bluuebunny/crossref_metadata_2025 huggingface dataset:
Delivery of B Cell Receptor–internalized Antigen to Endosomes and Class II Vesicles
Authors: Drake James R. , Webster Paul , Cambier John C. , Mellman Ira
Published: July 2002

B cell receptor (BCR)-mediated antigen processing is a mechanism that allows class II–restricted presentation of specific antigen by B cells at relatively low antigen concentrations. Although BCR-mediated antigen processing and class II peptide loading may occur within one or more endocytic compartments, the functions of these compartments and their relationships to endosomes and lysosomes remain uncertain. In murine B cells, at least one population of class II– containing endocytic vesicles (i.e., CIIV) has been identified and demonstrated to be distinct both physically and functionally from endosomes and lysosomes. We now demonstrate the delivery of BCR-internalized antigen to CIIV within the time frame during which BCR-mediated antigen processing and formation of peptide–class II complexes occurs. Only a fraction of the BCR-internalized antigen was delivered to CIIV, with the majority of internalized antigen being delivered to lysosomes that are largely class II negative. The extensive colocalization of BCR-internalized antigen and newly synthesized class II molecules in CIIV suggests that CIIV may represent a specialized subcellular compartment for BCR-mediated antigen processing. Additionally, we have identified a putative CIIV-marker protein, immunologically related to the Igα subunit of the BCR, which further illustrates the unique nature of these endocytic vesicles.
Murine Cytotoxic T Lymphocytes Recognize an Epitope in an EBNA-1 Fragment, but Fail to Lyse EBNA-1–expressing Mouse Cells
Authors: Mukherjee Siddhartha , Trivedi Pankaj , Dorfman David M. , Klein George , Townsend Alain
Published: July 2002

Major histocompatibility complex class I–restricted cytotoxic T lymphocytes (CTLs) specific for epitopes within eight of the nine Epstein Barr Virus (EBV)-encoded latency-associated proteins have been recovered from EBV-infected human subjects by restimulation of lymphocytes in vitro. However, human class I–restricted CTL responses capable of recognizing EBNA-1 expressing cells were not detected in these studies. We have raised a murine CTL line that recognizes an epitope within EBNA-1 by immunizing mice with a vaccinia virus encoding a COOH-terminal EBNA-1 fragment. This novel CTL line was used to investigate whether the epitope (positions 509–517 in EBNA-1, presented through Kd) was presented to CTL by mouse cells expressing full-length EBNA-1 or a deletion mutant of EBNA-1, lacking the Glycine-Alanine (Gly-Ala)–rich region. Cells expressing full-length EBNA-1 are not lysed by the CTL line, whereas cells expressing the Gly-Ala deletion mutant are recognized. These results suggest that epitopes from full-length EBNA-1 are poorly presented, and that the Gly-Ala–rich region is responsible for this phenomenon. The inefficient presentation of EBNA-1–derived epitopes may explain the absence or rarity of EBNA-1–specific CTLs in vivo, a strategy that may allow EBV to maintain persistence within the immunocompetent host without being eliminated by CTLs.
p56lck Signals for Regulating Thymocyte Development Can Be Distinguished by Their Dependency on Rho Function
Authors: Henning Stefan W. , Cantrell Doreen A.
Published: July 2002

The tyrosine kinase p56lck regulates the differentiation and proliferative expansion of pre-T cells. However, nothing is known about other signaling molecules that operate with p56lck to mediate the pleiotropic changes that occur at this stage of thymocyte development. We used a genetic strategy to examine the requirement for the GTPase Rho in p56lck-mediated signals in the thymus. By generating mice double transgenic for a constitutively activated form of p56lck (p56lckF505) and the Rho inhibitor C3 transferase we were able to compare thymocyte development in mice expressing active p56lck on a wild-type or Rho− background. Thymocytes expressing active p56lck show enhanced proliferation of pre-T cells resulting in increased numbers of late pre-T cells, however, this dramatic effect on pre-T cell proliferation is lost when the p56lck transgene is expressed in thymocytes lacking endogenous Rho GTPase function. Expression of active p56lck also generates double positive (DP) thymocytes with low levels of CD2 antigen expression. Again, p56lck cannot prevent expression of CD2 when expressed on a Rho− background. CD4+CD8+ DP cells expressing active p56lck have been shown to lack functional α/β–T cell receptor (TCR) complexes due to p56lck-mediated inhibition of TCR gene Vβ-Dβ rearrangement. This inhibition of TCR expression by active p56lck is unimpaired in the absence of Rho function. The signaling pathways that are mediated by p56lck and control thymocyte proliferation, α/β-TCR and CD2 antigen expression can thus be distinguished by their dependency on Rho function.
A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation
Authors: Hill Laurie L. , Shreedhar Vijay K. , Kripke Margaret L. , Owen-Schaub Laurie B.
Published: July 2002

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.
A Targeted Deletion of a Region Upstream from the Jκ Cluster Impairs κ Chain Rearrangement In Cis in Mice and in the 103/bcl2 Cell Line
Authors: Cocea Laurentiu , De Smet Annie , Saghatchian Mahasti , Fillatreau Simon , Ferradini Laurent , Schurmans Stéphane , Weill Jean-Claude , Reynaud Claude-Agnès
Published: July 2002

