bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term variation of the polar wind velocity and its implication for the ion acceleration process: Akebono/suprathermal ion mass spectrometer observations
Authors: Abe Takumi , Yau Andrew W. , Watanabe Shigeto , Yamada Manabu , Sagawa Eiichi
Published: September 2004

We present the solar activity dependence and seasonal variation of H+ and O+ polar wind velocity profiles observed by the suprathermal ion mass spectrometer (SMS) on Akebono. These observations spanned a solar cycle and covered a wide range of altitudes and invariant latitudes (ILAT) in the polar ionosphere and a variety of geomagnetic activity conditions from 1500 km to 8500 km altitude and from the poleward edge of the ionospheric trough (∼60° ILAT) to the polar cap (>85° ILAT). At low (high) altitudes below (above) 4000 km, the increase of the averaged H+ and O+ ion velocities with altitude was larger (smaller) at solar minimum than at solar maximum. For example, the averaged H+ velocity on the dayside at 4000 km altitude was approximately 8 km s−1 at low solar activity but ∼5 km s−1 at high activity. This suggests that the averaged polar wind velocity correlates differently with solar activity and the dominant acceleration process may be different at low and high altitudes, respectively. For both H+ and O+ the observed ion velocity at high altitude was largest in the summer under essentially all magnetic and solar activity conditions. The O+ velocity at high altitude (>4000 km) was significant and largest in the summer at solar maximum, when the solar energy input into the polar cap was largest; theoretically, the velocity of O+ ions in the polar wind is expected to be negligible below 10,000 km. We consider geophysical processes that may contribute to the observed velocities and their solar activity and seasonal dependences, including the possible contributions of photoelectrons and elevated electron temperatures to the ambipolar electric field that drives the polar wind.
Impact of vibrational excitation on ionospheric parameters and artificial airglow during HF heating in the F region
Authors: Vlasov Michael N. , Kelley Michael C. , Gerken Elizabeth
Published: September 2004

Vibrational excitation by the impact of electrons on molecular nitrogen in the energy range of 1.8–3.2 eV is well known. Electrons heated by high‐power HF radio waves can effectively lose energy due to this vibrational excitation, which, in turn, creates a sharp energy barrier. Electrons must overcome this barrier in order to reach higher energies. A model for this vibrational barrier has been developed, and deviations of the electron energy distribution from a Maxwellian distribution have been estimated under different conditions. The depletion of electrons with energy higher than 2 eV decreases the excitation rate of the optical emissions (for example, 630.0 nm airglow) observed during HF heating. We show that the vibrational barrier can explain why the 630 nm airglow reported by Gustavsson et al. [2001] was only slightly enhanced during HF heating, in spite of the measured electron temperature being higher than 3000 K. In some cases, vibrationally excited molecules can accumulate in the ionosphere due to slow deactivation. These species increase the recombination coefficient, which, in turn, may result in the decrease of electron density. This effect can also contribute to the saturation of the optical emission strength as a function of heater power, as reported by Pedersen et al. [2003].
Correlations between low‐frequency and high‐frequency auroral kilometric radiation plasma wave intensity bursts and X rays in the auroral zone
Authors: Imhof W. L. , Petrinec S. M. , Anderson R. R. , Walt M. , Mobilia J. , Matsumoto H.
Published: September 2004

Comparisons are made between X‐ray (>2 keV) emissions emanating from the Earth's Northern Hemisphere aurora observed on the Polar satellite and auroral kilometric radiation (AKR) plasma wave intensities detected on the Geotail satellite. For this comparison the plasma wave frequencies were divided into a low‐frequency (LF‐AKR) (30–100 kHz) band and a high‐frequency (HF‐AKR) (100–800 kHz) band. For the LF‐AKR band the correlation coefficients with auroral X‐ray emissions are generally high and significantly larger than the corresponding coefficients between X‐ray and HF‐AKR variations. It is found that short time‐scale variations of the LF‐AKR activity often correspond to the temporal fine structure of the intensity (5–10 min) of X‐ray auroral emissions. HF‐AKR intensity enhancements generally precede enhancements of the X‐ray emissions, while the LF‐AKR intensity enhancements generally lag the X‐ray enhancements. This sequence implies that auroral acceleration begins at lower altitudes and then moves to higher altitudes. In addition, the time profiles of the X‐ray intensities often display slower recovery times than do the LF‐AKR.
Direct imaging of Titan's extended haze layer from HST observations
Authors: Young E. F. , Puetter R. , Yahil A.
Published: September 2004

In the early 1980s, both Voyager spacecraft imaged a detached haze layer surrounding Titan, separated from the main haze distribution by a gap at around ∼300 km and merging into a hood of more concentrated haze at Titan's north pole. We have processed Hubble Space Telescope images of Titan with Lucy‐Richardson and PIXON deconvolution software and point spread functions generated by TinyTim 6.0 to detect the extended haze layer for the first time since the Voyager encounters. Images taken from 1994 through 2000 show not only that the extended haze layer still exists, but also that it has migrated from south to north during that interval.
On measuring the off‐equatorial conductivity before and during convective ionospheric storms
Authors: Kelley M. C. , Wong V. K. , Hajj G. A. , Mannucci A. J.
Published: September 2004

