bluuebunny/crossref_metadata_2025 huggingface dataset:
replication or monopoly? the economies of invention and discovery in galileo's observations of 1610
Authors: biagioli mario
Published: October 2005

i propose a revisionist account of the production and reception of galileo's telescopic observations of 1609–10, an account that focuses on the relationship between credit and disclosure. galileo, i argue, acted as though the corroboration of his observations were easy, not difficult. his primary worry was not that some people might reject his claims, but rather that those able to replicate them could too easily proceed to make further discoveries on their own and deprive him of credit. consequently, he tried to slow down potential replicators to prevent them from becoming competitors. he did so by not providing other practitioners access to high-power telescopes and by withholding information about how to build them. this essay looks at the development of galileo's monopoly on early telescopic astronomy to understand how the relationship between disclosure and credit changed as he moved from being an instrument-maker to becoming a discoverer and, eventually, a court philosopher.
a forgotten controversy introductory note to the appendix
Authors: renn jürgen
Published: October 2005

more than a century ago three eminent galileo scholars, raffaello caverni, antonio favaro, and emil wohlwill, discussed the emergence of galileo's science of motion and the documentary evidence pertaining to it. among the works of these scholars, only favaro's edizione nazionale of galileo's works is still widely used, while the contents of their other writings only play a minor if any role in the current english-speaking literature. the disappearance from historical memory of many of the substantial contributions by these authors is closely associated with a narrowing of the perspective under which galileo's science and its context have been discussed in more recent scholarship.
an excerpt from history of the experimental method in italy
Authors: caverni raffaello
Published: October 2005

we consider this merit, however, to have almost no value in comparison to one which we wish to acquire from the offended worshippers of galileo. we announce to them that after having identified and reordered the scattered writings which complete the sixth dialogue as far as percussion is concerned, we were also able to reintegrate the dialogue with regard to the use of a little chain to provide a rule for aiming artillery, without having to resort to laborious calculations.
apocryphal galilean writings
Authors: favaro antonio
Published: October 2005

the historians of science have only recently learned of the existence of a sixth volume of the grandly conceived work of the abbé raffaello caverni entitled storia del metodo sperimentale in italia. five volumes had already been published between 1891 and 1898. the sixth volume was published, one might say, in an almost furtive way. in fact, the first notice of it was given in a journal by aldo mieli just a few months ago. among materials he is collecting under the heading, “for a biography of the italian historians of science,” in addition to other things already said about caverni in a previous issue, mieli has published the following “information received from g. vacca”: “the printing of the sixth volume of the history of the experimental method in italy dealing with the history of hydraulics had been started but was interrupted by the author's death. about 450 pages have been printed, the greater part of the copies of the loose sheets have been lost.”
Meeting Basic Needs? Forced Migrants and Welfare
Authors: Dwyer Peter , Brown David
Published: October 2005

As the number of forced migrants entering Britain has risen, increasingly restrictive immigration and asylum policy has been introduced. Simultaneously, successive governments have sought to limit the welfare entitlements of forced migrants. Drawing on two sets of semi-structured qualitative interviews, with migrants and key respondents providing welfare services, this paper considers the adequacy of welfare provisions in relation to the financial and housing needs of four different groups of forced migrants i.e. refugees, asylum seekers, those with humanitarian protection status and failed asylum seekers/‘overstayers’. There is strong evidence to suggest that statutory provisions are failing to meet the basic financial and housing needs of many forced migrants.
‘Frozen Landscapes’ Revisited: Path Creation in the European Social Model
Authors: Lessenich Stephan
Published: October 2005

The institutional paralysis of Continental European social policy has become common wisdom in comparative welfare state research. The article seeks to challenge the all too simplistic picture of an inherently immovable and inflexible ‘conservative’ world of welfare capitalism. In confronting ‘path dependence’ theory with the concept of ‘path creation’, it is argued that there are – typically inconspicuous or even hidden – paths out of ‘path dependence’ precisely in those welfare states that most obviously embody the institutional heritage of what may be called the ‘European Social Model’. The fundamental ambivalence of Continental European welfare state institutions opens a permanent window of opportunity for ‘institutional entrepreneurs’ pursuing welfare state change. A short account of the recent transformation of social insurance institutions in Germany is presented as a first illustration of this thesis.
Policy Transfer and the Internationalisation of Social Policy
Authors: Hulme Rob
Published: October 2005

This article analyses the theoretical utility of policy transfer in developing perspectives on international and comparative social policy. It argues that existing work on policy transfer provides us with a theoretical tool to connect perspectives on international policy change, by focussing on the knowledge base of policy and the motivations of actors throughout the policy process from the global level to the context of practice. In doing so, it explores the role of epistemic communities in policy-oriented learning, particularly in education. The article concludes by suggesting four areas for future work on transfer which would serve to advance international policy analysis.
A simple setup for the study of microvolume frozen samples using Raman spectroscopy
Authors: Kriek Marco , Neylon Cameron , Roach Peter L. , Clark Ian P. , Parker Anthony W.
Published: October 2005

