bluuebunny/crossref_metadata_2025 huggingface dataset:
Ly49A Transgenic Mice Provide Evidence for a Major Histocompatibility Complex–dependent Education Process in Natural Killer Cell Development
Authors: Held Werner , Raulet David H.
Published: July 2002

The Ly49 natural killer (NK) cell receptors are class I MHC–specific inhibitory receptors that are distributed to overlapping NK cell subsets. The formation of the Ly49 receptor repertoire was examined with transgenic mice that express Ly49A in all NK cells. In MHC class I–deficient mice, the Ly49A transgene did not prevent expression of endogenous Ly49 genes. However, in H-2d mice that express a Ly49A ligand, the transgene caused clear alterations in the endogenous Ly49 repertoire. The frequency of NK cells expressing another H-2d–specific receptor, Ly49G2+, was substantially reduced. Reduced numbers of cells expressing endogenous Ly49A was suggested by reduced endogenous Ly49A mRNA levels. These results support the existence of an MHC-dependent education process that limits the number of NK cells that coexpress multiple self-specific Ly49 receptors. Ligand-dependent downregulation of Ly49 cell surface levels was also examined. Cell-surface downregulation occurred even when the transgene was expressed at low levels. The results demonstrate that downregulation of Ly49A cell surface levels is a posttranscriptional event, and argue against a model in which Ly49 receptors are calibrated to specific cell surface levels depending on the available class I ligands.
CD80 (B7-1) Binds Both CD28 and CTLA-4 with a Low Affinity and Very Fast Kinetics
Authors: van der Merwe P.  Anton , Bodian Dale L. , Daenke Susan , Linsley Peter , Davis Simon J.
Published: July 2002

The structurally related T cell surface molecules CD28 and CTLA-4 interact with cell surface ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APC) and modulate T cell antigen recognition. Preliminary reports have suggested that CD80 binds CTLA-4 and CD28 with affinities (Kd values ∼12 and ∼200 nM, respectively) that are high when compared with other molecular interactions that contribute to T cell–APC recognition. In the present study, we use surface plasmon resonance to measure the affinity and kinetics of CD80 binding to CD28 and CTLA-4. At 37°C, soluble recombinant CD80 bound to CTLA-4 and CD28 with Kd values of 0.42 and 4 μM, respectively. Kinetic analysis indicated that these low affinities were the result of very fast dissociation rate constants (koff); sCD80 dissociated from CD28 and CTLA-4 with koff values of ⩾1.6 and ⩾0.43 s−1, respectively. Such rapid binding kinetics have also been reported for the T cell adhesion molecule CD2 and may be necessary to accommodate dynamic T cell–APC contacts and to facilitate scanning of APC for antigen.
CpG Oligodeoxynucleotides Act as Adjuvants that Switch on T Helper 1 (Th1) Immunity
Authors: Chu Rose S. , Targoni Oleg S. , Krieg Arthur M. , Lehmann Paul V. , Harding Clifford V.
Published: July 2002

Synthetic oligodeoxynucleotides (ODN) that contain unmethylated CpG motifs (CpG ODN) induce macrophages to secrete IL-12, which induces interferon (IFN)-γ secretion by natural killer (NK) cells. Since these cytokines can induce T helper 1 (Th1) differentiation, we examined the effects of coadministered CpG ODN on the differentiation of Th responses to hen egg lysozyme (HEL). In both BALB/c (Th2-biased) and B10.D2 (Th1-biased) mice, immunization with HEL in incomplete Freund's adjuvant (IFA) resulted in Th2-dominated immune responses characterized by HEL-specific secretion of IL-5 but not IFN-γ. In contrast, immunization with IFA-HEL plus CpG ODN switched the immune response to a Th1-dominated cytokine pattern, with high levels of HEL-specific IFN-γ secretion and decreased HEL-specific IL-5 production. IFA-HEL plus CpG ODN also induced anti-HEL IgG2a (a Th1-associated isotype), which was not induced by IFA-HEL alone. Control non–CpG ODN did not induce IFN-γ or IgG2a, excepting lesser increases in B10.D2 (Th1-biased) mice. Thus, CpG ODN provide a signal to switch on Th1-dominated responses to coadministered antigen and are potential adjuvants for human vaccines to elicit protective Th1 immunity.
B Lymphocytes Induce the Formation of Follicular Dendritic Cell Clusters in a Lymphotoxin α–dependent Fashion
Authors: Fu Yang-Xin , Huang Guangming , Wang Yang , Chaplin David D.
Published: July 2002