One of the biggest unknowns in the CIS/ESF (Convective Ionospheric Storms/Equatorial Spread F) Space Weather problem now can be measured. Radio occultations of the GPS constellation will be measurable on a regular basis during the COSMIC (Constellation Observing System for Meteorology, Ionosphere and Climate) and C/NOFS (Communications/Navigation Outage Forecast System) satellite era. These measurements can be used to determine the plasma density versus height and hence, the off‐equatorial height‐integrated conductivity.
The streaming potential of liquid carbon dioxide in Berea sandstone
Authors: Moore Jeffrey R. , Glaser Steven D. , Morrison H. Frank , Hoversten G. Michael
Published: September 2004

We report here, for the first time, evolution of the streaming potential coupling coefficient as liquid carbon dioxide infiltrates Berea sandstone. Using 125 Ω‐m tap water, the coupling coefficient determined before and after each CO2 flood of five samples averaged approximately −30 mV/0.1 MPa. After liquid CO2 passed through the specimens displacing all mobile pore water, trapped water remained and the coupling coefficient was approximately −3 mV/0.1 MPa. A bound water limit of the coupling coefficient for liquid CO2 flow was found using an air‐dried sample to be −0.02 mV/0.1 MPa. For initially water‐saturated samples, bulk resistivity varied during CO2 invasion from 330 Ω‐m, to 150 Ω‐m during CO2/water mixing, to a final value of 380 Ω‐m. Results suggest that trapped and bound water control electrical conduction and the electrokinetic response. Applications include monitoring CO2 injectate in subsurface reservoirs using the self potential method.
A coherent model of the crustal magnetic field of Mars
Authors: Arkani‐Hamed Jafar
Published: September 2004

The immense amount of the mapping‐phase Mars Global Surveyor (MGS) magnetic data allows us to derive a highly accurate magnetic map of Mars. The data acquired at nighttimes within the first ∼3 years of the mapping phase are divided into two almost equal parts, and each part is expressed in spherical harmonics of degree up to 90. The two models are almost identical over harmonics of degree up to 62 but show appreciable differences over higher‐degree harmonics, indicating that the higher‐degree harmonic coefficients have appreciable noncrustal contribution. The most repeatable components of the two models are combined to produce an accurate 62‐degree harmonic model of the magnetic field of the Martian crust. It is further demonstrated that the altitude of MGS is the major limiting factor of the resolution of the mapping‐phase data. The small‐scale features of the data, with wavelengths shorter than ∼400 km, have significant contribution from noncrustal sources. They are not useful for delineating the details of the magnetic source bodies in the crust.
Folate biofortification in tomatoes by engineering the pteridine branch of folate synthesis
Authors: de la Garza Rocío Díaz , Quinlivan Eoin P. , Klaus Sebastian M. J. , Basset Gilles J. C. , Gregory Jesse F. , Hanson Andrew D.
Published: September 2004

Plants are the main source of folate in human diets, but many fruits, tubers, and seeds are poor in this vitamin, and folate deficiency is a worldwide problem. Plants synthesize folate from pteridine,
p
-aminobenzoate (PABA), and glutamate moieties. Pteridine synthesis capacity is known to drop in ripening tomato fruit; therefore, we countered this decline by fruit-specific overexpression of GTP cyclohydrolase I, the first enzyme of pteridine synthesis. We used a synthetic gene based on mammalian GTP cyclohydrolase I, because this enzyme is predicted to escape feedback control
in planta
. This engineering maneuver raised fruit pteridine content by 3- to 140-fold and fruit folate content by an average of 2-fold among 12 independent transformants, relative to vector-alone controls. Most of the folate increase was contributed by 5-methyltetrahydrofolate polyglutamates and 5,10-methenyltetrahydrofolate polyglutamates, which were also major forms of folate in control fruit. The accumulated pteridines included neopterin, monapterin, and hydroxymethylpterin; their reduced forms, which are folate biosynthesis intermediates; and pteridine glycosides not previously found in plants. Engineered fruit with intermediate levels of pteridine overproduction attained the highest folate levels. PABA pools were severely depleted in engineered fruit that were high in folate, and supplying such fruit with PABA by means of the fruit stalk increased their folate content by up to 10-fold. These results demonstrate that engineering a moderate increase in pteridine production can significantly enhance the folate content in food plants and that boosting the PABA supply can produce further gains.
Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors
Authors: Prell George D. , Martinelli Giorgio P. , Holstein Gay R. , Matulić-Adamić Jasenka , Watanabe Kyoichi A. , Chan Susan L. F. , Morgan Noel G. , Haxhiu Musa A. , Ernsberger Paul
Published: September 2004

