bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor
Authors: Abe Keisuke , Shoji Mamoru , Chen Jiang , Bierhaus Angelika , Danave Indrani , Micko Cornelia , Casper Katherine , Dillehay Dirck L. , Nawroth Peter P. , Rickles Frederick R.
Published: July 2002

Tissue factor (TF), a transmembrane receptor for coagulation factor VII/VIIa, is aberrantly expressed in human cancers. We demonstrated a significant correlation between TF and vascular endothelial growth factor (VEGF) production in 13 human malignant melanoma cell lines (
r
2
= 0.869,
P
< 0.0001). Two of these cell lines, RPMI-7951, a high TF and VEGF producer, and WM-115, a low TF and VEGF producer, were grown s.c. in severe combined immunodeficient mice. The high-producer cell line generated solid tumors characterized by intense vascularity, whereas the low producer generated relatively avascular tumors, as determined by immunohistologic staining of tumor vascular endothelial cells with anti-von Willebrand factor antibody. To investigate the structure-function relationship of TF and VEGF, a low-producer melanoma cell line (HT144) was transfected with a TF cDNA containing the full-length sequence, a cytoplasmic deletion mutant lacking the coding sequence for the distal three serine residues (potential substrates for protein kinase C), or an extracellular domain mutant, which has markedly diminished function for activation of factor X. Cells transfected with the full-length sequence produced increased levels of both TF and VEGF. Transfectants with the full-length sequence and the extracellular domain mutant produced approximately equal levels of VEGF mRNA. However, cells transfected with the cytoplasmic deletion mutant construct produced increased levels of TF, but little or no VEGF. Thus, the cytoplasmic tail of TF plays a role in the regulation of VEGF expression in some tumor cells.
Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases
Authors: Beltinger Christian , Fulda Simone , Kammertoens Thomas , Meyer Eric , Uckert Wolfgang , Debatin Klaus-Michael
Published: July 2002

Suicide gene therapy systems such as the herpes simplex thymidine kinase/ganciclovir system (TK/GCV) may kill cancer cells by apoptosis through as yet undefined mechanisms. Here we show that TK/GCV treatment induces p53 accumulation and increases cell surface expression of CD95 and tumor necrosis factor receptor, which is likely to involve p53-mediated translocation of CD95 to the cell surface. TK/GCV-induced apoptosis involves CD95-L-independent CD95 aggregation leading to the formation of a Fas-associated death domain protein (FADD) and caspase-8-containing, death-inducing signaling complex. Dominant negative FADD, the caspase-8 inhibitor zIETD-fmk [Z-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethylketone], and zVAD-fmk (Z-Val-Ala-Asp-fluoromethylketone) partially abrogate TK/GCV-induced apoptosis. In addition to apoptosis induction, TK/GCV treatment strongly sensitizes for CD95-L-, TNF-, and TNF-related, apoptosis-inducing, ligand (TRAIL)-induced cell death in constitutively resistant cells. These findings may be used to increase the efficacy of TK/GCV and other suicide gene therapy systems for the treatment of cancer.
Why hunter-gatherer populations do not show signs of Pleistocene demographic expansions
Authors: Excoffier Laurent , Schneider Stefan
Published: July 2002

The mitochondrial DNA diversity of 62 human population samples was examined for potential signals of population expansions. Stepwise expansion times were estimated by taking into account heterogeneity of mutation rates among sites. Assuming an mtDNA divergence rate of 33% per million years, most populations show signals of Pleistocene expansions at around 70,000 years (70 KY) ago in Africa and Asia, 55 KY ago in America, and 40 KY ago in Europe and the Middle East, whereas the traces of the oldest expansions are found in East Africa (110 KY ago for the Turkana). The genetic diversity of two groups of populations (most Amerindian populations and present-day hunter-gatherers) cannot be explained by a simple stepwise expansion model. A multivariate analysis of the genetic distances among 61 populations reveals that populations that did not undergo demographic expansions show increased genetic distances from other populations, confirming that the demography of the populations strongly affects observed genetic affinities. The absence of traces of Pleistocene expansions in present-day hunter-gatherers seems best explained by the occurrence of recent bottlenecks in those populations, implying a difference between Pleistocene (≈1,800 KY to 10 KY ago) and Holocene (10 KY to present) hunter-gatherers demographies, a difference that occurred after, and probably in response to, the Neolithic expansions of the other populations.
Differential regulation of mammalian
Period
genes and circadian rhythmicity by cryptochromes 1 and 2
Authors: Vitaterna Martha Hotz , Selby Christopher P. , Todo Takeshi , Niwa Hitoshi , Thompson Carol , Fruechte Ethan M. , Hitomi Kenichi , Thresher Randy J. , Ishikawa Tomoko , Miyazaki Junichi , Takahashi Joseph S. , Sancar Aziz
Published: July 2002

