bluuebunny/crossref_metadata_2025 huggingface dataset:
The Subcellular Localization of an Aquaporin-2 Tetramer Depends on the Stoichiometry of Phosphorylated and Nonphosphorylated Monomers
Authors: Kamsteeg E.J. , Heijnen I. , van Os C.H. , Deen P.M.T.
Published: July 2002

In renal principal cells, vasopressin regulates the shuttling of the aquaporin (AQP)2 water channel between intracellular vesicles and the apical plasma membrane. Vasopressin-induced phosphorylation of AQP2 at serine 256 (S256) by protein kinase A (PKA) is essential for its localization in the membrane. However, phosphorylated AQP2 (p-AQP2) has also been detected in intracellular vesicles of noninduced principal cells. As AQP2 is expressed as homotetramers, we hypothesized that the number of p-AQP2 monomers in a tetramer might be critical for the its steady state distribution. Expressed in oocytes, AQP2-S256D and AQP2-S256A mimicked p-AQP2 and non–p-AQP2, respectively, as routing and function of AQP2-S256D and wild-type AQP2 (wt-AQP2) were identical, whereas AQP2-S256A was retained intracellularly. In coinjection experiments, AQP2-S256A and AQP2-S256D formed heterotetramers. Coinjection of different ratios of AQP2-S256A and AQP2-S256D cRNAs revealed that minimally three AQP2-S256D monomers in an AQP2 tetramer were essential for its plasma membrane localization. Therefore, our results suggest that in principal cells, minimally three monomers per AQP2 tetramer have to be phosphorylated for its steady state localization in the apical membrane. As other multisubunit channels are also regulated by phosphorylation, it is anticipated that the stoichiometry of their phosphorylated and nonphosphorylated subunits may fine-tune the activity or subcellular localization of these complexes.
Listeriolysin O
Authors: Dramsi Shaynoor , Cossart Pascale
Published: July 2002

Cholesterol-dependent cytolysins (CDCs)**Abbreviations used in this paper: CDC, cholesterol-dependent cytolysin; LLO, listeriolysin O; PFO, perfringolysin O; SLO, streptolysin O. are produced by a large number of pathogenic gram–positive bacteria. A member of this family, listeriolysin O (LLO), is produced by the intracellular pathogen Listeria monocytogenes. A unique feature of LLO is its low optimal pH activity (∼6) which permits escape of the bacterium from the phagosome into the host cell cytosol without damaging the plasma membrane of the infected cell. In a recent study (Glomski et al., 2002, this issue), Portnoy's group has addressed the molecular mechanism underlying the pH sensitivity of LLO. Unexpectedly, a single amino acid substitution in LLO L461T results in a molecule more active at neutral pH and promoting premature permeabilization of the infected cells, leading to attenuated virulence. This finding highlights how subtle changes in proteins can be exploited by bacterial pathogens to establish and maintain the integrity of their specific niches.
CTLA-4–B7 Interaction Is Sufficient to Costimulate T Cell Clonal Expansion
Authors: Wu Yan , Guo Yong , Huang Andy , Zheng Pan , Liu Yang
Published: July 2002

T cell costimulation, particularly by the B7 family members B7-1 and B7-2, plays a critical role in regulating T cell–mediated immunity. Two molecules on T cells, CD28 and CTLA-4, are known to bind to B7. It has been suggested that CD28–B7 interaction promotes T cell response, whereas B7–CTLA-4 interaction downregulates T cell clonal expansion. However, the proposed responses of individual receptors to B7 have not been verified directly. Here, we report that B7-1 promotes clonal expansion of CD28-deficient T cells, and that the CD28-independent costimulatory activity is mediated by CTLA-4, as it is completely blocked by intact and Fab of anti–CTLA-4 mAb. In addition, a mutant B7-1 molecule, B7W88 >A, which has lost binding to CD28 but retained significant CTLA-4 binding activity, promotes T cell clonal expansion. Furthermore, while presence of CD28 enhances T cell response to B7-1, such response is also completely blocked by anti–CTLA-4 mAb. Taken together, our results demonstrate that B7–CTLA-4 interaction promotes T cell clonal expansion, and that optimal T cell response to B7 is achieved when both CD28 and CTLA-4 interact with B7. These results establish an important function of CTLA-4 in promoting T cell activation, and suggest an alternative interpretation of the function of CTLA-4 in T cell activation.
A Mechanism for the Major Histocompatibility Complex–linked Resistance to Autoimmunity
Authors: Schmidt Dennis , Verdaguer Joan , Averill Nuzhat , Santamaria Pere
Published: July 2002