We identified the previously unknown structures of ribosylated imidazoleacetic acids in rat, bovine, and human tissues to be imidazole-4-acetic acid-ribotide (IAA-RP) and its metabolite, imidazole-4-acetic acid-riboside. We also found that IAA-RP has physicochemical properties similar to those of an unidentified substance(s) extracted from mammalian tissues that interacts with imidazol(in)e receptors (I-Rs). [“Imidazoline,” by consensus (International Union of Pharmacology), includes imidazole, imidazoline, and related compounds. We demonstrate that the imidazole IAA-RP acts at I-Rs, and because few (if any) imidazolines existin vivo, we have adopted the term “imidazol(in)e-Rs.”] The latter regulate multiple functions in the CNS and periphery. We now show that IAA-RP (i) is present in brain and tissue extracts that exhibit I-R activity; (ii) is present in neurons of brainstem areas, including the rostroventrolateral medulla, a region where drugs active at I-Rs are known to modulate blood pressure; (iii) is present within synaptosome-enriched fractions of brain where its release is Ca2+-dependent, consistent with transmitter function; (iv) produces I-R-linked effectsin vitro(e.g., arachidonic acid and insulin release) that are blocked by relevant antagonists; and (v) produces hypertension when microinjected into the rostroventrolateral medulla. Our data also suggest that IAA-RP may interact with a novel imidazol(in)e-like receptor at this site. We propose that IAA-RP is a neuroregulator acting via I-Rs.
A new model for vitamin K-dependent carboxylation: The catalytic base that deprotonates vitamin K hydroquinone is not Cys but an activated amine
Authors: Rishavy Mark A. , Pudota B. Nirmala , Hallgren Kevin W. , Qian Wen , Yakubenko Anna V. , Song Jee-Hyeon , Runge Kurt W. , Berkner Kathleen L.
Published: September 2004

Vitamin K-dependent (VKD) proteins require carboxylation for diverse functions that include hemostasis, apoptosis, and Ca
2+
homeostasis, yet the mechanism of carboxylation is not well understood. Combined biochemical and chemical studies have led to a long-standing model in which a carboxylase Cys catalytic base deprotonates vitamin K hydroquinone (KH
2
), leading to KH
2
oxygenation and Glu carboxylation. We previously identified human carboxylase Cys-99 and Cys-450 as catalytic base candidates: Both were modified by
N
-ethylmaleimide (NEM) and Ser-substituted mutants retained partial activity, suggesting that the catalytic base is activated for increased basicity. Mutants with Cys-99 or Cys-450 substituted by Ala, which cannot ionize to function as a catalytic base, were therefore analyzed. Both single and double mutants had activity, indicating that Cys-99 and Cys-450 do not deprotonate KH
2
. [
14
C]NEM modification of C99A/C450A revealed one additional reactive group; however, Ser-substituted mutants of each of the eight remaining Cys retained substantial activity. To unequivocally test, then, whether any Cys or Cys combination acts as the catalytic base, a mutant with all 10 Cys substituted by Ala was generated. This mutant showed 7% wild-type activity that depended on factor IX coexpression, indicating a VKD protein effect on carboxylase maturation. NEM and diethyl pyrocarbonate inhibition suggested that the catalytic base is an activated His. These results change the paradigm for VKD protein carboxylation. The identity of the catalytic base is critical to understanding carboxylase mechanism and this work will therefore impact both reinterpretation of previous studies and future ones that define how this important enzyme functions.
Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration
Authors: Hahn Paul , Qian Ying , Dentchev Tzvete , Chen Lin , Beard John , Harris Zena Leah , Dunaief Joshua L.
Published: September 2004

Mechanisms of brain and retinal iron homeostasis have become subjects of increased interest after the discovery of elevated iron levels in brains of patients with Alzheimer's disease and retinas of patients with age-related macular degeneration. To determine whether the ferroxidase ceruloplasmin (Cp) and its homolog hephaestin (Heph) are important for retinal iron homeostasis, we studied retinas from mice deficient in
Cp
and/or
Heph
. In normal mice, Cp and Heph localize to Müller glia and retinal pigment epithelium, a blood–brain barrier. Mice deficient in both
Cp
and
Heph
, but not each individually, had a striking, age-dependent increase in retinal pigment epithelium and retinal iron. The iron storage protein ferritin was also increased in
Cp
–/–
Heph
–/
Y
retinas. After retinal iron levels had increased,
Cp
–/–
Heph
–/
Y
mice had age-dependent retinal pigment epithelium hypertrophy, hyperplasia and death, photoreceptor degeneration, and subretinal neovascularization, providing a model of some features of the human retinal diseases aceruloplasminemia and age-related macular degeneration. This pathology indicates that Cp and Heph are critical for CNS iron homeostasis and that loss of Cp and Heph in the mouse leads to age-dependent retinal neurodegeneration, providing a model that can be used to test the therapeutic efficacy of iron chelators and antiangiogenic agents.
Mixing active-site components: A recipe for the unique enzymatic activity of a telomere resolvase
Authors: Bankhead Troy , Chaconas George
Published: September 2004