We have shown previously that a mutation of the KI-KII site immediately 5′ to Jκ1 on the mouse immunoglobulin light chain κ locus reduces the rearrangement level in cis, although it does not affect transcription. Here we deleted by homologous recombination in mouse embryonic stem cells a 4-kb DNA fragment, located immediately upstream of the KI-KII element, which contains the promoter of the long germline transcript. Analysis of gene-targeted heterozygous mouse splenic B cells showed a strong decrease in rearrangement for the allele bearing the deletion. When both the KI-KII mutation and the 4-kb deletion were present on the same allele, the overall reduction in rearrangement was stronger than with the 4-kb deletion alone underlying the role of these two elements in the regulation of rearrangement. The same deletion was performed by homologous recombination on one allele of the rearrangement- inducible mouse 103/bcl2-hygroR pre-B cell line, and resulted in a similar reduction in the induction of rearrangement of the mutated allele. This result validates this cell line as an in vitro model for studying the incidence of gene-targeted modifications of the κ locus on the regulation of rearrangement.
The Ccr7 Ligand ELC (Ccl19) Is Transcytosed in High Endothelial Venules and Mediates T Cell Recruitment
Authors: Baekkevold Espen S. , Yamanaka Takeshi , Palframan Roger T. , Carlsen Hege S. , Reinholt Finn P. , von Andrian Ulrich H. , Brandtzaeg Per , Haraldsen Guttorm
Published: July 2002

Lymphocyte homing to secondary lymphoid tissue is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial selectin-mediated tethering and rolling, firm adhesion of lymphocytes requires rapid upregulation of lymphocyte integrin adhesiveness. This step is mediated in part by the HEV-derived chemokine SLC (secondary lymphoid-tissue chemokine, or CCL21) that binds to the CC chemokine receptor (CCR)7 on lymphocytes. However, the CC chemokine ELC (Epstein-Barr virus–induced molecule 1 ligand chemokine, or CCL19) shares the same receptor, and ELC transcripts have been observed in the T cell areas of lymphoid organs. Here, we show that perivascular ELC is transcytosed to the luminal surfaces of HEVs and enables efficient T cell homing to lymph nodes. In situ hybridization on sections of human tonsil showed no ELC mRNA in HEVs, but immunostaining revealed ELC protein in cytoplasmic vesicles of HEV cells. Furthermore, ELC injected into the footpads of mice entered the draining lymph nodes and was presented by HEVs. Finally, intracutaneous injections of ELC in mice lacking functionally relevant ELC and SLC (plt/plt mice) restored T cell trafficking to draining lymph nodes as efficiently as SLC. We conclude that perivascular ELC is transcytosed to the luminal surfaces of HEVs and participates in CCR7-mediated triggering of lymphocyte arrest.
Isotype-specific Selection of High Affinity Memory B Cells in Nasal-associated Lymphoid Tissue
Authors: Shimoda Michiko , Nakamura Toru , Takahashi Yoshimasa , Asanuma Hideki , Tamura Shin-ichi , Kurata Takeshi , Mizuochi Tsuguo , Azuma Norihiro , Kanno Choemon , Takemori Toshitada
Published: July 2002

Mucosal immunoglobulin (Ig)A dominance has been proposed to be associated with preferential class switch recombination (CSR) to the IgA heavy chain constant region, Cα. Here, we report that B cell activation in nasal-associated lymphoid tissue (NALT) upon stimulation with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken γ globulin caused an anti-NP memory response dominated by high affinity IgA antibodies. In the response, however, NP-specific IgG+ B cells expanded and sustained their number as a major population in germinal centers (GCs), supporting the view that CSR to IgG heavy chain constant region, Cγ, operated efficiently in NALT. Both IgG+ and IgA+ GC B cells accumulated somatic mutations, indicative of affinity maturation to a similar extent, suggesting that both types of cell were equally selected by antigen. Despite the selection in GCs, high affinity NP-specific B cells were barely detected in the IgG memory compartment, whereas such cells dominated the IgA memory compartment. Taken together with the analysis of the VH gene clonotype in GC and memory B cells, we propose that NALT is equipped with a unique machinery providing IgA-specific enrichment of high affinity cells into the memory compartment, facilitating immunity with high affinity and noninflammatory secretory antibodies.
Major Histocompatibility Complex Class II–Positive Cortical Epithelium Mediates the Selection of Cd4+25+ Immunoregulatory T Cells
Authors: Bensinger Steven J. , Bandeira Antonio , Jordan Martha S. , Caton Andrew J. , Laufer Terri M.
Published: July 2002