A method for obtaining resonance Raman spectra from microvolume (2–5μl) frozen samples is described. The procedure involves trapping and freezing a microdroplet in a specially designed sample holder using a cryostream. The method makes it possible to prepare numerous low-volume air-sensitive samples in a suitable environment for spectroscopic studies. We have demonstrated the potential of the setup measuring the resonance Raman spectra of 4-thiouracil and horse heart myoglobin.
Close-coupling study of rotational energy transfer of CO (υ=2) by collisions with He atoms
Authors: Yang Benhui , Stancil P. C. , Balakrishnan N. , Forrey R. C.
Published: October 2005

Quantum close-coupling scattering calculations of rotational energy transfer in the vibrationally excited CO due to collisions with He atom are presented for collision energies between 10−5 and ∼1000cm−1 with CO being initially in the vibrational level υ=2 and rotational levels j=0,1,4, and 6. The He–CO interaction potential of Heijmen et al. [J. Chem. Phys. 107, 9921 (1997)] was adopted for the calculations. Cross sections for rovibrational transitions and state-to-state rotational energy transfer from selected initial rotational levels were computed and compared with recent measurements of Carty et al. [J. Chem. Phys. 121, 4671 (2004)] and available theoretical results. Comparison in all cases is found to be excellent, providing a stringent test for the scattering calculations as well as the reliability of the He–CO interaction potential by Heijmen et al.
Supercollisions and energy transfer of highly vibrationally excited molecules
Authors: Liu Chen-Lin , Hsu Hsu Chen , Lyu Jia-Jia , Ni Chi-Kung
Published: October 2005

Collisional energy-transfer probability distribution functions of highly vibrationally excited molecules and the existence of supercollisions remain as the outstanding questions in the field of intermolecular energy transfer. In this investigation, collisional interactions between ground state Kr atoms and highly vibrationally excited azulene molecules (4.66eV internal energy) were examined at a collision energy of 410cm−1 using a crossed molecular beam apparatus and time-sliced ion imaging techniques. A large amount of energy transfer (1000–5000cm−1) in the backward direction was observed. We report the experimental measurement for the shape of the energy-transfer probability distribution function along with a direct observation of supercollisions.
Influence of κ-distributed ions on the two-stream instability
Authors: Langmayr D. , Biernat H. K. , Erkaev N. V.
Published: October 2005

This paper is the first approach for analyzing the influence of κ-distributed particles on the modified two-stream instability (MTSI). It is assumed that the plasma consists of a magnetized Maxwellian electron contribution and unmagnetized κ-distributed ions drifting across the electrons. Within an electrostatic approximation, the influence of the κ parameter on the maximum growth rate of the MTSI is evaluated for the special case of parallel drift velocity and wave propagation.
Radio-frequency heating of sloshing ions in a straight field line mirror
Authors: Moiseenko V. E. , Ågren O.
Published: October 2005

A scenario to sustain a sloshing ion population with radio-frequency heating in a newly proposed mirror device, the straight field line mirror, is examined. The possibilities of ion cyclotron heating in two-ion species plasma have been analyzed and a scheme with longitudinal wave conversion and fundamental harmonic heating of deuterium ions in tritium plasma has been investigated. This scheme provides efficient ion heating for high deuterium “minority” concentration without substantial conversion to slow waves and heating of the electrons. Numerical calculations carried out for a reactor-scale device show that conversion of the fast magnetosonic wave to the fast Alfvén wave occurs. For reasons of strong cyclotron absorption of the fast Alfvén wave, only a small portion of the wave energy transits through the cyclotron layer and penetrates to the central part of the trap. The power deposition is peaked at the plasma core. The amount of deposited power does not depend sensitively on the parameters of the discharge. The study uses numerical three-dimensional calculations for the time-harmonic boundary problem for Maxwell’s equations. For radio-frequency heating in this scheme, a simple efficient strap antenna is proposed. It has low Q antenna and operates in the regime of global resonance overlapping.
Shapiro steps in a dc quantum interference device with multiple identical junctions in each arm
Authors: De Luca R. , Romeo F.
Published: October 2005

Integer and half-integer Shapiro step amplitudes in the current-voltage characteristics of symmetric superconducting quantum interference devices (SQUIDS), containing more than one Josephson junction on each arm, are analytically calculated for small values of the parameter β and in the absence of noise. This analysis is made possible by the reduction of the dynamical equations of the multiple-junction SQUID to the dynamical equation of a single Josephson junction possessing a nonconventional current-phase relation.
A force sensor for atomic point contacts
Authors: Valkering A. M. C. , Mares A. I. , Untiedt C. , Gavan K. Babaei , Oosterkamp T. H. , van Ruitenbeek J. M.
Published: October 2005

We have developed a sensor to study the mechanical stiffness of atomic-size contacts. It consists of a modification of the mechanically controllable break-junction technique, using a quartz tuning fork resonator as force sensor. We present first results of measurements of the force constants in gold atomic contacts. In the formation of chains of single-metal atoms, the folding in of individual atoms from the banks into the chain can be observed. This sensor allows one to measure forces in atomic contacts for a wide variety of metals, as illustrated with the first measurements on platinum.
Cupric oxide nanoparticles in SiO2 fabricated by copper-ion implantation combined with thermal oxidation
Authors: Amekura H. , Kono K. , Takeda Y. , Kishimoto N.
Published: October 2005

