragms are opened
Authors: Lightstone A. W. , Videla N. , Mason D. L. D.
Published: July 2002

Some linac manufacturers provide cones for defining circular electron fields. During commissioning of one of our new radiotherapy units, we noted that the output of these cones has a strong dependence on the diaphragm opening that precedes the cone. In particular, for the 8 MeV beam, the output of a 3 cm diameter cone increased by more than a factor of 2 as the diaphragm was opened from 5×5 to 20×20 cm. One concludes that the particular mechanical design results in an output factor dependency that is exceptional when compared to the data presented in standard texts such as Khan's “The Physics of Radiation Therapy.” The importance of quality assurance and communications with the manufacturer is underscored by this example.
Shielding for thermal neutrons
Authors: McCall Richard C.
Published: July 2002

The problem of calculating the neutron capture γ‐ray dose rate due to thermal neutron capture in a boron or cadmium rectangular shield is considered. An example is given for shielding for a door at the exit of medical accelerator room maze in order to determine the optimum location of lead relative to the borated polyethylene.