Cryptochromes regulate the circadian clock in animals and plants. Humans and mice have two cryptochrome (
Cry
) genes. A previous study showed that mice lacking the
Cry2
gene had reduced sensitivity to acute light induction of the circadian gene
mPer1
in the suprachiasmatic nucleus (SCN) and had an intrinsic period 1 hr longer than normal. In this study,
Cry1
−/−
and

Cry1
−/−

Cry2
−/−
mice were generated and their circadian clocks were analyzed at behavioral and molecular levels. Behaviorally, the
Cry1
−/−
mice had a circadian period 1 hr shorter than wild type and the

Cry1
−/−

Cry2
−/−
mice were arrhythmic in constant darkness (DD). Biochemically, acute light induction of
mPer1
mRNA in the SCN was blunted in
Cry1
−/−
and abolished in

Cry1
−/−

Cry2
−/−
mice. In contrast, the acute light induction of
mPer2
in the SCN was intact in
Cry1
−/−
and

Cry1
−/−

Cry2
−/−
animals. Importantly, in double mutants,
mPer1
expression was constitutively elevated and no rhythmicity was detected in either 12-hr light/12-hr dark or DD, whereas
mPer2
expression appeared rhythmic in 12-hr light/12-hr dark, but nonrhythmic in DD with intermediate levels. These results demonstrate that
Cry1
and
Cry2
are required for the normal expression of circadian behavioral rhythms, as well as circadian rhythms of
mPer1
and
mPer2
in the SCN. The differential regulation of
mPer1
and
mPer2
by light in
Cry
double mutants reveals a surprising complexity in the role of cryptochromes in mammals.
Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults
Authors: Skibola Christine F. , Smith Martyn T. , Kane Eleanor , Roman Eve , Rollinson Sara , Cartwright Raymond A. , Morgan Gareth
Published: July 2002

Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). A common 677 C → T polymorphism in the
MTHFR
gene results in thermolability and reduced MTHFR activity that decreases the pool of methylTHF and increases the pool of methyleneTHF. Recently, another polymorphism in MTHFR (1298 A → C) has been identified that also results in diminished enzyme activity. We tested whether carriers of these variant alleles are protected from adult acute leukemia. We analyzed DNA from a case–control study in the United Kingdom of 308 adult acute leukemia patients and 491 age- and sex-matched controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. The MTHFR 677TT genotype was lower among 71 acute lymphocytic leukemia (ALL) cases compared with 114 controls, conferring a 4.3-fold decrease in risk of ALL [odds ratio (OR = 0.23; 95% CI = 0.06–0.81]. We observed a 3-fold reduction in risk of ALL in individuals with the MTHFR 1298AC polymorphism (OR = 0.33; 95% CI = 0.15–0.73) and a 14-fold decreased risk of ALL in those with the MTHFR 1298CC variant allele (OR = 0.07; 95% CI = 0.00–1.77). In acute myeloid leukemia, no significant difference in MTHFR 677 and 1298 genotype frequencies was observed between 237 cases and 377 controls. Individuals with the MTHFR 677TT, 1298AC, and 1298CC genotypes have a decreased risk of adult ALL, but not acute myeloid leukemia, which suggests that folate inadequacy may play a key role in the development of ALL.
A remarkable, precisely timed release of hyperglycemic hormone from endocrine cells in the gut is associated with ecdysis in the crab
Carcinus
maenas
Authors: Chung J. Sook , Dircksen Heinrich , Webster Simon G.
Published: July 2002

Molting or ecdysis is the most fundamentally important process in arthropod life history, because shedding of the exoskeleton is an absolute prerequisite for growth and metamorphosis. Although the hormonal mechanisms driving ecdysis in insects have been studied extensively, nothing is known about these processes in crustaceans. During late premolt and during ecdysis in the crab
Carcinus maenas
, we observed a precise and reproducible surge in hemolymph hyperglycemic hormone (CHH) levels, which was over 100-fold greater than levels seen in intermolt animals. The source of this hormone surge was not from the eyestalk neurosecretory tissues but from previously undescribed endocrine cells (paraneurons), in defined areas of the foregut and hindgut. During premolt (the only time when CHH is expressed by these tissues), the gut is the largest endocrine tissue in the crab. The CHH surge, which is a result of an unusual, almost complete discharge of the contents of the gut endocrine cell, regulates water and ion uptake during molting, thus allowing the swelling necessary for successful ecdysis and the subsequent increase in size during postmolt. This study defines an endocrine brain/gut axis in the arthropods. We propose that the ionoregulatory process controlled by CHH may be common to arthropods, in that, for insects, a similar mechanism seems to be involved in antidiuresis. It also seems likely that a cascade of very precisely coordinated release of (neuro) hormones controls ecdysis.
Silver-based crystalline nanoparticles, microbially fabricated
Authors: Klaus Tanja , Joerger Ralph , Olsson Eva , Granqvist Claes-Göran
Published: July 2002