The ResT protein, a telomere resolvase from
Borrelia burgdorferi
, processes replication intermediates into linear replicons with hairpin ends by using a catalytic mechanism similar to that for tyrosine recombinases and type IB topoisomerases. We have identified in ResT a hairpin binding region typically found in cut-and-paste transposases. We show that substitution of residues within this region results in a decreased ability of these mutants to catalyze telomere resolution. However, the mutants are capable of resolving heteroduplex DNA substrates designed to allow spontaneous destabilization and prehairpin formation. These findings support the existence of a hairpin binding region in ResT, the only known occurrence outside a transposase. The combination of transposase-like and tyrosine-recombinase-like domains found in ResT indicates the use of a composite active site and helps explain the unique breakage-and-reunion reaction observed with this protein. Comparison of the ResT sequence with other known telomere resolvases suggests that a hairpin binding motif is a common feature in this class of enzyme; the sequence motif also appears in the RAG recombinases. Finally, our data support a mechanism of action whereby ResT induces prehairpin formation before the DNA cleavage step.
Listeria-based cancer vaccines that segregate immunogenicity from toxicity
Authors: Brockstedt Dirk G. , Giedlin Martin A. , Leong Meredith L. , Bahjat Keith S. , Gao Yi , Luckett William , Liu Weiqun , Cook David N. , Portnoy Daniel A. , Dubensky Thomas W.
Published: September 2004

The facultative intracellular bacteriumListeria monocytogenesis being developed as a cancer vaccine platform because of its ability to induce potent innate and adaptive immunity. For successful clinical application, it is essential to develop aListeriaplatform strain that is safe yet retains the potency of vaccines based on wild-type bacteria. Here, we report the development of a recombinant live-attenuated vaccine platform strain that retains the potency of the fully virulent pathogen, combined with a >1,000-fold reduction in toxicity, as compared with wild-typeListeria. By selectively deleting two virulence factors, ActA (ΔactA) and Internalin B (ΔinlB), the immunopotency ofListeriawas maintained and its toxicity was diminishedin vivo, largely by blocking the direct internalin B-mediated infection of nonphagocytic cells, such as hepatocytes, and the indirect ActA-mediated infection by cell-to-cell spread from adjacent phagocytic cells. In contrast, infection of phagocytic cells was not affected, leaving intact the ability ofListeriato stimulate innate immunity and to induce antigenspecific cellular responses.ListeriaΔactA/ΔinlB-based vaccines were rapidly cleared from mice after immunization and induced potent and durable effector and memory T-cell responses with no measurable liver toxicity. Therapeutic vaccination of BALB/c mice bearing murine CT26 colon tumor lung metastases or palpable s.c. tumors (>100 mm3) with recombinantListeriaΔactA/ΔinlBexpressing an endogenous tumor antigen resulted in breaking of self-tolerance and long-term survival. We propose that recombinantListeriaΔactA/ΔinlBexpressing human tumor-associated antigens represents an attractive therapeutic strategy for further development and testing in human clinical trials.
Differential Requirements for Vav Proteins in DAP10- and ITAM-mediated NK Cell Cytotoxicity
Authors: Cella Marina , Fujikawa Keiko , Tassi Ilaria , Kim Sunjin , Latinis Kevin , Nishi Shinzo , Yokoyama Wayne , Colonna Marco , Swat Wojciech
Published: September 2004

Natural killer (NK) cells express multiple activating receptors that initiate signaling cascades through DAP10- or immunoreceptor tyrosine-based activation motif–containing adapters, including DAP12 and FcRγ. Among downstream signaling mediators, the guanine nucleotide exchange factor Vav1 carries out a key role in activation. However, whether Vav1 regulates only some or all NK cell–activating pathways is matter of debate. It is also possible that two other Vav family molecules, Vav2 and Vav3, are involved in NK cell activation. Here, we examine the relative contribution of each of these exchange factors to NK cell–mediated cytotoxicity using mice lacking one, two, or all three Vav proteins. We found that Vav1 deficiency is sufficient to disrupt DAP10-mediated cytotoxicity, whereas lack of Vav2 and Vav3 profoundly impairs FcRγ- and DAP12-mediated cytotoxicity. Our results provide evidence that these three Vav proteins function specifically in distinct pathways that trigger NK cell cytotoxicity.
IL-7 Receptor Signals Inhibit Expression of Transcription Factors TCF-1, LEF-1, and RORγt
Authors: Yu Qing , Erman Batu , Park Jung-Hyun , Feigenbaum Lionel , Singer Alfred
Published: September 2004