Cupric oxide (CuO) nanoparticles (NPs) are fabricated in silica glasses (SiO2) by Cu-ion implantation and following thermal oxidation. First, Cu metal NPs were formed in SiO2 by the implantation of Cu negative ions of 60 keV to ∼6×1016ions∕cm2, and then the Cu NPs were oxidized to CuO NPs by annealing at 400–1000 °C in oxygen-gas flow. After the oxidation at 600 °C for 1 h, the surface plasmon resonance peak of metallic Cu NPs disappears. Grazing-incidence x-ray diffraction confirms the disappearance of Cu NPs and the formation of CuO NPs, but excludes the formation of Cu2O NPs which are thermodynamically less stable under atmospheric oxygen pressure. The CuO NPs show higher thermal stability up to ∼1000°C than Cu NPs.
Piezoelectrically transduced low-impedance microelectromechanical resonators
Authors: Yan Le , Pang Wei , Kim Euk Sok , Tang William C.
Published: October 2005

This letter presents the design, fabrication, and testing results of a piezoelectrically transduced UHF micromechanical resonator. The resonator is designed to vibrate in the (2, i) in-plane mode, and thin-film zinc oxide is used for piezoelectric transduction. A four-mask process is developed to fabricate the resonator on silicon on insulator wafer, and the maximum processing temperature is kept below 250°C. Prototypes with various diameters are fabricated, with a measured resonant frequencies span from 44.97 MHz to 1.14 GHz. Quality factors around 200 are obtained on different devices. Motional impedance in the range of several hundred ohms is demonstrated.
Thermal management in microfluidics using micro-Peltier junctions
Authors: Maltezos George , Johnston Matthew , Scherer Axel
Published: October 2005

We report refrigeration and heating of nanoliter fluid volumes with micro-Peltier junctions. The temperature of small liquid reservoirs can be rapidly changed and controlled within a range between −3°C to over 120 °C with good long-term stability. These thermal management systems enable the fabrication of complex chip-based chemical and biochemical reaction systems in which the temperature of many processes can be controlled independently.
All-optical switches on a silicon chip realized using photonic crystal nanocavities
Authors: Tanabe Takasumi , Notomi Masaya , Mitsugi Satoshi , Shinya Akihiko , Kuramochi Eiichi
Published: October 2005

We demonstrate all-optical switching in the telecommunication band, in silicon photonic crystals at high speed (∼50ps), with extremely low switching energy (a few 100fJ), and high switching contrast (∼10dB). The devices consist of ultrasmall high-quality factor nanocavities connected to input and output waveguides. Switching is induced by a nonlinear refractive-index change caused by the plasma effect of carriers generated by two-photon absorption in silicon. The high-quality factor and small mode volume led to an extraordinarily large reduction in switching energy. The estimated internal switching energy in the nanocavity is as small as a few tens of fJ, indicating that further reduction on the operating energy is possible.
MAP-1 is a mitochondrial effector of Bax
Authors: Tan Kuan Onn , Fu Nai Yang , Sukumaran Sunil K. , Chan Shing-Leng , Kang Jiunn Hian , Poon Kar Lai , Chen Bin Shun , Yu Victor C.
Published: October 2005

Apoptotic stimuli induce conformational changes in Bax and trigger its translocation from cytosol to mitochondria. Upon assembling into the mitochondrial membrane, Bax initiates a death program through a series of events, culminating in the release of apoptogenic factors such as cytochrome
c
. Although it is known that Bax is one of the key factors for integrating multiple death signals, the mechanism by which Bax functions in mitochondria remains controversial. We have previously identified modulator of apoptosis-1 (MAP-1) as a Bax-associating protein, but its functional relationship with Bax in contributing to apoptosis regulation remains to be established. In this study, we show that MAP-1 is a critical mitochondrial effector of Bax. MAP-1 is a mitochondria-enriched protein that associates with Bax only upon apoptotic induction, which coincides with the release of cytochrome
c
from mitochondria. Small interfering RNAs that diminish MAP-1 levels in mammalian cell lines confer selective inhibition of Bax-mediated apoptosis. Mammalian cells with stable expression of MAP-1 small interfering RNAs are resistant to multiple apoptotic stimuli in triggering apoptotic death as well as in inducing conformation change and translocation of Bax. Similar to Bax-deficient cells, MAP-1-deficient cells exhibit aggressive anchorage-independent growth. Remarkably, recombinant Bax- or tBid-mediated release of cytochrome
c
from isolated mitochondria is significantly compromised in the MAP-1 knockdown cells. We propose that MAP-1 is a direct mitochondrial target of Bax.
Dual roles for cholesterol in mammalian cells
Authors: Xu Fang , Rychnovsky Scott D. , Belani Jitendra D. , Hobbs Helen H. , Cohen Jonathan C. , Rawson Robert B.
Published: October 2005