One mechanism of silver resistance in microorganisms is accumulation of the metal ions in the cell. Here, we report on the phenomenon of biosynthesis of silver-based single crystals with well-defined compositions and shapes, such as equilateral triangles and hexagons, in
Pseudomonas stutzeri
AG259. The crystals were up to 200 nm in size and were often located at the cell poles. Transmission electron microscopy, quantitative energy-dispersive x-ray analysis, and electron diffraction established that the crystals comprise at least three different types, found both in whole cells and thin sections. These Ag-containing crystals are embedded in the organic matrix of the bacteria. Their possible potential as organic-metal composites in thin film and surface coating technology is discussed.
Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography
Authors: Llinás Rodolfo R. , Ribary Urs , Jeanmonod Daniel , Kronberg Eugene , Mitra Partha P.
Published: July 2002

Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency θ rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent θ activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic γ-band activation, which we refer to as the “edge effect.” This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level.
Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities
Authors: Lyons W. Ernest , Mamounas Laura A. , Ricaurte George A. , Coppola Vincenzo , Reid Susan W. , Bora Susan H. , Wihler Cornelia , Koliatsos Vassilis E. , Tessarollo Lino
Published: July 2002

Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established
in vivo
because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF
+/−
mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF
+/−
mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF
+/−
mice show a blunted
c-fos
induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF
+/−
mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.
Modulation of type M
2
pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein
Authors: Zwerschke Werner , Mazurek Sybille , Massimi Paola , Banks Lawrence , Eigenbrodt Erich , Jansen-Dürr Pidder
Published: July 2002

We report here that the E7 oncoprotein encoded by the oncogenic
human papillomavirus (HPV) type 16 binds to the glycolytic enzyme type
M
2
pyruvate kinase (M2-PK). M2-PK occurs in a tetrameric
form with a high affinity to its substrate phosphoenolpyruvate and a
dimeric form with a low affinity to phosphoenolpyruvate, and the
transition between both conformations regulates the glycolytic flux in
tumor cells. The glycolytic intermediate fructose 1,6-bisphosphate
induces the reassociation of the dimeric to the tetrameric form of
M2-PK. The expression of E7 in an experimental cell line shifts the
equilibrium to the dimeric state despite a significant increase in the
fructose 1,6-bisphosphate levels. Investigations of HPV-16 E7 mutants
and the nononcogenic HPV-11 subtype suggest that the interaction of
HPV-16 E7 with M2-PK may be linked to the transforming potential of the
viral oncoprotein.
Dynamic and quantitative Ca
2+
measurements using improved cameleons
Authors: Miyawaki Atsushi , Griesbeck Oliver , Heim Roger , Tsien Roger Y.
Published: July 2002

Cameleons are genetically-encoded fluorescent indicators for Ca
2+
based on green fluorescent protein variants and calmodulin (CaM). Because cameleons can be targeted genetically and imaged by one- or two-photon excitation microscopy, they offer great promise for monitoring Ca
2+
in whole organisms, tissues, organelles, and submicroscopic environments in which measurements were previously impossible. However, the original cameleons suffered from significant pH interference, and their Ca
2+
-buffering and cross-reactivity with endogenous CaM signaling pathways was uncharacterized. We have now greatly reduced the pH-sensitivity of the cameleons by introducing mutations V68L and Q69K into the acceptor yellow green fluorescent protein. The resulting new cameleons permit Ca
2+
measurements despite significant cytosolic acidification. When Ca
2+
is elevated, the CaM and CaM-binding peptide fused together in a cameleon predominantly interact with each other rather than with free CaM and CaM-dependent enzymes. Therefore, if cameleons are overexpressed, the primary effect is likely to be the unavoidable increase in Ca
2+
buffering rather than specific perturbation of CaM-dependent signaling.
Efficient IgG-mediated suppression of primary antibody responses in Fcγ receptor-deficient mice
Authors: Karlsson Mikael C. I. , Wernersson Sara , Diaz de Ståhl Teresita , Gustavsson Susanne , Heyman Birgitta
Published: July 2002

IgG antibodies can suppress more than 99% of the antibody response against the antigen to which they bind. This is used clinically to prevent rhesus-negative (Rh−) women from becoming immunized against Rh+erythrocytes from their fetuses. The suppressive mechanism is poorly understood, but it has been proposed that IgG/erythrocyte complexes bind to the inhibitory Fc receptor for IgG (FcγRIIB) on the B cell surface, thereby triggering negative signals that turn off the B cell. We show that IgG induces the same degree of suppression of the response to sheep erythrocytes in animals lacking the known IgG-binding receptors FcγRIIB, FcγRI + III, FcγRI + IIB + III, and FcRn (the neonatal Fc receptor) as in wild-type animals. Reinvestigation of the ability of F(ab′)2fragments to suppress antibody responses demonstrated that they were nearly as efficient as intact IgG. In addition, monoclonal IgE also was shown to be suppressive. These findings suggest that IgG inhibits antibody responses through Fc-independent mechanisms, most likely by masking of antigenic epitopes, thereby preventing B cells from binding and responding to antigen. In agreement with this, we show that T cell priming is not abolished by passively administered IgG. The results have implications for the understanding ofin vivoregulation of antibody responses and Rh prophylaxis.
Biological impact on mineral dissolution: Application of the lichen model to understanding mineral weathering in the rhizosphere
Authors: Banfield Jillian F. , Barker William W. , Welch Susan A. , Taunton Anne
Published: July 2002