CD4+25+ T cells are a unique population of immunoregulatory T cells which are critical for the prevention of autoimmunity. To address the thymic selection of these cells we have used two models of attenuated thymic deletion. In K14-Aβb mice, major histocompatibility complex (MHC) class II I-Ab expression is limited to thymic cortical epithelium and deletion by hematopoietic antigen-presenting cells does not occur. In H2-DMα–deficient mice, MHC class II molecules contain a limited array of self-peptides resulting in inefficient clonal deletion. We find that CD4+25+ T cells are present in the thymus and periphery of K14-Aβb and H2-DMα–deficient mice and, like their wild-type counterparts, suppress the proliferation of cocultured CD4+25− effector T cells. In contrast, CD4+25+ T cells from MHC class II–deficient mice do not suppress responder CD4+ T cells in vitro or in vivo. Thus, development of regulatory CD4+25+ T cells is dependent on MHC class II-positive thymic cortical epithelium. Furthermore, analysis of the specificities of CD4+25+ T cells in K14-Aβb and H2-DMα–deficient mice suggests that a subset of CD4+25+ T cells is subject to negative selection on hematopoietic antigen-presenting cells.
The resolution of the Gibbs phenomenon for spherical harmonics
Authors: Gelb Anne
Published: July 2002

Spherical harmonics have been important tools for solving geophysical and astrophysical problems. Methods have been developed to effectively implement spherical harmonic expansion approximations. However, the Gibbs phenomenon was already observed by Weyl for spherical harmonic expansion approximations to functions with discontinuities, causing undesirable oscillations over the entire sphere.

Recently, methods for removing the Gibbs phenomenon for one-dimensional discontinuous functions have been successfully developed by Gottlieb and Shu. They proved that the knowledge of the first

N
N

expansion coefficients (either Fourier or Gegenbauer) of a piecewise analytic function

f
(
x
)

f(x)

is enough to recover an exponentially convergent approximation to the point values of

f
(
x
)

f(x)

in any subinterval in which the function is analytic.

Here we take a similar approach, proving that knowledge of the first

N
N

spherical harmonic coefficients yield an exponentially convergent approximation to a spherical piecewise smooth function

f
(
θ
,
ϕ
)

f(\theta ,\phi )

in any subinterval

[

θ
1

,

θ
2

]
,
ϕ
∈
[
0
,
2
π
]

[\theta _1,\theta _2], \phi \in [0,2\pi ]

, where the function is analytic. Thus we entirely overcome the Gibbs phenomenon.
Protein Phosphatases 1 and 2A Transiently Associate with Myosin during the Peak Rate of Secretion from Mast Cells
Authors: Holst Jeff , Sim Alistair T.R. , Ludowyke Russell I.
Published: July 2002

Mast cells undergo cytoskeletal restructuring to allow secretory granules passage through the cortical actomyosin barrier to fuse with the plasma membrane and release inflammatory mediators. Protein phosphorylation is believed to regulate these rearrangements. Although some of the protein kinases implicated in this phosphorylation are known, the relevant protein phosphatases are not. At the peak rate of antigen-induced granule mediator release (2.5 min), protein phosphatases PP1 and PP2A, along with actin and myosin II, are transiently relocated to ruffles on the apical surface and a band at the peripheral edge of the cell. This leaves an area between the nucleus and the peripheral edge significantly depleted (3–5-fold) in these proteins. Phorbol 12-myristate 13-acetate (PMA) plus A23187 induces the same changes, at a time coincident with its slower rate of secretion. Coimmunoprecipitation experiments demonstrated a significantly increased association of myosin with PP1 and PP2A at the time of peak mediator release, with levels of association decreasing by 5 min. Jasplakinolide, an inhibitor of actin assembly, inhibits secretion and the cytoskeletal rearrangements. Surprisingly, jasplakinolide also affects myosin, inducing the formation of short rods throughout the cytoplasm. Inhibition of PP2A inhibited secretion, the cytoskeletal rearrangements, and led to increased phosphorylation of the myosin heavy and light chains at protein kinase C-specific sites. These findings indicate that a dynamic actomyosin cytoskeleton, partially regulated by both PP1 and PP2A, is required for mast cell secretion.
GeneFIND web server for protein family identification and information retrieval.
Authors: Wu C H , Shivakumar S , Shivakumar C V , Chen S C
Published: July 2002

SUMMARY: An integrated database and search system has been developed for protein family identification and information retrieval, as an approach to undertake the highly complex, genomic-scale problem of molecular sequence database search and organization. AVAILABILITY: http://diana.uthct.edu CONTACT: wu@uthct.edu
PredAcc: prediction of solvent accessibility.
Authors: Mucchielli-Giorgi M H , Hazout S , Tuff√©ry P
Published: July 2002

SUMMARY: PredAcc is a tool for predicting the solvent accessibility of protein residues from the sequence at different relative accessibility levels (0-55%). The prediction rate varies between 70. 7% (for 25% relative accessibility) and 85.7% (for 0% relative accessibility). Amino acids are predicted in four categories: almost certainly hidden and almost certainly exposed with a given a posteriori prediction error, probably hidden and probably exposed otherwise. AVAILABILITY: http://condor.urbb.jussieu.fr/PredAccCfg.html CONTACT: tuffery@urbb.jussieu.fr
MIPSIM: similarity analysis of molecular interaction potentials
Authors: Miquel de
   Càceres  , Villà Jordi , Lozano Juan J. , Sanz Ferran
Published: July 2002

Summary: MIPSIM is a computational package designed to analyse and compare 3D distributions of molecular interaction potentials (MIP) of series of biomolecules.