Lymphotoxin (LT)α is expressed by activated T cells, especially CD4+ T helper type 1 cells, and by activated B and natural killer cells, but the functions of this molecule in vivo are incompletely defined. We have previously shown that follicular dendritic cell (FDC) clusters and germinal centers (GCs) are absent from the peripheral lymphoid tissues of LTα-deficient (LTα−/−) mice. LTα−/− mice produce high levels of antigen-specific immunoglobulin (Ig)M, but very low levels of IgG after immunization with sheep red blood cells. We show here that LTα-expressing B cells are essential for the recovery of primary, secondary, and memory humoral immune responses in LTα−/− mice. It is not necessary for T cells to express LTα to support these immune functions. Importantly, LTα-expressing B cells alone are essential and sufficient for the formation of FDC clusters. Once these clusters are formed by LTα-expressing B cells, then LTα-deficient T cells can interact with B cells to generate GCs and productive class-switched antibody responses. Thus, B cells themselves provide an essential signal that induces and maintains the lymphoid microenvironment essential for GC formation and class-switched Ig responses.
T Helper Type 2 Cell Differentiation Occurs in the Presence of Interleukin 12 Receptor β2 Chain Expression and Signaling
Authors: Nishikomori Ryuta , Ehrhardt Rolf O. , Strober Warren
Published: July 2002

The differentiation of CD4+ T cells into T helper type 1 (Th1) cells is driven by interleukin (IL)-12 through the IL-12 receptor β2 (IL-12Rβ2) chain, whereas differentiation into Th2 cells is driven by IL-4, which downregulates IL-12Rβ2 chain. We reexamined such differentiation using IL-12Rβ2 chain transgenic mice. We found that CD4+ T cells from such mice were able to differentiate into Th2 cells when primed with IL-4 or IL-4 plus IL-12. In the latter case, the presence of IL-4 suppressed interferon (IFN)-γ production 10–100-fold compared with cells cultured in IL-12 alone. Finally, in studies of the ability of IL-12 to convert Th2 cells bearing a competent IL-12R to the Th1 cells, we showed that: (a) T cells bearing the IL-12Rβ2 chain transgene and primed under Th2 conditions could not be converted to Th1 cells by repeated restimulation under Th1 conditions; and (b) established Th2 clones transfected with the IL-12Rβ2 chain construct continued to produce IL-4 when cultured with IL-12. These studies show that IL-4–driven Th2 differentiation can occur in the presence of persistent IL-12 signaling and that IL-4 inhibits IFN-γ production under these circumstances. They also show that established Th2 cells cannot be converted to Th1 cells via IL-12 signaling.
Complement C4 Inhibits Systemic Autoimmunity through a Mechanism Independent of Complement Receptors Cr1 and Cr2
Authors: Chen Zhibin , Koralov Sergei B. , Kelsoe Garnett
Published: July 2002

The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4−/− mice. This systemic lupus erythematosus–like autoimmunity is highly penetrant; by 10 mo of age, all C4−/− females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2−/− mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4−/− but not Cr2−/− mice. C4−/−, but not Cr2−/−, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4−/−, but not Cr2−/−, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.
Migration and Function of Antigen-Primed Nonpolarized T Lymphocytes in Vivo
Authors: Iezzi Giandomenica , Scheidegger Doris , Lanzavecchia Antonio
Published: July 2002

Upon antigenic stimulation, naive T lymphocytes proliferate and a fraction of the activated cells acquire a T helper cell type 1 (Th1) or Th2 phenotype as well as the capacity to migrate to inflamed tissues. However, the antigen-primed T cells that receive a short T cell receptor (TCR) stimulation do not acquire effector function and remain in a nonpolarized state. Using TCR transgenic CD4+ T cells in an adoptive transfer system, we compared the in vivo migratory capacities of naive, nonpolarized, Th1 or Th2 cells. Although all cell types migrated to the spleen, only naive and nonpolarized T cells efficiently migrated to lymph nodes. In addition Th1, but not Th2, migrated to inflamed tissues. In the lymph nodes, nonpolarized T cells proliferated and acquired effector function in response to antigenic stimulation, displaying lower activation threshold and faster kinetics compared with naive T cells. These results suggest that nonpolarized T cells are in an intermediate state of differentiation characterized by lymph node homing capacity and increased responsiveness that allows them to mount a prompt and effective secondary response.
Hyperactivation of P21ras and the Hematopoietic-Specific Rho Gtpase, Rac2, Cooperate to Alter the Proliferation of Neurofibromin-Deficient Mast Cells in Vivo and in Vitro
Authors: Ingram David A. , Hiatt Kelly , King Alastair J. , Fisher Lucy , Shivakumar Rama , Derstine Christina , Wenning Mary Jo , Diaz Bruce , Travers Jeffrey B. , Hood Antoinette , Marshall Mark , Williams David A. , Clapp D. Wade
Published: July 2002

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients or Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21ras activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific p21ras effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21ras may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1+/− and Rac2−/− mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal–regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21ras-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1+/− mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21ras-ERK pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.
CC Chemokine Receptor (CCR)4 and the CCR10 Ligand Cutaneous T Cell–attracting Chemokine (CTACK) in Lymphocyte Trafficking to Inflamed Skin
Authors: Reiss Yvonne , Proudfoot Amanda E. , Power Christine A. , Campbell James J. , Butcher Eugene C.
Published: July 2002

