bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Control of Deactivation Gating by a Soluble Amino-Terminal Domain in HERG K+ Channels
Authors: Wang Jinling , Myers Cena D. , Robertson Gail A.
Published: July 2002

K+ channels encoded by the human ether-à-go-go-related gene (HERG) are distinguished from most other voltage-gated K+ channels by an unusually slow deactivation process that enables cardiac IKr, the corresponding current in ventricular cells, to contribute to the repolarization of the action potential. When the first 16 amino acids are deleted from the amino terminus of HERG, the deactivation rate is much faster (Wang, J., M.C. Trudeau, A.M. Zappia, and G.A. Robertson. 1998. J. Gen. Physiol. 112:637–647). In this study, we determined whether the first 16 amino acids comprise a functional domain capable of slowing deactivation. We also tested whether this “deactivation subdomain” slows deactivation directly by affecting channel open times or indirectly by a blocking mechanism. Using inside-out macropatches excised from Xenopus oocytes, we found that a peptide corresponding to the first 16 amino acids of HERG is sufficient to reconstitute slow deactivation to channels lacking the amino terminus. The peptide acts as a soluble domain in a rapid and readily reversible manner, reflecting a more dynamic regulation of deactivation than the slow modification observed in a previous study with a larger amino-terminal peptide fragment (Morais Cabral, J.H., A. Lee, S.L. Cohen, B.T. Chait, M. Li, and R. Mackinnon. 1998. Cell. 95:649–655). The slowing of deactivation by the peptide occurs in a dose-dependent manner, with a Hill coefficient that implies the cooperative action of at least three peptides per channel. Unlike internal TEA, which slows deactivation indirectly by blocking the channels, the peptide does not reduce current amplitude. Nor does the amino terminus interfere with the blocking effect of TEA, indicating that the amino terminus binding site is spatially distinct from the TEA binding site. Analysis of the single channel activity in cell-attached patches shows that the amino terminus significantly increases channel mean open time with no alteration of the mean closed time or the addition of nonconducting states expected from a pore block mechanism.We propose that the four amino-terminal deactivation subdomains of the tetrameric channel interact with binding sites uncovered by channel opening to specifically stabilize the open state and thus slow channel closing.
Distinct Mg2+-dependent Steps Rate Limit Opening and Closing of a Single CFTR Cl− Channel
Authors: Dousmanis Athanasios G. , Nairn Angus C. , Gadsby David C.
Published: July 2002

The roles played by ATP binding and hydrolysis in the complex mechanisms that open and close cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channels remain controversial. In this work, the contributions made by ATP and Mg2+ ions to the gating of phosphorylated cardiac CFTR channels were evaluated separately by measuring the rates of opening and closing of single channels in excised patches exposed to solutions in which [ATP] and [Mg2+] were varied independently. Channel opening was found to be rate-limited not by the binding of ATP alone, but by a Mg2+-dependent step that followed binding of both ATP and Mg2+. Once a channel had opened, sudden withdrawal of all Mg2+ and ATP could prevent it from closing for tens of seconds. But subsequent exposure of such an open channel to Mg2+ ions alone could close it, and the closing rate increased with [Mg2+] over the micromolar range (half maximal at ∼50 μM [Mg2+]). A simple interpretation is that channel closing is stoichiometrically coupled to hydrolysis of an ATP molecule that remains tightly associated with the open CFTR channel despite continuous washing. If correct, that ATP molecule appears able to reside for over a minute in the catalytic site that controls channel closing, implying that the site must entrap, or have an intrinsically high apparent affinity for, ATP, even without a Mg2+ ion. Such stabilization of the open-channel conformation of CFTR by tight binding, or occlusion, of an ATP molecule echoes the stabilization of the active conformation of a G protein by GTP.
The temperature and pressure dependence of the proton tunnelling frequency in KDP
Authors: M C Lawrence  , G N Robertson
Published: July 2002

A double-minimum potential, constructed by placing two Morse functions back to back, is used to calculate the single-particle proton energy levels in KDP. The potential well parameters are estimated from infrared and crystallographic data. The temperature and pressure dependence of the proton tunnelling frequency is computed. The soft-mode Raman scattering data of Percy (1973) are re-analysed, allowing for the temperature dependence of the tunnelling frequency and for its modulation by the oxygen-oxygen thermal motion.
Do isomorphic structural matrix rings have isomorphic graphs?
Authors: Dascalescu S. , van Wyk L.
Published: July 2002

We first provide an example of a ring

R
R

such that all possible

2
×
2

2\times 2

structural matrix rings over

R
R

are isomorphic. However, we prove that the underlying graphs of any two isomorphic structural matrix rings over a semiprime Noetherian ring are isomorphic, i.e. the underlying Boolean matrix

B
B

of a structural matrix ring

M

(
B
,
R
)

\mathbb M(B,R)

over a semiprime Noetherian ring

R
R

can be recovered, contrary to the fact that in general

R
R

cannot be recovered.
On the asymptoticity aspect of Hyers-Ulam stability of mappings
Authors: Hyers D. , Isac G. , Rassias Th.
Published: July 2002

The object of the present paper is to prove an asymptotic analogue of Th. M. Rassias’ theorem obtained in 1978 for the Hyers-Ulam stability of mappings.
Polynomials that are positive on an interval
Authors: Powers Victoria , Reznick Bruce
Published: July 2002