Availability: MIPSIM software is freely distributed to non-profit academic institutions through its web site: http://www1.imim.es/mipsim. Other organizations must contact the developers. GAMESS (http://www.msg.ameslab.gov/GAMESS/GAMESS.html) and GRID (peter@biop.ox.ac.uk) are external software required to perform some of the MIPSIM computations. They are obtained under conditions similar to MIPSIM’s.

Contact: mipsim@imim.es

* To whom correspondence should be addressed.
Physician Market Power—Evidence From the Allocation of Malpractice Premiums
Authors: Thurston Norman K.
Published: July 2002

Based on evidence from variations in malpractice premiums, physicians have local market power, at least in some dimensions. It is observed that higher‐cost physicians pass on a significant portion of idiosyncratic costs to patients as higher prices. I test two hypothesized sources of this market power: barriers to entry from specialization and relatively inelastic firm‐level demand for certain services. Examining the relationship of physician‐specific malpractice premiums to fees, I find no observable difference in the ability of surgeons and nonsurgeons to pass on these costs; however, both types of physicians pass them on more to surgical than to nonsurgical patients.
Werner's syndrome protein (WRN) migrates Holliday junctions and co‐localizes with RPA upon replication arrest
Authors: Constantinou Angelos , Tarsounas Madalena , Karow Julia K , Brosh Robert M , Bohr Vilhelm A , Hickson Ian D , West Stephen C
Published: July 2002

Individuals affected by the autosomal recessive disorder Werner's syndrome (WS) develop many of the symptoms characteristic of premature ageing. Primary fibroblasts cultured from WS patients exhibit karyotypic abnormalities and a reduced replicative life span. The WRN gene encodes a 3′–5′ DNA helicase, and is a member of the RecQ family, which also includes the product of the Bloom's syndrome gene (BLM). In this work, we show that WRN promotes the ATP‐dependent translocation of Holliday junctions, an activity that is also exhibited by BLM. In cells arrested in S‐phase with hydroxyurea, WRN localizes to discrete nuclear foci that coincide with those formed by the single‐stranded DNA binding protein replication protein A. These results are consistent with a model in which WRN prevents aberrant recombination events at sites of stalled replication forks by dissociating recombination intermediates.
Multilateral Contracting in Australian Mining: The Development of Hamersley Iron, 1961–1966
Authors: Boyce Gordon
Published: July 2002

Management theory andtransaction cost economics provide few insights into the dynamics of multilateral negotiations. A host of factors suggest that complex transactions—especially those that involve government agencies—face a high probability of failure. Yet history records many examples of successful multiple-party transactions. Using the records of a major Australian iron ore mining venture, Hamersley Iron, this article reveals a number of the tactics that are usedto engineer an agreement when the parties concerned have conflicting objectives, different cultural affiliations, and distinctive institutional ties. The essay also exposes some of the devices that the Japanese steel industry—Hamersley’s main customer—used to secure competitive advantages in raw material procurement during the industry’s rise to international prominence.
The pathogenesis ofShigella flexneriinfection: lessons fromin vitroand in vivo studies
Authors: Philpott Dana J. , Edgeworth Jonathan D. , Sansonetti Philippe J.
Published: July 2002

Shigella flexneriis a Gram–negative facultatively intracellular pathogen responsible for bacillary dysentery in humans. More than one million deaths occur yearly due to infections withShigellaspp. and the victims are mostly children of the developing world. The pathogenesis ofShigellacentres on the ability of this organism to invade the colonic epithelium where it induces severe mucosal inflammation. Much information that we have gained concerning the pathogenesis ofShigellahas been derived from the study ofin vitromodels of infection. Using these techniques, a number of the molecular mechanisms by whichShigellainvades epithelial cells and macrophages have been identified. in vivo models of shigellosis have been hampered since humans are the only natural hosts ofShigella. However, experimental infection of macaques as well as the murine lung and rabbit ligated ileal loop models have been important in defining some of the immune and inflammatory components of the disease. In particular, the murine lung model has shed light on the development of systemic and local immune protection againstShigellainfection. It would be naive to believe that any one model of Shigella infection could adequately represent the complexity of the disease in humans, and more sophisticated in vivo models are now necessary. These models require the use of human cells and tissue, but at present such models remain in the developmental stage. Ultimately, however, it is with such studies that novel treatments and vaccine candidates for the treatment and prevention of shigellosis will be designed.
The simple chicken major histocompatibility complex: life and death in the face of pathogens and vaccines
Authors: Kaufman Jim
Published: July 2002

In contrast to the major histocompatibility complex (MHC) of well-studied mammals such as humans and mice, the particular haplotype of the B-F/B-L region of the chicken B locus determines life and death in response to certain infectious pathogens as well as to certain vaccines. We found that the B-F/B-L region is much smaller and simpler than the typical mammalian MHC, with an important difference being the expression of a single class I gene at a high level of RNA and protein. The peptide-binding specificity of this dominantly expressed class I molecule in different haplotypes correlates with resistance to tumours caused by Rous sarcoma virus, while the cell-surface expression level correlates with susceptibility to tumours caused by Marek's disease virus. A similar story is developing with class II β genes and response to killed viral vaccines. This apparently suicidal strategy of single dominantly expressed class I and class II molecules may be due to coevolution between genes within the compact chicken MHC.
T–cell anergy and peripheral T–cell tolerance
Authors: Lechler Robert , Chai Jian-Guo , Marelli-Berg Federica , Lombardi Giovanna
Published: July 2002