Microorganisms modify rates and mechanisms of chemical and physical
weathering and clay growth, thus playing fundamental roles in soil and
sediment formation. Because processes in soils are inherently complex
and difficult to study, we employ a model based on the lichen–mineral
system to identify the fundamental interactions. Fixed carbon released
by the photosynthetic symbiont stimulates growth of fungi and other
microorganisms. These microorganisms directly or indirectly induce
mineral disaggregation, hydration, dissolution, and secondary mineral
formation. Model polysaccharides were used to investigate direct
mediation of mineral surface reactions by extracellular polymers.
Polysaccharides can suppress or enhance rates of chemical weathering by
up to three orders of magnitude, depending on the pH, mineral surface
structure and composition, and organic functional groups. Mg, Mn, Fe,
Al, and Si are redistributed into clays that strongly adsorb ions.
Microbes contribute to dissolution of insoluble secondary phosphates,
possibly via release of organic acids. These reactions significantly
impact soil fertility. Below fungi–mineral interfaces, mineral
surfaces are exposed to dissolved metabolic byproducts. Through this
indirect process, microorganisms can accelerate mineral dissolution,
leading to enhanced porosity and permeability and colonization by
microbial communities.
Negative pH, efflorescent mineralogy, and consequences for environmental restoration at the Iron Mountain Superfund site, California
Authors: Nordstrom D. Kirk , Alpers Charles N.
Published: July 2002

The Richmond Mine of the Iron Mountain copper deposit contains some
of the most acid mine waters ever reported. Values of pH have been
measured as low as −3.6, combined metal concentrations as high as 200
g/liter, and sulfate concentrations as high as 760
g/liter. Copious quantities of soluble metal sulfate salts such
as melanterite, chalcanthite, coquimbite, rhomboclase, voltaite,
copiapite, and halotrichite have been identified, and some of these are
forming from negative-pH mine waters. Geochemical calculations show
that, under a mine-plugging remediation scenario, these salts would
dissolve and the resultant 600,000-m
3
mine pool would have
a pH of 1 or less and contain several grams of dissolved metals per
liter, much like the current portal effluent water. In the absence of
plugging or other at-source control, current weathering rates indicate
that the portal effluent will continue for approximately 3,000 years.
Other remedial actions have greatly reduced metal loads into downstream
drainages and the Sacramento River, primarily by capturing the major
acidic discharges and routing them to a lime neutralization plant.
Incorporation of geochemical modeling and mineralogical expertise into
the decision-making process for remediation can save time, save money,
and reduce the likelihood of deleterious consequences.
Mitochondrial sequences show diverse evolutionary histories of African hominoids
Authors: Gagneux Pascal , Wills Christopher , Gerloff Ulrike , Tautz Diethard , Morin Phillip A. , Boesch Christophe , Fruth Barbara , Hohmann Gottfried , Ryder Oliver A. , Woodruff David S.
Published: July 2002

Phylogenetic trees for the four extant species of African hominoids are presented, based on mtDNA control region-1 sequences from 1,158 unique haplotypes. We include 83 new haplotypes of western chimpanzees and bonobos. Phylogenetic analysis of this enlarged database, which takes intraspecific geographic variability into account, reveals different patterns of evolution among species and great heterogeneity in species-level variation. Several chimpanzee and bonobo clades (and even single social groups) have retained substantially more mitochondrial variation than is seen in the entire human species. Among the 811 human haplotypes, those that branch off early are predominantly but not exclusively African. Neighbor joining trees provide strong evidence that eastern chimpanzee and human clades have experienced reduced effective population sizes, the latter apparently since theHomo sapiens–neanderthalensissplit. Application of topiary pruning resolves ambiguities in the phylogenetic tree that are attributable to homoplasies in the data set. The diverse patterns of mtDNA sequence variation seen in today’s hominoid taxa probably reflect historical differences in ecological plasticity, female-biased dispersal, range fragmentation over differing periods of time, and competition among social groups. These results are relevant to the origin of zoonotic diseases, including HIV-1, and call into question some aspects of the current taxonomic treatment and conservation management of gorillas and chimpanzees.
Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a
Authors: Ramsahoye Bernard H. , Biniszkiewicz Detlev , Lyko Frank , Clark Victoria , Bird Adrian P. , Jaenisch Rudolf
Published: July 2002

