bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a family of Fc receptor homologs with preferential B cell expression
Authors: Davis Randall S. , Wang Yui-Hsi , Kubagawa Hiromi , Cooper Max D.
Published: July 2002

Investigation of human genome sequences with a consensus sequence derived from receptors for the Fc region of Igs (FcR) led to the identification of a subfamily of five Ig superfamily members that we term the Fc receptor homologs (FcRHs). The closely linkedFcRHgenes are located in a chromosome 1q21 region in the midst of previously recognizedFcRgenes. This report focuses on theFcRH1,FcRH2, andFcRH3members of this gene family. Their cDNAs encode type I transmembrane glycoproteins with 3–6 Ig-like extracellular domains and cytoplasmic domains containing consensus immunoreceptor tyrosine-based activating and/or inhibitory signaling motifs. The fiveFcRHgenes are structurally related, and their protein products share 28–60% extracellular identity with each other. They also share 15–31% identity with their closest FcR relatives. TheFcRHgenes are expressed primarily, although not exclusively, by mature B lineage cells. Their conserved structural features, patterns of cellular expression, and the inhibitory and activating signaling potential of their transmembrane protein products suggest that the members of thisFcRHmultigene family may serve important regulatory roles in normal and neoplastic B cell development.
Sulindac inhibits neointimal formation after arterial injury in wild-type and apolipoprotein E-deficient mice
Authors: Reis Ernane D. , Roqué Mercè , Dansky Hayes , Fallon John T. , Badimon Juan J. , Cordon-Cardo Carlos , Shiff Steven J. , Fisher Edward A.
Published: July 2002

Neointimal hyperplasia is a critical component of restenosis, a
major complication of angioplasty and related therapeutic procedures.
We studied the effects of hyperlipidemia and the nonsteroidal
anti-inflammatory drugs, aspirin (acetyl-salicylic acid; ASA), and
sulindac, on neointimal formation in a mouse femoral arterial injury
model. At 2 months of age, normolipidemic, wild-type (WT), and
hyperlipidemic, apolipoprotein E-deficient (apoE−/−) mice were
divided into three treatment groups: Western-type diet (WD), WD + ASA
(200 mg/kg food), and WD + sulindac (300 mg/kg food). After 1 week,
mice underwent arterial injury and treatments were maintained for 4
weeks. Histomorphometry of the injured arteries showed striking effects
of plasma cholesterol levels and drug treatment on neointimal
hyperplasia. In the WD or WD + ASA groups, apoE−/− mice had twice
the neointimal area than WT mice (≈30,000 vs. 13,000
μm
2
per section;
P
< 0.0001).
Compared with ASA or WD alone, sulindac treatment resulted in
≈70% (
P
= 0.0001) and 50%
(
P
= 0.01) reductions in the neointimal area in
apoE−/− and WT mice, respectively. ASA, at a dose sufficient to
inhibit platelet aggregation, did not affect neointimal formation in
mice of either genotype. Evidence of macrophages was noted in the
lesions of apoE−/− mice in the WD and WD + ASA groups, but
remarkably, none was detectable with sulindac treatment, despite
hyperlipidemia, suggesting early steps in the response to injury were
abrogated. These results demonstrate sulindac reduces neointimal
formation in both normolipidemic and hyperlipidemic settings and raise
the possibility that similar benefits may be obtained in patients
undergoing angioplasty and related procedures.
Early membrane estrogenic effects required for full expression of slower genomic actions in a nerve cell line
Authors: Vasudevan Nandini , Kow Lee-Ming , Pfaff Donald W.
Published: July 2002

Interpretations of steroid hormone actions as slow, nuclear, transcriptional events have frequently been seen as competing against inferences of rapid membrane actions. We have discovered conditions where membrane-limited effects potentiate later transcriptional actions in a nerve cell line. Making use of a two-pulse hormonal schedule in a transfection system, early and brief administration of conjugated, membrane-limited estradiol was necessary but not sufficient for full transcriptional potency of the second estrogen pulse. Efficacy of the first pulse depended on intact signal transduction pathways. Surprisingly, the actions of both pulses were blocked by a classical estrogen receptor (ER) antagonist. Thus, two different modes of steroid hormone action can synergize.
Transient uptake of serotonin by newborn olfactory projection neurons
Authors: Beltz Barbara S. , Benton Jeanne L. , Sullivan Jeremy M.
Published: July 2002

A life-long turnover of sensory and interneuronal populations has been documented in the olfactory pathways of both vertebrates and invertebrates, creating a situation where the axons of new afferent and interneuronal populations must insert into a highly specialized glomerular neuropil. A dense serotonergic innervation of the primary olfactory processing areas where these neurons synapse also is a consistent feature across species. Prior studies in lobsters have shown that serotonin promotes the branching of olfactory projection neurons. This paper presents evidence that serotonin also regulates the proliferation and survival of projection neurons in lobsters, and that the serotonergic effects are associated with a transient uptake of serotonin into newborn neurons.
Theoretical prediction of a crystal structure.
Authors: Wawak R J , Gibson K D , Liwo A , Scheraga H A
Published: July 2002

