bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone Marrow–generated Dendritic Cells Pulsed with Tumor Extracts or Tumor RNA Induce Antitumor Immunity against Central Nervous System Tumors
Authors: Ashley David M. , Faiola Brenda , Nair Smita , Hale Laura P. , Bigner Darell D. , Gilboa Eli
Published: July 2002

Recent studies have shown that the brain is not a barrier to successful active immunotherapy that uses gene-modified autologous tumor cell vaccines. In this study, we compared the efficacy of two types of vaccines for the treatment of tumors within the central nervous system (CNS): dendritic cell (DC)-based vaccines pulsed with either tumor extract or tumor RNA, and cytokine gene–modified tumor vaccines. Using the B16/F10 murine melanoma (B16) as a model for CNS tumor, we show that vaccination with bone marrow–generated DCs, pulsed with either B16 cell extract or B16 total RNA, can induce specific cytotoxic T lymphocytes against B16 tumor cells. Both types of DC vaccines were able to protect animals from tumors located in the CNS. DC-based vaccines also led to prolonged survival in mice with tumors placed before the initiation of vaccine therapy. The DC-based vaccines were at least as effective, if not more so, as vaccines containing B16 tumor cells in which the granulocytic macrophage colony-stimulating factor gene had been modified. These data support the use of DC-based vaccines for the treatment of patients with CNS tumors.
Evolution of a Complex T Cell Receptor Repertoire during Primary and Recall Bacterial Infection
Authors: Busch Dirk H. , Pilip Ingrid , Pamer Eric G.
Published: July 2002

The mechanisms underlying the genesis and maintenance of T cell memory remain unclear. In this study, we examined the evolution of a complex, antigen-specific T cell population during the transition from primary effector to memory T cells after Listeria monocytogenes infection. T cell populations specific for listeriolysin O (LLO)91–99, the immunodominant epitope recognized by H2-Kd–restricted T lymphocytes, were directly identified in immune spleens using tetrameric H2-Kd–epitope complexes. The T cell receptor (TCR) Vβ repertoire of specific T cells was determined by direct, ex vivo staining with a panel of mAbs. We demonstrate that LLO91–99-specific, primary effector T cell populations have a diverse TCR Vβ repertoire. Analyses of memory T cell populations demonstrated similar TCR diversity. Furthermore, experiments with individual mice demonstrated that primary effector and memory T cells have indistinguishable TCR repertoires. Remarkably, after reinfection with L. monocytogenes, LLO91–99-specific T cells have a narrower TCR repertoire than do primary effector or memory T cells. Thus, our studies show that the TCR repertoire of primary effector T lymphocytes is uniformly transmitted to memory T cells, whereas expansion of memory T cells is selective.
Interleukin 12–mediated Prevention of Spontaneous Mammary Adenocarcinomas in Two Lines of Her-2/neu Transgenic Mice
Authors: Boggio Katia , Nicoletti Giordano , Di Carlo Emma , Cavallo Federica , Landuzzi Lorena , Melani Cecilia , Giovarelli Mirella , Rossi Ilaria , Nanni Patrizia , De Giovanni Carla , Bouchard Page , Wolf Stanley , Modesti Andrea , Musiani Piero , Lollini Pier Luigi , Colombo Mario P. , Forni Guido
Published: July 2002

The ability of interleukin (IL)-12 to prevent tumors when administered to individuals with a genetic risk of cancer was studied in two lines of transgenic mice expressing rat HER-2/neu oncogene in the mammary gland. Female BALB/c (H-2d) mice carrying the activated HER-2/ neu oncogene show no morphological abnormalities of the mammary gland until 3 wk of age. They then progress through atypical hyperplasia to in situ lobular carcinoma and at 33 wk of age all 10 mammary glands display invasive carcinomas. Adult FVB mice (H-2q) carrying the HER-2/neu protooncogene develop mammary carcinomas with a longer latency (38-49 wk) and a lower multiplicity (mean of 2.6 tumors/mice). Treatment with IL-12 (5 daily intraperitoneal injections, 1 wk on, 3 wk off; the first course with 50 ng IL-12/day, the second with 100 ng IL-12/day) begun at 2 wk of age in BALB/c mice and at 21 wk of age in FVB mice markedly delayed tumor onset and reduced tumor multiplicity. Analogous results were obtained in immunocompetent and permanently CD8+ T lymphocyte–depleted mice. In both transgenic lines, tumor inhibition was associated with mammary infiltration of reactive cells, production of cytokines and inducible nitric oxide synthase, and reduction in microvessel number, in combination with a high degree of hemorrhagic necrosis.
The Avidity Spectrum of  T Cell Receptor Interactions Accounts for T Cell Anergy in a Double Transgenic Model
Authors: Girgis Laila , Davis Mark M. , de St. Groth Barbara Fazekas
Published: July 2002