Current evidence indicates that methylation of cytosine in mammalian DNA is restricted to both strands of the symmetrical sequence CpG, although there have been sporadic reports that sequences other than CpG may also be methylated. We have used a dual-labeling nearest neighbor technique and bisulphite genomic sequencing methods to investigate the nearest neighbors of 5-methylcytosine residues in mammalian DNA. We find that embryonic stem cells, but not somatic tissues, have significant cytosine-5 methylation at CpA and, to a lesser extent, at CpT. As the expression of the
de novo
methyltransferase Dnmt3a correlates well with the presence of non-CpG methylation, we asked whether Dnmt3a might be responsible for this modification. Analysis of genomic methylation in transgenic
Drosophila
expressing Dnmt3a reveals that Dnmt3a is predominantly a CpG methylase but also is able to induce methylation at CpA and at CpT.
Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis
Authors: Nanthakumar N. Nanda , Fusunyan Robert D. , Sanderson Ian , Walker W. Allan
Published: July 2002

Necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in premature infants, occurs after the introduction of oral feedings in conjunction with initial bacterial colonization of the gut and is hypothesized to be due to an immature (inappropriate) enterocyte response to bacterial stimuli. To test this hypothesis, we compared the enterocyte IL-8 response to inflammatory stimuli [lipopolysaccharide (LPS) and IL-1β] in immature vs. mature human small intestine. Initial
in vitro
studies comparing confluent Caco-2 cells, a model for mature human enterocytes, with a primary human fetal intestinal cell line (H4 cells) demonstrated that after inflammatory stimulation fetal cells secreted more IL-8 (LPS, 8-fold; IL-1β, 20-fold) than Caco-2 cells. IL-8 mRNA activity in fetal compared to Caco-2 cells was proportionately increased by the same magnitude with both stimuli. To validate the
in vitro
observations, small intestinal organ cultures from fetuses vs. older children were exposed to LPS and IL-1β. Again in human organ cultures from fetuses compared to older children, IL-8 secretion was greater (LPS, 2.5-fold; IL-1β, 200-fold) and mRNA activity after stimulation was comparably higher, suggesting that increased transcription of the IL-8 gene may account for the excessive response. Using immunohistochemical staining to identify the cellular source of IL-8, activity was noted predominantly in villous and crypt epithelium but also in a few immunoresponsive lymphoid cells. The observation that immature human enterocytes react with excessive pro-inflammatory cytokine production after inflammatory stimulation may help in part explain why prematures exposed to initial colonizing bacteria develop necrotizing enterocolitis.
Flower color variation: A model for the experimental study of evolution
Authors: Clegg Michael T. , Durbin Mary L.
Published: July 2002

We review the study of flower color polymorphisms in the morning
glory as a model for the analysis of adaptation. The pathway involved
in the determination of flower color phenotype is traced from the
molecular and genetic levels to the phenotypic level. Many of the genes
that determine the enzymatic components of flavonoid biosynthesis are
redundant, but, despite this complexity, it is possible to associate
discrete floral phenotypes with individual genes. An important finding
is that almost all of the mutations that determine phenotypic
differences are the result of transposon insertions. Thus, the flower
color diversity seized on by early human domesticators of this plant is
a consequence of the rich variety of mobile elements that reside in the
morning glory genome. We then consider a long history of research aimed
at uncovering the ecological fate of these various flower phenotypes in
the southeastern U.S. A large body of work has shown that insect
pollinators discriminate against white phenotypes when white
flowers are rare in populations. Because the plant is
self-compatible, pollinator bias causes an increase in
self-fertilization in white maternal plants, which should lead to an
increase in the frequency of white genes, according to modifier gene
theory. Studies of geographical distributions indicate other, as yet
undiscovered, disadvantages associated with the white phenotype. The
ultimate goal of connecting ecology to molecular genetics through the
medium of phenotype is yet to be attained, but this approach may
represent a model for analyzing the translation between these two
levels of biological organization.
Coupling between changes in human brain temperature and oxidative metabolism during prolonged visual stimulation
Authors: Yablonskiy Dmitriy A. , Ackerman Joseph J. H. , Raichle Marcus E.
Published: July 2002

A fundamental discovery of modern human brain imaging with positron-emission tomography that the blood flow to activated regions of the normal human brain increases substantially more than the oxygen consumption has led to a broad discussion in the literature concerning possible mechanisms responsible for this phenomenon. Presently no consensus exists. It is well known that oxygen delivery is not the only function of systemic circulation. Additional roles include delivery of nutrients and other required substances to the tissue, waste removal, and temperature regulation. Among these other functions, the role of regional cerebral blood flow in local brain temperature regulation has received scant attention. Here we present a theoretical analysis supported by empirical data obtained with functional magnetic resonance suggesting that increase in regional cerebral blood flow during functional stimulation can cause local changes in the brain temperature and subsequent local changes in the oxygen metabolism. On average, temperature decreases by 0.2°C, but individual variations up to ±1°C were also observed. Major factors contributing to temperature regulation during functional stimulation are changes in the oxygen consumption, changes in the temperature of incoming arterial blood, and extensive heat exchange between activated and surrounding brain tissue.
An initiator element mediates autologous downregulation of the human type A γ-aminobutyric acid receptor β1 subunit gene
Authors: Russek Shelley J. , Bandyopadhyay Sabita , Farb David H.
Published: July 2002