The diffusion equation method of global minimization is applied to compute the crystal structure of S6, with no a priori knowledge about the system. The experimental lattice parameters and positions and orientations of the molecules in the unit cell are predicted correctly.
Gene transfer by guanidinium-cholesterol cationic lipids into airway epithelial cellsin vitroandin vivo
Authors: Oudrhiri Noufissa , Vigneron Jean-Pierre , Peuchmaur Michel , Leclerc Tony , Lehn Jean-Marie , Lehn Pierre
Published: July 2002

Synthetic vectors represent an attractive alternative approach to viral vectors for gene transfer, in particular into airway epithelial cells for lung-directed gene therapy for cystic fibrosis. Having recently found that guanidinium-cholesterol cationic lipids are efficient reagents for gene transfer into mammalian cell linesin vitro, we have investigated their use for gene delivery into primary airway epithelial cellsin vitroandin vivo. The results obtained indicate that the lipid bis(guanidinium)-tren-cholesterol (BGTC) can be used to transfer a reporter gene into primary human airway epithelial cells in culture. Furthermore, liposomes composed of BGTC and dioleoyl phosphatidylethanolamine (DOPE) are efficient for gene delivery to the mouse airway epitheliumin vivo. Transfected cells were detected both in the surface epithelium and in submucosal glands. In addition, the transfection efficiency of BGTC/DOPE liposomesin vivowas quantitatively assessed by using the luciferase reporter gene system.
Transfection and overexpression of the calcium binding protein calbindin-D
28k
results in a stimulatory effect on insulin synthesis in a rat β cell line (RIN 1046-38)
Authors: Reddy Daphne , Pollock Allan S. , Clark Samuel A. , Sooy Karen , Vasavada Rupangi C. , Stewart Andrew F. , Honeyman Thomas , Christakos Sylvia
Published: July 2002

Calbindin-D
28k
, a calcium binding protein that is thought to act as a facilitator of calcium diffusion in intestine and kidney, is known to be regulated by vitamin D in these tissues. Calbindin-D
28k
is also present in pancreatic β cells, but its function in these cells is not known. To determine a role for calbindin-D
28k
in the β cell, rat calbindin-D
28k
was overexpressed in the pancreatic β cell line RIN 1046-38 by transfection of calbindin in expression vector, and changes in insulin mRNA were examined. Five transfected RIN cell clones were found to overexpress calbindin 6- to 35-fold as determined by radioimmunoassay. Northern blot analysis revealed increases in abundance in calbindin mRNA (>20-fold for most clones). Overexpressed calbindin was functional because it was capable of buffering calcium in response to a rapid calcium influx induced by 1 and 5 μM calcium ionophore. In cells transfected with calbindin, there was a marked increase in the expression of insulin mRNA (>20-fold for most clones compared with vector transfected cells). Besides an increase in insulin mRNA, calbindin overexpression was also associated with an increase in insulin content and release (a 5.8-fold increase in insulin release was noted for clone C10, and a 54-fold increase was noted for clone C2). To begin to address the mechanism whereby overexpression of calbindin results in increased insulin gene expression, calbindin-overexpressing clones were transiently transfected with plasmids incorporating various regions of the rat insulin I (rInsI) promoter linked to the chloramphenicol acetyltransferase coding sequence. Transient transfection with reporter plasmids bearing the regulatory sequences of the rInsI promoter (−345/+1) or five copies of the Far-FLAT minienhancer (−247/−198) from the rInsI promoter suggests that increased insulin mRNA in calbindin transfected cells is due, at least in part, to enhanced insulin gene transcription. These studies provide the first direct evidence (to our knowledge) for a role for calbindin in β cell function.
Promiscuous coassembly of serotonin 5-HT
3
and nicotinic α4 receptor subunits into Ca
2+
-permeable ion channels
Authors: van Hooft Johannes A. , Spier Avron D. , Yakel Jerrel L. , Lummis Sarah C. R. , Vijverberg Henk P. M.
Published: July 2002

Serotonin (5-hydroxytryptamine) type 3 receptors (5-HT
3
R) and nicotinic acetylcholine receptors are structurally and functionally related proteins, yet distinct members of the family of ligand-gated ion channels. For most members of this family a diversity of heteromeric receptors is known at present. In contrast, known 5-HT
3
R subunits are all homologs of the same 5-HT
3
R-A subunit and form homopentameric receptors. Here we show, by heterologous expression followed by immunoprecipitation, that 5-HT
3
R and nicotinic acetylcholine receptor α4 subunits coassemble into a novel type of heteromeric ligand-gated ion channel, which is activated by 5-HT. The Ca
2+
permeability of this heteromeric ion channel is enhanced as compared with that of the homomeric 5-HT
3
R channel. Heteromeric 5-HT
3
/α4 and homomeric 5-HT
3
Rs have similar pharmacological profiles, but distinct sensitivities to block by the antagonist
d
-tubocurarine. Coassembly of subunits beyond the boundaries of ligand-gated ion channel families may constitute an important mechanism contributing to the diverse properties and functions of native neurotransmitter receptors.
Ethylene-insensitive tobacco lacks nonhost resistance against soil-borne fungi
Authors: Knoester Marga , van Loon Leendert C. , van den Heuvel Joop , Hennig Jacek , Bol John F. , Linthorst Huub J. M.
Published: July 2002