The mechanism of self-tolerance in the CD4+ T cell compartment was examined in a double transgenic (Tg) model in which T cell receptor (TCR)-α/β Tg mice with specificity for the COOH-terminal peptide of moth cytochrome c in association with I-Ek were crossed with antigen Tg mice. Partial deletion of cytochrome-reactive T cells in the thymus allowed some self-specific CD4+ T cells to be selected into the peripheral T cell pool. Upon restimulation with peptide in vitro, these cells upregulated interleukin (IL)-2 receptor but showed substantially lower cytokine production and proliferation than cells from TCR Tg controls. Proliferation and cytokine production were restored to control levels by addition of saturating concentrations of IL-2, consistent with the original in vitro definition of T cell anergy. However, the response of double Tg cells to superantigen stimulation in the absence of exogenous IL-2 was indistinguishable from that of TCR Tg controls, indicating that these self-reactive cells were not intrinsically hyporesponsive. Measurement of surface expression of Tg-encoded TCR α and β chains revealed that cells from double Tg mice expressed the same amount of TCR-β as cells from TCR Tg controls, but only 50% of TCR-α, implying expression of more than one α chain. Naive CD4+ T cells expressing both Tg-encoded and endogenous α chains also manifested an anergic phenotype upon primary stimulation with cytochrome c in vitro, suggesting that low avidity for antigen can produce an anergic phenotype in naive cells. The carboxyfluorescein diacetate succinimidyl ester cell division profiles in response to titered peptide ± IL-2 indicated that expression of IL-2 receptor correlated with peptide concentration but not TCR level, whereas IL-2 production was profoundly affected by the twofold decrease in specific TCR expression. Addition of exogenous IL-2 recruited double Tg cells into division, resulting in a pattern of cell division indistinguishable from that of controls. Thus, in this experimental model, cells expressing more than one α chain escaped negative selection to a soluble self-protein in the thymus and had an anergic phenotype indistinguishable from that of low avidity naive cells. The data are consistent with the notion that avidity-mediated selection for self-reactivity in the thymus may lead to the appearance of anergy within the peripheral, self-reactive T cell repertoire, without invoking the induction of hyporesponsiveness to TCR-mediated signals.
The Natural Killer T (NKT) Cell Ligand α-Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells
Authors: Kitamura Hidemitsu , Iwakabe Kenji , Yahata Takashi , Nishimura Shin-ichiro , Ohta Akio , Ohmi Yasushi , Sato Marimo , Takeda Kazuyoshi , Okumura Ko , Van Kaer Luc , Kawano Tetsu , Taniguchi Masaru , Nishimura Takashi
Published: July 2002

The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.
Two Roads Diverged: Interferon α/β– and Interleukin 12–mediated Pathways in Promoting T Cell Interferon γ Responses during Viral Infection
Authors: Cousens Leslie P. , Peterson Ron , Hsu Sang , Dorner Andrew , Altman John D. , Ahmed Rafi , Biron Christine A.
Published: July 2002

Viral infections induce CD8 T cell expansion and interferon (IFN)-γ production for defense, but the innate cytokines shaping these responses have not been identified. Although interleukin (IL)-12 has the potential to contribute, IL-12–dependent T cell IFN-γ has not been detected during viral infections. Moreover, certain viruses fail to induce IL-12, and elicit high levels of IFN-α/β to negatively regulate it. The endogenous factors promoting virus-induced T cell IFN-γ production were defined in studies evaluating CD8 T cell responses during lymphocytic choriomeningitis virus infections of mice. Two divergent supporting pathways were characterized. Under normal conditions of infections, the CD8 T cell IFN-γ response was dependent on endogenous IFN-α/β effects, but was IL-12 independent. In contrast, in the absence of IFN-α/β functions, an IL-12 response was revealed and substituted an alternative pathway to IFN-γ. IFN-α/β–mediated effects resulted in enhanced, but the alternative pathway also promoted, resistance to infection. These observations define uniquely important IFN-α/β–controlled pathways shaping T cell responses during viral infections, and demonstrate plasticity of immune responses in accessing divergent innate mechanisms to achieve similar ultimate goals.
Instruction for Cytokine Expression in T Helper Lymphocytes in Relation to Proliferation and Cell Cycle Progression
Authors: Richter Anne , Löhning Max , Radbruch Andreas
Published: July 2002

T helper (Th) lymphocytes, when reactivated, recall expression of those cytokines they had been instructed to express in earlier activations, even in the absence of specific cytokine-inducing factors. In cells that memorize their expression, the cytokine genes are modified by chromatin rearrangement and demethylation, suggesting that they have been somatically imprinted. Here we show, by using inhibitors blocking the cell cycle in various stages, that for the instruction of a Th cell to express interleukin (IL)-4 or IL-10 upon restimulation, entry of the cell into the S phase of the first cell cycle after initial activation is required. Separation of the IL-4 receptor (IL-4R) and T cell antigen receptor (TCR) signals in time, demonstrates that this instruction is dependent on concomitant signaling from both receptors. In Th cells, inhibited to progress into the first S phase after activation, the IL-4R and TCR signals can be memorized for at least 1 d, priming the T cell to become instructed for expression of IL-4 upon restimulation, when entering the S phase after release of the cell cycle block. The requirement of the initial S phase of T cell activation, for instruction of Th cells to express IL-4 or IL-10 upon restimulation points to the decisive role of epigenetic modification of cytokine genes as a molecular correlate of the memory to express particular cytokines.
Immunotherapy with Dendritic Cells Directed against Tumor Antigens Shared with Normal Host Cells Results in Severe Autoimmune Disease
Authors: Ludewig Burkhard , Ochsenbein Adrian F. , Odermatt Bernhard , Paulin Denise , Hengartner Hans , Zinkernagel Rolf M.
Published: July 2002