The discovery that T–cell recognition of antigen can have distinct outcomes has advanced understanding of peripheral T–cell tolerance, and opened up new possibilities in immunotherapy. Anergy is one such outcome, and results from partial T–cell activation. This can arise either due to subtle alteration of the antigen, leading to a lower–affinity cognate interaction, or due to a lack of adequate co–stimulation. The signalling defects in anergic T cells are partially defined, and suggest that T–cell receptor (TCR) proximal, as well as downstream defects negatively regulate the anergic T cell's ability to be activated. Most importantly, the use of TCR–transgenic mice has provided compelling evidence that anergy is anin vivophenomenon, and not merely anin vitroartefact. These findings raise the question as to whether anergic T cells have any biological function. Studies in rodents and in man suggest that anergic T cells acquire regulatory properties; the regulatory effects of anergic T cells require cell to cell contact, and appear to be mediated by inhibition of antigen–presenting cell immunogenicity. Close similarities exist between anergic T cells, and the recently defined CD4+CD25+population of spontaneously arising regulatory cells that serve to inhibit autoimmunity in mice. Taken together, these findings suggest that a spectrum of regulatory T cells exists. At one end of the spectrum are cells, such as anergic and CD4+CD25+T cells, which regulate via cell–to–cell contact. At the other end of the spectrum are cells which secrete antiinflammatory cytokines such as interleukin 10 and transforming growth factor–β. The challenge is to devise strategies that reliably induce T–cell anergyin vivo, as a means of inhibiting immunity to allo– and autoantigens.
Host races in plant–feeding insects and their importance in sympatric speciation
Authors: Drès Michele , Mallet James
Published: July 2002

The existence of a continuous array of sympatric biotypes—from polymorphisms, through ecological or host races with increasing reproductive isolation, to good species—can provide strong evidence for a continuous route to sympatric speciation via natural selection. Host races in plant–feeding insects, in particular, have often been used as evidence for the probability of sympatric speciation. Here, we provide verifiable criteria to distinguish host races from other biotypes: in brief, host races are genetically differentiated, sympatric populations of parasites that use different hosts and between which there is appreciable gene flow. We recognize host races as kinds of species that regularly exchange genes with other species at a rate of more thanca. 1% per generation, rather than as fundamentally distinct taxa. Host races provide a convenient, although admittedly somewhat arbitrary intermediate stage along the speciation continuum. They are a heuristic device to aid in evaluating the probability of speciation by natural selection, particularly in sympatry. Speciation is thereby envisaged as having two phases: (i) the evolution of host races from within polymorphic, panmictic populations; and (ii) further reduction of gene flow between host races until the diverging populations can become generally accepted as species. We apply this criterion to 21 putative host race systems. Of these, only three are unambiguously classified as host races, but a further eight are strong candidates that merely lack accurate information on rates of hybridization or gene flow. Thus, over one–half of the cases that we review are probably or certainly host races, under our definition.

Our review of the data favours the idea of sympatric speciation via host shift for three major reasons: (i) the evolution of assortative mating as a pleiotropic by–product of adaptation to a new host seems likely, even in cases where mating occurs away from the host; (ii) stable genetic differences in half of the cases attest to the power of natural selection to maintain multilocus polymorphisms with substantial linkage disequilibrium, in spite of probable gene flow; and (iii) this linkage disequilibrium should permit additional host adaptation, leading to further reproductive isolation via pleiotropy, and also provides conditions suitable for adaptive evolution of mate choice (reinforcement) to cause still further reductions in gene flow. Current data are too sparse to rule out a cryptic discontinuity in the apparently stable sympatric route from host–associated polymorphism to host–associated species, but such a hiatus seems unlikely on present evidence. Finally, we discuss applications of an understanding of host races in conservation and in managing adaptation by pests to control strategies, including those involving biological control or transgenic parasite–resistant plants.
Knockout of Arabidopsis ACCELERATED-CELL-DEATH11 encoding a sphingosine transfer protein causes activation of programmed cell death and defense
Authors: Brodersen Peter , Petersen Morten , Pike Helen M. , Olszak Brian , Skov Søren , Ødum Niels , Jørgensen Lise Bolt , Brown Rhoderick E. , Mundy John
Published: July 2002