Enhanced ethylene production is an early response of plants to pathogen attack and has been associated with both resistance and susceptibility to disease. Tobacco plants were transformed with the mutant
etr1–1
gene from
Arabidopsis
, conferring dominant ethylene insensitivity. Besides lacking known ethylene responses, these transformants (Tetr) did not slow growth when contacting neighboring plants, hardly expressed defense-related basic pathogenesis-related proteins, and developed spontaneous stem browning. Whereas hypersensitive resistance to tobacco mosaic virus was unimpaired, Tetr plants had lost nonhost resistance against normally nonpathogenic soil-borne fungi.
Cytomegalovirus encodes a potent α chemokine
Authors: Penfold Mark E. T. , Dairaghi Daniel J. , Duke Gregory M. , Saederup Noah , Mocarski Edward S. , Kemble George W. , Schall Thomas J.
Published: July 2002

Cytomegalovirus is a widespread opportunistic pathogen affecting immunocompromised individuals in whom neutrophils may mediate virus dissemination and contribute to progression of disease. Recent sequence analysis suggests that genes absent or altered in attenuated strains may influence pathogenesis. We have found two genes,UL146andUL147, whose products have sequence similarity to α (CXC) chemokines.UL146encodes a protein, designated vCXC-1, that is a 117-aa glycoprotein secreted into the culture medium as a late gene product, where its presence correlates with the ability to attract human neutrophils. Recombinant vCXC-1 is a fully functional chemokine, inducing calcium mobilization, chemotaxis, and degranulation of neutrophils. High-affinity vCXC-1 binding is shown to be mediated via CXCR2, but not CXCR1. vCXC-1 exhibits a potency approaching that of human IL-8. As the first example of a virus-encoded α chemokine, vCXC-1 may ensure the active recruitment of neutrophils during cytomegalovirus infection, thereby providing for efficient dissemination during acute infection and accounting for the prominence of this leukocyte subset in cytomegalovirus disease.
The active digestion of uniparental chloroplast DNA in a single zygote of
Chlamydomonas reinhardtii
is revealed by using the optical tweezer
Authors: Nishimura Yoshiki , Misumi Osami , Matsunaga Sachihiro , Higashiyama Tetsuya , Yokota Akiho , Kuroiwa Tsuneyoshi
Published: July 2002

The non-Mendelian inheritance of organelle genes is a phenomenon common to almost all eukaryotes, and in the isogamous alga
Chlamydomonas reinhardtii
, chloroplast (cp) genes are transmitted from the mating type positive (
mt
+
) parent. In this study, the preferential disappearance of the fluorescent cp nucleoids of the mating type negative (
mt
−
) parent was observed in living young zygotes. To study the change in cpDNA molecules during the preferential disappearance, the cpDNA of
mt
+
or
mt
−
origin was labeled separately with bacterial
aadA
gene sequences. Then, a single zygote with or without cp nucleoids was isolated under direct observation by using optical tweezers and investigated by nested PCR analysis of the
aadA
sequences. This demonstrated that cpDNA molecules are digested completely during the preferential disappearance of
mt
−
cp nucleoids within 10 min, whereas
mt
+
cpDNA and mitochondrial DNA are protected from the digestion. These results indicate that the non-Mendelian transmission pattern of organelle genes is determined immediately after zygote formation.
A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: Possible role of membrane TNF
Authors: Herrera Pedro Luis , Harlan David M. , Vassalli Pierre
Published: July 2002

Double transgenic mice [rat insulin promoter (RIP)-tumor necrosis factor (TNF) and RIP-CD80] whose pancreatic β cells release TNF and bear CD80 all develop an acute early (6 wk) and lethal diabetes mediated by CD8 T cells. The first ultrastructural changes observed in β cells, so far unreported, are focal lesions of endoplasmic reticulum swelling at the points of contact with islet-infiltrating lymphoblasts, followed by cytoplasmic, but not nuclear, apoptosis. Such double transgenic mice were made defective in either the perforin, Fas, or TNF pathways. Remarkably, diabetes was found to be totally independent of perforin and Fas. Mice lacking TNF receptor (TNFR) II had no or late diabetes, but only a minority had severe insulitis. Mice lacking the TNF-lymphotoxin (LTα) locus (whose sole source of TNF are the β cells) all had insulitis comparable to that of nondefective mice, but no diabetes or a retarded and milder form, with lesions suggesting different mechanisms of injury. Because both TNFR II and TNF-LTα mutations have complex effects on the immune system, these data do not formally incriminate membrane TNF as the major T cell mediator of this acute autoimmune diabetes; nevertheless, in the absence of involvement of the perforin or Fas cytotoxic pathways, membrane TNF appears to be the likeliest candidate.
Polymorphisms at the DRD2 locus in early‐onset alcohol dependence in the Indian population
Authors: Shaikh Kauser J. , Naveen Daniel , Sherrin Tessi , Murthy Ashlesh , Thennarasu K. , Anand Anuranjan , Benegal Vivek , Jain Sanjeev
Published: July 2002