The chemokine thymus and activation-regulated chemokine (TARC; CCL17) is displayed by cutaneous (but not intestinal) venules, and is thought to trigger vascular arrest of circulating skin homing memory T cells, which uniformly express the TARC receptor CC chemokine receptor (CCR)4. Cutaneous T cell–attracting chemokine (CTACK; CCL27), expressed by skin keratinocytes, also attracts cutaneous memory T cells, and is hypothesized to assist in lymphocyte recruitment to skin as well. Here we show that chronic cutaneous inflammation induces CD4 T cells expressing E-selectin binding activity (a marker of skin homing memory cells) in draining lymph node, and that these E-selectin ligand+ T cells migrate efficiently to TARC and to CTACK. In 24 h in vivo homing assays, stimulated lymph node T cells from wild-type mice or, surprisingly, from CCR4-deficient donors migrate efficiently to inflamed skin; and an inhibitory anti-CTACK antibody has no effect on wild-type lymphocyte recruitment. However, inhibition with anti-CTACK monoclonal antibody abrogates skin recruitment of CCR4-deficient T cells. We conclude that CTACK and CCR4 can both support homing of T cells to skin, and that either one or the other is required for lymphocyte recruitment in cutaneous delayed type hypersensitivity.
c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Signaling Pathways Have Divergent Roles in CD8+ T Cell–mediated Antiviral Immunity
Authors: Arbour Nathalie , Naniche Denise , Homann Dirk , Davis Roger J. , Flavell Richard A. , Oldstone Michael B.A.
Published: July 2002

c-Jun NH2-terminal kinases (JNK) play important roles in T helper cell (Th) proliferation, differentiation, and maintenance of Th1/Th2 polarization. To determine whether JNKs are involved in antiviral T cell immunity, and whether JNK1 and JNK2 bear biological differences, we investigated the immune responses of JNK1-deficient and JNK2-deficient mice to lymphocytic choriomeningitis virus (LCMV). After LCMV infection, wild-type (JNK+/+) mice had a 5- to 10-fold increase in splenic CD8+ T cells. In contrast, infected JNK1−/− mice showed a significantly lower virus-specific CD8+ T cell expansion. However, JNK1−/− mice cleared LCMV infection with similar kinetics as JNK+/+ mice. Splenic T cells from LCMV-infected JNK1−/− animals produced interferon γ after stimulation with viral peptides. However, fewer JNK1−/− T cells acquired an activated phenotype (CD44hi) and more JNK1−/−CD8+CD44hi cells underwent apoptosis than JNK+/+ cells at the peak of the primary response. In contrast, LCMV-infected JNK2−/− mice generated more virus-specific CD8+ T cells than JNK+/+ mice. These results indicate that JNK1 and JNK2 signal pathways have distinct roles in T cell responses during a viral infection. JNK1 is involved in survival of activated T cells during immune responses, and JNK2 plays a role in control of CD8+ T cell expansion in vivo.
V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites
Authors: Marculescu Rodrig , Le Trang , Simon Paul , Jaeger Ulrich , Nadel Bertrand
Published: July 2002

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin’s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.
Inactivation of Gating Currents of L-Type Calcium Channels
Authors: Shirokov Roman , Ferreira Gonzalo , Yi Jianxun , Ríos Eduardo
Published: July 2002

In studies of gating currents of rabbit cardiac Ca channels expressed as α1C/β2a or α1C/β2a/α2δ subunit combinations in tsA201 cells, we found that long-lasting depolarization shifted the distribution of mobile charge to very negative potentials. The phenomenon has been termed charge interconversion in native skeletal muscle (Brum, G., and E. Ríos. 1987. J. Physiol. (Camb.). 387:489–517) and cardiac Ca channels (Shirokov, R., R. Levis, N. Shirokova, and E. Ríos. 1992. J. Gen. Physiol. 99:863–895). Charge 1 (voltage of half-maximal transfer, V1/2 ≃ 0 mV) gates noninactivated channels, while charge 2 (V1/2 ≃ −90 mV) is generated in inactivated channels. In α1C/β2a cells, the available charge 1 decreased upon inactivating depolarization with a time constant τ ≃ 8, while the available charge 2 decreased upon recovery from inactivation (at −200 mV) with τ ≃ 0.3 s. These processes therefore are much slower than charge movement, which takes <50 ms. This separation between the time scale of measurable charge movement and that of changes in their availability, which was even wider in the presence of α2δ, implies that charges 1 and 2 originate from separate channel modes. Because clear modal separation characterizes slow (C-type) inactivation of Na and K channels, this observation establishes the nature of voltage-dependent inactivation of L-type Ca channels as slow or C-type. The presence of the α2δ subunit did not change the V1/2 of charge 2, but sped up the reduction of charge 1 upon inactivation at 40 mV (to τ ≃ 2 s), while slowing the reduction of charge 2 upon recovery (τ ≃ 2 s). The observations were well simulated with a model that describes activation as continuous electrodiffusion (Levitt, D. 1989. Biophys. J. 55:489–498) and inactivation as discrete modal change. The effects of α2δ are reproduced assuming that the subunit lowers the free energy of the inactivated mode.
Symmetric powers of complete modules over a two-dimensional regular local ring
Authors: Katz Daniel , Kodiyalam Vijay
Published: July 2002