Intrathymic T cell development depends on signals transduced by both T cell receptor and cytokine receptors. Early CD4−CD8− (double negative) thymocytes require interleukin (IL)-7 receptor (IL-7R) signals for survival and proliferation, but IL-7R signals are normally extinguished by the immature single positive (ISP) stage of thymocyte development. We now demonstrate that IL-7R signals inhibit expression of transcription factors TCF-1, LEF-1, and RORγt that are required for the ISP to double positive (DP) transition in the thymus. In addition, we demonstrate that IL-7R signals also inhibit TCF-1 and LEF-1 expression in mature peripheral T cells. Thus, the present work has identified several important downstream target genes of IL-7R signaling in T cells and thymocytes that provide a molecular mechanism for the inhibitory influence of IL-7R signaling on DP thymocyte development. We conclude that IL-7R signals down-regulate transcription factors required for the ISP to DP transition and so must be terminated by the ISP stage of thymocyte development.
The Functional Basis for Hemophagocytic Lymphohistiocytosis in a Patient with Co-inherited Missense Mutations in the Perforin (PFN1) Gene
Authors: Voskoboinik Ilia , Thia Marie-Claude , De Bono Annette , Browne Kylie , Cretney Erika , Jackson Jacob T. , Darcy Phillip K. , Jane Stephen M. , Smyth Mark J. , Trapani Joseph A.
Published: September 2004

About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated (∼45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure–function relationships for lymphocyte perforin.
Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract
Authors: Mehandru Saurabh , Poles Michael A. , Tenner-Racz Klara , Horowitz Amir , Hurley Arlene , Hogan Christine , Boden Daniel , Racz Paul , Markowitz Martin
Published: September 2004

Given its population of CCR5-expressing, immunologically activated CD4+ T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4+ T cells would be observed in HIV-1–infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4+ T cells compared with peripheral blood CD4+ T cells is seen during primary HIV-1 infection. CD4+ T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4+ T cell population, a significantly greater CD4+ T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.
Stabilizing the Closed S6 Gate in the Shaker K v Channel Through Modification of a Hydrophobic Seal
Authors: Kitaguchi Tetsuya , Sukhareva Manana , Swartz Kenton J.
Published: September 2004

The primary activation gate in K+ channels is thought to reside near the intracellular entrance to the ion conduction pore. In a previous study of the S6 activation gate in Shaker (Hackos et al., 2002), we found that mutation of V478 to W results in a channel that cannot conduct ions even though the voltage sensors are competent to translocate gating charge in response to membrane depolarization. In the present study we explore the mechanism underlying the nonconducting phenotype in V478W and compare it to that of W434F, a mutation located in an extracellular region of the pore that is nonconducting because the channel is predominantly found in an inactivated state. We began by examining whether the intracellular gate moves using probes that interact with the intracellular pore and by studying the inactivation properties of heterodimeric channels that are competent to conduct ions. The results of these experiments support distinct mechanisms underlying nonconduction in W434F and V478W, suggesting that the gate in V478W either remains closed, or that the mutation has created a large barrier to ion permeation in the open state. Single channel recordings for heterodimeric and double mutant constructs in which ion conduction is rescued suggest that the V478W mutation does not dramatically alter unitary conductance. Taken together, our results suggest that the V478W mutation causes a profound shift of the closed to open equilibrium toward the closed state. This mechanism is discussed in the context of the structure of this critical region in K+ channels.
Gating of the Bacterial Sodium Channel, NaChBac
Authors: Kuzmenkin Alexey , Bezanilla Francisco , Correa Ana M.
Published: September 2004

The bacterial sodium channel, NaChBac, from Bacillus halodurans provides an excellent model to study structure–function relationships of voltage-gated ion channels. It can be expressed in mammalian cells for functional studies as well as in bacterial cultures as starting material for protein purification for fine biochemical and biophysical studies. Macroscopic functional properties of NaChBac have been described previously (Ren, D., B. Navarro, H. Xu, L. Yue, Q. Shi, and D.E. Clapham. 2001. Science. 294:2372–2375). In this study, we report gating current properties of NaChBac expressed in COS-1 cells. Upon depolarization of the membrane, gating currents appeared as upward inflections preceding the ionic currents. Gating currents were detectable at −90 mV while holding at −150 mV. Charge–voltage (Q–V) curves showed sigmoidal dependence on voltage with gating charge saturating at −10 mV. Charge movement was shifted by −22 mV relative to the conductance–voltage curve, indicating the presence of more than one closed state. Consistent with this was the Cole-Moore shift of 533 μs observed for a change in preconditioning voltage from −160 to −80 mV. The total gating charge was estimated to be 16 elementary charges per channel. Charge immobilization caused by prolonged depolarization was also observed; Q–V curves were shifted by approximately −60 mV to hyperpolarized potentials when cells were held at 0 mV. The kinetic properties of NaChBac were simulated by simultaneous fit of sodium currents at various voltages to a sequential kinetic model. Gating current kinetics predicted from ionic current experiments resembled the experimental data, indicating that gating currents are coupled to activation of NaChBac and confirming the assertion that this channel undergoes several transitions between closed states before channel opening. The results indicate that NaChBac has several closed states with voltage-dependent transitions between them realized by translocation of gating charge that causes activation of the channel.
Amino‐truncated amyloid β‐peptide (Aβ5‐40/42) produced from caspase‐cleaved amyloid precursor protein is deposited in Alzheimer’s disease brain
Authors: Takeda Kazuya , Araki Wataru , Akiyama Haruhiko , Tabira Takeshi
Published: September 2004