The regulated expression of type A γ-aminobutyric acid receptor (GABA
A
R) subunit genes is postulated to play a role in neuronal maturation, synaptogenesis, and predisposition to neurological disease. Increases in GABA levels and changes in GABA
A
R subunit gene expression, including decreased β1 mRNA levels, have been observed in animal models of epilepsy. Persistent exposure to GABA down-regulates GABA
A
R number in primary cultures of neocortical neurons, but the regulatory mechanisms remain unknown. Here, we report the identification of a TATA-less minimal promoter of 296 bp for the human GABA
A
R β1 subunit gene that is neuron specific and autologously down-regulated by GABA. β1 promoter activity, mRNA levels, and subunit protein are decreased by persistent GABA
A
R activation. The core promoter, 270 bp, contains an initiator element (Inr) at the major transcriptional start site. Three concatenated copies of the 10-bp Inr and its immediate 3′ flanking sequence produce full neural specific activity that is down-regulated by GABA in transiently transfected neocortical neurons. Taking these results together with those of DNase I footprinting, electrophoretic mobility shift analysis, and 2-bp mutagenesis, we conclude that GABA-induced down-regulation of β1 subunit mRNAs involves the differential binding of a sequence-specific basal transcription factor(s) to the Inr. The results support a transcriptional mechanism for the down-regulation of β1 subunit GABA
A
R gene expression and raises the possibility that altered levels of sequence-specific basal transcription factors may contribute to neurological disorders such as epilepsy.
Increased adipose tissue in male and female estrogen receptor-α knockout mice
Authors: Heine P. A. , Taylor J. A. , Iwamoto G. A. , Lubahn D. B. , Cooke P. S.
Published: July 2002

Estrogen regulates the amount of white adipose tissue (WAT) in
females, but its role in males and whether WAT effects involve estrogen
receptor-α (ERα) or ERβ were unclear. We analyzed the role of
ERα in WAT and brown adipose tissue by comparing these tissues in
wild-type (WT) and ERα-knockout (αERKO) male and female mice. Brown
adipose tissue weight was similar in αERKO and WT males at all ages.
Progressive increases in WAT were seen in αERKO males with advancing
age. Epididymal, perirenal, and inguinal WAT weighed 139–185% more in
αERKO than in WT males by 270–360 days of age. Epididymal and
perirenal adipocyte size was increased 20% in αERKO males. Adipocyte
number was 82–168% greater in fat pads of αERKO vs. WT males.
Compared with WT, 90-day-old αERKO females had increases in fat pad
weights (54–103%), adipocyte size, and number. Both αERKO males and
females had insulin resistance and impaired glucose tolerance, similar
to humans lacking ERα or aromatase. Energy intake was equal in WT and
αERKO males, indicating that obesity was not induced by hyperphagia.
In contrast, energy expenditure was reduced by 11% in αERKO compared
with WT males, indicating that altered energy expenditure may be
important for the observed obesity. In summary, ERα absence causes
adipocyte hyperplasia and hypertrophy, insulin resistance, and glucose
intolerance in both sexes. These results are evidence that
estrogen/ERα signaling is critical in female and male WAT; obesity
in αERKO males involves a mechanism of reduced energy expenditure
rather than increased energy intake.
Top-down processing mediated by interareal synchronization
Authors: von Stein Astrid , Chiang Carl , König Peter
Published: July 2002

Perception and cortical responses are not only driven
“bottom-up” by the external stimulus but are altered by internal
constraints such as expectancy or the current behavioral goal. To
investigate neurophysiological mechanisms of such top-down effects, we
analyzed the temporal interactions of neurons on different levels of
the cortical hierarchy during perception of stimuli with varying
behavioral significance. We found that interareal interactions in a
middle-frequency range (θ and α; 4–12 Hz) strongly depend on the
associated behavior, with a phase relationship and a layer specificity
indicating a top-down-directed interaction. For novel unexpected
stimuli, presumably processed in a feed-forward fashion, no such
interactions occurred but high-frequency interactions (γ; 20–100 Hz)
were observed. Thus corticocortical synchronization reflects the
internal state of the animal and may mediate top-down processes.
Self-assembly of large, ordered lamellae from non-bilayer lipids and integral membrane proteinsin vitro
Authors: Simidjiev Ilian , Stoylova Svetla , Amenitsch Heinz , Jávorfi Tamás , Mustárdy László , Laggner Peter , Holzenburg Andreas , Garab Győző
Published: July 2002