The susceptibility to alcohol dependence is probably of polygenic origin. Association studies have attempted to identify possible candidate genes that may contribute to the risk to developing dependence. Severe forms of the alcoholism phenotype have been associated with an increased frequency of the Taq A1 allele at the DRD2 locus. Ethnic stratification and non‐comparable phenotype may have contributed to the contradictory results in previous studies. We identified probands, using the Schedules of Assessment of Neuropsychiatry (SCAN) schedule, who had onset of alcohol dependence (ICD‐10) before 25 years of age. Family members were interviewed using the Family Interview for Genetic Studies (FIGS) schedule to identify patients who had two first‐degree relatives with alcohol dependence. Fifty subjects who fulfilled the criteria were selected for the study. These were compared to a normal population from a similar background. The allele frequencies did not differ between the two groups. The Taq1a polymorphism does not seem to be associated with alcoholism in this group of severely affected, young age of onset probands in the southern Indian population.
Intramitochondrial Localization of Universal Minicircle Sequence-Binding Protein, a Trypanosomatid Protein That Binds Kinetoplast Minicircle Replication Origins
Authors: Abu-Elneel Kawther , Robinson Derrick R. , Drew Mark E. , Englund Paul T. , Shlomai Joseph
Published: July 2002

Kinetoplast DNA (kDNA), the mitochondrial DNA of the trypanosomatid Crithidia fasciculata, is a unique structure containing 5,000 DNA minicircles topologically linked into a massive network. In vivo, the network is condensed into a disk-shaped structure. Replication of minicircles initiates at unique origins that are bound by universal minicircle sequence (UMS)-binding protein (UMSBP), a sequence-specific DNA-binding protein. This protein, encoded by a nuclear gene, localizes within the cell's single mitochondrion. Using immunofluorescence, we found that UMSBP localizes exclusively to two neighboring sites adjacent to the face of the kDNA disk nearest the cell's flagellum. This site is distinct from the two antipodal positions at the perimeter of the disk that is occupied by DNA polymerase β, topoisomerase II, and a structure-specific endonuclease. Although we found constant steady-state levels of UMSBP mRNA and protein and a constant rate of UMSBP synthesis throughout the cell cycle, immunofluorescence indicated that UMSBP localization within the kinetoplast is not static. The intramitochondrial localization of UMSBP and other kDNA replication enzymes significantly clarifies our understanding of the process of kDNA replication.
Two Metabotropic γ-Aminobutyric Acid Receptors Differentially Modulate Calcium Currents in Retinal Ganglion Cells
Authors: Zhang Jian , Shen Wen , Slaughter Malcolm M.
Published: July 2002

Metabotropic γ-aminobutyric acid (GABA) receptors were studied in amphibian retinal ganglion cells using whole cell current and voltage clamp techniques. The aim was to identify the types of receptor present and their mechanisms of action and modulation. Previous results indicated that ganglion cells possess two ionotropic GABA receptors: GABAAR and GABACR. This study demonstrates that they also possess two types of metabotropic GABAB receptor: one sensitive to baclofen and another to cis-aminocrotonic acid (CACA). The effects of these selective agonists were blocked by GDP-β-S. Baclofen suppressed an ω-conotoxin–GVIA-sensitive barium current, and this action was reversed by prepulse facilitation, indicative of a direct G-protein pathway. The effect of baclofen was also partially occluded by agents that influence the protein kinase A (PKA) pathway. But the effect of PKA activation was unaffected by prepulse facilitation, indicating PKA acted through a parallel pathway. Calmodulin antagonists reduced the action of baclofen, whereas inhibitors of calmodulin phosphatase enhanced it. Antagonists of internal calcium release, such as heparin and ruthenium red, did not affect the baclofen response. Thus, the baclofen-sensitive receptor may respond to influx of calcium. The CACA-sensitive GABA receptor reduced current through dihydropyridine-sensitive channels. Sodium nitroprusside and 8-bromo-cGMP enhanced the action of CACA, indicating that a nitric oxide system can up-regulate this receptor pathway. CACA-sensitive and baclofen-sensitive GABAB receptors reduced spike activity in ganglion cells. Overall, retinal ganglion cells possess four types of GABA receptor, two ionotropic and two metabotropic. Each has a unique electrogenic profile, providing a wide range of neural integration at the final stage of retinal information processing.
A Mathematical Model of Solute Coupled Water Transport in Toad Intestine Incorporating Recirculation of the Actively Transported Solute
Authors: Larsen Erik Hviid , Sørensen Jakob Balslev , Sørensen Jens Nørkær
Published: July 2002

A mathematical model of an absorbing leaky epithelium is developed for analysis of solute coupled water transport. The non-charged driving solute diffuses into cells and is pumped from cells into the lateral intercellular space (lis). All membranes contain water channels with the solute passing those of tight junction and interspace basement membrane by convection-diffusion. With solute permeability of paracellular pathway large relative to paracellular water flow, the paracellular flux ratio of the solute (influx/outflux) is small (2–4) in agreement with experiments. The virtual solute concentration of fluid emerging from lis is then significantly larger than the concentration in lis. Thus, in absence of external driving forces the model generates isotonic transport provided a component of the solute flux emerging downstream lis is taken up by cells through the serosal membrane and pumped back into lis, i.e., the solute would have to be recirculated. With input variables from toad intestine (Nedergaard, S., E.H. Larsen, and H.H. Ussing, J. Membr. Biol. 168:241–251), computations predict that 60–80% of the pumped flux stems from serosal bath in agreement with the experimental estimate of the recirculation flux. Robust solutions are obtained with realistic concentrations and pressures of lis, and with the following features. Rate of fluid absorption is governed by the solute permeability of mucosal membrane. Maximum fluid flow is governed by density of pumps on lis-membranes. Energetic efficiency increases with hydraulic conductance of the pathway carrying water from mucosal solution into lis. Uphill water transport is accomplished, but with high hydraulic conductance of cell membranes strength of transport is obscured by water flow through cells. Anomalous solvent drag occurs when back flux of water through cells exceeds inward water flux between cells. Molecules moving along the paracellular pathway are driven by a translateral flow of water, i.e., the model generates pseudo-solvent drag. The associated flux-ratio equation is derived.
A Metabotropic Glutamate Receptor Regulates Transmitter Release from Cone Presynaptic Terminals in Carp Retinal Slices
Authors: Hirasawa Hajime , Shiells Richard , Yamada Masahiro
Published: July 2002