Let

(
R
,
m
)

(R,m)

be a two-dimensional regular local ring with infinite residue field. For a finitely generated, torsion-free

R
R

-module

A
A

, write

A

n

A_{n}

for the

n
n

th symmetric power of

A
A

, mod torsion. We study the modules

A

n

A_{n}

,

n
≥
1

n \geq 1

, when

A
A

is complete (i.e., integrally closed). In particular, we show that

B
⋅
A
=

A

2

B\cdot A = A_{2}

, for any minimal reduction

B
⊆
A

B \subseteq A

and that the ring

⊕

n
≥
1

A

n

\oplus _{n \geq 1} A_{n}

is Cohen-Macaulay.
The iterated transfer analogue of the new doomsday conjecture
Authors: Minami Norihiko
Published: July 2002

A strong general restriction is given on the stable Hurewicz image of the classifying spaces of elementary abelian

p
p

-groups. In particular, this implies the iterated transfer analogue of the new doomsday conjecture.
On some inequalities for the incomplete gamma function
Authors: Alzer Horst
Published: July 2002

Let

p
≠
1

p\ne 1

be a positive real number. We determine all real numbers

α
=
α
(
p
)

\alpha = \alpha (p)

and

β
=
β
(
p
)

\beta =\beta (p)

such that the inequalities
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="left-bracket 1 minus e Superscript minus beta x Super Superscript p Superscript Baseline right-bracket Superscript 1 slash p Baseline greater-than StartFraction 1 Over normal upper Gamma left-parenthesis 1 plus 1 slash p right-parenthesis EndFraction integral Subscript 0 Superscript x Baseline e Superscript minus t Super Superscript p Baseline d t greater-than left-bracket 1 minus e Superscript minus alpha x Super Superscript p Superscript Baseline right-bracket Superscript 1 slash p">

[
1
−

e

−
β

x
p

]

1

/

p

>

1

Γ
(
1
+
1

/

p
)

∫
0
x

e

−

t
p

d
t
>
[
1
−

e

−
α

x
p

]

1

/

p

[1-e^{-\beta x^p}]^{1/p}> \frac 1{\Gamma (1+1/p)} \int ^x_0 e^{-t^p} \,dt >[1-e^{-\alpha x^p}]^{1/p}

\]
are valid for all

x
>
0

x>0

. And, we determine all real numbers

a
a

and

b
b

such that
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="minus log left-parenthesis 1 minus e Superscript minus a x Baseline right-parenthesis less-than-or-equal-to integral Subscript x Superscript normal infinity Baseline StartFraction e Superscript negative t Baseline Over t EndFraction d t less-than-or-equal-to minus log left-parenthesis 1 minus e Superscript minus b x Baseline right-parenthesis">

−
log
⁡
(
1
−

e

−
a
x

)
≤

∫
x
∞

e

−
t

t

d
t
≤
−
log
⁡
(
1
−

e

−
b
x

)

-\log (1-e^{-ax})\le \int ^\infty _x \frac {e^{-t}}t\,dt\le -\log (1-e^{-bx})

\]
hold for all

x
>
0

x>0

.
Local dimensions for Poincaré recurrences
Authors: Afraimovich Valentin , Chazottes Jean-René , Saussol Benoît
Published: July 2002

Pointwise dimensions and spectra for measures associated with Poincaré recurrences are calculated for arbitrary weakly specified subshifts with positive entropy and for the corresponding special flows. It is proved that the Poincaré recurrence for a “typical” cylinder is asymptotically its length. Examples are provided which show that this is not true for some systems with zero entropy. Precise formulas for dimensions of measures associated with Poincaré recurrences are derived, which are comparable to Young’s formula for the Hausdorff dimension of measures and Abramov’s formula for the entropy of special flows.
Relative zeta determinants and the geometry of the determinant line bundle
Authors: Scott Simon
Published: July 2002

The spectral

ζ
\zeta

-function regularized geometry of the determinant line bundle for a family of first-order elliptic operators over a closed manifold encodes a subtle relation between the local family’s index theorem and fundamental non-local spectral invariants. A great deal of interest has been directed towards a generalization of this theory to families of elliptic boundary value problems. We give here precise formulas for the relative zeta metric and curvature in terms of Fredholm determinants and traces of operators over the boundary. This has consequences for anomalies over manifolds with boundary.
AN EMPIRICAL INVESTIGATION OF THE RELATIONS AMONG WAGE DIFFERENTIALS, PRODUCTIVITY GROWTH, AND TRADE
Authors: Ghosh Koushik , Saunders Peter J. , Biswas Basudeb
Published: July 2002

This article investigates the relations among productivity growth, wage differentials, and net exports in the United States. The time periods considered are the long run and the short run. Cointegration test results indicate that all the test variables are cointegrated. Therefore, productivity growth, wage differentials, and trade are all related in the long run. A short‐run investigation of the relations among productivity growth, wage differentials, and trade is conducted within a vector error correction (VEC) estimation structure. The VEC tests indicate that, contrary to the prevailing view, productivity growth and trade have no impact on wage differentials in the short run. At the same time, it is apparent that wage differentials and trade have a positive and statistically significant impact on productivity growth in the United States in the short run.
Wage Differentials of Transportation Industries: Deregulation Versus Regulation
Authors: Talley Wayne K.
Published: July 2002