Certain major histocompatibility complex (MHC) class II haplotypes encode elements providing either susceptibility or dominant resistance to the development of spontaneous autoimmune diseases via mechanisms that remain undefined. Here we show that a pancreatic beta cell–reactive, I-Ag7–restricted, transgenic TCR that is highly diabetogenic in nonobese diabetic mice (H-2g7) undergoes thymocyte negative selection in diabetes-resistant H-2g7/b, H-2g7/k, H-2g7/q, and H-2g7/nb1 NOD mice by engaging antidiabetogenic MHC class II molecules on thymic bone marrow–derived cells, independently of endogenous superantigens. Thymocyte deletion is complete in the presence of I-Ab, I-Ak + I-Ek or I-Anb1 + I-Enb1 molecules, partial in the presence of I-Aq or I-Ak molecules alone, and absent in the presence of I-As molecules. Mice that delete the transgenic TCR develop variable degrees of insulitis that correlate with the extent of thymocyte deletion, but are invariably resistant to diabetes development. These results provide an explanation as to how protective MHC class II genes carried on one haplotype can override the genetic susceptibility to an autoimmune disease provided by allelic MHC class II genes carried on a second haplotype.
Nuclear Factor of Activated T Cells (NFAT)-dependent Transactivation Regulated by the Coactivators p300/CREB-binding Protein (CBP)
Authors: García-Rodríguez Carmen , Rao Anjana
Published: July 2002

p300 and cAMP response element–binding protein (CREB)–binding protein (CBP) are members of a family of coactivators involved in the regulation of transcription and chromatin. We show that transcription factors of the nuclear factor of activated T cells (NFAT) family bind p300/CBP and recruit histone acetyltransferase activity from T cell nuclear extracts. The NH2-terminal transactivation domain of NFAT1 and the phospho-CREB- and E1A-binding sites of p300/CBP are involved in the interaction. The viral oncoprotein E1A inhibits NFAT-dependent transactivation in a p300-dependent manner. Recruitment of the coactivators p300/CBP by the transactivation domains of NFAT proteins is likely to play a critical role in NFAT-dependent gene expression during the immune response.
Conserved T Cell Receptor Repertoire in Primary and Memory CD8 T Cell Responses to an Acute Viral Infection
Authors: Sourdive David J.D. , Murali-Krishna Kaja , Altman John D. , Zajac Allan J. , Whitmire Jason K. , Pannetier Christophe , Kourilsky Philippe , Evavold Brian , Sette Alessandro , Ahmed Rafi
Published: July 2002

Viral infections often induce potent CD8 T cell responses that play a key role in antiviral immunity. After viral clearance, the vast majority of the expanded CD8 T cells undergo apoptosis, leaving behind a stable number of memory cells. The relationship between the CD8 T cells that clear the acute viral infection and the long-lived CD8 memory pool remaining in the individual is not fully understood. To address this issue, we examined the T cell receptor (TCR) repertoire of virus-specific CD8 T cells in the mouse model of infection with lymphocytic choriomeningitis virus (LCMV) using three approaches: (a) in vivo quantitative TCR β chain V segment and complementarity determining region 3 (CDR3) length repertoire analysis by spectratyping (immunoscope); (b) identification of LCMV-specific CD8 T cells with MHC class I tetramers containing viral peptide and costaining with TCR Vβ–specific antibodies; and (c) functional TCR fingerprinting based on recognition of variant peptides. We compared the repertoire of CD8 T cells responding to acute primary and secondary LCMV infections, together with that of virus-specific memory T cells in immune mice. Our analysis showed that CD8 T cells from several Vβ families participated in the anti-LCMV response directed to the dominant cytotoxic T lymphocyte (CTL) epitope (NP118–126). However, the bulk (∼70%) of this CTL response was due to three privileged T cell populations systematically expanding during LCMV infection. Approximately 30% of the response consisted of Vβ10+ CD8 T cells with a β chain CDR3 length of nine amino acids, and 40% consisted of Vβ8.1+ (β CDR3 = eight amino acids) and Vβ8.2+ cells (β CDR3 = six amino acids). Finally, we showed that the TCR repertoire of the primary antiviral CD8 T cell response was similar both structurally and functionally to that of the memory pool and the secondary CD8 T cell effectors. These results suggest a stochastic selection of memory cells from the pool of CD8 T cells activated during primary infection.
Immunocytochemical Colocalization of Specific Immunoglobulin A with Sendai Virus Protein in Infected Polarized Epithelium
Authors: Fujioka Hisashi , Emancipator Steven N. , Aikawa Masamichi , Huang Dennis S. , Blatnik Frank , Karban Tracy , DeFife Kristin , Mazanec Mary B.
Published: July 2002

Immunoglobulin (Ig)A provides the initial immune barrier to viruses at mucosal surfaces. Specific IgA interrupts viral replication in polarized epithelium during receptor-mediated transport, probably by binding to newly synthesized viral proteins. Here, we demonstrate by immunoelectron microscopy that specific IgA monoclonal antibodies (mAbs) accumulate within Sendai virus–infected polarized cell monolayers and colocalize with the hemagglutinin– neuraminidase (HN) viral protein in a novel intracellular structure. Neither IgG specific for HN nor irrelevant IgA mAbs colocalize with viral protein. Treatment of cultures with viral-specific IgA but not with viral-specific IgG or irrelevant IgA decreases viral titers. These observations provide definitive ultrastructural evidence of a subcellular compartment in which specific IgA and viral envelope proteins interact, further strengthening our hypothesis of intracellular neutralization of virus by specific IgA antibodies. Our results have important implications for intracellular protein trafficking, viral replication, and viral vaccine development.
The Dual Nature of Specific Immunological Activity of Tumor-derived gp96 Preparations
Authors: Chandawarkar Rajiv Y. , Wagh Mihir S. , Srivastava Pramod K.
Published: July 2002