The role of group III metabotropic glutamate receptors (mGluRs) in photoreceptor-H1 horizontal cell (HC) synaptic transmission was investigated by analyzing the rate of occurrence and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in H1 HCs uncoupled by dopamine in carp retinal slices. Red light steps or the application of 100 μM cobalt reduced the sEPSC rate without affecting their peak amplitude, which is consistent with hyperpolarization or the suppression of Ca2+ entry into cone synaptic terminals reducing vesicular transmitter release. Conversely, postsynaptic blockade of H1 HC AMPA receptors by 500 nM CNQX reduced the amplitude of sEPSCs without affecting their rate. This analysis of sEPSCs represents a novel methodology for distinguishing between presynaptic and postsynaptic sites of action. The selective agonist for group III mGluRs, l-2-amino-4-phosphonobutyrate (L-APB or L-AP4; 20 μM), reduced the sEPSC rate with a slight reduction in amplitude, which is consistent with a presynaptic action on cone synaptic terminals to reduce transmitter release. During L-APB application, recovery of sEPSC rate occurred with 500 μM (s)-2-methyl-2-amino-4-phosphonobutyrate (MAP4), a selective antagonist of group III mGluR, and with 200 μM 4-aminopyridine (4-AP), a blocker of voltage-dependent potassium channels. Whole-cell recordings from cones in the retinal slice showed no effect of L-APB on voltage-activated Ca2+ conductance. These results suggest that the activation of group III mGluRs suppresses transmitter release from cone presynaptic terminals via a 4-AP–sensitive pathway. Negative feedback, operating via mGluR autoreceptors, may limit excessive glutamate release from cone synaptic terminals.
The Orlicz-Pettis theorem for topological Riesz spaces
Authors: Drewnowski Lech , Labuda Iwo
Published: July 2002

A finitely additive vector measure from a

σ
\sigma

-ring to a Riesz space is countably additive (exhaustive) for all Hausdorff Lebesgue topologies on the range space, or for none of them. In particular, subseries convergent series are the same for all Hausdorff Lebesgue topologies on a Riesz space.
Farey polytopes and continued fractions associated with discrete hyperbolic groups
Authors: Vulakh L.
Published: July 2002

The known definitions of Farey polytopes and continued fractions are generalized and applied to diophantine approximation in

n
n

-dimensional euclidean spaces. A generalized Remak-Rogers isolation theorem is proved and applied to show that certain Hurwitz constants for discrete groups acting in a hyperbolic space are isolated. The approximation constant for the imaginary quadratic field of discriminant

−
15

-15

is found.
Relative class number of imaginary Abelian fields of prime conductor below 10000
Authors: Shokrollahi M.
Published: July 2002

In this paper we compute the relative class number of all imaginary Abelian fields of prime conductor below 10000. Our approach is based on a novel multiple evaluation technique, and, assuming the ERH, it has a running time of

O
(

p
2

log
2

⁡
(
p
)
log
⁡
log
⁡
(
p
)
)

O(p^2\log ^2(p)\log \log (p))

, where

p
p

is the conductor of the field.
Using traveling salesman problem algorithms for evolutionary tree construction
Authors: Korostensky Chantal , Gonnet Gaston H.
Published: July 2002

Motivation: The construction of evolutionary trees is one of the major problems in computational biology, mainly due to its complexity.

Results: We present a new tree construction method that constructs a tree with minimum score for a given set of sequences, where the score is the amount of evolution measured in PAM distances. To do this, the problem of tree construction is reduced to the Traveling Salesman Problem (TSP). The input for the TSP algorithm are the pairwise distances of the sequences and the output is a circular tour through the optimal, unknown tree plus the minimum score of the tree. The circular order and the score can be used to construct the topology of the optimal tree. Our method can be used for any scoring function that correlates to the amount of changes along the branches of an evolutionary tree, for instance it could also be used for parsimony scores, but it cannot be used for least squares fit of distances. A TSP solution reduces the space of all possible trees to \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(2^{n}\) \end{document}. Using this order, we can guarantee that we reconstruct a correct evolutionary tree if the absolute value of the error for each distance measurement is smaller than \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{x}{2}\) \end{document}, where \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(x\) \end{document}is the length of the shortest edge in the tree. For data sets with large errors, a dynamic programming approach is used to reconstruct the tree. Finally simulations and experiments with real data are shown.

Availability: The software may be used via our cbrg server at http://cbrg.inf.ethz.ch/MultAlign.

Contact: chantal.roth@nobilitas.com

Supplementary information: An html and postscript version of this paper is available at http://chantal.nobilitas.com/(Papers section).