This article investigates the wage differentials of similar occupations in three for‐hire transportation carrier industries, railroad, truck, and motor bus, under regulation and deregulation. The estimation results indicate that the union wage gaps among all occupations have widened under deregulation. Specifically, the union wages of railroad occupations have increased relative to those of truck drivers and the union wages of truck drivers have increased relative to those of motor bus drivers. Further, wage gaps for all occupations for this period are greater among nonunion than among union workers.
Marketing in Mexico: Sears, Roebuck Company, J. Walter Thompson, and the Culture of North American Commerce in Mexico City during the 1940s
Authors: Moreno Julio E.
Published: July 2002

When the Sears, Roebuck Company opened its first store in Mexico City on February 28, 1947, an observer reported that the crowds on opening day were generally “well behaved, but impatient; they wanted to buy! buy! and buy!” Saleswomen panicked “as a sea of hands thrust pesos toward them, into their pockets, into their blouses, anywhere—just to complete a purchase.” Customers not only refused to leave at the end of the day; they stayed outside the store after closing. They jammed the street at night trying to look through the windows. On Saturday, two days after the store opened, Sears observers reported that customers outside the store screamed, “Let us in! Let us in! They waved money at us. They tried to sneak in through the back doors, and they cut the ropes guarding the entrance.” About 110,000 guests visited the store during its first three days of operation. So many customers visited Sears during its first two weeks in Mexico City that, according to John F. Gallagher, the vice-president of Sears' Latin American operations, “There were employees and lady customers who fainted due to the heat, agitation, and the crowdedness in the store.”
Model scenarios for evolution of the eukaryotic cell cycle
Authors: Novak B. , Csikasz-Nagy A. , Gyorffy B. , Nasmyth K. , Tyson J. J.
Published: July 2002

Progress through the division cycle of present day eukaryotic cells is controlled by a complex network consisting of (i) cyclin–dependent kinases (CDKs) and their associated cyclins, (ii) kinases and phosphatases that regulate CDK activity, and (iii) stoichiometric inhibitors that sequester cyclin–CDK dimers. Presumably regulation of cell division in the earliest ancestors of eukaryotes was a considerably simpler affair. Nasmyth (1995) recently proposed a mechanism for control of a putative, primordial, eukaryotic cell cycle, based on antagonistic interactions between a cyclin–CDK and the anaphase promoting complex (APC) that labels the cyclin subunit for proteolysis. We recast this idea in mathematical form and show that the model exhibits hysteretic behaviour between alternative steady states: a G1–like state (APC on, CDK activity low, DNA unreplicated and replication complexes assembled) and an S/M–like state (APC off, CDK activity high, DNA replicated and replication complexes disassembled). In our model, the transition from G1 to S/M (‘Start’) is driven by cell growth, and the reverse transition (‘Finish’) is driven by completion of DNA synthesis and proper alignment of chromosomes on the metaphase plate. This simple and effective mechanism for coupling growth and division and for accurately copying and partitioning a genome consisting of numerous chromosomes, each with multiple origins of replication, could represent the core of the eukaryotic cell cycle. Furthermore, we show how other controls could be added to this core and speculate on the reasons why stoichiometric inhibitors and CDK inhibitory phosphorylation might have been appended to the primitive alternation between cyclin accumulation and degradation.
Mechanisms of maintenance of tropical freshwater fish communities in the face of disturbance
Authors: Martin–Smith Keith M. , Laird Lindsay M. , Bullough Luke , Lewis Matthew G.
Published: July 2002

Community resistance to, and resilience from, perturbation will determine the trajectory of recovery from disturbance. Although selective timber extraction is considered a severe disturbance, fish communities from headwater streams around Danum Valley Field Centre, Sabah, Malaysia, showed few long–term changes in species composition or abundance. However, some species showed short–term (< 18 months) absence or decrease in abundance. These observations suggested that both resistance and resilience were important in maintaining long–term fish community structure. Resistance to perturbation was tested by monitoring fish communities before and after the creation of log–debris dams, while resilience was investigated by following the time–course of recolonization following complete removal of all fish. High community resistance was generally shown although the response was site–specific, dependent on the composition of the starting community, the size of the stream and physical habitat changes. High resilience was demonstrated in all recolonization experiments with strong correlations between pre– and post–defaunation communities, although there was a significant difference between pool and riffle habitats in the time–course of recovery. These differences can be explained by the movement characteristics of the species found in the different habitats. Resilience appeared to be a more predictable characteristic of the community than resistance and the implications of this for ensuring the long–term persistence of fish in the area are discussed.
Quantitative aspects of metabolic organization: a discussion of concepts
Authors: Kooijman S.A.L.M
Published: July 2002