This paper discusses representations of polynomials that are positive on intervals of the real line. An elementary and constructive proof of the following is given: If

h
(
x
)
,
p
(
x
)
∈

R

[
x
]

h(x), p(x) \in \mathbb {R}[x]

such that

{
α
∈

R

∣
h
(
α
)
≥
0
}
=
[
−
1
,
1
]

\{ \alpha \in \mathbb {R} \mid h(\alpha ) \geq 0 \} = [-1,1]

and

p
(
x
)
>
0

p(x) > 0

on

[
−
1
,
1
]

[-1,1]

, then there exist sums of squares

s
(
x
)
,
t
(
x
)
∈

R

[
x
]

s(x), t(x) \in \mathbb {R}[x]

such that

p
(
x
)
=
s
(
x
)
+
t
(
x
)
h
(
x
)

p(x) = s(x) + t(x) h(x)

. Explicit degree bounds for

s
s

and

t
t

are given, in terms of the degrees of

p
p

and

h
h

and the location of the roots of

p
p

. This is a special case of Schmüdgen’s Theorem, and extends classical results on representations of polynomials positive on a compact interval. Polynomials positive on the non-compact interval

[
0
,
∞
)

[0,\infty )

are also considered.
Foxby duality and Gorenstein injective and projective modules
Authors: Enochs Edgar , Jenda Overtoun , Xu Jinzhong
Published: July 2002

In 1966, Auslander introduced the notion of the

G
G

-dimension of a finitely generated module over a Cohen-Macaulay noetherian ring and found the basic properties of these dimensions. His results were valid over a local Cohen-Macaulay ring admitting a dualizing module (also see Auslander and Bridger (Mem. Amer. Math. Soc., vol. 94, 1969)). Enochs and Jenda attempted to dualize the notion of

G
G

-dimensions. It seemed appropriate to call the modules with

G
G

-dimension 0 Gorenstein projective, so the basic problem was to define Gorenstein injective modules. These were defined in Math. Z. 220 (1995), 611–633 and were shown to have properties predicted by Auslander’s results. The way we define Gorenstein injective modules can be dualized, and so we can define Gorenstein projective modules (i.e. modules of

G
G

-dimension 0) whether the modules are finitely generated or not. The investigation of these modules and also Gorenstein flat modules was continued by Enochs, Jenda, Xu and Torrecillas. However, to get good results it was necessary to take the base ring Gorenstein. H.-B. Foxby introduced a duality between two full subcategories in the category of modules over a local Cohen-Macaulay ring admitting a dualizing module. He proved that the finitely generated modules in one category are precisely those of finite

G
G

-dimension. We extend this result to modules which are not necessarily finitely generated and also prove the dual result, i.e. we characterize the modules in the other class defined by Foxby. The basic result of this paper is that the two classes involved in Foxby’s duality coincide with the classes of those modules having finite Gorenstein projective and those having finite Gorenstein injective dimensions. We note that this duality then allows us to extend many of our results to the original Auslander setting.
An isometry theorem for quadratic differentials on Riemann surfaces of finite genus
Authors: Lakic Nikola
Published: July 2002

Assume both

X
X

and

Y
Y

are Riemann surfaces which are subsets of compact Riemann surfaces

X
1

X_1

and

Y
1

,

Y_1,

respectively, and that the set

X
1

−
X

X_1 - X

has infinitely many points. We show that the only surjective complex linear isometries between the spaces of integrable holomorphic quadratic differentials on

X
X

and

Y
Y

are the ones induced by conformal homeomorphisms and complex constants of modulus 1. It follows that every biholomorphic map from the Teichmüller space of

X
X

onto the Teichmüller space of

Y
Y

is induced by some quasiconformal map of

X
X

onto

Y
Y

. Consequently we can find an uncountable set of Riemann surfaces whose Teichmüller spaces are not biholomorphically equivalent.
Rotation and entropy
Authors: Geller William , Misiurewicz Michał
Published: July 2002

For a given mapf:X→Xf: X \to Xand an observableφ:X→Rd,\varphi : X \to \mathbb {R} ^{d},rotation vectors are the limits of ergodic averages ofφ.\varphi .We study which part of the topological entropy offfis associated to a given rotation vector and which part is associated with many rotation vectors. According to this distinction, we introduce directional and lost entropies. We discuss their properties in the general case and analyze them more closely for subshifts of finite type and circle maps.
Representing nonnegative homology classes of ℂℙ²#𝕟\overline{ℂℙ}² by minimal genus smooth embeddings
Authors: Li Bang-He
Published: July 2002

For any nonnegative class

ξ
\xi

in

H
2

(

C

P
2

#
n

C

P

¯

2

,

Z

)

H_2({\mathbb C}P^2\#n{\overline {{\mathbb C}P}}{}^2, {\mathbf Z})

, the minimal genus of smoothly embedded surfaces which represent

ξ
\xi

is given for

n
≤
9

n\leq 9

, and in some cases with

n
≥
10

n\geq 10

, the minimal genus is also given. For the finiteness of orbits under diffeomorphisms with minimal genus

g
g

, we prove that it is true for

n
≤
8

n\leq 8

with

g
≥
1

g\geq 1

and for

n
≤
9

n\leq 9

with

g
≥
2

g\geq 2

.
The Toda molecule equation and the 𝜖-algorithm
Authors: Nagai Atsushi , Tokihiro Tetsuji , Satsuma Junkichi
Published: July 2002