* To whom correspondence should be addressed.
Curbing the nuclear activities of β‐catenin
Authors: Hecht Andreas , Kemler Rolf
Published: July 2002

Wnt molecules control numerous developmental processes by altering specific gene expression patterns, and deregulation of Wnt signaling can lead to cancer. Many Wnt factors employ β‐catenin as a nuclear effector. Upon Wnt stimulation, β‐catenin heterodimerizes with T‐cell factor (TCF) DNA‐binding proteins to form a transcriptional activator complex. As the activating subunit of this complex, β‐catenin performs dual tasks: it alleviates repression of target gene promoters and subsequently it activates them. β‐catenin orchestrates these effects by recruiting chromatin modifying cofactors and contacting components of the basal transcription machinery. Although β‐catenin and TCFs are universal activators in Wnt signaling, their target genes display distinct temporal and spatial expression patterns. Apparently, post‐translational modifications modulate the interactions between TCFs and β‐catenin or DNA, and certain transcription factors can sequester β‐catenin from TCFs while others synergize with β‐catenin–TCF complexes in a promoter‐specific manner. These mechanisms provide points of intersection with other signaling pathways, and contribute to the complexity and specificity of Wnt target gene regulation.
Sensory processing of water currents by fishes
Authors: Montgomery John , Carton Guy , Voigt Rainer , Baker Cindy , Diebel Carol
Published: July 2002

Water currents are extremely important in the aquatic environment and play a very significant role in the lives of fishes. Sensory processing of water currents involves a number of sensory modalities including the inner ear, vision, tactile sense and the mechanosensory lateral line. The inner ear will detect whole–body accelerations generated by changes in flow, or by turbulence, whereas visual and tactile inputs will signal translational movement with respect to an external visual or tactile reference frame. The superficial neuromasts of the mechanosensory lateral line detect flow over the surface of the body and have the appropriate anatomical distribution and physiological properties to signal the strength and the direction of flow and, hence, contribute to the detection of regional differences in flow over different parts of the body.
Basilar-membrane response to multicomponent stimuli in chinchilla
Authors: Rhode William S. , Recio Alberto
Published: July 2002

The response of chinchilla basilar membrane in the basal region of the cochlea to multicomponent (1, 3, 5, 6, or 7) stimuli was studied using a laser interferometer. Three-component stimuli were amplitude-modulated signals with modulation depths that varied from 25% to 200% and the modulation frequency varied from 100 to 2000 Hz while the carrier frequency was set to the characteristic frequency of the region under study (∼6.3 to 9 kHz). Results indicate that, for certain modulation frequencies and depths, there is enhancement of the response. Responses to five equal-amplitude sine wave stimuli indicated the occurrence of nonlinear phenomena such as spectral edge enhancement, present when the frequency spacing was less than 200 Hz, and mutual suppression. For five-component stimuli, the first, third, or fifth component was placed at the characteristic frequency and the component frequency separation was varied over a 2-kHz range. Responses to seven component stimuli were similar to those of five-component stimuli. Six-component stimuli were generated by leaving out the center component of the seven-component stimuli. In the latter case, the center component was restored in the basilar-membrane response as a result of distortion-product generation in the nonlinear cochlea.
Sources of variation in profile analysis. I. Individual differences and extended training
Authors: Drennan Ward R. , Watson Charles S.
Published: July 2002

This study investigated two sources of variance in the ability to discriminate auditory profiles: individual differences and extended training. The goals of the study were (1) to determine the range and origins of individual differences in profile analysis and (2) to determine whether those who initially had poor sensitivity to changes in spectral shape could eventually acquire finer sensitivity. Profile stimuli had 11 components with equal-log spacing from 200–2200 Hz. Thresholds ranged from −1 to −25 dB (signal level relative to the context level) across 46 listeners. The correlation between spectral-shape discrimination thresholds after 2000 trials and pure-tone intensity-discrimination thresholds was 0.36. The range of individual differences for pure-tone intensity discrimination and spectral-shape discrimination was about the same. Two groups of listeners were given extended practice on the profile task, one group that showed low thresholds after an initial 2000 trials of practice and another that showed much higher initial thresholds. All listeners improved during the course of the first 2000 trials of training. Most of the poor listeners continued to improve during 9000 trials of training. Individual differences in the listeners’ sensitivity to changes in spectral shape still existed after the extended practice.
Profile analysis with an asynchronous target: Evidence for auditory grouping
Authors: Hill Nicholas I. , Bailey Peter J.
Published: July 2002

Green and Dai [ in Auditory Physiology and Perception, edited by Y. Cazals, L. Demany, and K. Horner (Pergamon, Oxford, 1992)] reported a series of experiments which suggested that listeners’ ability to perform simultaneous across-frequency comparisons of intensity is severely impaired when the target and flanking components begin or end at different times. The present experiment sought to replicate the effect of onset asynchrony and included an additional condition in which the leading portion of the asynchronous target component was accompanied by a pair of “captor” tones. The intended purpose of the captor tones was to promote a perceptual organization in which the leading and synchronous portions of the asynchronous target component were grouped with different auditory objects. For all six listeners an asynchrony of 320 ms raised thresholds substantially relative to the synchronous onset condition, the magnitude of the increase ranging between 6 and 16 dB. By contrast, the mean elevation of threshold in the presence of the captor was only 3 dB, although for all listeners thresholds were still greater than for the synchronous onset condition. The results support the view that the deleterious effect of onset asynchrony on profile analysis performance is due to the operation of auditory grouping principles.
Perceptual differences in infant cries revealed by modifications of acoustic features
Authors: Protopapas Athanassios , Eimas Peter D.
Published: July 2002