In many biological membranes, the major lipids are “non-bilayer lipids,” which in purified form cannot be arranged in a lamellar structure. The structural and functional roles of these lipids are poorly understood. This work demonstrates that thein vitroassociation of the two main components of a membrane, the non-bilayer lipid monogalactosyldiacylglycerol (MGDG) and the chlorophyll-a/b light-harvesting antenna protein of photosystem II (LHCII) of pea thylakoids, leads to the formation of large, ordered lamellar structures: (i) thin-section electron microscopy and circular dichroism spectroscopy reveal that the addition of MGDG induces the transformation of isolated, disordered macroaggregates of LHCII into stacked lamellar aggregates with a long-range chiral order of the complexes; (ii) small-angle x-ray scattering discloses that LHCII perturbs the structure of the pure lipid and destroys the inverted hexagonal phase; and (iii) an analysis of electron micrographs of negatively stained 2D crystals indicates that in MGDG-LHCII the complexes are found in an ordered macroarray. It is proposed that, by limiting the space available for MGDG in the macroaggregate, LHCII inhibits formation of the inverted hexagonal phase of lipids; in thylakoids, a spatial limitation is likely to be imposed by the high concentration of membrane-associated proteins.
Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor
Authors: Waldner Hanspeter , Whitters Matthew J. , Sobel Raymond A. , Collins Mary , Kuchroo Vijay K.
Published: July 2002

Proteolipid protein (PLP)-139–151 is the dominant encephalitogenic peptide that induces experimental autoimmune encephalomyelitis (EAE) in SJL (H-2s) mice. To examine the contribution of T cell receptor (TCR) specificity in the induction of EAE, we generated transgenic mice expressing the rearranged TCR genes from an encephalitogenic or a nonencephalitogenic PLP-139–151/I-As-specific T cell clone. Both types of transgenic lines developed spontaneous EAE, but, remarkably, the lines expressing the TCR from the nonencephalitogenic clone showed increasingly higher frequencies of disease (60–83%) in progressive SJL backcrosses and could not be propagated on the susceptible background. The T cells from the transgenic mice were not tolerized, because they responded vigorously to the antigenin vitroand mediated EAE when the mice were immunized with antigen. Besides being the only description of a TCR transgenic mice for the PLP-139–151/I-Asepitope, the results demonstrate that the TCR from a nonencephalitogenic PLP-specific T cell clone can induce autoimmune disease when expressed appropriatelyin vivo.
To walk or to fly? How birds choose among foraging modes
Authors: Bautista Luis M. , Tinbergen Joost , Kacelnik Alejandro
Published: July 2002

We test the predictive value of the main energetic currencies
used in foraging theory using starlings that choose between two
foraging modes (walking versus flying). Walking is low-cost, low-yield,
whereas flying is the opposite. We fixed experimentally, at 11
different values, the amount of flight required to get one food reward,
and for each flight cost value, we titrated the amount of walking until
the birds showed indifference between foraging modes. We then compared
the indifference points to those predicted by gross rate of gain over
time, net rate of gain over time, and the ratio of gain to expenditure
(efficiency). The results for the choice between modes show strong
qualitative and quantitative support for net rate of gain over time
over the alternatives. However, the birds foraged for only a fraction
of the available time, indicating that the choice between foraging and
resting could not be explained by any of these currencies. We suggest
that this discrepancy could be accounted for functionally because
nonenergetic factors such as predation risk may differ between resting
and foraging in any mode but may not differ much between foraging
modes, hence releasing the choice between foraging modes from the
influence of such factors. Alternatively, the discrepancy may be
attributable to the use of predictable (rather than stochastic) ratios
of effort per prey in our experiment, and it may thus be better
understood with mechanistic rather than functional arguments.
Interaction of the herbicide glyphosate with its target enzyme 5-enolpyruvylshikimate 3-phosphate synthase in atomic detail
Authors: Schönbrunn Ernst , Eschenburg Susanne , Shuttleworth Wendy A. , Schloss John V. , Amrhein Nikolaus , Evans Jeremy N. S. , Kabsch Wolfgang
Published: July 2002

Biosynthesis of aromatic amino acids in plants, many
bacteria, and microbes relies on the enzyme 5-enolpyruvylshikimate
3-phosphate (EPSP) synthase, a prime target for drugs and herbicides.
We have identified the interaction of EPSP synthase with one of its two
substrates (shikimate 3-phosphate) and with the widely used herbicide
glyphosate by x-ray crystallography. The two-domain enzyme closes on
ligand binding, thereby forming the active site in the interdomain
cleft. Glyphosate appears to occupy the binding site of the second
substrate of EPSP synthase (phosphoenol pyruvate), mimicking an
intermediate state of the ternary enzyme⋅substrates complex. The
elucidation of the active site of EPSP synthase and especially of the
binding pattern of glyphosate provides a valuable roadmap for
engineering new herbicides and herbicide-resistant crops, as well as
new antibiotic and antiparasitic drugs.
Neuroimaging evidence implicating cerebellum in the experience of hypercapnia and hunger for air
Authors: Parsons Lawrence M. , Egan Gary , Liotti Mario , Brannan Stephen , Denton Derek , Shade Robert , Robillard Rachael , Madden Lisa , Abplanalp Bart , Fox Peter T.
Published: July 2002