Caspase activation and apoptosis are implicated in Alzheimer’s disease (AD). In view of the finding that the amyloid precursor protein (APP) undergoes caspase‐mediated cleavage in the cytoplasmic region, we analyzed amyloid β‐peptide (Aβ) production in human neuronal and nonneuronal cells expressing wild‐type APP and the caspase‐cleaved form of APP (APPΔC). Biochemical analyses, including immunoprecipitation/mass spectrometry, revealed that APPΔC‐expressing cells secrete increased levels of amino‐terminally truncated Aβ5‐40/42 and reduced levels of Aβ1‐40/42, compared with wild‐type APP‐expressing cells. We propose that Aβ5‐40/42 is derived from alternative β‐cleavage of APP by α‐secretase‐like protease(s), based on data from treatment of cells with inhibitors of BACE and α‐secretase. Apoptosis induction resulted in this alternative cleavage of APP in wild‐type APP‐expressing cells. Moreover, immunohistochemical staining of the AD brain with an end‐specific antibody to Aβ5‐40/42 revealed peptide deposits in vascular lesions with amyloid angiopathy. The data collectively suggest that caspase cleavage of APP leads to increased production and deposition of Aβ5‐40/42 in the AD brain, and highlight the significance of amino‐truncated Aβ in the pathogenesis of AD.
Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension
Authors: Xu Weiling , Kaneko F. Takao , Zheng Shuo , Comhair Suzy A. A. , Janocha Allison J. , Goggans Tannishia , Thunnissen Frederik B. J. M. , Farver Carol , Hazen Stanley L. , Jennings Constance , Dweik Raed A. , Arroliga Alejandro C. , Erzurum Serpil C.
Published: September 2004

Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I–III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high‐level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.
Analytic solutions of the radiation modes problem and the active control of sound power
Authors: Maury Cedric , Elliott Stephen J.
Published: September 2004

This paper explores the common mathematical foundation of two different problems: the first one arises in electrical engineering for the detection and the spectral estimation of signals in noise and the second one appears in acoustics for the calculation of the acoustic radiation modes of rectangular structures. Although apparently unrelated, it is found that both applications draw on the so–called concentration problem: of determining which functions that are band–limited in one domain have maximal energy concentration within a region of the transform domain. The analytic solutions to problems of this form are seen to involve prolate spheroidal wave functions. In particular, exact expressions are given for the radiation efficiencies and shapes of the radiation modes of a baffled beam as well as their asymptotics. It is shown that a generalization of the concentration problem to the two–dimensional case provides analytic solutions that solve with a good accuracy, although approximately, the radiation problem. The properties of these special functions provide a rigorous basis of understanding some previously observed features of these applications, namely the grouping property of the radiation modes of a baffled panel and the physical limitations for the active control of sound from a panel.
Wetting of rough surfaces: a homogenization approach
Authors: Alberti Giovanni , DeSimone Antonio
Published: September 2004

The contact angle of a drop in equilibrium on a solid is strongly affected by the roughness of the surface on which it rests. We study the roughness–induced enhancement of the hydrophobic or hydrophilic properties of a solid surface through homogenization theory. By relying on a variational formulation of the problem, we show that the macroscopic contact angle is associated with the solution of two cell problems, giving the minimal energy per unit macroscopic area for a transition layer between the rough solid surface and a liquid or vapour phase. Our results are valid for both chemically heterogeneous and homogeneous surfaces. In the latter case, a very transparent structure emerges from the variational approach: the classical laws of Wenzel and Cassie–Baxter give bounds for the optimal energy, and configurations of minimal energy are those leading to the smallest macroscopic contact angle in the hydrophobic case, to the largest one in the hydrophilic case.
Human, Mouse, and Rat Genome Large-Scale Rearrangements: Stability Versus Speciation
Authors: Zhao Shaying , Shetty Jyoti , Hou Lihua , Delcher Arthur , Zhu Baoli , Osoegawa Kazutoyo , de Jong Pieter , Nierman William C. , Strausberg Robert L. , Fraser Claire M.
Published: September 2004