We describe the lethal, recessive accelerated-cell-death11 Arabidopsis mutant (acd11). Cell death in acd11exhibits characteristics of animal apoptosis monitored by flow cytometry, and acd11 constitutively expresses defense-related genes that accompany the hypersensitive response normally triggered by avirulent pathogens. Global transcriptional changes during programmed cell death (PCD) and defense activation in acd11 were monitored by cDNA microarray hybridization. The PCD and defense pathways activated in acd11 are salicylic acid (SA) dependent, but do not require intact jasmonic acid or ethylene signaling pathways. Light is required for PCD execution in acd11, as application of an SA-analog to SA-deficient acd11 induced death in the light, but not in the dark. Epistatic analysis showed that the SA-dependent pathways require two regulators of SA-mediated resistance responses, PAD4 and EDS1. Furthermore, acd11 PR1 gene expression, but not cell death, depends on the SA signal tranducer NPR1, suggesting that the npr1-1 mutation uncouples resistance responses and cell death in acd11. The acd11 phenotype is caused by deletion of the ACD11 gene encoding a protein homologous to a mammalian glycolipid transfer protein (GLTP). In contrast to GLTP, ACD11 accelerates the transfer of sphingosine, but not of glycosphingolipids, between membranes in vitro.
The winged helix transcription factor Foxc1a is essential for somitogenesis in zebrafish
Authors: Topczewska Jolanta M. , Topczewski Jacek , Shostak Alena , Kume Tsutomu , Solnica-Krezel Lilianna , Hogan Brigid L.M.
Published: July 2002

Previous studies identified zebrafish foxc1a andfoxc1b as homologs of the mouse forkhead gene, Foxc1. Both genes are transcribed in the unsegmented presomitic mesoderm (PSM), newly formed somites, adaxial cells, and head mesoderm. Here, we show that inhibiting synthesis of Foxc1a (but not Foxc1b) protein with two different morpholino antisense oligonucleotides blocks formation of morphological somites, segment boundaries, and segmented expression of genes normally transcribed in anterior and posterior somites and expression of paraxis implicated in somite epithelialization. Patterning of the anterior PSM is also affected, as judged by the absence of mesp-b, ephrinB2, and ephA4expression, and the down-regulation of notch5 andnotch6. In contrast, the expression of other genes, includingmesp-a and papc, in the anterior of somite primordia, and the oscillating expression of deltaC and deltaD in the PSM appear normal. Nevertheless, this expression is apparently insufficient for the maturation of the presumptive somites to proceed to the stage when boundary formation occurs or for the maintenance of anterior/posterior patterning. Mouse embryos that are compound null mutants for Foxc1 and the closely related Foxc2 have no morphological somites and show abnormal expression of Notch signaling pathway genes in the anterior PSM. Therefore, zebrafish foxc1aplays an essential and conserved role in somite formation, regulating both the expression of paraxis and the A/P patterning of somite primordia.
Charge‐coupled‐device based scanner for tomography of fluorescent near‐infrared probes in turbid media
Authors: Ntziachristos Vasilis , Weissleder Ralph
Published: July 2002

We present a novel tomographer for three‐dimensional reconstructions of fluorochromes in diffuse media. Photon detection is based on charge‐coupled device technology that allows the implementation of a large parallel array of detection channels with high sensitivity. Using this instrument we studied the response and detection limits of near‐infrared fluorochromes in diffuse media as a function of light intensity and for a wide range of biologically relevant concentrations. We further examined the resolution of the scanner and the reconstruction linearity achieved. We demonstrate that the instrument attains better than 3 mm resolution, is linear within more than two orders of magnitude of fluorochrome concentration, and can detect fluorescent objects at femto‐mole quantities in small animal‐like geometries. These measurements delineate detection and reconstruction characteristics associated with imaging of novel classes of fluorescent probes developed for in vivo molecular and functional probing of tissues.
Experimental determination of the TG‐43 dosimetric characteristics of EchoSeed™ model 6733 brachytherapy source
Authors: Meigooni A. S. , Dini Sharifeh A. , Sowards Keith , Hayes Joshua L. , Al‐Otoom Awni
Published: July 2002

Recently an improved design of a brachytherapy source has been introduced for interstitial seed implants, particularly for prostate seed implants. This design improves the in situ ultrasound visualization of the source compared to the conventional seed. In this project, the TG‐43 recommended dosimetric characteristics of the new brachytherapy source have been experimentally determined in Solid Water™ phantom material. The measured dosimetric characteristics of the new source have been compared with data reported in the literature for other source designs. The measured dose rate constant, Λ, in Solid Water was multiplied by 1.05 to extract the dose rate constant in water. The dose rate constant of the new source in water was found to be The radial dose function was measured at distances between 0.5 and 10 cm using LiF TLDs in Solid Water™ phantom. The anisotropy function, was measured at distances of 2, 3, 5, and 7 cm.
Feasibility of a large area x‐ray sensitive vidicon for medical fluoroscopy: Signal and noise factors
Authors: Luhta R. , Rowlands J. A.
Published: July 2002

A large area x‐ray sensitive vidicon is being investigated as an alternative to the x‐ray image intensifier and television camera combination for medical fluoroscopy. Signal generation in an x‐ray vidicon involves an x‐ray photoconductive layer whose surface is scanned by an electron beam. The single x‐ray to electron conversion stage of the x‐ray vidicon offers a greatly improved modulation transfer function (MTF) over the x‐ray image intensifier. This superior MTF allows signal and x‐ray quantum noise at high spatial frequencies to be passed to the preamplifier with less attenuation. In cardiac cine applications this would allow quantum noise limited operation at higher spatial frequencies than is possible with the x‐ray image intensifier system.
Velocity measurement based on bolus tracking with the aid of three‐dimensional reconstruction from digital subtraction angiography
Authors: Huang Sui Ping , Decker Robert J. , Goodrich K. Craig , Parker Daniel J. , Muhlestein Joseph B. , Blatter Duane D. , Parker Dennis L.
Published: July 2002