Metabolic organization of individual organisms follows simple quantitative rules that can be understood from basic physical chemical principles. Dynamic energy budget (DEB) theory identifies these rules, which quantify how individuals acquire and use energy and nutrients. The theory provides constraints on the metabolic organization of subcellular processes. Together with rules for interaction between individuals, it also provides a basis to understand population and ecosystem dynamics. The theory, therefore, links various levels of biological organization. It applies to all species of organisms and offers explanations for body–size scaling relationships of natural history parameters that are otherwise difficult to understand. A considerable number of popular empirical models turn out to be special cases of the DEB model, or very close numerical approximations. Strong and weak homeostasis and the partitionability of reserve kinetics are cornerstones of the theory and essential for understanding the evolution of metabolic organization.
Comparative genomics provides evidence for an ancient genome duplication event in fish
Authors: Taylor John S. , Van de Peer Yves , Braasch Ingo , Meyer Axel
Published: July 2002

There are approximately 25 000 species in the division Teleostei and most are believed to have arisen during a relatively short period of timeca.200 Myr ago. The discovery of ‘extra’Hoxgene clusters in zebrafish (Danio rerio), medaka (Oryzias latipes), and pufferfish (Fugu rubripes), has led to the hypothesis that genome duplication provided the genetic raw material necessary for the teleost radiation. We identified 27 groups of orthologous genes which included one gene from man, mouse and chicken, one or two genes from tetraploidXenopusand two genes from zebrafish. A genome duplication in the ancestor of teleost fishes is the most parsimonious explanation for the observations that for 15 of these genes, the two zebrafish orthologues are sister sequences in phylogenies that otherwise match the expected organismal tree, the zebrafish gene pairs appear to have been formed at approximately the same time, and are unlinked. Phylogenies of nine genes differ a little from the tree predicted by the fish–specific genome duplication hypothesis: one tree shows a sister sequence relationship for the zebrafish genes but differs slightly from the expected organismal tree and in eight trees, one zebrafish gene is the sister sequence to a clade which includes the second zebrafish gene and orthologues fromXenopus, chicken, mouse and man. For these nine gene trees, deviations from the predictions of the fish–specific genome duplication hypothesis are poorly supported. The two zebrafish orthologues for each of the three remaining genes are tightly linked and are, therefore, unlikely to have been formed during a genome duplication event. We estimated that the unlinked duplicated zebrafish genes are between 300 and 450 Myr. Thus, genome duplication could have provided the genetic raw material for teleost radiation. Alternatively, the loss of different duplicates in different populations (i.e. ‘divergent resolution’) may have promoted speciation in ancient teleost populations.
Introduction
Authors: Schilling Thomas , Wilson Stephen
Published: July 2002

Striking similarities between the molecular and genetic mechanisms that control development in very diverse animals are causing biologists to reassess hypotheses regarding the evolution of body plans, particularly in the light of the recent availability of whole genome sequence information for some species. This recent convergence of developmental and evolutionary analyses is the subject of this issue, addressed both at the level of morphology and molecular biology as well as emerging work on whole animal genomes. We wanted to assemble a volume that highlights some of the molecular advances made in genetically tractable systems including worms, zebrafish and ascidians, and also introduce some of the new genomic and theoretical approaches that may be less familiar to mainstream developmental biologists. The result is an edition that focuses primarily on brain evolution, axial patterning and vertebrate origins, biases that in part reflect our own specific interests.
Effects of characteristic x rays on the noise power spectra and detective quantum efficiency of photoconductive x‐ray detectors
Authors: Zhao Wei , Ji W. G. , Rowlands J. A.
Published: July 2002

The effects of K fluorescence on the imaging performance of photoconductor‐based x‐ray imaging systems are investigated. A cascaded linear systems model was developed, where a parallel cascaded process was implemented to take into account the effect of K‐fluorescence reabsorption on the modulation transfer function (MTF), noise power spectrum (NPS), and the spatial frequency dependent detective quantum efficiency [DQE(f)] of an imaging system. The investigation was focused on amorphous selenium (a‐Se), which is the most highly developed photoconductor material for x‐ray imaging. The results were compared to those obtained with Monte Carlo simulation using the same imaging condition and detector parameters, so that the validity of the cascaded linear system model could be confirmed. Our results revealed that K‐fluorescence reabsorption in a‐Se is responsible for a 18% drop in NPS at high spatial frequencies with an incident x‐ray photon energy of E=20 keV (which is just above the K edge of 12.5 keV). When E increases to 60 keV, the effects of K‐fluorescence reabsorption on NPS decrease to ∼12% at high spatial frequencies. Because the high frequency drop is present in both MTF and NPS, the effect of K fluorescence on DQE(f) is minimal, especially for E that is much higher than the K edge. We also applied the cascaded linear system model to a newly developed compound photoconductor, lead iodide and found that at 60 keV there is a high frequency drop in NPS of 19%. The calculated NPS were compared to previously published measurements of detectors.
Dose calculation along the nonwedged direction for externally wedged beams: Improvement of dosimetric accuracy with comparatively moderate effort
Authors: Myler U. , Szabo J. J.
Published: July 2002