One of the well-known convergence acceleration methods, the

ε
\varepsilon

-algorithm is investigated from the viewpoint of the Toda molecule equation. It is shown that the error caused by the algorithm is evaluated by means of solutions for the equation. The acceleration algorithm based on the discrete Toda molecule equation is also presented.
A new proof of D. Popescu’s theorem on smoothing of ring homomorphisms
Authors: Spivakovsky Mark
Published: July 2002

We give a new proof of D. Popescu’s theorem which says that if

σ
:
A
→
B

\sigma :A\rightarrow B

is a regular homomorphism of noetherian rings, then

B
B

is a filtered inductive limit of smooth finite type

A
A

-algebras. We strengthen Popescu’s theorem in two ways. First, we show that a finite type

A
A

-algebra

C
C

, mapping to

B
B

, has a desingularization

C
→
D

C\rightarrow D

which is smooth wherever possible (roughly speaking, above the smooth locus of

C
C

). Secondly, we give sufficient conditions for

B
B

to be a filtered inductive limit of its smooth finite type

A
A

-subalgebras. We also give counterexamples to the latter statement in cases when our sufficient conditions do not hold.
Regulation of Protein Transport from the Golgi Complex to the Endoplasmic Reticulum by CDC42 and N-WASP
Authors: Luna Ana , Matas Olga B. , Martı́nez-Menárguez José Angel , Mato Eugenia , Durán Juan M. , Ballesta José , Way Michael , Egea Gustavo
Published: July 2002

Actin is involved in the organization of the Golgi complex and Golgi-to-ER protein transport in mammalian cells. Little, however, is known about the regulation of the Golgi-associated actin cytoskeleton. We provide evidence that Cdc42, a small GTPase that regulates actin dynamics, controls Golgi-to-ER protein transport. We located GFP-Cdc42 in the lateral portions of Golgi cisternae and in COPI-coated and noncoated Golgi-associated transport intermediates. Overexpression of Cdc42 and its activated form Cdc42V12 inhibited the retrograde transport of Shiga toxin from the Golgi complex to the ER, the redistribution of the KDEL receptor, and the ER accumulation of Golgi-resident proteins induced by the active GTP-bound mutant of Sar1 (Sar1[H79G]). Coexpression of wild-type or activated Cdc42 and N-WASP also inhibited Golgi-to-ER transport, but this was not the case in cells expressing Cdc42V12 and N-WASP(ΔWA), a mutant form of N-WASP that lacks Arp2/3 binding. Furthermore, Cdc42V12 recruited GFP-N-WASP to the Golgi complex. We therefore conclude that Cdc42 regulates Golgi-to-ER protein transport in an N-WASP–dependent manner.
Yeast Vps55p, a Functional Homolog of Human Obesity Receptor Gene-related Protein, Is Involved in Late Endosome to Vacuole Trafficking
Authors: Belgareh-Touzé Naı̈ma , Avaro Sandrine , Rouillé Yves , Hoflack Bernard , Haguenauer-Tsapis Rosine
Published: July 2002

The Saccharomyces cerevisiae VPS55(YJR044c) gene encodes a small protein of 140 amino acids with four potential transmembrane domains. VPS55belongs to a family of genes of unknown function, including the human gene encoding the obesity receptor gene-related protein (OB-RGRP). Yeast cells with a disrupted VPS55 present normal vacuolar morphology, but exhibit an abnormal secretion of the Golgi form of the soluble vacuolar carboxypeptidase Y. However, trafficking of the membrane-bound vacuolar alkaline phosphatase remains normal. The endocytosis of uracil permease, used as an endocytic marker, is normal in vps55Δ cells, but its degradation is delayed and this marker transiently accumulates in late endosomal compartments. We also found that Vps55p is mainly localized in the late endosomes. Collectively, these results indicate that Vps55p is involved in late endosome to vacuole trafficking. Finally, we show that human OB-RGRP displays the same distribution as Vps55p and corrects the phenotypic defects of the vps55Δ strain. Therefore, the function of Vps55p has been conserved throughout evolution. This study highlights the importance of the multispanning Vps55p and OB-RGRP in membrane trafficking to the vacuole/lysosome of eukaryotic cells.
Reduced space hidden Markov model training.
Authors: Tarnas C , Hughey R
Published: July 2002

MOTIVATION: Complete forward-backward (Baum-Welch) hidden Markov model training cannot take advantage of the linear space, divide-and-conquer sequence alignment algorithms because of the examination of all possible paths rather than the single best path. RESULTS: This paper discusses the implementation and performance of checkpoint-based reduced space sequence alignment in the SAM hidden Markov modeling package. Implementation of the checkpoint algorithm reduced memory usage from O(mn) to O (m square root n) with only a 10% slowdown for small m and n, and vast speed-up for the larger values, such as m = n = 2000, that cause excessive paging on a 96 Mbyte workstation. The results are applicable to other types of dynamic programming. AVAILABILITY: A World-Wide Web server, as well as information on obtaining the Sequence Alignment and Modeling (SAM) software suite, can be found at http://www.cse.ucsc. edu/research/compbio/sam.html. CONTACT: rph@cse.ucsc.edu
Frequency-domain analysis of biomolecular sequences
Authors: Anastassiou Dimitris
Published: July 2002

Motivation: Frequency-domain analysis of biomolecular sequences is hindered by their representation as strings of characters. If numerical values are assigned to each of these characters, then the resulting numerical sequences are readily amenable to digital signal processing.