The problem of blood flow measurement in x‐ray angiography using measurements of the leading edge of the contrast bolus as it traverses the vascular bed is considered. A new technique for velocity measurement is presented based upon the ratio of the temporal derivative to the spatial derivative of the contrast bolus in the direction of flow. With the addition of a small correction factor, the value obtained is shown to reflect the transport velocity, or the velocity at which the contrast is transported down the vessel of interest. Most blood flow measurements based on bolus tracking techniques are actually using the contrast transport velocity to represent the blood flow velocity. Because of the streaming that occurs due to laminary flow conditions, the measured transport velocity is found to be somewhere between the average and the peak (central) fluid velocities for measurements taken during the traversal of the bolus leading edge. The spatial and temporal variation of the transport velocity are found to be consistent with the bolus motion expected in the presence of laminar flow. From x‐ray images of contrast passage through simple tubes, we find that the derivative method measures the transport velocity during passage of the bolus leading edge. In most cases of laminar blood flow, the leading edge transport velocity can be 20%–40% higher than the average blood velocity.
Refinements of the finite‐size pencil beam model of three‐dimensional photon dose calculation
Authors: Ostapiak O. Z. , Zhu Y. , Van Dyk J.
Published: July 2002

Modern three‐dimensional (3‐D) photon dose calculation algorithms need to be fast and accurate if they are to be practical for treatment optimization. Refinements to a previously proposed finite‐size pencil beam (FSPB) method are presented in order to fulfill these needs. Specifically, a fast Fourier transform (FFT) convolution technique is used to speed calculation of the FSPB; the fluence spectrum is modeled, and the effects of finite source size, a Gaussian x‐ray source intensity profile and partial transmission through a multileaf collimator (MLC) leaf are approximated. The use of FFT techniques in the calculation of small diverging fields involves approximations that are investigated for a 6 MV beam and shown to introduce errors that vary with energy but do not exceed 0.7% on the central axis. Dose distributions calculated by FSPB superposition are in excellent agreement with those calculated by full field FFT convolution. Two key advances over the original implementation of the FSPB model are demonstrated: the fast calculation of the FSPB facilitates development, and the incorporation of realistic beam parameters enables accurate modeling of clinical beams.
Physical–technical basis of invasive microwave hyperthermia—Simulation, construction, and characterization of miniaturized interstitial microwave antennas for the treatment of malignant tumors (in German)
Authors: Erb Jürgen
Published: July 2002

The electromagnetic field of dipole antennas for interstitial microwave hyperthermia was investigated using the field evaluation program MAFIA (MAxwell's equations using the Finite Integration Algorithm). The numerical method was applied to clinically used applicators running at ISM frequencies: 434 MHz and 915 MHz. The method was also used for improvement and optimization of more sophisticated applicators, e.g., those in a triaxial technique having a λ/4 choke section to reduce RF currents on the outer coaxial conductor. Simulations of the frequency dependent impedance match, the electrical field and the specific absorption rate (SAR) distribution of different applicators immersed in a muscle phantom were compared with measurements. Moreover, arrays of two and four applicators, various surrounding tissue properties (bone, fat, tissue), catheter types, and semi‐rigid coaxial cable materials were investigated. Compared with coaxial antennas only triaxial antenna designs produce a homogeneous, symmetric energy deposition pattern below the choke section at all insertion depths. Only triaxial dipole antennas can be designed to run at a specific frequency while the reflection factor ( parameter) does not change with insertion depth. The field simulation allowed studying realistic effects at all discontinuities of the rotational symmetric applicator‐catheter‐tissue system and gave a better understanding of heating phenomena occurring during interstitial hyperthermia treatment.
Values of “S,” and for dosimetry using alpha‐particle emitters
Authors: Stinchcomb Thomas G. , Roeske John C.
Published: July 2002

In a recent paper [J. Nucl. Med. 38, 1923–1929 (1997)], the authors presented a dosimetry system which combines the computational ease of the MIRD schema with additional information provided by microdosimetry for use with alpha‐particle emitters. In addition to the absorbed dose (average specific energy) to the targets (cell nuclei), this system gives the spread (standard deviation) in values of this specific energy received by individual targets. It also gives the fraction of targets receiving zero (or any number of) hits. In this paper, input quantities are presented for alpha‐particle energies and cell and nuclear sizes appropriate for the radionuclides being investigated. The quantities include S values for the usual determination of the absorbed dose along with the microdosimetric quantities, and the average and average square, respectively, of the single‐hit specific energy. Using analytical procedures described previously [Med. Phys. 19, 1385–1393 (1992)], the single‐hit distributions of specific energy are determined for the given alpha‐particle energies, source locations, and target sizes. From these distributions, the values for the input quantities are calculated. Sources considered are (1) those located inside and on the surface of the target cell and an unbounded source in the medium external to the cell; (2) those distributed uniformly on either side of a plane boundary or on the surface of the plane with a spherical target at various distances from the plane; and (3) those located either inside or on the surface of a spherical boundary centered externally to the target. Examples show how the input quantities are used to provide the spread in specific‐energy values and the probability of any number of hits for nuclei of cells exposed to these sources. Thus a complete micro‐dosimetric analysis involving the calculation of multi‐hit specific energy distributions is not necessary to provide this information. Such information may be useful in interpreting the biological response due to alpha‐particle emitters.
A lesion detectability simulation method for digital x‐ray imaging
Authors: Cooper V. N. , Boone J. M. , Seibert J. A.
Published: July 2002