Mice immunized with optimal doses of autologous tumor–derived gp96 resist a challenge with the tumor that was the source of gp96. Immunization with quantities of gp96 5–10 times larger than the optimal dose does not elicit tumor immunity. This lack of effect is shown to be an active, antigen-specific effect, in that immunization with high doses of tumor-derived gp96, but not normal tissue–derived gp96, downregulates the antitumor immune response. Furthermore, immunization with fractionated doses of gp96 elicits the same kind and level of response as elicited by a single dose equivalent to the total of the fractionated doses. This is true of  the tumor-protective doses as well as the high downregulatory doses of gp96. The downregulatory activity can be adoptively transferred by CD4+ but not CD8+ T lymphocytes from mice immunized with high doses of gp96. These observations indicate that immunization with gp96 induces a highly regulated immune response that, depending upon the conditions of immunization, results in tumor immunity or downregulation.
Measuring Recent Thymic Emigrants in Blood of Normal and HIV-1–Infected Individuals before and after Effective Therapy
Authors: Zhang Linqi , Lewin Sharon R. , Markowitz Martin , Lin Hsi-Hsun , Skulsky Eva , Karanicolas Rose , He Yuxian , Jin Xia , Tuttleton Sarah , Vesanen Mika , Spiegel Hans , Kost Rhonda , van Lunzen Jan , Stellbrink Hans-Juergen , Wolinsky Steven , Borkowsky William , Palumbo Paul , Kostrikis Leondios G. , Ho David D.
Published: July 2002

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed α1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that α1 circle numbers in blood remain high for the first 10–15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, α1 circle numbers in HIV-1–infected adults were significantly reduced; however, there were many individuals with normal α1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on α1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in α1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as α1 circle numbers are normal in a substantial subset of HIV-1–infected individuals.
Cell-Specific Transcriptional Regulation of Human Leukotriene B4 Receptor Gene
Authors: Kato Kazuhiko , Yokomizo Takehiko , Izumi Takashi , Shimizu Takao
Published: July 2002

Leukotriene B4 (LTB4) is a lipid mediator that activates leukocytes and is involved in host defense and inflammation. BLT1, a high-affinity receptor for LTB4 (originally termed BLT), is expressed exclusively in inflammatory cells and is inducible in macrophages upon activation. The mechanisms of tissue-specific expression and induction of BLT1 are important for the understanding of mechanism of onset and the potential treatment of inflammatory disorders. Here, we report the genomic structure and a promoter analysis of the human BLT1 gene, with an emphasis on the mechanism of cell-specific transcription. No TATA or CAAT elements exist around the transcription initiation sites, but a GC-rich sequence is observed in this region. A reporter gene assay revealed that a region ∼80 basepair upstream from the initiator sequence is required for the basal transcription of the BLT1 gene. Sp1 was found to be a major activator of basal transcription by electrophoretic mobility shift assays and site-directed mutagenesis. The CpG sites of the BLT1 promoter region were highly methylated in BLT1-nonexpressing cells, but not methylated in BLT1-expressing cells. Further, methylation of this region in vitro inhibited the promoter activity to ∼15% of the control. Thus, methylation at CpG sites in the promoter region is important for cell-specific transcription of the BLT1 gene. The promoter region of the BLT1 gene is localized within the open reading frame (ORF) of the BLT2 gene, which encodes a low-affinity receptor for LTB4 (Yokomizo, T., K. Kato, K. Terawaki, T. Izumi, and T. Shimizu. 2000. J. Exp. Med. 192:421–431). To our knowledge, this is the first example of “promoter in ORF” in higher eukaryotes.
Preformed Membrane-Associated Stores of Interleukin (Il)-12 Are a Previously Unrecognized Source of Bioactive IL-12 That Is Mobilized within Minutes of Contact with an Intracellular Parasite
Authors: Quinones Marlon , Ahuja Sunil K. , Melby Peter C. , Pate Lyle , Reddick Robert L. , Ahuja Seema S.
Published: July 2002

The prevailing paradigm is that production of the interleukin (IL)-12 p70 heterodimer, a critical T helper cell type 1 (Th1)–inducing cytokine, depends on the induced transcription of the p40 subunit. Concordant with this paradigm, we found that dendritic cells (DCs) produced IL-12 p70 only after at least 2–4 h of stimulation with lipopolysaccharide plus interferon γ. However, using several complementary experimental approaches, including electron and confocal microscopy, we now show that resting murine and human myeloid cells, including macrophages/DCs and DC-rich tissues, contain a novel source of bioactive IL-12 that is preformed and membrane associated. These preformed, membrane-associated IL-12 p70 stores are released within minutes after in vitro or in vivo contact with Leishmania donovani, an intracellular pathogen. Our findings highlight a novel source of bioactive IL-12 that is readily available for the rapid initiation of Th1 host responses to pathogens such as Leishmania species.
Blockade of T Lymphocyte Costimulation with Cytotoxic T Lymphocyte–Associated Antigen 4–Immunoglobulin (Ctla4ig) Reverses the Cellular Pathology of Psoriatic Plaques, Including the Activation of Keratinocytes, Dendritic Cells, and Endothelial Cells
Authors: Abrams Judith R. , Kelley Susan L. , Hayes Elizabeth , Kikuchi Toyoko , Brown Michael J. , Kang Sewon , Lebwohl Mark G. , Guzzo Cynthia A. , Jegasothy Brian V. , Linsley Peter S. , Krueger James G.
Published: July 2002

Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC–lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.
Role of Promyelocytic Leukemia (Pml) Protein in Tumor Suppression
Authors: Rego Eduardo M. , Wang Zhu-Gang , Peruzzi Daniela , He Le-Zhen , Cordon-Cardo Carlos , Pandolfi Pier Paolo
Published: July 2002

The promyelocytic leukemia (PML) gene encodes a putative tumor suppressor gene involved in the control of apoptosis, which is fused to the retinoic acid receptor α (RARα) gene in the vast majority of acute promyelocytic leukemia (APL) patients as a consequence of chromosomal translocations. The PMLRARα oncoprotein is thought to antagonize the function of PML through its ability to heterodimerize with and delocalize PML from the nuclear body. In APL, this may be facilitated by the reduction to heterozygosity of the normal PML allele. To determine whether PML acts as a tumor suppressor in vivo and what the consequences of deregulated programmed cell death in leukemia and epithelial cancer pathogenesis are, we crossed PML−/− mice with human cathepsin G (hCG)-PMLRARα or mammary tumor virus (MMTV)/neu transgenic mice (TM), models of leukemia and breast cancer, respectively. The progressive reduction of the dose of PML resulted in a dramatic increase in the incidence of leukemia, and in an acceleration of leukemia onset in PMLRARα TM. By contrast, PML inactivation did not affect neu-induced tumorigenesis. In hemopoietic cells from PMLRARα TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vitamin D3 as well as in a marked survival advantage upon proapoptotic stimuli. These results demonstrate that: (a) PML acts in vivo as a tumor suppressor by rendering the cells resistant to proapoptotic and differentiating stimuli; (b) PML haploinsufficiency and the functional impairment of PML by PMLRARα are critical events in APL pathogenesis; and (c) aberrant control of programmed cell death plays a differential role in solid tumor and leukemia pathogenesis.
Invasion and Persistent Intracellular Colonization of Erythrocytes
Authors: Schülein Ralf , Seubert Anja , Gille Christian , Lanz Christa , Hansmann Yves , Piémont Yves , Dehio Christoph
Published: July 2002

The expanding genus Bartonella includes zoonotic and human-specific pathogens that can cause a wide range of clinical manifestations. A productive infection allowing bacterial transmission by blood-sucking arthropods is marked by an intraerythrocytic bacteremia that occurs exclusively in specific human or animal reservoir hosts. Incidental human infection by animal-adapted bartonellae can cause disease without evidence for erythrocyte parasitism. A better understanding of the intraerythrocytic lifestyle of bartonellae may permit the design of strategies to control the reservoir and transmittable stages of these emerging pathogens. We have dissected the process of Bartonella erythrocyte parasitism in experimentally infected animals using a novel approach for tracking blood infections based on flow cytometric quantification of green fluorescent protein–expressing bacteria during their interaction with in vivo–biotinylated erythrocytes. Bacteremia onset occurs several days after inoculation by a synchronous wave of bacterial invasion into mature erythrocytes. Intracellular bacteria replicate until reaching a stagnant number, which is sustained for the remaining life span of the infected erythrocyte. The initial wave of erythrocyte infection is followed by reinfection waves occurring at intervals of several days. Our findings unravel a unique bacterial persistence strategy adapted to a nonhemolytic intracellular colonization of erythrocytes that preserves the pathogen for efficient transmission by blood-sucking arthropods.
Acetylcholine-induced Calcium Signaling and Contraction of Airway Smooth Muscle Cells in Lung Slices
Authors: Bergner Albrecht , Sanderson Michael J.
Published: July 2002

The Ca2+ signaling and contractility of airway smooth muscle cells (SMCs) were investigated with confocal microscopy in murine lung slices (∼75-μm thick) that maintained the in situ organization of the airways and the contractility of the SMCs for at least 5 d. 10–500 nM acetylcholine (ACH) induced a contraction of the airway lumen and a transient increase in [Ca2+]i in individual SMCs that subsequently declined to initiate multiple intracellular Ca2+ oscillations. These Ca2+ oscillations spread as Ca2+ waves through the SMCs at ∼48 μm/s. The magnitude of the airway contraction, the initial Ca2+ transient, and the frequency of the subsequent Ca2+ oscillations were all concentration-dependent. In a Ca2+-free solution, ACH induced a similar Ca2+ response, except that the Ca2+ oscillations ceased after 1–1.5 min. Incubation with thapsigargin, xestospongin, or ryanodine inhibited the ACH-induced Ca2+ signaling. A comparison of airway contraction with the ACH-induced Ca2+ response of the SMCs revealed that the onset of airway contraction correlated with the initial Ca2+ transient, and that sustained airway contraction correlated with the occurrence of the Ca2+ oscillations. Buffering intracellular Ca2+ with BAPTA prohibited Ca2+ signaling and airway contraction, indicating a Ca2+-dependent pathway. Cessation of the Ca2+ oscillations, induced by ACH-esterase, halothane, or the absence of extracellular Ca2+ resulted in a relaxation of the airway. The concentration dependence of the airway contraction matched the concentration dependence of the increased frequency of the Ca2+ oscillations. These results indicate that Ca2+ oscillations, induced by ACH in murine bronchial SMCs, are generated by Ca2+ release from the SR involving IP3- and ryanodine receptors, and are required to maintain airway contraction.
Injective resolutions of Noetherian rings and cogenerators
Authors: Miyachi Jun-ichi
Published: July 2002