Recent neuroimaging and neurological data implicate cerebellum in nonmotor sensory, cognitive, vegetative, and affective functions. The present study assessed cerebellar responses when the urge to breathe is stimulated by inhaled CO2. Ventilation changes follow arterial blood partial pressure CO2changes sensed by the medullary ventral respiratory group (VRG) and hypothalamus, entraining changes in midbrain, pons, thalamus, limbic, paralimbic, and insular regions. Nearly all these areas are known to connect anatomically with the cerebellum. Using positron emission tomography, we measured regional brain blood flow during acute CO2-induced breathlessness in humans. Separable physiological and subjective effects (air hunger) were assessed by comparisons with various respiratory control conditions. The conjoint physiological effects of hypercapnia and the consequent air hunger produced strong bilateral, near-midline activations of the cerebellum in anterior quadrangular, central, and lingula lobules, and in many areas of posterior quadrangular, tonsil, biventer, declive, and inferior semilunar lobules. The primal emotion of air hunger, dissociated from hypercapnia, activated midline regions of the central lobule. The distributed activity across the cerebellum is similar to that for thirst, hunger, and their satiation. Four possible interpretations of cerebellar function(s) here are that: it subserves implicit intentions to access air; it provides predictive internal models about the consequences of CO2inhalation; it modulates emotional responses; and that while some cerebellar regions monitor sensory acquisition in the VRG (CO2concentration), others influence VRG to adjust respiratory rate to optimize partial pressure CO2, and others still monitor and optimize the acquisition of other sensory data in service of air hunger aroused vigilance.
The authority of complexity*
Authors: Stehr Nico , Grundmann Reiner
Published: July 2002

The assertion about the unique ‘complexity’ or the peculiarly intricate character of social phenomena has, at least within sociology, a long, venerable and virtually uncontested tradition. At the turn of the last century, classical social theorists, for example, Georg Simmel and Emile Durkheim, made prominent and repeated reference to this attribute of the subject matter of sociology and the degree to which it complicates, even inhibits the development and application of social scientific knowledge. Our paper explores the origins, the basis and the consequences of this assertion and asks in particular whether the classic complexity assertion still deserves to be invoked in analyses that ask about the production and the utilization of social scientific knowledge in modern society. We present John Maynard Keynes' economic theory and its practical applications as an illustration. We conclude that the practical value of social scientific knowledge is not dependent on a faithful, in the sense of complete, representation of social reality. Instead, social scientific knowledge that wants to optimize its practicality has to attend and attach itself to elements of social situations that can be altered or are actionable.
Justice and Social Conflict
Authors: Mikula Gerold , Wenzel Michael
Published: July 2002

This article analyzes possible effects of ideas of justice, perceptions of injustice, and the use of justice arguments on the emergence, course, and resolution of social conflicts. Four functions of justice are identified: (1) ideas of justice and perceptions of injustice can elicit or evoke social conflicts; (2) justice arguments and rhetorics can be used to support one's own position in a dispute; (3) the basic value and the principles and rules of justice can restrict social conflicts and help to generate ways of conflict resolution; (4) the labelling of conflict resolutions as just can increase the acceptance of the resolution. The analysis is illustrated by making reference to a recent case of international conflict and diplomatic controversy.
Cultural influences on artistic creativity and its evaluation
Authors: Niu Weihua , Sternberg Robert J.
Published: July 2002

Two studies were designed to compare (a) the rated creativity of artworks created by American and Chinese college students, and (b) the criteria used by American and Chinese judges to evaluate these artworks. The study demonstrated that the two groups of students differed in their artistic creativity. American participants produced more creative and aesthetically pleasing artworks than did their Chinese counterparts, and this difference in performance was recognized by both American and Chinese judges. The difference between the use of criteria by American and Chinese judges was small, and consisted mainly of the American judges' use of stricter standards in evaluating overall creativity. Moreover, in general, there was a greater consensus among Chinese judges regarding what constitutes creativity than among American judges. The study also revealed, but preliminarily, that the artistic creativity of Chinese students was more likely to be reduced as a function of restrictive task constraints or of the absence of explicit instructions to be creative. The results of this study seem to support the hypothesis that an independent self‐oriented culture is more encouraging of the development of artistic creativity than is an interdependent self‐oriented culture. Other possible explanations, such as differences in people's attitudes toward and motivation for engaging in art activities, or socioeconomic factors might also account for differences in people's artistic creativity.
The Influence of Long‐term Memory Factors on Immediate Serial Recall: An Item and Order Analysis
Authors: Saint‐Aubin Jean , Poirier Marie
Published: July 2002

In immediate serial recall, an error can occur because the presented item is not recalled (item error) or because it is recalled at the wrong serial position (order error). Even if these two types of information can be selectively influenced, in most current studies, a global performance measure confounding item and order information is used. Here, the issues associated with the measure of memory for item and order information are discussed. First, it is argued that in some circumstances it is very important that item information be controlled for when measuring order retention, by for example, conditionalizing order memory on memory for item information. Second, using such measures, it is shown that long‐term memory factors recently investigated in immediate serial recall produce a different pattern of results than what is predicted by most current models: Semantic similarity, word frequency, and lexicality all influence item recall, but only lexicality affects order information. These findings are discussed in the light of a retrieval‐based account suggesting that degraded phonological traces must undergo a reconstruction process calling upon long‐term knowledge of the to‐be‐remembered items.