A simulation method is described in this work that aids in quantifying the upper limits of lesion detectability as a function of lesion size, lesion contrast, pixel size, and x‐ray exposure for digital x‐ray imaging systems. The method entails random lesion placement with subsequent simulated imaging on idealized x‐ray detectors with no additive noise and 100% quantum detective efficiency. Lesions of different size and thickness were simulated. Mean (expectation) lesion signal‐to‐noise ratios (LSNRs) were calculated and receiver operating characteristic (ROC) curves were constructed based on LSNR ensembles. Mean (expectation) values of the areas under the ROC curves were calculated for lesions of varying size on pixel arrays of varying size at different exposures. Analyses were performed across several parameters, including lesion size, pixel size, and exposure levels representative of various areas of radiography. As expected, lesion detectability increased with lesion size, contrast, pixel size, and exposure. The model suggests that lesion detectability is strongly dependent on the relative alignment (phase) of the lesion with the pixel matrix for lesions on the order of the pixel size.
Limitations of the straight‐line assumption for endobronchial HDR brachytherapy treatments
Authors: Ezzell Gary A.
Published: July 2002

It is useful to expedite high dose rate brachytherapy endobronchial treatments by using standardized dwell weights and worksheets, avoiding computerized planning where possible. Such methods assume the treatment catheter is straight. This study uses inverse‐square considerations to quantify the curvature that invalidates the straight‐line approximation. The ratio of the distance between end dwell positions and the active length can be used as a measure of the curvature. The variation in mean dose and maximum dose at the prescription points is presented as a function of active length and curvature, allowing the planner to determine quickly when a pre‐treatment computer plan is necessary.
Detection of internal organ movement in prostate cancer patients using portal images
Authors: Stroom Joep C. , Kroonwijk Marco , Pasma Kasper L. , Koper Peter C. M. , van Dieren Erik B. , Heijmen Ben J. M.
Published: July 2002

Previous research has indicated that the appearance of large gas pockets in portal images of prostate cancer patients might imply internal prostate motion. This was verified with simulations based on multiple computed tomography (CT) data for 15 patients treated in supine position. Apart from the planning CT scan, three extra scans were made during treatment. The clinical target volume (CTV) and the rectum were outlined in all scans. Lateral portal images were simulated from the CT data and difference images were calculated for all possible combinations of CT scans per patient; each scan was used both as reference and repeat scan but gas pockets in the reference scan were removed. Gas pockets in a repeat CT scan then show up as black areas in a difference image. Due to gravity, they normally appear in the ventral part of the rectum. The distances between the ventral edge of a gas pocket in a difference image and the projection of the delineated ventral rectum wall in the reference scan were calculated. These distances were correlated with the “true” rectum wall shifts (determined from direct comparison of the rectum delineations in reference and repeat scan) and with CTV movements determined by three‐dimensional chamfer matching. Gas pockets occurred in 23% of cases. Nevertheless, about 50% of rectum wall shifts larger than 5 mm could be detected because they were associated with gas pockets with a lateral diameter When gas pockets were visible in the repeat scan, rectum wall shifts could be accurately detected by the ventral gas pocket edge in the difference images The shift of the rectum wall as detected from gas pockets also correlated significantly with the anterior‐posterior shift of the center of mass of the CTV In conclusion, the simulations showed that lateral pelvic images contain more information than the bony structures that are normally used for setup verification. If large gas pockets appear in those images, a quantitative estimate of the position of prostate and rectum wall can be obtained by determination of the ventral edge of the gas pocket.
The Poynting vector and power in a simple circuit
Authors: Majcen Slavko , Haaland Ryan K. , Dudley Scott C.
Published: July 2002

This paper outlines a simple technique for visualizing the flow of energy from a power supply to elements in a circuit as a flow through the electric and magnetic fields—or the Poynting vector—surrounding the circuit. In addition to providing the reader experience with the Poynting vector and its relation to energy flow and power, we also present a quick method for solving Laplace’s equation in two dimensions.
Physical aspects of the greenhouse effect and global warming
Authors: Knox Robert S.
Published: July 2002

According to the simplest model of the earth’s radiative balance, global warming will occur with certainty as humankind increases its production and consumption of nonsolar energy. This prediction is revisited, using a broader model that allows the greenhouse effect to be considered. The new model predicts a global warming of ΔTE=(114 K)ε, where ε is the rate of surface energy release in units of the average incident solar radiation, 342 W m−2, and ΔTE is the average temperature rise at the earth’s surface. Present values of these quantities, excluding geothermal sources, are ε=0.69×10−4 and ΔTE=7.9 mK. The model assigns a small number of optical parameters to the atmosphere and surface and qualifies the simple warming prediction: It is rigorous only if parameters other than ε are unchanged. The model is not complex and should serve as an aid to an elementary understanding of global warming.