We give new construction of injective resolutions of complexes and bimodules. Applying this construction to an injective resolution of a Noetherian ring, we construct a

Σ
\Sigma

-embedding cogenerator for the category of modules of projective dimension

≤
n

\leq n

. Moreover, for a Noetherian projective

k
k

-algebra

R
R

, we show that

R
R

satisfies the Auslander condition if and only if the flat dimension of every

R
R

-module

M
M

is equal to or larger than the one of the injective hull

E
⁡
(
M
)

\operatorname {E}(M)

.
Nonlinear equations and weighted norm inequalities
Authors: Kalton N. , Verbitsky I.
Published: July 2002

We study connections between the problem of the existence of positive solutions for certain nonlinear equations and weighted norm inequalities. In particular, we obtain explicit criteria for the solvability of the Dirichlet problem
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout 1st Row 1st Column minus normal upper Delta u 2nd Column a m p semicolon equals v u Superscript q Baseline plus w comma u greater-than-or-equal-to 0 3rd Column a m p semicolon 4th Column a m p semicolon on normal upper Omega comma 2nd Row 1st Column u 2nd Column a m p semicolon equals 0 3rd Column a m p semicolon on partial-differential normal upper Omega comma EndLayout">

−
Δ
u

a
m
p
;
=
v

u

q

+
w
,

u
≥
0

a
m
p
;

a
m
p
;

on 

Ω

,

u

a
m
p
;
=
0

a
m
p
;

on 

∂
Ω

,

\begin {aligned} - \Delta u & = v u^{q} + w, \quad u \ge 0 && \text {on $\Omega $},\\ u &= 0 & \text {on $\partial \Omega $}, \end {aligned}

\]
on a regular domain

Ω
\Omega

in

R

n

\mathbf {R}^{n}

in the “superlinear case”

q
>
1

q > 1

. The coefficients

v
,
w

v, w

are arbitrary positive measurable functions (or measures) on

Ω
\Omega

. We also consider more general nonlinear differential and integral equations, and study the spaces of coefficients and solutions naturally associated with these problems, as well as the corresponding capacities. Our characterizations of the existence of positive solutions take into account the interplay between

v
v

,

w
w

, and the corresponding Green’s kernel. They are not only sufficient, but also necessary, and are established without any a priori regularity assumptions on

v
v

and

w
w

; we also obtain sharp two-sided estimates of solutions up to the boundary. Some of our results are new even if

v
≡
1

v \equiv 1

and

Ω
\Omega

is a ball or half-space. The corresponding weighted norm inequalities are proved for integral operators with kernels satisfying a refined version of the so-called

3
G

3 G

-inequality by an elementary “integration by parts” argument. This also gives a new unified proof for some classical inequalities including the Carleson measure theorem for Poisson integrals and trace inequalities for Riesz potentials and Green potentials.
Model theory of difference fields
Authors: Chatzidakis Zoé , Hrushovski Ehud
Published: July 2002

A difference field is a field with a distinguished automorphismσ\sigma. This paper studies the model theory of existentially closed difference fields. We introduce a dimension theory on formulas, and in particular on difference equations. We show that an arbitrary formula may be reduced into one-dimensional ones, and analyze the possible internal structures on the one-dimensional formulas when the characteristic is00.
Canonical construction of finite elements
Authors: Hiptmair R.
Published: July 2002

The mixed variational formulation of many elliptic boundary value problems involves vector valued function spaces, like, in three dimensions,

H
(

curl

;
Ω
)

\boldsymbol H(\mathbf {\operatorname {curl}};\Omega )

and

H

(
Div
;
Ω
)

{{\boldsymbol H}(\operatorname {Div};\Omega )}

. Thus finite element subspaces of these function spaces are indispensable for effective finite element discretization schemes. Given a simplicial triangulation of the computational domain

Ω
\Omega

, among others, Raviart, Thomas and Nédélec have found suitable conforming finite elements for

H
(
Div
;
Ω
)

\boldsymbol H(\operatorname {Div};\Omega )

and

H
(

curl

;
Ω
)

\boldsymbol H(\mathbf {\operatorname {curl}};\Omega )

. At first glance, it is hard to detect a common guiding principle behind these approaches. We take a fresh look at the construction of the finite spaces, viewing them from the angle of differential forms. This is motivated by the well-known relationships between differential forms and differential operators:

div
\operatorname {div}

,

c
u
r
l

\operatorname {\mathbf {curl}}

and

g
r
a
d

\operatorname {\mathbf {grad}}

can all be regarded as special incarnations of the exterior derivative of a differential form. Moreover, in the realm of differential forms most concepts are basically dimension-independent. Thus, we arrive at a fairly canonical procedure to construct conforming finite element subspaces of function spaces related to differential forms. In any dimension we can give a simple characterization of the local polynomial spaces and degrees of freedom underlying the definition of the finite element spaces. With unprecedented ease we can recover the familiar