Results: We introduce new computational and visual tools for biomolecular sequences analysis. In particular, we provide an optimization procedure improving upon traditional Fourier analysis performance in distinguishing coding from noncoding regions in DNA sequences. We also show that the phase of a properly defined Fourier transform is a powerful predictor of the reading frame of protein coding regions. Resulting color maps help in visually identifying not only the existence of protein coding areas for both DNA strands, but also the coding direction and the reading frame for each of the exons. Furthermore, we demonstrate that color spectrograms can visually provide, in the form of local ‘texture’, significant information about biomolecular sequences, thus facilitating understanding of local nature, structure and function.

Availability: All software for techniques described in this paper is available from the author upon request.

Contact: anastas@ee.columbia.edu
Gene recognition in eukaryotic DNA by comparison of genomic
sequences
Authors: Novichkov P. S. , Gelfand M. S. , Mironov A. A.
Published: July 2002

Motivation: Sequencing of complete eukaryotic genomes and large syntenic fragments of genomes makes it possible to apply genomic comparison for gene recognition.

Results: This paper describes a spliced alignment algorithm that aligns candidate exon chains of two homologous genomic sequence fragments from different species. The algorithm is implemented in Pro-Gen software. Unlike other algorithms, Pro-Gen does not assume conservation of the exon–intron structure. Amino acid sequences obtained by the formal translation of candidate exons are aligned instead of nucleotide sequences, which allows for distant comparisons. The algorithm was tested on a sample of human–mammal (mouse), human–vertebrate (Xenopus ) and human–invertebrate (Drosophila ) gene pairs. Surprisingly, the best results, 97–98% correlation between the actual and predicted genes, were obtained for more distant comparisons, whereas the correlation on the human–mouse sample was only 93%. The latter value increases to 95% if conservation of the exon–intron structure is assumed. This is caused by a large amount of sequence conservation in non-coding regions of the human and mouse genes probably due to regulatory elements.

Availaility: Pro-Gen v. 3.0 is available to academic researchers free of charge at http://www.anchorgen.com/pro_gen/pro_gen.html.

Contact: misha@imb.imb.ac.ru

* To whom correspondence should be addressed.
MRBAYES: Bayesian inference of phylogenetic trees
Authors: Huelsenbeck John P. , Ronquist Fredrik
Published: July 2002

Summary: The program MRBAYES performs Bayesian inference of phylogeny using a variant of Markov chain Monte Carlo.

Availability: MRBAYES, including the source code, documentation, sample data files, and an executable, is available at http://brahms.biology.rochester.edu/software.html.

Contact: johnh@brahms.biology.rochester.edu
A MODEL OF GROWTH AND CONVERGENCE IN THE PRESENCE OF INPUT‐ENHANCING FACTORS: AN EMPIRICAL STUDY
Authors: Panik Michael J. , Rassekh Farhad
Published: July 2002

We introduce and estimate a growth model involving non‐neutral technical change characterized by the presence of input‐enhancing factors that vary across countries and serve to offset (and potentially eliminate) diminishing returns to capital. Our empirical results, however, indicate that diminishing returns to capital proves too strong to be overcome by, say, capital‐enhancing factors. Consequently, our model predicts a conditional convergence of output per worker across countries, with the speed of convergence being slower than that found in earlier models involving neutral technical change.
Novel critical role of a human Mediator complex for basal RNA polymerase II transcription
Authors: Mittler Gerhard , Kremmer Elisabeth , Timmers H Th. Marc , Meisterernst Michael
Published: July 2002

Human Mediator complexes have been described as important bridging factors that enhance the effect of activators in purified systems and in chromatin. Here we report a novel basal function of a human Mediator complex. A monoclonal antibody was generated that depleted the majority of Mediator components from crude cell extracts. The removal of human Mediator abolished transcription by RNA polymerase II. This was observed on all genes tested, on TATA‐containing and TATA‐less promoters, both in the presence and absence of activators. To identify the relevant complex a combined biochemical and immunopurification protocol was applied. Two variants termed Mediator and basal Mediator were functionally and structurally distinguished. Basal Mediator function relies on additional constraints, which is reflected in the observation that it is essential in crude but not in purified systems. We conclude that basal Mediator is a novel general transcription factor of RNA polymerase II.
A Toc75‐like protein import channel is abundant in chloroplasts
Authors: Eckart Kerstin , Eichacker Lutz , Sohrt Karen , Schleiff Enrico , Heins Lisa , Soll Jürgen
Published: July 2002

Chloroplasts import post‐translationally most of their constituent polypeptides via two distinct translocon units located in the outer and inner envelope. The protein import channel of the translocon of the outer envelope of chloroplasts, Toc75, is the most abundant protein in that membrane. We identify a novel Toc75 homologous protein, atToc75‐V, a prominent protein that is clearly localized in the chloroplastic outer envelope. Phylogenetic analysis indicates that Toc75‐V is more closely related to its prokaryotic ancestors than to Toc75 from plants. The presence of a second translocation channel suggests that alternative, previously unrecognized import routes into chloroplasts might exist.
Gender and Business History
Authors: Kwolek-Folland Angel
Published: July 2002