Using paired-end sequences from bacterial artificial chromosomes, we have constructed high-resolution synteny and rearrangement breakpoint maps among human, mouse, and rat genomes. Among the >300 syntenic blocks identified are segments of over 40 Mb without any detected interspecies rearrangements, as well as regions with frequently broken synteny and extensive rearrangements. As closely related species, mouse and rat share the majority of the breakpoints and often have the same types of rearrangements when compared with the human genome. However, the breakpoints not shared between them indicate that mouse rearrangements are more often interchromosomal, whereas intrachromosomal rearrangements are more prominent in rat. Centromeres may have played a significant role in reorganizing a number of chromosomes in all three species. The comparison of the three species indicates that genome rearrangements follow a path that accommodates a delicate balance between maintaining a basic structure underlying all mammalian species and permitting variations that are necessary for speciation.
A Novel Class of Mammalian-Specific Tailless Retropseudogenes
Authors: Schmitz Jürgen , Churakov Gennady , Zischler Hans , Brosius Jürgen
Published: September 2004

In addition to their central function in protein biosynthesis, tRNAs also play a pervasive role in genome evolution and architecture because of their extensive ability to serve as templates for retroposition. Close to half of the human genome consists of discernible transposable elements, a vast majority of which are derived from RNA via reverse transcription and genomic integration. Apart from the presence of direct repeats (DRs) that flank the integrated sequence of retroposons, genomic integrations are usually marked by an oligo(A) tail. Here, we describe a novel class of retroposons that lack A-tails and are therefore termed tailless retropseudogenes. Analysis of ∼2500 tRNA-related young tailless retropseudogene sequences revealed that they comprise processed and unprocessed (pre-)tRNAs, 3′-truncated in their loop regions, or truncated tRNA-derived SINE RNAs. Surprisingly, their mostly nonrandom integration is dependent on the priming of reverse transcription at sites determined by their 3′-terminal 2-18 nucleotides and completely independent from oligoadenylation of the template RNA. Thus, tailless retropseudogenes point to a novel, variant mechanism for the biogenesis of retrosequences.
Pattern of Sequence Variation Across 213 Environmental Response Genes
Authors: Livingston Robert J. , von Niederhausern Andrew , Jegga Anil G. , Crawford Dana C. , Carlson Christopher S. , Rieder Mark J. , Gowrisankar Sivakumar , Aronow Bruce J. , Weiss Robert B. , Nickerson Deborah A.
Published: September 2004

To promote the clinical and epidemiological studies that improve our understanding of human genetic susceptibility to environmental exposure, the Environmental Genome Project (EGP) has scanned 213 environmental response genes involved in DNA repair, cell cycle regulation, apoptosis, and metabolism for single nucleotide polymorphisms (SNPs). Many of these genes have been implicated by loss-of-function mutations associated with severe diseases attributable to decreased protection of genomic integrity. Therefore, the hypothesis for these studies is that individuals with functionally significant polymorphisms within these genes may be particularly susceptible to genotoxic environmental agents. On average, 20.4 kb of baseline genomic sequence or 86% of each gene, including a substantial amount of introns, all exons, and 1.3 kb upstream and downstream, were scanned for variations in the 90 samples of the Polymorphism Discovery Resource panel. The average nucleotide diversity across the 4.2 MB of these 213 genes is 6.7 × 10-4, or one SNP every 1500 bp, when two random chromosomes are compared. The average candidate environmental response gene contains 26 PHASE inferred haplotypes, 34 common SNPs, 6.2 coding SNPs (cSNPs), and 2.5 nonsynonymous cSNPs. SIFT and Polyphen analysis of 541 nonsynonymous cSNPs identified 57 potentially deleterious SNPs. An additional eight polymorphisms predict altered protein translation. Because these genes represent 1% of all known human genes, extrapolation from these data predicts the total genomic set of cSNPs, nonsynonymous cSNPs, and potentially deleterious nonsynonymous cSNPs. The implications for the use of these data in direct and indirect association studies of environmentally induced diseases are discussed.
Sir Walter Scott: the reference companion
Authors: Day Alan
Published: September 2004

Outlines the aims, purposes and contents of the various reference guides to the manuscripts, poems and novels of Sir Walter Scott, to the dramatizations of the novels, to contemporary and subsequent reviews and critiques of his literary work, and to bibliographical studies.
Introduction: Britain's new deals
Authors: Fraser Neil
Published: September 2004

This paper introduces the active labour market policies or job search policies in the UK known as the New Deal, a major part of the Labour Government's package of welfare‐to‐work policies. Topics covered include estimates of their overall impact on employment; their limited effectiveness with disadvantaged job‐seekers, including increasing numbers of inactive, but not formally unemployed, people; and debates about these policies in relation to skill needs and areas of job decline.
New deal option effects on employment entry and unemployment exit
Authors: Lissenburgh Stephen
Published: September 2004