H
(
Div
;
Ω
)

\boldsymbol H (\operatorname {Div};\Omega )

- and

H
(

curl

;
Ω
)

\boldsymbol H(\mathbf {\operatorname {curl}};\Omega )

-conforming finite elements, and establish the unisolvence of degrees of freedom. In addition, the use of differential forms makes it possible to establish crucial algebraic properties of the canonical interpolation operators and representation theorems in a single sweep for all kinds of spaces.
Volumes of hyperbolic manifolds and mixed Tate motives
Authors: Goncharov Alexander
Published: July 2002

Two different constructions of an invariant of an odd-dimensional hyperbolic manifold with values in

K

2
n
−
1

(

Q

¯

)
⊗

Q

K_{2n-1}(\overline {\mathbb Q})\otimes \mathbb Q

are given. We prove that the volume of the manifold equals the value of the Borel regulator on this invariant. The scissors congruence groups in noneuclidean geometries are studied and related to mixed Tate motives and algebraic K-theory of

C

\mathbb C

. We contribute to the general theory of mixed Hodge structures by introducing for Hodge-Tate structures the big period map with values in

C

⊗

C

∗

(
n
−
2
)

\mathbb C \otimes \mathbb C^*(n-2)

.
Restrictions on harmonic morphisms
Authors: Mustafa M.
Published: July 2002

We consider horizontally (weakly) conformal mapsϕ\phibetween Riemannian manifolds and calculate a formula for the Laplacian of the dilation ofϕ\phi, using the language of moving frames. Applying this formula to harmonic horizontally (weakly) conformal maps or equivalently to harmonic morphisms we obtain a Weitzenböck formula similar to an earlier result of the author (J. London Math. Soc. (2)57(1998), 746–756), and hence vanishing results for harmonic morphisms from compact manifolds of positive curvature. Further, a method is developed to obtain restrictions on harmonic morphisms from somenon-compactandnon-positively curveddomains. Finally, a discussion of restrictions on harmonic morphisms between simply connected space forms is given.
StochSim: modelling of stochastic biomolecular processes
Authors: Le

   Novère Nicolas , Shimizu Thomas Simon
Published: July 2002

Summary: StochSim is a stochastic simulator for chemical reactions. Molecules are represented as individual software objects that react according to probabilities derived from concentrations and rate constants. Version 1.2 of StochSim provides a novel cross-platform graphical interface written in Perl/Tk. A simple two-dimensional spatial structure has also been implemented, in which nearest-neighbour interactions of molecules in a 2-D lattice can be simulated.

Availability: Various ports of the program can be retrieved at ftp://ftp.cds.caltech.edu/pub/dbray/

Contact: nl223@cus.cam.ac.uk; tss26@cam.ac.uk

* To whom correspondence should be addressed.
Gender Differences in Labor Turnover and the Development of Internal Labor Markets in the United States during the 1920s
Authors: Owen Laura J.
Published: July 2002

Exploring the relationship between gender differences in labor turnover—which have been linked to male-female wage differentials—and the early twentieth-century development of internal labor markets, this case study suggests that observed gender differences in labor turnover in the twentieth century can be attributed, at least in part, to the specific employment policy decisions of firms. These policies, and the internal labor markets they helped create, directly addressed some of the causes of male turnover but did little to confront the sources (often non-market) of female turnover. The results of this analysis call into question the assumption that the higher rate of female turnover is exogenously determined.
Tolerance and pancreatic islet transplantation
Authors: Inverardi Luca , Ricordi Camillo
Published: July 2002

Islet transplantation holds renewed promise as a cure for type I diabetes mellitus. Results of recent clinical trials have shown remarkable success, and have reignited universal optimism for this procedure. In spite of this success, the need for life–long immunosuppression of the recipient still limits islet transplantation to patients with poorly controlled diabetes or to those requiring kidney transplantation. It is obvious that the achievement of immunological tolerance would broaden the indication for islet transplantation to a much larger cohort of patients with type I diabetes mellitus, most likely preventing long–term complications and contributing to a much improved quality of life. Increased understanding of the basic mechanisms of tolerance induction has resulted in the implementation of numerous experimental approaches to achieve long–term survival of islet grafts in the absence of chronic immunosuppression. In this brief review we will attempt to summarize the current status of research and knowledge.
Activation of the JNK pathway during dorsal closure in Drosophila requires the mixed lineage kinase, slipper
Authors: Stronach Beth , Perrimon Norbert
Published: July 2002

The Jun kinase (JNK) pathway has been characterized for its role in stimulating AP-1 activity and for modulating the balance between cell growth and death during development, inflammation, and cancer. Six families of mammalian kinases acting at the level of JNKKK have emerged as upstream regulators of JNK activity (MLK, LZK, TAK, ASK, MEKK, and TPL); however, the specificity underlying which kinase is utilized for transducing a distinct signal is poorly understood. InDrosophila, JNK signaling plays a central role in dorsal closure, controlling cell fate and cell sheet morphogenesis during embryogenesis. Notably, in the fly genome, there are single homologs of each of the mammalian JNKKK families. Here, we identify mutations in one of those, a mixed lineage kinase, named slipper(slpr), and show that it is required for JNK activation during dorsal closure. Furthermore, our results show that other putative JNKKKs cannot compensate for the loss of slpr function and, thus, may regulate other JNK or MAPK-dependent processes.
Soft protein–protein docking in internal coordinates
Authors: Fernández‐Recio Juan , Totrov Maxim , Abagyan Ruben
Published: July 2002