Vaccination with dendritic cells (DCs) presenting tumor antigens induces primary immune response or amplifies existing cytotoxic antitumor T cell responses. This study documents that antitumor treatment with DCs may cause severe autoimmune disease when the tumor antigens are not tumor-specific but are also expressed in peripheral nonlymphoid organs. Growing tumors with such shared tumor antigens that were, at least initially, strictly located outside of secondary lymphoid organs were successfully controlled by specific DC vaccination. However, antitumor treatment was accompanied by fatal autoimmune disease, i.e., autoimmune diabetes in transgenic mice expressing the tumor antigen also in pancreatic β islet cells or by severe arteritis, myocarditis, and eventually dilated cardiomyopathy when arterial smooth muscle cells and cardiomyocytes expressed the transgenic tumor antigen. These results reveal the delicate balance between tumor immunity and autoimmunity and therefore point out important limitations for the use of not strictly tumor-specific antigens in antitumor vaccination with DCs.
M11l
Authors: Everett Helen , Barry Michele , Lee Siow Fong , Sun Xuejun , Graham Kathryn , Stone James , Bleackley R. Chris , McFadden Grant
Published: July 2002

M11L, a novel 166–amino acid membrane-associated protein expressed by the poxvirus, myxoma virus, was previously found to modulate apoptosis after infection of rabbit leukocytes. Furthermore, infection of rabbits with an M11L knockout virus unexpectedly produced lesions with a profound proinflammatory phenotype. We show here that M11L is antiapoptotic when expressed independently of other viral proteins, and is directed specifically to mitochondria by a short COOH-terminal region that is necessary and sufficient for targeting. This targeting region consists of a hydrophobic domain flanked by basic amino acid residues, adjacent to a positively charged tail. M11L blocks staurosporine-induced apoptosis by preventing mitochondria from undergoing a permeability transition, and the mitochondrial localization of this protein is essential for this function. We show that M11L is specifically required to inhibit the apoptotic response of monocytes/macrophages during virus infection, as cells of this lineage undergo apoptosis when infected with the M11L knockout virus. As monocyte apoptosis is uniquely proinflammatory, we propose that this observation reconciles the paradoxical proapoptotic and proinflammatory phenotypes of the M11L knockout virus. We suggest that apoptosis of tissue macrophages represents an important antiviral defense, and that the inhibition of apoptosis by viral proteins can be directed in a cell-specific fashion.
The Serpin Proteinase Inhibitor 9 Is an Endogenous Inhibitor of Interleukin 1β–Converting Enzyme (Caspase-1) Activity in Human Vascular Smooth Muscle Cells
Authors: Young James L. , Sukhova Galina K. , Foster Don , Kisiel Walter , Libby Peter , Schönbeck Uwe
Published: July 2002

Interleukin-1β–converting enzyme (ICE, caspase-1) regulates key steps in inflammation and immunity, by activating the proinflammatory cytokines interleukin (IL-)1β and IL-18, or mediating apoptotic processes. We recently provided evidence for the regulation of caspase-1 activity via an endogenous inhibitor expressed by human vascular smooth muscle cells (SMCs) (Schönbeck, U., M. Herzberg, A. Petersen, C. Wohlenberg, J. Gerdes, H.-D. Flad, and H. Loppnow. 1997. J. Exp. Med. 185:1287–1294). However, the molecular identity of this endogenous inhibitor remained undefined. We report here that the serine proteinase inhibitor (serpin) PI-9 accounts for the endogenous caspase-1 inhibitory activity in human SMCs and prevents processing of the enzyme's natural substrates, IL-1β and IL-18 precursor. Treatment of SMC lysates with anti–PI-9 antibody abrogated the caspase-1 inhibitory activity and coprecipitated the enzyme, demonstrating protein–protein interaction. Furthermore, PI-9 antisense oligonucleotides coordinately reduced PI-9 expression and promoted IL-1β release. Since SMCs comprise the majority of cells in the vascular wall, and because IL-1 is implicated in atherogenesis, we tested the biological validity of our in vitro findings within human atheroma in situ. The unaffected arterial wall contains abundant and homogeneously distributed PI-9. In human atherosclerotic lesions, however, PI-9 expression correlated inversely with immunoreactive IL-1β, supporting a potential role of the endogenous caspase-1 inhibitor in this chronic inflammatory disease. Thus, our results provide new insights into the regulation of this enzyme involved in immune and inflammatory processes of chronic inflammatory diseases, and point to an endogenous antiinflammatory action of PI-9, dysregulated in a prevalent human disease.
Differential Regulation of B Cell Development, Activation, and Death by the Src Homology 2 Domain–Containing 5′ Inositol Phosphatase (Ship)
Authors: Brauweiler Anne , Tamir Idan , Dal Porto Joseph , Benschop Robert J. , Helgason Cheryl D. , Humphries R. Keith , Freed John H. , Cambier John C.
Published: July 2002