Wedge filters ideally modify photon intensities only in one direction. However, in the other, the “nonwedged” direction, the intensity is affected too; it usually decreases with increasing off‐axis distance. For external wedges on a particular treatment machine (Varian Clinac 2100C) and 6 MV photons, for example, this decrease is as big as 8%, depending on wedge angle and material, off‐axis distance, and phantom depth. We present a way to account for this effect in prescriptions to points off‐center in the nonwedged direction. The goal was to minimize the amount of additional data required for this purpose, without unduly compromising the final prescription accuracy. We measure the effective attenuation coefficients in narrow beam geometry for the wedge materials (lead and steel) as a function of thickness and off‐axis angle, and the corresponding attenuation in water, again as a function of wedge material thickness and off‐axis angle. The data allow us to extract a correction factor for off‐axis distances in the nonwedged direction. Neglecting the contribution of scattered radiation and using primary beam data only, shortens data acquisition and simplifies calculations, but still yields surprisingly accurate results. Application of the derived correction reduces the off‐axis distance related dose calculation error in wedged fields to ⩽1%.
Quality control of measured x‐ray beam data
Authors: Bjärngard Bengt E. , Vadash Paul , Ceberg Crister P.
Published: July 2002

The purpose of this study was to examine whether the quality of measured x‐ray beam data can be judged from how well the data agree with a semiempirical formula. Tissue‐phantom ratios (TPR) and output factors for several accelerators in the energy range 4–25 MV were fitted to the formula, separating the dose contributions from primary and phantom‐scattered photons. The former was described by exponential attenuation in water, with beam hardening, and the latter by the scatter‐to‐primary dose ratio using two parameters related to the probability and the directional distribution of the scattered photons. Electron disequilibrium was not considered. Two approaches were evaluated. In one, the attenuation and hardening coefficients were determined from measurements in a narrow‐beam geometry; in the other, they were extracted by the fitting procedure. Measured and fitted data agreed within in both cases. The differences were randomly distributed and had a standard deviation of typically 0.7%. Singular points with errors were easily identified. Systematic errors were revealed by increased standard deviation. However, when the attenuation was derived by the fitting algorithm, the attenuation coefficient deviated significantly from the experimental value. It is concluded that the semiempirical formula can serve to evaluate and verify beam data measured in water and that the physically most accurate description requires that the attenuation and hardening coefficients be determined in a narrow‐beam geometry. The attenuation coefficient is an excellent measure of both the primary and the scatter dose component, i.e., of beam quality.
Design of a compact high energy treatment unit combining narrow pencil beam scanning and multileaf collimation
Authors: Svensson Roger
Published: July 2002

The thesis describes the design of scanned narrow photon beam in combination with a few optimally selected collimator settings delivered by a compact treatment machine to effectively produce a truly conformal treatment. The racetrack microtron generates moving photon beams by scanning the electron beam over a thin transmission target of low Z material, such as 3 mm beryllium. The transmitted electrons with an energy of about 49 MeV are removed by a strong purging magnet that will safely bend the beam to a dedicated electron stopper. The photon beam has a full width at half‐maximum of about 20 mm at a 70 cm source to the isocenter distance and the intensity in the forward direction is almost the same as from a full range target. The narrow photon beams are only scanned where the leaf collimator is open so the photons are effectively and safely used during the treatment. Only a few beam directions are needed to achieve almost optimal results. By using three fixed heads, it is possible to simultaneously scan three photon beams synchronously over the target volume. The increased instantaneous dose rate in the tumor enhances the biological effect. The mechanical construction will be very robust and of high mechanical stability since there are few moving parts. The compact size of the treatment heads and the whole gantry will make it an ergonomic and easy to handle unit. When biologically based optimized plans are delivered by such a compact machine, the highest possible complication free tumor control is nearly reached according to radiobiological models for treatment evaluation of intensity modulated beams. At the same time the treatment time will be short and the probability of tumor induction outside the target low. [References to the authors' papers on the thesis topic: Phys. Med. Biol. 39, 37–61 (1994); Med. Phys. 22, 1141–1156 (1995); Phys. Med. Biol. 41, 1353–1397 (1996); Phys. Med. Biol. 43, 1091–1112 (1998).]
Kinetics of ‐labeled anti‐CEA antibodies in pigs; Aspects of dosimetry and PET imaging properties
Authors: Lövqvist Anna , Lundqvist Hans , Lubberink Mark , Tolmachev Vladimir , Carlsson Jörgen , Sundin Anders
Published: July 2002