In response to an invitation from the editor of Enterprise & Society, last year David Sicilia and I put out a call for papers for a special issue of the journal that would focus on gender and business history. The call elicited twenty-five submissions, an impressive array of scholarship from authors who addressed the subject from a range of theoretical and disciplinary approaches. From these submissions, we chose the four articles that appear in this volume and three others that will be published in the next issue of Enterprise & Society (June 2001). We made our final selections on the basis of thematic, national, and organizational representativeness and on the ways in which the articles complemented each other and revealed aspects of the “state of the field.” Let me thank the more than fifty referees who generously read and commented anonymously on the original submissions. I enjoyed working with them, with the authors, and with David in this communal endeavor.
Human respiratory syncytial virus vaccine antigen produced in plants
Authors: Belanger Helene , Fleysh Nina , Cox Shannon , Hartman Greg , Deka Deepali , Trudel Michel , Koprowski Hilary , Yusibov Vidadi
Published: July 2002

Human respiratory syncytial virus (RSV) is the primary cause of respiratory infection in infants worldwide. Currently there is no available vaccine, although studies in animal models have demonstrated protective immunity induced by an epitope of the RSV G‐protein representing amino acids 174–187. Two peptides containing amino acids 174–187 of the G‐protein of the human RSV A2 strain (NF1‐RSV/172–187 and NF2‐RSV/170–191) were separately engineered as translational fusions with the alfalfa mosaic virus coat protein and individually expressed in Nicotiana tabacum cv. Samsun NN plants through virus infection. RSV G‐protein peptides were expressed in infected plant tissues at significant levels within 2 wk of inoculation and purified as part of recombinant alfalfa mosaic virions. BALB/c mice immunized intraperitoneally with three doses of the purified recombinant viruses showed high levels of serum antibody specific for RSV G‐protein and were protected against infection with RSV Long strain.—Belanger, H., Fleysh, N., Cox, S., Bartman, G., Deka, D., Trudel, M., Koprowski, H., Yusibov, V. Human respiratory syncytial virus vaccine antigen produced in plants. FASEB J. 14, 2323–2328 (2000)
Physiological temperature regulation by flowers of the sacred lotus
Authors: Seymour Roger S. , Schultze–Motel Paul
Published: July 2002

Flowers of the sacred lotus,Nelumbo nuciferaGaertn. (Nelumbonaceae) are thermogenic and physiologically thermoregulatory. The 42 g flowers remain between 30–36°C during a 2 to 4–day period despite fluctuations in environmental temperatures between about 10–45°C. As the ambient temperature drops, the flowers increase heat production in proportion. Temperature regulation apparently occurs at a cellular level, by a steep, reversible thermal inhibition of respiration at flower temperatures above 30°C. There was a marked time lag between change in flower temperature and compensatory response, suggesting regulation through a biochemical feedback mechanism rather than structural changes in enzymes or membranes. By oxidizing carbohydrate, the flowers produce up to 1 W, with about half of the heat coming from the 8.5 g carpellary receptacle. The period of temperature regulation begins before petal opening and continues through the period of stigma receptivity. Temperature regulation may reward insect pollinators with a warm, equable environment, or it possibly enhances and coordinates flower development.
New information about the skull and dentary of the Miocene platypusObdurodon dicksoni, and a discussion of ornithorhynchid relationships
Authors: Musser A. M. , Archer M.
Published: July 2002

A reconstruction of the skull, dentary and dentition of the middle Miocene ornithorhynchidObdurodon dicksonihas been made possible by acquisition of nearly complete cranial and dental material. Access to new anatomical work on the living platypus,Ornithorhynchus anatinus, and the present comparative study of the cranial foramina ofOb. dicksoniandOr. anatinushave provided new insights into the evolution of the ornithorhynchid skull. The hypertrophied bill inOb. dicksoniis seen here as possibly apomorphic, although evidence from ontogenetic studies ofOr. anatinussuggests that the basic form of the bill inOb. dicksoni(where the rostral crura meet at the midline) may be ancestral to the form of the bill inOr. anatinus(where the rostral crura meet at the midline in the embryonic platypus but diverge in the adult). Differences in the relative positions of cranial structures, and in the relationships of certain cranial foramina, indicate that the cranium may have become secondarily shortened inOr. anatinus, possibly evolving from a more elongate skull type such as that ofOb. dicksoni. The plesiomorphic dentary ofOb. dicksoni, with well–developed coronoid and angular processes, contrasts with the dentary ofOr. anatinus, in which the processes are almost vestigial, as well as with the dentary of the late Oligocene, congenericOb. insignis, in which the angular process appears to be reduced (the coronoid process is missing). In this regard the dentary ofOb. insignisseems to be morphologically closer toOr. anatinusthan is the dentary of the youngerOb. dicksoni. Phylogenetic conclusions differ from previous analyses in viewing the northern AustralianOb. dicksonias possibly derived in possessing a hypertrophied bill and dorsoventrally flattened skull and dentary, perhaps being a specialized branch of theObdurodonline rather than ancestral to species ofOrnithorhynchus. The presence of functional teeth and the robust, flattened skull and dentary inOb. dicksoniargue for differences in diet and lifestyle between this extinct ornithorhynchid and the livingOrnithorhynchus.
Diurnal activity in the Samoan flying fox, Pteropus samoensis
Authors: Thomson S. C. , Brooke A. P. , Speakman J. R.
Published: July 2002