The association of two biological macromolecules is a fundamental biological phenomenon and an unsolved theoretical problem. Docking methods for ab initio prediction of association of two independently determined protein structures usually fail when they are applied to a large set of complexes, mostly because of inaccuracies in the scoring function and/or difficulties on simulating the rearrangement of the interface residues on binding. In this work we present an efficient pseudo‐Brownian rigid‐body docking procedure followed by Biased Probability Monte Carlo Minimization of the ligand interacting side‐chains. The use of a soft interaction energy function precalculated on a grid, instead of the explicit energy, drastically increased the speed of the procedure. The method was tested on a benchmark of 24 protein–protein complexes in which the three‐dimensional structures of their subunits (bound and free) were available. The rank of the near‐native conformation in a list of candidate docking solutions was <20 in 85% of complexes with no major backbone motion on binding. Among them, as many as 7 out of 11 (64%) protease‐inhibitor complexes can be successfully predicted as the highest rank conformations. The presented method can be further refined to include the binding site predictions and applied to the structures generated by the structural proteomics projects. All scripts are available on the Web.
Rapid structural fluctuations of the free HIV protease flaps in solution: Relationship to crystal structures and comparison with predictions of dynamics calculations
Authors: Freedberg Darón I. , Ishima Rieko , Jacob Jaison , Wang Yun‐Xing , Kustanovich Irina , Louis John M. , Torchia Dennis A.
Published: July 2002

Crystal structures have shown that the HIV‐1 protease flaps, domains that control access to the active site, are closed when the active site is occupied by a ligand. Although flap structures ranging from closed to semi‐open are observed in the free protease, crystal structures reveal that even the semi‐open flaps block access to the active site, indicating that the flaps are mobile in solution. The goals of this paper are to characterize the secondary structure and fast (sub‐ns) dynamics of the flaps of the free protease in solution, to relate these results to X‐ray structures and to compare them with predictions of dynamics calculations. To this end we have obtained nearly complete backbone and many sidechain signal assignments of a fully active free‐protease construct that is stabilized against autoproteolysis by three point mutations. The secondary structure of this protein was characterized using the chemical shift index, measurements of 3hJNC′ couplings across hydrogen bonds, and NOESY connectivities. Analysis of these measurements indicates that the protease secondary structure becomes irregular near the flap tips, residues 49–53. Model‐free analysis of 15N relaxation parameters, T1, T2 (T1ρ) and 15N‐{1H} NOE, shows that residues in the flap tips are flexible on the sub‐ns time scale, in contrast with previous observations on the inhibitor‐bound protease. These results are compared with theoretical predictions of flap dynamics and the possible biological significance of the sub‐ns time scale dynamics of the flap tips is discussed.
Optimization of Gamma Knife treatment planning via guided evolutionary simulated annealing
Authors: Zhang Pengpeng , Dean David , Metzger Andrew , Sibata Claudio
Published: July 2002

We present a method for generating optimized Gamma Knife™ (Elekta, Stockholm, Sweden) radiosurgery treatment plans. This semiautomatic method produces a highly conformal shot packing plan for the irradiation of an intracranial tumor. We simulate optimal treatment planning criteria with a probability function that is linked to every voxel in a volumetric (MR or CT) region of interest. This sigmoidal parameter models the requirement of conformality (i.e., tumor ablation and normal tissue sparing). After determination of initial radiosurgery treatment parameters, a guided evolutionary simulated annealing (GESA) algorithm is used to find the optimal size, position, and weight for each shot. The three‐dimensional GESA algorithm searches the shot parameter space more thoroughly than is possible during manual shot packing and provides one plan that is suitable to the treatment criteria of the attending neurosurgeon and radiation oncologist. The result is a more conformal plan, which also reduces redundancy, and saves treatment administration time.
A physical dosimetry intercomparison for BNCT
Authors: Riley Kent J. , Binns Peter J. , Greenberg Dennis D. , Harling Otto K.
Published: July 2002

An intercomparison of physical dosimetry methods used at the Massachusetts Institute of Technology (MIT) and Brookhaven National Laboratory was completed to enable retrospective analysis of BNCT trials. Measurements were performed under reference conditions pertinent to clinical irradiations at the epithermal neutron beam facility of the Brookhaven Medical Research Reactor (BMRR) using procedures developed at MIT during similar trials. Thermal neutron flux was determined from gold foil activation experiments and good agreement was found between the depth profiles measured in‐phantom by the two groups. At a depth of 3.5 cm where the measured flux is greatest, the ratio of the MIT/BMRR measurements is if the same reporting procedures are applied. Photon and fast neutron absorbed dose rates were assessed using ionization chambers with separate graphite and A‐150 plastic walls. Measurement of the in‐phantom photon depth dose component agreed favorably with that previously reported by the BMRR group using thermoluminescent dosimeters. At a depth of 3.5 cm the ratio of the MIT measurements to those made by the BMRR group was In‐air measurements of the fast neutron and photon absorbed dose rates agreed within the limits of experimental uncertainty. Additional studies were performed in the ellipsoidal water phantom regularly used for beam characterizations at MIT. No significant differences in the thermal neutron flux measured in either a solid PMMA cube or an ellipsoidal shaped water phantom were observed on the central axis of the beam. This study confirms the reproducibility and uniformity of dosimetry measurements performed by the two independent groups undertaking BNCT trials in the USA and provides the physical data necessary to compare BMRR treatment protocols with those applied at Harvard‐MIT.
Performance and beam characteristics of the Siemens Primus linear accelerator
Authors: Sontag Marc R. , Steinberg Todd H.
Published: July 2002