The structural features of sterols required to support mammalian cell growth have not been fully defined. Here, we use mutant CHO cells that synthesize only small amounts of cholesterol to test the capacity of various sterols to support growth. Sterols with minor modifications of the side chain (e.g., campesterol, β-sitosterol, and desmosterol) supported long-term growth of mutant cells, but sterols with more complex modifications of the side chain, the sterol nucleus, or the 3-hydroxy group did not. After 60 days in culture, the exogenous sterol comprised >90% of cellular sterols. Inactivation of residual endogenous synthesis with the squalene epoxidase inhibitor NB-598 prevented growth in β-sitosterol and greatly reduced growth in campesterol. Growth of cells cultured in β-sitosterol and NB-598 was restored by adding small amounts of cholesterol to the medium. Surprisingly, enantiomeric cholesterol also supported cell growth, even in the presence of NB-598. Thus, sterols fulfill two roles in mammalian cells: (
i
) a bulk membrane requirement in which phytosterols can substitute for cholesterol and (
ii
) other processes that specifically require small amounts of cholesterol but are not enantioselective.
MLL associates specifically with a subset of transcriptionally active target genes
Authors: Milne Thomas A. , Dou Yali , Martin Mary Ellen , Brock Hugh W. , Roeder Robert G. , Hess Jay L.
Published: October 2005

MLL (mixed-lineage leukemia) is a histone H3 Lys-4 specific methyltransferase that is a positive regulator of
Hox
expression.
MLL
rearrangements and amplification are common in acute lymphoid and myeloid leukemias and myelodysplastic disorders and are associated with abnormal up-regulation of
Hox
gene expression. Although MLL is expressed throughout hematopoiesis,
Hox
gene expression is sharply down-regulated during differentiation, suggesting that either the activity of MLL or its association with target promoters must be regulated. Here we show that MLL associates with actively transcribed genes but does not remain bound after transcriptional down-regulation. Surprisingly, MLL is associated not only with promoter regions but also is distributed across the entire coding regions of genes. MLL interacts with RNA polymerase II (pol II) and colocalizes with RNA pol II at a subset of actively transcribed target
in vivo
. Loss of function
Mll
results in defects in RNA pol II distribution. Together the results suggest that an intimate association between MLL and RNA pol II occurs at MLL target genes
in vivo
that is required for normal initiation and/or transcriptional elongation.
Delay-induced stochastic oscillations in gene regulation
Authors: Bratsun Dmitri , Volfson Dmitri , Tsimring Lev S. , Hasty Jeff
Published: October 2005

The small number of reactant molecules involved in gene regulation can lead to significant fluctuations in intracellular mRNA and protein concentrations, and there have been numerous recent studies devoted to the consequences of such noise at the regulatory level. Theoretical and computational work on stochastic gene expression has tended to focus on instantaneous transcriptional and translational events, whereas the role of realistic delay times in these stochastic processes has received little attention. Here, we explore the combined effects of time delay and intrinsic noise on gene regulation. Beginning with a set of biochemical reactions, some of which are delayed, we deduce a truncated master equation for the reactive system and derive an analytical expression for the correlation function and power spectrum. We develop a generalized Gillespie algorithm that accounts for the non-Markovian properties of random biochemical events with delay and compare our analytical findings with simulations. We show how time delay in gene expression can cause a system to be oscillatory even when its deterministic counterpart exhibits no oscillations. We demonstrate how such delay-induced instabilities can compromise the ability of a negative feedback loop to reduce the deleterious effects of noise. Given the prevalence of negative feedback in gene regulation, our findings may lead to new insights related to expression variability at the whole-genome scale.
A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings
Authors: Nagasaka Yosuke , Dillner Karin , Ebise Hayao , Teramoto Reiji , Nakagawa Hiroyuki , Lilius Lena , Axelman Karin , Forsell Charlotte , Ito Akira , Winblad Bengt , Kimura Toru , Graff Caroline
Published: October 2005

Alzheimer's disease (AD) is a neurodegenerative disease with an insidious onset and progressive course that inevitably leads to death. The current diagnostic tools do not allow for diagnosis until the disease has lead to irreversible brain damage. Genetic studies of autosomal dominant early onset familial AD has identified three causative genes: amyloid precursor protein (
APP
), presenilin 1 and 2 (
PSEN1
and
PSEN2
). We performed a global gene expression analysis on fibroblasts from 33 individuals (both healthy and demented mutation carriers as well as wild-type siblings) from three families segregating the
APP
SWE
,
APP
ARC
and
PSEN1
H163Y mutations, respectively. The mutations cause hereditary progressive cognitive disorder, including typical autosomal dominant AD. Our data show that the mutation carriers share a common gene expression profile significantly different from that of their wild-type siblings. The results indicate that the disease process starts several decades before the onset of cognitive decline, suggesting that presymptomatic diagnosis of AD and other progressive cognitive disorders may be feasible in the near future.
Role of the WASP family proteins for
Mycobacterium marinum
actin tail formation
Authors: Stamm Luisa M. , Pak Melissa A. , Morisaki J. Hiroshi , Snapper Scott B. , Rottner Klemens , Lommel Silvia , Brown Eric J.
Published: October 2005