Speakman and co–workers suggested the diurnal Samoan flying fox,Pteropus samoensis, may be at risk of hyperthermia when flying during the day, particularly at high levels of insolation. We monitored activity of this bat and climate simultaneously at two different sites and four times of year in American Samoa. Flight activity varied significantly with time of day, between days, study sites and seasons. Out of the six data sets collected, the four with the highest mean levels of insolation showed a significant decrease in bat numbers with increasing temperature and sunlight. When each individual activity count was directly compared to the predictions of Speakman and co–workers' biophysical model, 85 to 95% of bat flight activity was found to be in conditions the model suggested would not pose a risk of hyperthermia. This supports the suggestion that in extreme conditions the animals would not fly as they risked overheating. The 5 to 15% of counts in which animals were seen to fly in conditions the model predicted they should not may be explained by erroneous assumptions underlying the model predictions.
On immunological memory
Authors: Zinkernagel Rolf M.
Published: July 2002

Immunological memory may not represent a special characteristic of lymphocytes but simply reflect lowlevel responses driven by antigen that is re–encountered or persists within the host. T–cell memory is important to control persistent infections within the individual host and cannot be transmitted to offspring because of MHC polymorphism and MHC–restricted T–cell recognition. In contrast, antibody memory is transmissible from mother to offspring and may function essentially to protect offspring during the phase of physiological immuno–incompetence before, at and shortly after birth. This physiological immuno–incompetence is a result of MHC polymorphism and the dangers of the graft–versus–host and host–versus–graft reaction between mother and embryo, which necessitate immunosuppression of the mother and immuno–incompetence of the offspring. One may argue therefore that immunological memory of transmissible immunological experience is the basis on which MHC–restricted T–cell recognition could develop or coevolve.
Fruits, foliage and the evolution of primate colour vision
Authors: Regan B. C. , Julliot C. , Simmen B. , Viénot F. , Charles–Dominique P. , Mollon J. D.
Published: July 2002

Primates are apparently unique amongst the mammals in possessing trichromatic colour vision. However, not all primates are trichromatic. Amongst the haplorhine (higher) primates, the catarrhines possess uniformly trichromatic colour vision, whereas most of the platyrrhine species exhibit polymorphic colour vision, with a variety of dichromatic and trichromatic phenotypes within the population.

It has been suggested that trichromacy in primates and the reflectance functions of certain tropical fruits are aspects of a coevolved seed–dispersal system: primate colour vision has been shaped by the need to find coloured fruits amongst foliage, and the fruits themselves have evolved to be salient to primates and so secure dissemination of their seeds. We review the evidence for and against this hypothesis and we report an empirical test: we show that the spectral positioning of the cone pigments found in trichromatic South American primates is well matched to the task of detecting fruits against a background of leaves. We further report that particular trichromatic platyrrhine phenotypes may be better suited than others to foraging for particular fruits under particular conditions of illumination; and we discuss possible explanations for the maintenance of polymorphic colour vision amongst the platyrrhines.
Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis
Authors: de Graaff Esther , Srinivas Shankar , Kilkenny Carol , D'Agati Vivette , Mankoo Baljinder S. , Costantini Frank , Pachnis Vassilis
Published: July 2002

The RET receptor tyrosine kinase has a critical role in kidney organogenesis and the development of the enteric nervous system. Two major isoforms, RET9 and RET51, differ in the amino acid sequence of the C-terminal tail as a result of alternative splicing. To determine the roles of these isoforms in vivo, we used targeted mutagenesis to generate mice that express either RET9 or RET51. Monoisoformic RET9 mice, which lack RET51, are viable and appear normal. In contrast, monoisoformic RET51 animals, which lack RET9, have kidney hypodysplasia and lack enteric ganglia from the colon. To study the differential activities of the two RET isoforms further, we generated transgenic mice expressing ligand-dependent and constitutively active forms of RET9 or RET51 under the control of the Hoxb7 regulatory sequences. Such RET9 transgenes are capable of rescuing the kidney agenesis in RET-deficient mice or causing kidney hypodysplasia in wild-type animals. In contrast, similar RET51 transgenes fail to rescue the kidney agenesis or cause hypodysplasia. Our findings show that RET9 and RET51 have different signaling properties in vivo and define specific temporal and spatial requirements of c-Ret function during renal development and histogenesis of the enteric nervous system.
SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation
Authors: Matsuda Morihiro , Korn Bobby S. , Hammer Robert E. , Moon Young-Ah , Komuro Ryutaro , Horton Jay D. , Goldstein Joseph L. , Brown Michael S. , Shimomura Iichiro
Published: July 2002