A monoclonal antibody labeled with the positron‐emitting radionuclide has previously been shown useful for positron emission tomography (PET) imaging of experimental tumors. Our aim in the present study was to investigate the effects of the complex decay scheme of this radionuclide on normal organ dosimetry and PET image quality. Three mini‐pigs were injected intravenously with 46–75 MBq of the ‐labeled anti‐CEA antibody 38S1, and the whole‐body kinetics followed by PET imaging for 19 h. From PET data, absorbed doses in human organs were estimated using the MIRDOSE 3.0 software. The highest concentrations were found in lungs, after a correction for the air volume in this organ. The lungs received the highest absorbed dose (mGy/MBq, followed by liver, and small intestine, while the effective dose equivalent was The PET imaging properties of in a two‐dimensional 2D PET camera, including central area resolution and scattering effects, were investigated in phantoms and compared to those of In a 0.97 g/cm3 material, approximating soft tissue density, the FMHW (“full width at half‐maximum”) value of the point spread function was for and for In conclusion, radioimmuno PET using ‐labeled antibodies resulted in a fairly even distribution of the radiation dose, where the highest absorbed organ doses were only about two to three times higher than the mean absorbed body dose. The high energy spectrum in the decay had only minor effects on the resolution, but may decrease the quantification accuracy, especially in organs with a lower density such as a lung.
Monte Carlo studies for the optimization of hardware used in conformal radiation therapy (in English)
Authors: Küster Gunilla
Published: July 2002

The Monte Carlo system GEANT was applied to characterize and develop devices used in conformal radiation therapy. First, the Siemens Primus accelerator head was modeled. Second, two alternative techniques for intensity modulation were investigated: (1) Two multileaf collimators were modeled with respect to their penumbra and leakage radiation. To reduce the penumbra, an optimized shape of the leaf face was determined. The effectiveness of a new collimator design for leakage reduction was confirmed, showing a decrease in the average leakage from 4.7% to 2.6%. (2) The feasibility of a scanned narrow photon beam was examined for accelerators with an electron energy of about 20 MeV. The simulated photon intensity distributions were verified by comparison with both data and the theoretical prediction. With a thin beryllium bremsstrahlung target and a purging magnet, a photon beamwidth of about 40 mm at 100 cm source‐to‐surface distance can be achieved. The cost of the narrow distribution is a lower yield, which increases the irradiation time. To narrow down the beamwidth, a design for a fixed collimator with parallel holes was developed that yields a lateral resolution of about 1.5 mm at 100 cm source‐to‐surface distance and a penumbra of less than 1 mm. The use of this collimator requires that the scanned incident electron beam is always perpendicular to the target. This approach has the potential to improve both the cost‐effectiveness and the beam characteristics of intensity modulated radiation therapy.
What is the best proton energy for accelerator‐based BNCT using the reaction?
Authors: Allen D. A. , Beynon T. D.
Published: July 2002

With a growing interest in the use of accelerator‐based epithermal neutron sources for BNCT programs, in particular those based upon the reaction, there is a need to address the question of “what is the best proton energy to use?” This paper considers this question by using radiation transport calculations to investigate a range of proton energies from 2.15 to 3.5 MeV and a range of moderator sizes. This study has moved away completely from the use of empty therapy beam parameters and instead defines the beam quality and optimizes the moderator design using widely accepted in‐phantom treatment planning figures of merit. It is concluded that up to a proton energy of about 2.8 MeV there is no observed variation in the achievable therapy beam quality, but a price is paid in terms of treatment time for not choosing the upper limit of this range. For higher proton energies, the beam quality falls, but with no improvement in treatment time for optimum configurations.
Mode detuning in systems of weakly coupled oscillators
Authors: Spencer Ross L. , Robertson Richard D.
Published: July 2002

A system of weakly magnetically coupled oscillating blades is studied experimentally, computationally, and theoretically. It is found that when the uncoupled natural frequencies of the blades are nearly equal, the normal modes produced by the coupling are almost impossible to find experimentally if the random variation level in the system parameters is on the order of (or larger than) the relative differences between mode frequencies. But if the uncoupled natural frequencies are made to vary (detuned) in a smooth way such that the total relative spread in natural frequency exceeds the random variations, normal modes are rather easy to find. And if the detuned uncoupled frequencies of the system are parabolically distributed, the modes are found to be shaped like Hermite functions.
Computer simulation of fluid phase transitions
Authors: Wilding Nigel B.
Published: July 2002

The goal of accurately locating fluid phase boundaries by means of computer simulation is hampered by difficulties associated with sampling both coexisting phases in a single simulation. We explain the background to these difficulties and describe how they can be tackled using a synthesis of biased Monte Carlo sampling and histogram extrapolation methods, in conjunction with a standard fluid simulation algorithm. The combined approach provides a powerful method for tracing fluid phase boundaries.
An investigation of student understanding of single-slit diffraction and double-slit interference
Authors: Ambrose Bradley S. , Shaffer Peter S. , Steinberg Richard N. , McDermott Lillian C.
Published: July 2002

Results from an investigation of student understanding of physical optics indicate that university students who have studied this topic at the introductory level and beyond often cannot account for the pattern produced on a screen when light is incident on a single or double slit. Many do not know whether to apply geometrical or physical optics to a given situation and may inappropriately combine elements of both. Some specific difficulties that were identified for single and double slits proved to be sufficiently serious to preclude students from acquiring even a qualitative understanding of the wave model for light. In addition, we found that students in advanced courses often had mistaken beliefs about photons, which they incorporated into their interpretation of the wave model for matter. A major objective of this investigation was to build a research base for the design of a curriculum to help students develop a functional understanding of introductory optics.