Siemens Primus is a small footprint, klystron driven medical linear accelerator incorporating a compact solid state modulator. A double focused multileaf collimator (MLC) replaces the lower jaw. The first Primus in the world was installed at St. Jude Children's Research Hospital in early 1997 with x‐ray energies of 6 and 15 MV and electron energies of 8, 10, 12, 15, 18, and 21 MeV. The 10 cm depth dose for a 100 cm SSD beam is 68% and 77% for 6 and 15 MV x rays, respectively. For both x‐ray energies, beam flatness is slightly better than the manufacturers specification of 3% and beam symmetry is considerably better than 1%. The double focus design of the MLC produces a sharp penumbra (5–7 mm at 6 MV and 6–8 mm at 15 MV), increasing modestly with beam size. MLC leaf leakage is less than 1.25%. The depths of the 80% depth dose for the six electron energies of 8, 10, 12, 15, 18, and 21 MeV are 2.6, 3.2, 4.0, 4.9, 6.0, and 7.4 cm, respectively. Beam flatness is typically 2%–3% for all electron energies except 21 MeV, where it reaches 4% for a 25×25 cm2 cone. Electron beam symmetry is better than 1% for all energies except 21 MeV, where it is equal to 1%. The results are stored electronically and may be retrieved using anonymous ftp from the American Institute of Physics, Physics Auxiliary Publication Service.
Fractal analysis of radiographs: Assessment of trabecular bone structure and prediction of elastic modulus and strength
Authors: Majumdar Sharmila , Lin John , Link Thomas , Millard Jacob , Augat Peter , Ouyang Xiaolong , Newitt David , Gould Robert , Kothari Manish , Genant Harry
Published: July 2002

The purpose of this study was to determine whether fractal dimension of radiographs provide measures of trabecular bone structure which correlate with bone mineral density (BMD) and bone biomechanics, and whether these relationships depend on the technique used to calculate the fractal dimension. Eighty seven cubic specimen of human trabecular bone were obtained from the vertebrae and femur. The cubes were radiographed along all three orientations—superior–inferior (SI), medial–lateral (ML), and anterior–posterior (AP), digitized, corrected for background variations, and fractal based techniques were applied to quantify trabecular structure. Three different techniques namely, semivariance, surface area, and power spectral methods were used. The specimens were tested in compression along three orientations and the Young's modulus (YM) was determined. Compressive strength was measured along the SI direction. Quantitative computed tomography was used to measure trabecular BMD. High‐resolution magnetic‐resonance images were used to obtain three‐dimensional measures of trabecular architecture such as the apparent bone volume fraction, trabecular thickness, spacing, and number. The measures of trabecular structure computed in the different directions showed significant differences The correlation between BMD, YM, strength, and the fractal dimension were direction and technique dependent. The trends of variation of the fractal dimension with BMD and biomechanical properties also depended on the technique and the range of resolutions over which the data was analyzed. The fractal dimension showed varying trends with bone mineral density changes, and these trends also depended on the range of frequencies over which the fractal dimension was measured. For example, using the power spectral method the fractal dimension increased with BMD when computed over a lower range of spatial frequencies and decreased for higher ranges. However, for the surface area technique the fractal dimension increased with increasing BMD. Fractal measures showed better correlation with trabecular spacing and number, compared to trabecular thickness. In a multivariate regression model inclusion of some of the fractal measures in addition to BMD improved the prediction of strength and elastic modulus. Thus, fractal based texture analysis of radiographs are technique dependent, but may be used to quantify trabecular structure and have a potentially valuable impact in the study of osteoporosis.
Evaluation of the contribution of capture gamma rays, x‐ray leakage, and scatter to the photon dose at the maze door for a high energy medical electron accelerator using a Monte Carlo particle transport code
Authors: McGinley Patton H. , Dhaba'an Anees H. , Reft Chester S.
Published: July 2002

A Monte Carlo simulation of the photon dose due to scattered x rays, head leakage photons, and capture gamma rays in the maze of an 18 MeV accelerator facility was carried out. The results of the Monte Carlo simulation were compared with dose measurements made in the maze and also with values calculated using an empirical equation. Agreement within ±26% was found among the three techniques used to evaluate the capture gamma ray dose. It was found that the empirical equation overestimated the scattered x ray plus head leakage photon dose by a factor as large as 2.9 as compared to the other methods. It was concluded that the photon dose, for mazes greater than 3 m in length, is produced predominately by capture gamma rays.