Mycobacterium marinum
, a natural pathogen of fish and frogs and an occasional pathogen of humans, is capable of inducing actin tail formation within the cytoplasm of macrophages, leading to actin-based motility and intercellular spread. Actin tail formation by
M. marinum
is markedly reduced in macrophages deficient in the Wiskott-Aldrich syndrome protein (WASP), which still contain the closely related and ubiquitously expressed protein N-WASP (neuronal WASP). In fibroblasts lacking both WASP and N-WASP,
M. marinum
is incapable of efficient actin polymerization and of intercellular spread. By reconstituting these cells, we find that
M. marinum
is able to use either WASP or N-WASP to induce actin polymerization. Inhibition or genetic deletion of tyrosine phosphorylation, Nck, WASP-interacting protein, and Cdc42 does not affect
M. marinum
actin tail formation, excluding the participation of these molecules as upstream activators of N-WASP in the initiation of actin-based motility. In contrast, deletion of the phosphatidylinositol 4,5-bisphosphate-binding basic motif in N-WASP eliminates
M. marinum
actin tail formation. Together, these data demonstrate that
M. marinum
subversion of host actin polymerization is most similar to distantly related Gram-negative organisms but that its mechanism for activating WASP family proteins is unique.
Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors
Authors: Akiyama‡ Haruhiko , Kim‡ Jung-Eun , Nakashima Kazuhisa , Balmes Gener , Iwai Naomi , Deng Jian Min , Zhang Zhaoping , Martin James F. , Behringer Richard R. , Nakamura Takashi , de Crombrugghe Benoit
Published: October 2005

The transcription factor Sox9 is expressed in all chondroprogenitors and has an essential role in chondrogenesis.
Sox9
is also expressed in other tissues, including central nervous system, neural crest, intestine, pancreas, testis, and endocardial cushions, and plays a crucial role in cell proliferation and differentiation in several of these tissues. To determine the cell fate of
Sox9
-expressing cells during mouse embryogenesis, we generated mice in which a Cre recombinase gene preceded by an internal ribosome entry site was inserted into the 3′ untranslated region of the
Sox9
gene (
Sox9-Cre
knock-in). In the developing skeleton,
Sox9
was expressed before
Runx2
, an early osteoblast marker gene. Cell fate mapping by using
Sox9-Cre;ROSA26
reporter (
R26R
) mice revealed that
Sox9
-expressing limb bud mesenchymal cells gave rise to both chondrocytes and osteoblasts. Furthermore, a mutant in which the
Osterix
gene was inactivated in
Sox9
-expressing cells exhibited a lack of endochondral and intramembranous ossification and a lack of mature osteoblasts comparable with
Osterix
-null mutants. In addition,
Sox9
-expressing limb bud mesenchymal cells also contributed to tendon and synovium formation. By using
Sox9-Cre
;
R26R
mice, we also were able to systematically follow
Sox9
-expressing cells from embryonic day 8.0 to 17.0. Our results showed that
Sox9
-expressing cells contributed to the formation of all cell types of the spinal cord, epithelium of the intestine, pancreas, and mesenchyme of the testis. Thus, our results strongly suggest that all osteo-chondroprogenitor cells, as well as progenitors in a variety of tissues, are derived from Sox9-expressing precursors during mouse embryogenesis.
Pattern-dependent, simultaneous plasticity differentially transforms the input-output relationship of a feedforward circuit
Authors: Smith Spencer LaVere , Otis Thomas Stephen
Published: October 2005

Memories are believed to be encoded by changes in the synaptic connections between neurons. Although many forms of synaptic plasticity have been identified, it remains unknown how such changes affect local circuits. Feedforward inhibitory networks are a common type of local circuitry and occur when principal neurons and their afferent inhibitory interneurons receive the same input. Using slices of cerebellar cortex, we explored how synaptic plasticity at multiple sites within a feedforward inhibitory network consisting of parallel fibers, interneurons, and Purkinje neurons alters the output of this circuit. We found that stimuli resembling baseline activity potentiated feedforward excitatory and simultaneously depressed feedforward inhibitory pathways. In contrast, stimuli resembling sensory-evoked patterns of firing potentiated both types of feedforward connections. These distinct forms of ensemble plasticity change the way Purkinje neurons subsequently respond to inputs. Such concerted changes in the circuitry of cerebellar cortex may contribute to certain forms of sensorimotor learning.
Changes in hydrogen-bond strengths explain reduction potentials in 10 rubredoxin variants
Authors: Lin I-Jin , Gebel Erika B. , Machonkin Timothy E. , Westler William M. , Markley John L.
Published: October 2005