Although the Src homology 2 domain–containing 5′ inositol phosphatase (SHIP) is a well-known mediator of inhibitory signals after B cell antigen receptor (BCR) coaggregation with the low affinity Fc receptor, it is not known whether SHIP functions to inhibit signals after stimulation through the BCR alone. Here, we show using gene-ablated mice that SHIP is a crucial regulator of BCR-mediated signaling, B cell activation, and B cell development. We demonstrate a critical role for SHIP in termination of phosphatidylinositol 3,4,5-triphosphate (PI[3,4,5]P3) signals that follow BCR aggregation. Consistent with enhanced PI(3,4,5)P3 signaling, we find that splenic B cells from SHIP-deficient mice display enhanced sensitivity to BCR-mediated induction of the activation markers CD86 and CD69. We further demonstrate that SHIP regulates the rate of B cell development in the bone marrow and spleen, as B cell precursors from SHIP-deficient mice progress more rapidly through the immature and transitional developmental stages. Finally, we observe that SHIP-deficient B cells have increased resistance to BCR-mediated cell death. These results demonstrate a central role for SHIP in regulation of BCR signaling and B cell biology, from signal driven development in the bone marrow and spleen, to activation and death in the periphery.
Cross-Priming of Naive Cd8 T Cells against Melanoma Antigens Using Dendritic Cells Loaded with Killed Allogeneic Melanoma Cells
Authors: Berard Frederic , Blanco Patrick , Davoust Jean , Neidhart-Berard Eve-Marie , Nouri-Shirazi Mahyar , Taquet Nicolas , Rimoldi Donata , Cerottini Jean Charles , Banchereau Jacques , Palucka A. Karolina
Published: July 2002

The goal of tumor immunotherapy is to elicit immune responses against autologous tumors. It would be highly desirable that such responses include multiple T cell clones against multiple tumor antigens. This could be obtained using the antigen presenting capacity of dendritic cells (DCs) and cross-priming. That is, one could load the DC with tumor lines of any human histocompatibility leukocyte antigen (HLA) type to elicit T cell responses against the autologous tumor. In this study, we show that human DCs derived from monocytes and loaded with killed melanoma cells prime naive CD45RA+CD27+CD8+ T cells against the four shared melanoma antigens: MAGE-3, gp100, tyrosinase, and MART-1. HLA-A201+ naive T cells primed by DCs loaded with HLA-A201− melanoma cells are able to kill several HLA-A201+ melanoma targets. Cytotoxic T lymphocyte priming towards melanoma antigens is also obtained with cells from metastatic melanoma patients. This demonstration of cross-priming against shared tumor antigens builds the basis for using allogeneic tumor cell lines to deliver tumor antigens to DCs for vaccination protocols.
CD1d-restricted Human Natural Killer T Cells Are Highly Susceptible to Human Immunodeficiency Virus 1 Infection
Authors: Motsinger Alison , Haas David W. , Stanic Aleksandar K. , Van Kaer Luc , Joyce Sebastian , Unutmaz Derya
Published: July 2002

Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Vα24-Vβ11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Vα24+ T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with α-galactosylceramide (α-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4+ T cells. Furthermore, resting CD4+ NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4+ subset of NKT cells. In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals. Although the mechanisms of this decline are not clear, low numbers or absence of NKT cells may affect the course of HIV-1 infection. Taken together, our findings indicate that CD4+ NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.
Conjoint Control of Hippocampal Place Cell Firing by Two Visual Stimuli
Authors: Fenton André A. , Csizmadia Gyorgy , Muller Robert U.
Published: July 2002

Changing the angular separation between two visual stimuli attached to the wall of a recording cylinder causes the firing fields of place cells to move relative to each other, as though the representation of the floor undergoes a topological distortion. The displacement of the firing field center of each cell is a vector whose length is equal to the linear displacement and whose angle indicates the direction that the field center moves in the environment. Based on the observation that neighboring fields move in similar ways, whereas widely separated fields tend to move relative to each other, we develop an empirical vector-field model that accounts for the stated effects of changing the card separation. We then go on to show that the same vector-field equation predicts additional aspects of the experimental results. In one example, we demonstrate that place cell firing fields undergo distortions of shape after the card separation is changed, as though different parts of the same field are affected by the stimulus constellation in the same fashion as fields at different locations. We conclude that the vector-field formalism reflects the organization of the place-cell representation of the environment for the current case, and through suitable modification may be very useful for describing motions of firing patterns induced by a wide variety of stimulus manipulations.
Calcium Sparks in Intact Skeletal Muscle Fibers of the Frog
Authors: Hollingworth S. , Peet J. , Chandler W.K , Baylor S.M.
Published: July 2002