Previous studies of infant cry acoustics and their perceptual significance have remained inconclusive as to the graded nature of cry production and perception and to the exact role and importance of particular acoustic features. In this study, a set of infant cries were digitally analyzed and resynthesized to form natural-sounding cries with varying fundamental frequency (F0), degrees of jitter (period to period variations in F0), and rise time (time for F0 to reach its maximum value). In a perceptual rating task, higher-F0 cries as well as cries with larger amounts of jitter tended to be given more negative ratings than were lower-F0 cries and cries with less jitter, respectively. The perceptual ratings of the rise time manipulations were inconclusive. This study demonstrated a perceptual effect of F0 and jitter independently of other parameters, consistent with current notions of infant cry gradedness. It was also shown that digital signal processing techniques can be fruitfully applied to infant cry research.
On possible cues in profile analysis: Identification of the incremented component
Authors: Gockel Hedwig
Published: July 2002

The ability to identify the frequency of the incremented component in a multitone complex was assessed in two conditions, both using the same 11-tone complexes (fixed frequency, equilog spaced, random phases). In the standard-plus-signal complex all components had equal level, except one of the inner nine, which was incremented in level by an in-phase addition of a sinusoid of the same frequency (the signal). The overall level and signal position were randomly varied on each presentation. In the “Standard-absent” condition the standard-plus-signal complex was presented first, and it was followed by a single sinusoid either at the signal frequency or at that of an adjacent component (below or above). In the “Standard-present” condition, a complex with equal-level components (the standard complex) was also presented on each trial, either before or after the standard-plus-signal complex (in random order). These two complexes were followed by the single sinusoid. In both conditions, the subjects had to indicate whether the signal frequency was the same as or different from the frequency of the single sinusoid. In a third condition, the ability to discriminate between the standard complex and the standard-plus-signal complex (with signal frequency uncertainty) was investigated. In all three conditions, thresholds for the increment in level for each signal frequency were estimated by the use of nine independent interleaved adaptive procedures. Results showed that the ability to identify the signal frequency was at least as good as the ability to discriminate between the two complexes. The results suggest that an increase in pitch strength of the incremented component is a possible cue in profile analysis tasks.
Adaptive road noise cancellation for a midclass estate car
Authors: Letens Uwe , Koners Gregor , Saunders Timothy J.
Published: July 2002

It is well known that estate cars (in the US called ‘‘station wagon’’) tend to be sensitive to low-frequency vibration input caused by the stochastic macrostructure of the road surface. This may result in a strong low-frequency acoustic excitation within the passenger cabin which is subjectively felt to be uncomfortable. As a feasibility study an ANC system has been installed into an experimental car. The aim was to show the potential for a reduction of the unpleasant noise. To begin, an investigation of the vibrational behavior of the chassis was performed. Within the critical frequency range there were only a few dominant principal components that could be extracted. As primary sensors for a feedforward ANC system accelerometers have been mounted at positions on the axles, giving a maximum of multiple coherence coupled with the cabin noise. A PC-based data acquisition and processing system has been used to set up the ANC system which feeds loudspeakers as secondary sources for cancellation in the cabin. Adaption is maintained by error microphones installed into the headliner of the cabin. The resultant reduction of the road noise provides a considerable enhancement in the noise comfort of the estate car.
Measurement of the stiffness coefficients of a viscoelastic composite material with laser-generated and detected ultrasound
Authors: Guilbaud S. , Audoin B.
Published: July 2002

A point source-point receiver technique, based on laser generation and laser detection of acoustic waves, is used to measure the stiffness tensor of a composite material. Because of the dispersive nature of these materials, the acoustic signature provided in polymer matrix composites is difficult to interpret. A model for acoustic propagation in composites is developed to analyze the accuracy of the stiffness coefficients determined from the measured acoustic signals. The frequency dependence associated with viscoelastic rheology leads to the numerical implementation of a double inverse transform to calculate the surface displacement generated by a line impact. The model accurately predicts the focusing effects caused by anisotropy and the spreading of the signals caused by dispersion and attenuation. The predicted displacements are in good agreement with the result of experiments performed with a composite plate. The model is used to test a signal processing method based on wavelet transform to measure the group velocities of bulk waves propagating through the plate. Despite dispersion and echoes overlapping, the stiffness coefficients are identified from group velocities with good reliability. The process is then successfully applied to an actual viscoelastic composite material.
An Evaluation of Expressions Predicting Die Swell
Authors: Vlachopoulos John , Horie Michihiko , Lidorikis Stathis
Published: July 2002

Die swell measurements for polystyrene samples of narrow molecular weight distribution and their blends have been made using a capillary viscometer. For the capillaries studied, the swelling ratios were nearly independent of L/D (length/diameter) but strongly dependent on the distribution of molecular weights. The broader the distribution, the larger the swelling ratio for the same extrusion pressure. The recoverable shear at the wall, which is defined to be half the ratio of the first normal stress difference over the shear stress, was estimated using Graessley's correlation between experimental and Rouse shear compliance. The results were compared to predictions from the theories of Nakajima and Shida, Bagley and Duffey, Graessley et al., and Tanner.
Fentanyl Overdose
Authors: Walter Kristin
Published: December 2022