The rubredoxin from
Clostridium pasteurianum
(
Cp
Rd) provides an excellent system for investigating how the protein sequence modulates the reduction potential of the active site in an iron–sulfur protein.
15
N NMR spectroscopy has allowed us to determine with unprecedented accuracy the strengths of all six key hydrogen bonds between protein backbone amides and the sulfur atoms of the four cysteine residues that ligate the iron in the oxidized (Fe
III
) and reduced (Fe
II
) forms of wild-type
Cp
Rd and nine mutants (V44G, V44A, V44I, V44L, V8G, V8A, V8I, V8L, and V8G/V44G). The length (or strength) of each hydrogen bond was inferred from the magnitude of electron spin delocalized across the hydrogen bond from the iron atom onto the nitrogen. The aggregate lengths of these six hydrogen bonds are shorter in both oxidation states in variants with higher reduction potential than in those with lower reduction potential. Differences in aggregate hydrogen bonding upon reduction correlate linearly with the published reduction potentials for the 10
Cp
Rd variants, which span 126 mV. Sequence effects on the reduction potential can be explained fully by their influence on hydrogen-bond strengths.
Characterization of the folding landscape of monomeric lactose repressor: Quantitative comparison of theory and experiment
Authors: Das Payel , Wilson Corey J. , Fossati Giovanni , Wittung-Stafshede Pernilla , Matthews Kathleen S. , Clementi Cecilia
Published: October 2005

Recent theoretical/computational studies based on simplified protein models and experimental investigation have suggested that the native structure of a protein plays a primary role in determining the folding rate and mechanism of relatively small single-domain proteins. Here, we extend the study of the relationship between protein topology and folding mechanism to a larger protein with complex topology, by analyzing the folding process of monomeric lactose repressor (MLAc) computationally by using a Gō-like C
α
model. Next, we combine simulation and experimental results (see companion article in this issue) to achieve a comprehensive assessment of the folding landscape of this protein. Remarkably, simulated kinetic and equilibrium analyses show an excellent quantitative agreement with the experimental folding data of this study. The results of this comparison show that a simplified, completely unfrustrated C
α
model correctly reproduces the complex folding features of a large multidomain protein with complex topology. The success of this effort underlines the importance of synergistic experimental/theoretical approaches to achieve a broader understanding of the folding landscape.
Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
Authors: Subramanian Aravind , Tamayo Pablo , Mootha Vamsi K. , Mukherjee Sayan , Ebert Benjamin L. , Gillette Michael A. , Paulovich Amanda , Pomeroy Scott L. , Golub Todd R. , Lander Eric S. , Mesirov Jill P.
Published: October 2005

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning
Authors: Lin Chin-Hsing , Hansen Stacey , Wang Zhenshan , Storm Daniel R. , Tapscott Stephen J. , Olson James M.
Published: October 2005

The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA
A
receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.
Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy
Authors: Popovic Mikulas , Tenner-Racz Klara , Pelser Colleen , Stellbrink Hans-Jurgen , van Lunzen Jan , Lewis George , Kalyanaraman Vaniambadi S. , Gallo Robert C. , Racz Paul
Published: October 2005

Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody responses to HIV-1. Seven patients during the chronic phase of HIV-1 infection were analyzed for the presence of the capsid protein (HIV-1p24), matrix protein (HIV-1p17), and envelope glycoproteins (HIV-1gp120/gp41), as well as for viral RNA (vRNA) in biopsy specimens from LNs obtained before initiation of therapy and during HAART that lasted from 5 to 13 months. In parallel, these patients were also monitored for viremia and specific anti-HIV-1 antibody responses to structural proteins and glycoproteins both before and during treatment. Before-therapy viral levels, as determined by RT-PCR, ranged from 3 × 103to 6.3 × 105copies of vRNA per ml, whereas during treatment, vRNA was under detectable levels (<25 copies per ml). The pattern of vRNA detection in peripheral blood was concordant within situhybridization results of LN specimens. Before treatment, vRNA associated with follicular dendritic cells (FDCs) was readily detected in GCs of LNs of the patients, whereas during therapy, vRNA was consistently absent in the GCs of LN biopsies of treated patients. In contrast to vRNA hybridization results, viral structural proteins and glycoproteins, evaluated by immunohistochemical staining, were present and persisted in the GC light zone of LNs in abundant amounts not only before initiation of therapy but also during HAART, when no vRNA was detected in GCs. Consistent with immunohistochemical findings, specific antibody responses to HIV-1p17, -p24, and -gp120/gp41, as evaluated by ELISA and virus neutralization, persisted in patients under therapy for up to 13 months of follow-up. The implications of these findings are discussed in relation to HIV-1 persistence in infected individuals and the potential role of chronic antigenic stimulation by the deposited structural proteins in GCs for AIDS-associated B cell malignancies.
Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin
Authors: Li Mei , Messaddeq Nadia , Teletin Marius , Pasquali Jean-Louis , Metzger Daniel , Chambon Pierre
Published: October 2005

To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXRαβ
ep-/-
somatic mutants in which both RXRα and RXRβ are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXRαβ-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXRαβ-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.
Dynamic transport of SNARE proteins in the Golgi apparatus
Authors: Cosson Pierre , Ravazzola Mariella , Varlamov Oleg , Söllner Thomas H. , Di Liberto Maurizio , Volchuk Allen , Rothman James E. , Orci Lelio
Published: October 2005