Calcium sparks were studied in frog intact skeletal muscle fibers using a home-built confocal scanner whose point-spread function was estimated to be ∼0.21 μm in x and y and ∼0.51 μm in z. Observations were made at 17–20°C on fibers from Rana pipiens and Rana temporaria. Fibers were studied in two external solutions: normal Ringer's ([K+] = 2.5 mM; estimated membrane potential, −80 to −90 mV) and elevated [K+] Ringer's (most frequently, [K+] = 13 mM; estimated membrane potential, −60 to −65 mV). The frequency of sparks was 0.04–0.05 sarcomere−1 s−1 in normal Ringer's; the frequency increased approximately tenfold in 13 mM [K+] Ringer's. Spark properties in each solution were similar for the two species; they were also similar when scanned in the x and the y directions. From fits of standard functional forms to the temporal and spatial profiles of the sparks, the following mean values were estimated for the morphological parameters: rise time, ∼4 ms; peak amplitude, ∼1 ΔF/F (change in fluorescence divided by resting fluorescence); decay time constant, ∼5 ms; full duration at half maximum (FDHM), ∼6 ms; late offset, ∼0.01 ΔF/F; full width at half maximum (FWHM), ∼1.0 μm; mass (calculated as amplitude × 1.206 × FWHM3), 1.3–1.9 μm3. Although the rise time is similar to that measured previously in frog cut fibers (5–6 ms; 17–23°C), cut fiber sparks have a longer duration (FDHM, 9–15 ms), a wider extent (FWHM, 1.3–2.3 μm), and a strikingly larger mass (by 3–10-fold). Possible explanations for the increase in mass in cut fibers are a reduction in the Ca2+ buffering power of myoplasm in cut fibers and an increase in the flux of Ca2+ during release.
On the secant varieties to the tangential varieties of a Veronesean
Authors: Catalisano M. , Geramita A. , Gimigliano A.
Published: July 2002

We study the dimensions of the higher secant varieties to the tangent varieties of Veronese varieties. Our approach, generalizing that of Terracini, concerns 0-dimensional schemes which are the union of second infinitesimal neighbourhoods of generic points, each intersected with a generic double line.

We find the deficient secant line varieties for all the Veroneseans and all the deficient higher secant varieties for the quadratic Veroneseans. We conjecture that these are the only deficient secant varieties in this family and prove this up to secant projective 4-spaces.
Representation type of Hecke algebras of type 𝐴
Authors: Erdmann Karin , Nakano Daniel
Published: July 2002

In this paper we provide a complete classification of the representation type for the blocks for the Hecke algebra of type

A
A

, stated in terms of combinatorical data. The computation of the complexity of Young modules is a key component in the proof of this classification result.
Connection coefficients, matchings, maps and combinatorial conjectures for Jack symmetric functions
Authors: Goulden I. , Jackson D.
Published: July 2002

A power series is introduced that is an extension to three sets of variables of the Cauchy sum for Jack symmetric functions in the Jack parameter

α
.

\alpha .

We conjecture that the coefficients of this series with respect to the power sum basis are nonnegative integer polynomials in

b
b

, the Jack parameter shifted by

1
1

. More strongly, we make the Matchings-Jack Conjecture, that the coefficients are counting series in

b
b

for matchings with respect to a parameter of nonbipartiteness. Evidence is presented for these conjectures and they are proved for two infinite families. The coefficients of a second series, essentially the logarithm of the first, specialize at values

1
1

and

2
2

of the Jack parameter to the numbers of hypermaps in orientable and locally orientable surfaces, respectively. We conjecture that these coefficients are also nonnegative integer polynomials in

b
b

, and we make the Hypermap-Jack Conjecture, that the coefficients are counting series in

b
b

for hypermaps in locally orientable surfaces with respect to a parameter of nonorientability.
Minus class groups of the fields of the 𝑙-th roots of unity
Authors: Schoof René
Published: July 2002

We show that for any prime number

l
>
2

l>2

the minus class group of the field of the

l
l

-th roots of unity

Q

p

¯

(

ζ
l

)

\overline {\mathbf {Q}_p} (\zeta _l)

admits a finite free resolution of length 1 as a module over the ring

Z

^

[
G
]

/

(
1
+
ι
)

\widehat {\mathbf {Z}} [G]/(1+\iota )

. Here

ι
\iota

denotes complex conjugation in
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper G equals upper G a l left-parenthesis ModifyingAbove bold upper Q Subscript p Baseline With bar left-parenthesis zeta Subscript l Baseline right-parenthesis slash bold upper Q Subscript p Baseline overbar right-parenthesis approximately-equals left-parenthesis bold upper Z slash l bold upper Z right-parenthesis Superscript asterisk">

G
=

G
a
l

(

Q

p

¯

(

ζ
l

)

/

Q

p

¯

)
≅
(

Z

/

l

Z

)
∗

G={{Gal}}( \overline {\mathbf {Q}_p} (\zeta _l)/\overline {\mathbf {Q}_p} )\cong (\mathbf {Z} /l\mathbf {Z} )^*

. Moreover, for the primes

l
≤
509

l\le 509

we show that the minus class group is cyclic as a module over this ring. For these primes we also determine the structure of the minus class group.
On some applications of automorphic forms to number theory
Authors: Bump Daniel , Friedberg Solomon , Hoffstein Jeffrey
Published: July 2002

A basic idea of Dirichlet is to study a collection of interesting quantities

{

a
n

}

n
≥
1

\{a_n\}_{n\geq 1}

by means of its Dirichlet series in a complex variable

w
w

:

∑

n
≥
1

a
n

n

−
w

\sum _{n\geq 1}a_nn^{-w}

. In this paper we examine this construction when the quantities

a
n

a_n

are themselves infinite series in a second complex variable

s
s

, arising from number theory or representation theory. We survey a body of recent work on such series and present a new conjecture concerning them.
𝐺(𝐹_{𝑞})-invariants in irreducible 𝐺(𝐹_{𝑞²})-modules
Authors: Lusztig G.
Published: July 2002

We give an explicit formula for the dimension of the space of

G
(

F

q

)

G(F_{q})

-invariant vectors in an irreducible complex representation of

G
(

F

q

2

)

G(F_{q^{2}})

, where

G
G

is a connected reductive algebraic group defined over a finite field

F

q

F_{q}

with connected center.
Orbits in the flag variety and images of the moment map for classical groups I
Authors: Yamamoto Atsuko
Published: July 2002

We propose algorithms to get representatives and the images of the moment map of conormal bundles of

G
L
(
p
,

C

)
×
G
L
(
q
,

C

)

GL(p,\mathbb {C})\times GL(q,\mathbb {C} )

-orbits in the flag variety of

G
L
(
p
+
q
,

C

)

GL(p+q,\mathbb {C} )

, and

G
L
(
p
+
q
,

C

)

GL(p+q,\mathbb {C})

-orbits and

S
p
(
p
,

C

)
×
S
p
(
q
,

C

)

Sp(p,\mathbb {C} )\times Sp(q,\mathbb {C} )

-orbits in the flag variety of

S
p
(
p
+
q
,

C

)

Sp(p+q,\mathbb {C} )

and their signed Young diagrams.
Endoplasmic Reticulum Dynamics, Inheritance, and Cytoskeletal Interactions in Budding Yeast
Authors: Fehrenbacher K. L. , Davis D. , Wu M. , Boldogh I. , Pon Liza A.
Published: July 2002

The endoplasmic reticulum (ER) in Saccharomyces cerevisiae consists of a reticulum underlying the plasma membrane (cortical ER) and ER associated with the nuclear envelope (nuclear ER). We used a Sec63p-green fluorescent protein fusion protein to study motility events associated with inheritance of cortical ER and nuclear ER in living yeast cells. During M phase before nuclear migration, we observed thick, apparently rigid tubular extensions emanating from the nuclear ER that elongate, undergo sweeping motions along the cell cortex, and shorten. Two findings support a role for microtubules in this process. First, extension of tubular structures from the nuclear ER is inhibited by destabilization of microtubules. Second, astral microtubules, structures that undergo similar patterns of extension, cortical surveillance and retraction, colocalize with nuclear ER extensions. During S and G2 phases of the cell cycle, we observed anchorage of the cortical ER at the site of bud emergence and apical bud growth. Thin tubules of the ER that extend from the anchored cortical ER display undulating, apparently random movement and move into the bud as it grows. Finally, we found that cortical ER morphology is sensitive to a filamentous actin–destabilizing drug, latrunculin-A, and to mutations in the actin-encoding ACT1 gene. Our observations support 1) different mechanisms and cytoskeletal mediators for the inheritance of nuclear and cortical ER elements and 2) a mechanism for cortical ER inheritance that is cytoskeleton dependent but relies on anchorage, not directed movement.
Kinesin-like Protein CHO1 Is Required for the Formation of Midbody Matrix and the Completion of Cytokinesis in Mammalian Cells
Authors: Matuliene Jurgita , Kuriyama Ryoko
Published: July 2002

CHO1 is a mammalian kinesin-like motor protein of the MKLP1 subfamily. It associates with the spindle midzone during anaphase and concentrates to a midbody matrix during cytokinesis. CHO1 was originally implicated in karyokinesis, but the invertebrate homologues of CHO1 were shown to function in the midzone formation and cytokinesis. To analyze the role of the protein in mammalian cells, we mutated the ATP-binding site of CHO1 and expressed it in CHO cells. Mutant protein (CHO1F′) was able to interact with microtubules via ATP-independent microtubule-binding site(s) but failed to accumulate at the midline of the central spindle and affected the localization of endogenous CHO1. Although the segregation of chromosomes, the bundling of midzone microtubules, and the initiation of cytokinesis proceeded normally in CHO1F′-expressing cells, the completion of cytokinesis was inhibited. Daughter cells were frequently entering interphase while connected by a microtubule-containing cytoplasmic bridge from which the dense midbody matrix was missing. Depletion of endogenous CHO1 via RNA-mediated interference also affected the formation of midbody matrix in dividing cells, caused the disorganization of midzone microtubules, and resulted in abortive cytokinesis. Thus, CHO1 may not be required for karyokinesis, but it is essential for the proper midzone/midbody formation and cytokinesis in mammalian cells.
Bilayered Clathrin Coats on Endosomal Vacuoles Are Involved in Protein Sorting toward Lysosomes
Authors: Sachse Martin , Urbé Sylvie , Oorschot Viola , Strous Ger J. , Klumperman Judith
Published: July 2002