This JAMA Patient Page describes fentanyl and illicit fentanyl analogues, and the common signs and symptoms of fentanyl overdose, its treatment, and overdose prevention measures.
Number Needed to Treat in Trials of Targeted Therapies for Advanced Ovarian Cancer
Authors: Bartoletti Michele , Pignata Sandro , Lorusso Domenica , Perrone Francesco , Zara Diego , Puglisi Fabio
Published: December 2022

This comparative effectiveness study assesses the numbers needed to treat in targeted trials of agents for newly diagnosed ovarian cancer.
Working hours, side work, and depressive symptoms in physicians: A nationwide cross-sectional study in Japan
Authors: Okawara Makoto , Ishimaru Tomohiro , Yoshikawa Toru , Kido Michiko , Nakashima Yoshifumi , Nakayasu Anna , Kimori Kokuto , Imamura Satoshi , Matsumoto Kichiro
Published: December 2022

Objectives

Long working hours in Japan is a social concern. This is also true for the working hours of physicians, who often do side work in addition to working at their main hospital. New physician work regulations to be implemented in Japan require work-hour management, including side work. This study examined the association between physicians' overtime and side work hours and their health outcomes.

Methods

We conducted a cross-sectional study using data from a survey of working physicians conducted by the Japan Medical Association from 2021 to 2022. Questionnaires completed by 2906 full-time working physicians aged 24–69, excluding junior resident doctors, were analyzed. Depressive symptoms and the presence of thoughts of death or suicide using the Quick Inventory of Depressive Symptomatology - Japanese version was used to assess health outcomes. Logistic regression analysis was performed using overtime at the main place of employment and side work hours as exposure factors.

Results

Both depressive symptoms and thoughts of death or suicide increased in the group with longer overtime hours at the main place of work. A similar tendency was observed for side work but adjusting for overtime hours eliminated the association. In other words, total working hours had an impact on health, regardless of whether overtime work at the main place of employment or side work.

Conclusions

Despite the existence of multiple hurdles to managing working hours, including side work, the working environment for physicians needs to be improved to protect their health and quality of medical care.
Molecular Hydration Tunes the Cation–π Interaction Strength in Aqueous Solution
Authors: Park Sohee , Lee Yongjin , Jho Yongseok , Hwang Dong Soo
Published: December 2022

Cation–π interactions are considered to be among the most important strong noncovalent interactions in aqueous solutions and as regulators of various biological phenomena, including biological adhesion, signal transduction, and liquid–liquid phase separation (LLPS). Despite their significant roles, cation–π interactions in aqueous environments are not systematically and experimentally understood. Here, we directly experimentally examined cation–π interactions between cationic and aromatic moieties common to biological systems using a surface forces apparatus (SFA) augmented by computational methods. Specifically, we chose cationic and aromatic moieties with different levels of hydration and observed how the molecular hydration of these moieties affects the formation and strengths of cation–π bonds. To date, the charge densities of the interacting moieties are primarily considered to modulate the interaction strength; however, it is experimentally and computationally revealed that the hydration strengths (or hydrophobic properties) of the interacting moieties are more important for controlling in underwater interactions.
Comparative Study between the 3D‐Liver Spheroid Models Developed from HepG2 and Immortalized Hepatocyte‐Like Cells with Primary Hepatic Stellate Coculture for Drug Metabolism Analysis and Anticancer Drug Screening
Authors: Sae‐be Arunsajee , Wiwatpanit Teerawat , Varatthan Thaveechai , Namporn Thanaphon , Laungkulldej Sasiwat , Thiabma Ratthiya , Jaiboonma Atchara , Sa‐ngiamsuntorn Khanit , Elson Daniel , Porter Alexandra E. , Sathirakul Korbtham , Hongeng Suradej , Ruenraroengsak Pakatip
Published: December 2022

Liver spheroids may be the best alternative models for evaluating efficacy and toxicity of the new anticancer candidates and diagnostics for hepatocellular carcinoma (HCC). Here, novel 3D‐liver spheroid models are constructed from human hepatoma cells (HepG2)/ immortalized human hepatocyte‐like cells (imHCs) with primary hepatic stellate cells (HSCs) coculture using the ultralow attachment technique. Spheroid morphology, HSC distribution, metabolic activity, protein expressions, and drug penetration are evaluated. All developed 3D spheroid models exhibit in spherical shape with narrow size distribution, diameter between 639–743 (HepG2‐10%HSC) and 519–631 (imHC‐10%HSC) µm. Both imHC mono and coculture models significantly express normal liver biomarkers at the higher level than HepG2 models. While 3D‐HepG2 models significantly exhibit HCC biomarkers at the higher level than imHC models. HepG2 and imHC spheroids express basal cytochrom P450 (CYP450) enzymes at different levels depending on cell types, culture period, and ratio of coculture. Their metabolic activities for dextromethorphan (CYP2D6) tolbutamide (CYP2C9) and midazolam (CYP3A4) are routinely evaluated. For midazolam metabolism, imHC models allow the detection of phase II metabolic enzymes (UGT2B4 and UGT2B7). The presence of HSC in HepG2‐HSC model increases biological barrier for doxorubicin (DOX) penetration, and escalates IC50 of DOX from 61.4 to 127.2 µg mL−1.