Localization of a membrane protein in a subcellular compartment can be achieved by its retention in the compartment or by its continuous transport toward this compartment. Previous results have suggested that specific enzymes are localized in the Golgi apparatus at least in part by selective retention and exclusion from transport vesicles. However, the function of some Golgi SNARE (soluble
N
-ethylmaleimide-sensitive factor attachment protein receptor) proteins is not compatible with their exclusion from transport vesicles. To help understand the mechanism accounting for the localization of SNARE proteins in the Golgi apparatus, we analyzed their lateral distribution in the Golgi cisternae and their incorporation into transport vesicles. According to our results, all SNARE proteins are efficiently incorporated into transport vesicles, indicating that the localization of SNARE proteins in the Golgi apparatus is not based on a static retention mechanism. Detailed analysis suggested that incorporation into transport vesicles was more efficient for SNARE proteins restricted to the cis face of the Golgi as compared with SNAREs present at the trans face. Furthermore, overexpression of a cis-Golgi SNARE protein altered concomitantly its incorporation in transport vesicles and its intra-Golgi localization. These observations suggest that, contrary to resident Golgi enzymes, SNARE proteins are localized in the Golgi apparatus as the result of a dynamic transport equilibrium.
The DNA replication factor MCM5 is essential for Stat1-mediated transcriptional activation
Authors: Snyder Marylynn , He Wei , Zhang J. Jillian
Published: October 2005

The eukaryotic minichromosome maintenance (MCM) family of proteins (MCM2–MCM7) is evolutionarily conserved from yeast to human. These proteins are essential for DNA replication. The signal transducer and activator of transcription proteins are critical for the signal transduction of a multitude of cytokines and growth factors leading to the regulation of gene expression. We previously identified a strong interaction between Stat1 and MCM5. However, the physiological significance of this interaction was not clear. We show here by chromatin immunoprecipitation (ChIP) analyses that the MCM5 protein, as well as other members of the MCM family, is inducibly recruited to Stat1 target gene promoters in response to cytokine stimulation. Furthermore, the MCM proteins are shown to move along with the RNA polymerase II during transcription elongation. We have also identified an independent domain in MCM5 that mediates the interaction between Stat1 and MCM5; overexpression of this domain can disrupt the interaction between Stat1 and MCM5 and inhibit Stat1 transcriptional activity. Finally, we used the RNA interference technique to show that MCM5 is essential for transcription activation of Stat1 target genes. Together, these results demonstrate that, in addition to their roles in DNA replication, the MCM proteins are also necessary for transcription activation.
Rootletin forms centriole-associated filaments and functions in centrosome cohesion
Authors: Bahe Susanne , Stierhof York-Dieter , Wilkinson Christopher J. , Leiss Florian , Nigg Erich A.
Published: October 2005

After duplication of the centriole pair during S phase, the centrosome functions as a single microtubule-organizing center until the onset of mitosis, when the duplicated centrosomes separate for bipolar spindle formation. The mechanisms regulating centrosome cohesion and separation during the cell cycle are not well understood. In this study, we analyze the protein rootletin as a candidate centrosome linker component. As shown by immunoelectron microscopy, endogenous rootletin forms striking fibers emanating from the proximal ends of centrioles. Moreover, rootletin interacts with C-Nap1, a protein previously implicated in centrosome cohesion. Similar to C-Nap1, rootletin is phosphorylated by Nek2 kinase and is displaced from centrosomes at the onset of mitosis. Whereas the overexpression of rootletin results in the formation of extensive fibers, small interfering RNA–mediated depletion of either rootletin or C-Nap1 causes centrosome splitting, suggesting that both proteins contribute to maintaining centrosome cohesion. The ability of rootletin to form centriole-associated fibers suggests a dynamic model for centrosome cohesion based on entangling filaments rather than continuous polymeric linkers.
A Garland of Songs for a Nation of Singers: An Episode in the History of Russia, the Herderian Tradition and the Rise of Baltic Nationalism
Authors: Karnes Kevin C.
Published: October 2005

Analysis of the contents of Jānis Cimze's harmonized folksong collection A Garland of Songs (1872) and the cultural context in which it was published reveals its musical portrait of an emergent Latvian nation to be a synthetic construct. Drawing upon aspects of the German nationalist choral movement, the quasi-Herderian work of Baltic German folklorists and new opportunities for cultural expression afforded by mid-century Russian imperial reforms, Cimze's work inspired heated and increasingly xenophobic debate among his contemporary Latvians about the destiny of their community in pre-Revolutionary Russia.
Fatty Acids in Early Human Milk after Preterm and Full‐Term Delivery
Authors: Kovács Andrea , Funke Simone , Marosvölgyi Tamás , Burus István , Decsi Tamás
Published: October 2005

Background:

It has been much debated whether fatty acid composition of human milk differs after preterm as compared to full‐term delivery.

Subjects and Methods:

Human milk samples were obtained from mothers of preterm (n = 8, gestational age: 28.0 [4.2] weeks, birthweight: 1,235 [420] g, median [interquartile range]) and full‐term (n = 10, gestational age: 38.5 [2.7] weeks, birthweight: 3375 [282] g) infants every day during the first week and thereafter on the 14th, 21st, and 28th day of lactation. Fatty acid composition was measured by high‐resolution capillary gas‐liquid chromatography.