In many cells endosomal vacuoles show clathrin coats of which the function is unknown. Herein, we show that this coat is predominantly present on early endosomes and has a characteristic bilayered appearance in the electron microscope. By immunoelectron miscroscopy we show that the coat contains clathrin heavy as well as light chain, but lacks the adaptor complexes AP1, AP2, and AP3, by which it differs from clathrin coats on endocytic vesicles and recycling endosomes. The coat is insensitive to short incubations with brefeldin A, but disappears in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin. No association of endosomal coated areas with tracks of tubulin or actin was found. By quantitative immunoelectron microscopy, we found that the lysosomal-targeted receptors for growth hormone (GHR) and epidermal growth factor are concentrated in the coated membrane areas, whereas the recycling transferrin receptor is not. In addition, we found that the proteasomal inhibitor MG 132 induces a redistribution of a truncated GHR (GHR-369) toward recycling vesicles, which coincided with a redistribution of endosomal vacuole-associated GHR-369 to the noncoated areas of the limiting membrane. Together, these data suggest a role for the bilayered clathrin coat on vacuolar endosomes in targeting of proteins to lysosomes.
Accuracy of Alternative Approaches to Capture-Recapture Estimates of Disease Frequency: Internal Validity Analysis of Data from Five Sources
Authors: Hook Ernest B. , Regal Ronald R.
Published: July 2002

The authors used “internal validity analysis” to evaluate the performance of various capture-recapture methods. Data from studies with five overlapping, incomplete lists generated subgroups whose known sizes were compared with estimates derived from various four-source capture-recapture analyses. In 15 data sets unanalyzed previously (five subgroups of each of three new studies), the authors observed a trend toward mean underestimation of the known population size by 16–25%. (Coverage of the 90% confidence intervals associated with the method found to be optimal was acceptable (13/15), despite the downward bias.) The authors conjectured that (with the obvious exception of geographically disparate lists) most data sets used by epidemiologists tend to have a net positive dependence; that is, cases captured by one source are more likely to be captured by some other available source than are cases selected randomly from the population, and this trend results in a bias toward underestimation. Attempts to ensure that the underlying assumptions of the methods are met, such as minimizing (or adjusting adequately) for the possibility of loss due to death or migration, as was undertaken in one exceptional study, appear likely to improve the behavior of these methods. Am J Epidemiol 2000;152:771–9.
The complexities of genome analysis, the Retroid agent
perspective
Authors: McClure Marcella A.
Published: July 2002

Motivation: The sequences of Retroid agents from a wide diversity of organisms constitute the largest set of complete genomes currently available for the study of genomic architecture and the transfer of information within and between organisms. These agents are ubiquitous in Eukaryotes, comprising 50–90% of the genomic information in some cases.

Results: Analyses conducted for over a decade illustrate that Retroid agents are engaged in a wide spectrum of molecular evolutionary events. A description of these complexities is presented as a three parameter conceptual framework that considers type, size, and mechanism of events that contribute to the evolution of genes, genomes, and organisms. The results of new data mining studies further illustrate the complexity of the network of relationships among and between Retroid agents and other organisms. A hidden Markov model construction strategy is presented that generates a multiple alignment more similar to those refined by human experts.

Contact: mars@parvati.msu.montana.edu
Dynactin–membrane interaction is regulated by the C‐terminal domains of p150Glued
Authors: Kumar Santosh , Zhou Yi , Plamann Michael
Published: July 2002

Dynactin has been proposed to link the microtubule‐associated motor cytoplasmic dynein with membranous cargo; however, the mechanism by which dynactin–membrane interaction is regulated is unknown. Here we show that dynein and dynactin exist in discrete cytosolic and membrane‐bound states in the filamentous fungus Neurospora crassa. Results from in vitro membrane‐binding studies show that dynein and dynactin–membrane interaction is co‐dependent. p150Glued of dynactin has been shown to interact with dynein intermediate chain and dynactin Arp1 filament; however, it is not known to play a direct role in membrane binding. In this report we describe our analysis of 43 p150Glued mutants, and we show that C‐terminal deletions which remove the terminal coiled‐coil (CC2) and basic domain (BD) result in constitutive dynactin–membrane binding. In vitro addition of recombinant p150Glued CC2+BD protein blocks dynactin–membrane binding. We propose that the C‐terminal domains of p150Glued regulate dynactin–membrane binding through a steric mechanism that controls accessibility of the Arp1 filament of dynactin to membranous cargo.
The “Economic Miracle” and Italy’s Chemical Industry, 1950-1965: A Missed Opportunity
Authors: Fauri Francesca
Published: July 2002

The chemical industry was a leading sector in Italy’s “economic miracle,” but after remarkable growth in the 1950s, it declined in the next decade. Montecatini rose to a dominant position in inorganic chemicals and fertilizers in the 1950s, but its quasi-monopoly of traditional chemicals was soon challenged, first by the state-owned Eni and then by Edison, one of Italy’s giant electric power companies, which was diversifying into new sectors. The “chemical wars” of the late 1950s and early 1960s pitted the three companies against one another, as they competed for state support by building plants in Italy’s underdeveloped south, often with little commercial rationale. Although the “war” was finally resolved by a merger of Montecatini and Edison, the new company failed to achieve internal rationalization or to develop advanced chemical products. By the 1970s the sector was in disarray, and the opportunities of Italy’s rapid postwar development in chemicals had been squandered.
A quantitative method for the detection of edges in noisy time–series
Authors: Smith D. A.
Published: July 2002