In liver, the synthesis of cholesterol and fatty acids increases in response to cholesterol deprivation and insulin elevation, respectively. This regulatory mechanism underlies the adaptation to cholesterol synthesis inhibitors (statins) and high calorie diets (insulin). In nonhepatic cells, lipid synthesis is controlled by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose active domains are released proteolytically to enter the nucleus and activate genes involved in the synthesis and uptake of cholesterol and fatty acids. SCAP (SREBP cleavage-activating protein) is a sterol-regulated escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of cleavage in the Golgi. Here, we produced a conditional deficiency of SCAP in mouse liver by genomic recombination mediated by inducible Cre recombinase. SCAP-deficient mice showed an 80% reduction in basal rates of cholesterol and fatty acid synthesis in liver, owing to decreases in mRNAs encoding multiple biosynthetic enzymes. Moreover, these mRNAs failed to increase normally in response to cholesterol deprivation produced by a cholesterol synthesis inhibitor and to insulin elevation produced by a fasting–refeeding protocol. These data provide in vivo evidence that SCAP and the SREBPs are required for hepatic lipid synthesis under basal and adaptive conditions.
A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19ARF–p53 signaling
Authors: Shvarts Avi , Brummelkamp Thijn R. , Scheeren Ferenc , Koh Eugene , Daley George Q. , Spits Hergen , Bernards René
Published: July 2002

Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries, we identify BCL6 as a potent inhibitor of senescence.BCL6 is frequently activated in non-Hodgkin's lymphoma, but its mechanism of action has remained unclear. BCL6 efficiently immortalizes primary mouse embryonic fibroblasts and cooperates with RAS in oncogenic transformation. BCL6 overrides the senescence response downstream of p53 through a process that requires induction ofcyclin D1 expression, as cyclin D1 knockout fibroblasts are specifically resistant to BCL6 immortalization. We show that BCL6 expression also dramatically extends the replicative lifespan of primary human B cells in culture and induces cyclin D1 expression, indicating that BCL6 has a similar activity in lymphoid cells. Our results suggest that BCL6 contributes to oncogenesis by rendering cells unresponsive to antiproliferative signals from the p19ARF–p53 pathway.
Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer
Authors: Charité Jeroen , McFadden David G. , Merlo Giorgio , Levi Giovanni , Clouthier David E. , Yanagisawa Masashi , Richardson James A. , Olson Eric N.
Published: July 2002

Neural crest cells play a key role in craniofacial development. The endothelin family of secreted polypeptides regulates development of several neural crest sublineages, including the branchial arch neural crest. The basic helix–loop–helix transcription factor dHAND is also required for craniofacial development, and in endothelin-1(ET-1) mutant embryos, dHAND expression in the branchial arches is down-regulated, implicating it as a transcriptional effector of ET-1 action. To determine the mechanism that links ET-1 signaling to dHAND transcription, we analyzed the dHANDgene for cis-regulatory elements that control transcription in the branchial arches. We describe an evolutionarily conserveddHAND enhancer that requires ET-1 signaling for activity. This enhancer contains four homeodomain binding sites that are required for branchial arch expression. By comparing protein binding to these sites in branchial arch extracts from endothelin receptor A(EdnrA) mutant and wild-type mouse embryos, we identified Dlx6, a member of the Distal-less family of homeodomain proteins, as an ET-1-dependent binding factor. Consistent with this conclusion,Dlx6 was down-regulated in branchial arches from EdnrAmutant mice. These results suggest that Dlx6 acts as an intermediary between ET-1 signaling and dHAND transcription during craniofacial morphogenesis.
Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis
Authors: Weinmann Amy S. , Yan Pearlly S. , Oberley Matthew J. , Huang Tim Hui-Ming , Farnham Peggy J.
Published: July 2002

Previously, identification of promoters regulated by mammalian transcription factors has relied upon overexpression studies. Here we present the identification of a large set of promoters that are bound by E2F in physiological conditions. Probing a human CpG microarray with chromatin immunoprecipitated using an antibody to E2F4, we have identified 68 unique target loci; 15% are bidirectional promoters and 25% recruit E2F via a mechanism distinct from the defined consensus site. Interestingly, although E2F has been shown previously to regulate genes involved in cell cycle progression, many of the new E2F target genes encode proteins involved in DNA repair or recombination. We suggest that human CpG microarrays, in combination with chromatin immunoprecipitation, will allow rapid identification of target promoters for many mammalian transcription factors.
Polyproline II helical structure in protein unfolded states: Lysine peptides revisited
Authors: Rucker Adam L. , Creamer Trevor P.
Published: July 2002

The left‐handed polyproline II (PPII) helix gives rise to a circular dichroism spectrum that is remarkably similar to that of unfolded proteins. This similarity has been used as the basis for the hypothesis that unfolded proteins possess considerable PPII helical content. It has long been known that homopolymers of lysine adopt the PPII helical conformation at neutral pH, presumably a result of electrostatic repulsion between side chains. It is shown here that a seven‐residue lysine peptide also adopts the PPII conformation. In contrast with homopolymers of lysine, this short peptide is shown to retain PPII helical character under conditions in which side‐chain charges are heavily screened or even neutralized. The most plausible explanation for these observations is that the peptide backbone favors the PPII conformation to maximize favorable interactions with solvent. These data are evidence that unfolded proteins do indeed possess PPII content, indicating that the ensemble of unfolded states is significantly smaller than is commonly assumed.
Mercurial sensitivity of aquaporin 1 endofacial loop B residues
Authors: Kuang Kunyan , Haller Jorge F. , Shi Guangpu , Kang Fengying , Cheung Min , Iserovich Pavel , Fischbarg Jorge
Published: July 2002