Results:

Maternal age and body mass index did not differ, and food frequency questionnaire did not reveal significant differences in diet between the two groups. Fat contents of human milk did not differ between the two groups. Values of linoleic acid (C18:2n‐6) and alpha‐linolenic acid (C18:3n‐3) did not differ throughout the study. Values of the metabolites C18:3n‐6 and C20:3n‐6 as well as C18:4n‐3 and C20:3n‐3 were significantly higher after preterm as compared with full‐term delivery. Values of arachidonic acid (C20:4n‐6; e.g., day 4: 0.82 [0.4] vs. 0.44 [0.28]; day 7: 0.61 [0.25] vs. 0.34 [0.25]; day 21: 0.33 [0.18] vs. 0.44 [0.44]; in weight percent, preterm versus full‐term, P < 0.05) and docosahexaenoic acid (C22:6n‐3; e.g., day 4: 0.33 [0.23] vs. 0.15 [0.14]; day 7: 0.26 [0.16] vs. 0.13 [0.15]; day 21: 0.11 [0.08] vs. 0.21 [0.17]; P < 0.05) were significantly higher in human milk samples of mothers of preterm as compared with full‐term infants.

Conclusion:

In this study, percentage contributions of arachidonic and docosahexaenoic acids as well as the those of the intermediary metabolites of essential fatty acid metabolism were all significantly higher in early human milk samples of mothers giving birth to very low birth weight preterm as compared with full‐term infants.
Tolerance and Reliability of Wireless pH Monitoring in Children
Authors: Hochman Jay A , Favaloro‐Sabatier Jennifer
Published: October 2005

Objectives:

The purpose of this study was to determine whether the placement of a wireless capsule pH monitoring system improved the reproducibility and patient comfort of pH probe studies in children.

Methods:

The records of 50 children who underwent wireless pH monitoring were retrospectively reviewed. Among this group, 44 children (27 males and 17 females) met inclusion criteria. The average age was 11.8 years, with a range from 6 years to 19 years. Each of these patients had a capsule placed 6 cm above the squamocolumnar junction and underwent pH telemetry for 2 days. In addition, 38 of the 44 families were contacted for follow‐up to determine the tolerability of the catheter‐free monitoring.

Results:

Data analysis revealed that the overall reproducibility of a single 24 hour period was 77%. Studies were considered reproducible if the reflux index was normal (pH <4 for less than 5% of study period) or abnormal on both study days. Using McNemar's exact test, we found no significant difference between the two days (P = 0.11). Ten of 44 patients had conflicting results on day 1 compared with results on day 2. The majority (68%) of patients reported some degree of discomfort during the study; however, this pain was generally mild. Ninety‐five percent of parents would be willing to have their child undergo pH monitoring in the future with the wireless pH monitoring.

Conclusions:

Catheter‐free prolonged esophageal pH monitoring is feasible in children older than 6 years of age. A lack of consistent reproducibility in sequential 24 hour recordings with this technique concurs with findings using the conventional catheter methodologies. The catheter‐free system is often associated with discomfort during the study, but these symptoms were generally well tolerated.
Decreased Prevalence of Nonalcoholic Fatty Liver Disease in Black Obese Children
Authors: Louthan Miriam V , Theriot Judy A , Zimmerman Ellen , Stutts John T , McClain Craig J
Published: October 2005

Objectives:

Nonalcoholic fatty liver disease (NAFLD) is a common cause of pediatric liver disease. Studies suggest decreased prevalence in blacks, females, and younger children. However, the proportion of black subjects in these studies was small, and children under 12 were not included. We propose that abnormal alanine aminotransferase (ALT) is more common in whites than blacks, males than females, and children over 12 compared with younger children in a prospective study.

Methods:

We enrolled 181 consecutive asymptomatic obese children attending general pediatric clinics who denied recent fever or known liver disease. Obesity was defined as body mass index (BMI)zscore of greater than 1.64 (95th percentile for age and sex). Elevated ALT was defined as greater than 40 U/L. BMIzscore, race, sex, age, and parental obesity were compared using the chi‐square test and Fisher's exact test.

Results:

The population included 81 males and 100 females, 147 nonHispanic black, 33 nonHispanic white, and 1 Hispanic white. Elevated ALT occurred in 14 (8%) subjects. White children were significantly more likely to have abnormal ALT (odds ratio [OR] = 4.0,P< .02). Very obese children (BMIzscore >2.3) were more likely to have abnormal ALT compared with mildly obese children (OR = 4.0,P< 0.05). Sex, age, hepatomegaly, acanthosis nigricans, and parental obesity did not significantly predict elevated ALT.

Conclusion:

Eight percent of asymptomatic, obese children had an elevated ALT suggestive of NAFLD. White and very obese children are more likely to be affected. Sex and age are not good clinical predictors of NAFLD. We suggest that all obese children be screened for NAFLD.