A modification of the edge detector of Chung and Kennedy is proposed in which the output provides confidence limits for the presence or absence of sharp edges (steps) in the input waveform. Their switching method with forward and backward averaging windows is retained, but the output approximates an ideal output function equal to the difference in these averages divided by the standard deviation of the noise. Steps are associated with peak output above a pre-set threshold. Formulae for the efficiency and reliability of this ideal detector are derived for input waveforms with Gaussian white noise and sharp edges, and serve as benchmarks for the switching edge detector. Efficiency is kept high if the threshold is a fixed fraction of the step size of interest relative to noise, and reliability is improved by increasing the window width
W
to reduce false output. For different steps sizes
D
, the window width for fixed efficiency and reliability scales as 1/
D
2
. Versions with weighted averaging (flat, ramp, triangular) or median averaging but the same window width perform similarly. Binned above–threshold output is used to predict the locations and signs of detected steps, and simulations show that efficiency and reliability are close to ideal. Location times are accurate to order square root of
W
. Short pulses generate reduced output if the number of datapoints in the pulse is less than
W
. They are optimally detected by choosing
W
as above and collecting data at a rate such that the pulse contains approximately
W
datapoints. A Fortran program is supplied.
Evidence for both nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington'sdisease in cell culture and in transgenic mice expressing mutant huntingtin
Authors: Hackam Abigail S. , Hodgson J. Graeme , Singaraja Roshni , Zhang Taiqi , Gan Lu , Gutekunst Claire-Anne , Hersch Steven M. , Hayden Michael R.
Published: July 2002

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from
in vivo
and
in vitro
studies of mutant huntingtin have led to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington'sdisease (HD). We tested this hypothesis using a 293T cell culture model system by comparing the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. Insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. These studies, together with findings in transgenic mice, suggest two phases for the pathogenesis of HD, with the initial toxicity in the cytoplasm followed by proteolytic processing of huntingtin, nuclear translocation with increased nuclear concentration of N-terminal fragments, seeding of aggregates and resultant apoptotic death. These findings support the nucleus and cytosol as subcellular sites for pathogenesis in HD.
Pain and functional imaging
Authors: Ingvar Martin
Published: July 2002

Functional neuroimaging has fundamentally changed our knowledge about the cerebral representation of pain. For the first time it has been possible to delineate the functional anatomy of different aspects of pain in the medial and lateral pain systems in the brain. The rapid developments in imaging methods over the past years have led to a consensus in the description of the central pain responses between different studies and also to a definition of a central pain matrix with specialized subfunctions in man. In the near future we will see studies where a systems perspective allows for a better understanding of the regulatory mechanisms in the higher-order frontal and parietal cortices. Also, pending the development of experimental paradigms, the functional anatomy of the emotional aspects of pain will become better known.
A graphical anatomical database of neural connectivity
Authors: Press William A. , Olshausen Bruno A. , Van Essen David C.
Published: July 2002

We describe a graphical anatomical database program, called XANAT (so named because it was developed under the X window system in UNIX), that allows the results of numerous studies on neuroanatomical connections to be stored, compared and analysed in a standardized format. Data are entered into the database by drawing injection and label sites from a particular tracer study directly onto canonical representations of the neuroanatomical structures of interest, along with providing descriptive text information. Searches may then be performed on the data by querying the database graphically, for example by specifying a region of interest within the brain for which connectivity information is desired, or via text information, such as keywords describing a particular brain region, or an author name or reference. Analyses may also be performed by accumulating data across multiple studies and displaying a colour–coded map that graphically represents the total evidence for connectivity between regions. Thus, data may be studied and compared free of areal boundaries (which often vary from one laboratory to the next), and instead with respect to standard landmarks, such as the position relative to well–known neuro–anatomical substrates or stereotaxic coordinates. If desired, areal boundaries may also be defined by the user to facilitate the interpretation of results. We demonstrate the application of the database to the analysis of pulvinar–cortical connections in the macaque monkey, for which the results of over 120 neuro–anatomical experiments were entered into the database. We show how these techniques can be used to elucidate connectivity trends and patterns that may otherwise go unnoticed.
Neural systems underlying episodic memory: insights from animal research
Authors: Aggleton John P. , Pearce John M.
Published: July 2002

Two strategies used to uncover neural systems for episodic–like memory in animals are discussed: (i) an attribute of episodic memory (what?when?where?) is examined in order to reveal the neuronal interactions supporting that component of memory; and (ii) the connections of a structure thought to be central to episodic memory in humans are studied at a level of detail not feasible in humans. By focusing on spatial memory (where?) and the hippocampus, it has proved possible to bring the strategies together. A review of lesion, disconnection and immediate early–gene studies in animals reveals the importance of interactions between the hippocampus and specific nuclei in the diencephalon (most notably the anterior thalamic nuclei) for spatial memory. Other parts of this extended hippocampal system include the mammillary bodies and the posterior cingulate (retrosplenial) cortex. Furthermore, by combining lesion and immediate early–gene studies it is possible to show how the loss of one component structure or tract can influence the remaining regions in this group of structures. The validity of this convergent approach is supported by new findings showing that the same set of regions is implicated in anterograde amnesia in humans.