The water channel protein aquaporin‐1 (AQP1) has two asparagine‐proline‐alanine (NPA) repeats on loops B and E. From recent structural information, these loops are on opposite sides of the membrane and meet to form a pore. We replaced the mercury‐sensitive residue cysteine 189 in AQP1 by serine to obtain a mercury‐insensitive template (C189S). Subsequently, we substituted three consecutive cysteines for residues 71–73 near the first NPA repeat (76–78) in intracellular loop B, and investigated whether they were accessible to extracellular mercurials. AQP1 and its mutants were expressed in Xenopus laevis oocytes, and the osmotic permeability (Pf) of the oocytes was determined. C189S had wild‐type Pf but was not sensitive to HgCl2. Expression of all three C189S cysteine mutants resulted in increased Pf, and all three mutants regained mercurial sensitivity. These results, especially the inhibitions by the large mercurial p‐chloromercunbenzene‐sulfonic acid (pCMBS) (∼6Å wide), suggest that residues 71–73 at the pore are accessible to extracellular mercurials. A 30‐ps molecular dynamics simulation (at 300 K) starting with crystallographic coordinates of AQP1 showed that the width of the pore bottleneck (between Connolly surfaces) can vary (wavg = 3.9 Å, σ = 0.75; hydrated AQP1). Thus, although the pore width would be ≥ 6 Å only for 0.0026 of the time, this might suffice for pCMBS to reach residues 71–73. Alternative explanations such as passage of pCMBS across the AQP1 tetramer center or other unspecified transmembrane pathways cannot be excluded.
How common is the funnel‐like energy landscape in protein‐protein interactions?
Authors: Tovchigrechko Andrei , Vakser Ilya A.
Published: July 2002

The goal of this study is to verify the concept of the funnel‐like intermolecular energy landscape in protein–protein interactions by use of a series of computational experiments. Our preliminary analysis revealed the existence of the funnel in many protein–protein interactions. However, because of the uncertainties in the modeling of these interactions and the ambiguity of the analysis procedures, the detection of the funnels requires detailed quantitative approaches to the energy landscape analysis. A number of such approaches are presented in this study. We show that the funnel detection problem is equivalent to a problem of distinguishing between distributions of low‐energy intermolecular matches in the funnel and in the low‐frequency landscape fluctuations. If the fluctuations are random, the decision about whether the minimum is the funnel is equivalent to determining whether this minimum is significantly different from a would‐be random one. A database of 475 nonredundant cocrystallized protein–protein complexes was used to re‐dock the proteins by use of smoothed potentials. To detect the funnel, we developed a set of sophisticated models of random matches. The funnel was considered detected if the binding area was more populated by the low‐energy docking predictions than by the matches generated in the random models. The number of funnels detected by use of different random models varied significantly. However, the results confirmed that the funnel may be the general feature in protein–protein association.
Molecular design of Mycoplasma hominis Vaa adhesin
Authors: Boesen Thomas , Fedosova Natalya U. , Kjeldgaard Morten , Birkelund Svend , Christiansen Gunna
Published: July 2002

The variable adherence‐associated (Vaa) adhesin of the opportunistic human pathogen Mycoplasma hominis is a surface‐exposed, membrane‐associated protein involved in the attachment of the bacterium to host cells. The molecular masses of recombinant 1 and 2 cassette forms of the protein determined by a light‐scattering (LS) method were 23.9 kD and 36.5 kD, respectively, and corresponded to their monomeric forms. Circular dichroism (CD) spectroscopy of the full‐length forms indicated that the Vaa protein has an α‐helical content of ∼80%. Sequence analysis indicates the presence of coiled‐coil domains in both the conserved N‐terminal and antigenic variable C‐terminal part of the Vaa adhesin. Experimental results obtained with recombinant proteins corresponding to the N‐ or C‐terminal parts of the shortest one‐cassette form of the protein were consistent with the hypothesis of two distinct coiled‐coil regions. The one‐cassette Vaa monomer appears to be an elongated protein with a axial shape ratio of 1:10. Analysis of a two‐cassette Vaa type reveals a similar axial shape ratio. The results are interpreted in terms of the topological organization of the Vaa protein indicating the localization of the adherence‐mediating structure.
Evaluation of a cassette‐screen‐film combination for radiation therapy portal localization imaging with improved contrast
Authors: Haus Arthur G. , Dickerson Robert E. , Huff Kenneth E. , Monte Suzanne , Schlager Barbara A. , Atanas Meri , Matloubieh Ahmad
Published: July 2002

A traditional limitation with radiation therapy portal images is low image contrast, due in part to the low attenuation of the exposing radiation by the tissues being imaged, and the contrast capabilities of the image receptor. We have developed, and have clinically evaluated, a cassette‐screen‐film combination for portal localization imaging, which features a copper front screen plus fluorescent screens and a slow‐speed, fine grain, film emulsion with inherently high contrast coated on both sides of a 7 mil Estar base. The film can be processed in a conventional rapid‐process film processor. Sensitometric data indicate that the film contrast (average gradient) for the new combination is approximately 3.5 times higher than the conventional portal localization systems in current use. The new combination has been clinically compared with two conventional systems. The required monitor unit settings were found to be similar. Initial clinical results indicate portal images made with the new combination are superior to those obtained with the conventional combinations. The images have much higher contrast, subjective impressions of lower noise, show clearer definition of structures, and are much easier to read.