This paper uses propensity score matching techniques to evaluate the impact of new deal options on the chances of exiting unemployment for a cohort of entrants to the new deal for young people in Scotland between September 1998 and February 1999. The paper uses information from the new deal evaluation database and from a two‐stage survey based on a random sample of the cohort. It finds that the employment option was the most effective of the new deal options, both in terms of increasing the likelihood of exit from unemployment by February 2001 and increasing the amount of time spent off by JSA from February 2000 to February 2001. Remaining on the Gateway was the next most effective route for clients to take with regard to reducing the amount of time spent on JSA and increasing the likelihood of JSA exit.
Improving inter‐functional coordination to face high product variety and frequent modifications
Authors: Danese Pamela , Romano Pietro
Published: September 2004

In an effort to better respond to heterogeneous customer needs, an increasing number of companies in different sectors deal with the combination of high variety and frequent product changes/modifications. This entails planning, designing, purchasing and manufacturing activities and exacerbates the alignment of Sales, Production Planning and Engineering goals. This paper aims to suggest a way of improving coordination between such functional areas in contexts characterised by high variety and frequent product changes. Based on the data from an action Research study, a method for taking the contrasting requests of Sales, Production Planning and Engineering into account simultaneously and to facilitate the coordination of their activities is developed. It leverages Modular Bills and product modularity to improve inter‐functional coordination. Initial indications are promising. However, given the specific nature of the studied case, further research is required to evaluate the generalizability of the findings.
Emergent change and planned change – competitors or allies?
Authors: Burnes Bernard
Published: September 2004

In a fast‐moving and unpredictable world, there can be little doubt that organizational change is one of the most important issues facing organizations. This is especially so, when it is claimed that over 60 per cent of all change projects are considered to fail. Not surprisingly, therefore, there is also much debate about which approach to change is the best. Over the past 20 years, the emergent approach appears to have superseded the planned approach as the most appropriate. However, as this paper will argue, the idea that planned and emergent changes are competing approaches, rather than complementary, is contestable. This paper looks at the case of XYZ construction which, between 1996 and 2000, used both emergent and planned approaches to transform itself. The paper concludes that organizations need to avoid seeking an “one best way” approach to change and instead seek to identify the approach which is best suited to both type of changes they wish to undertake, according to the organization's context.
Critical success factors in UK budget hotel operations
Authors: Brotherton Bob
Published: September 2004

This study explores the nature of critical success factors (CSFs) in UK budget hotel operations through a questionnaire survey designed to ascertain the relevance and importance of a range of factors referred to as critical in the extant academic and trade literature. From a usable sample of 239 questionnaires the results show that budget hotel unit managers from the leading brands largely agree with the criticality of the factors stated in the literature, this being verified via the independent t‐test and reliability analysis results that show most of the CSFs to be highly statistically significant (p<0.001) and the set of CSF items to be consistent (α=0.9360). The data analysis, via principal components analysis, also facilitates the creation of a parsimonious model that identifies two dimensions and five CSFs as being the “most critical”.
Leadership style and post‐merger satisfaction
Authors: Joyce Covin Teresa , Kolenko Thomas A. , Sightler Kevin W. , Tudor R. Keith
Published: September 2004

Explores the relationship between leadership style and post‐merger satisfaction, noting from the results that leadership style is significantly related to merger satisfaction for both acquiring and acquired firm employees, but that effective leadership style profiles vary for these two groups of employees. Shows that, for acquiring firm employees, the use of reward power is the strongest predictor of merger satisfaction, while merger satisfaction for acquired firm employees is most closely associated with transformational leadership. Suggests that appropriate leadership style can greatly enhance merger effectiveness.
Relationships between various measurements of workplace performance
Authors: Savery Lawson K. , Soutar Geoffrey N.
Published: September 2004

Considers the relationship between various measurements of workplace performance. Examines data collected from 2,004 workplaces in the Australian Workplace Industrial Relations Survey. Identifies three groups, the first of which, just over half of the sample, was named the “successful internal group” because it had the lowest rate of return and the lowest industrial activity. The second group, approximately one‐third of the sample, had the highest rate of return and a similar level of industrial activity to that of the first group and was called the “successful both internal and external” group. The third group, approximately one‐sixth of the sample, had the highest level of industrial action, the second highest rate of return but the worst relationships between management and employees, and was designated the “successful external group”. The “successful internal” and the “successful internal and external” groups tended to occupy smaller, white‐collar workplaces and to employ a greater percentage of women.
Importers' relationships with exporters: does culture matter?
Authors: Ha Jungbok , Karande Kiran , Singhapakdi Anusorn
Published: September 2004

A model is presented that explains how importers' perceptions of five aspects of their relationship with an exporter (trust, dependence, cooperation, satisfaction, and commitment) are related at any point in time. The structure‐conduct‐outcomes and relationship marketing literature in distribution channels provides the theoretical background for the model. Specifically, this study investigates whether a model based on studies carried out mainly in the US and in a Western setting applies in the Eastern setting of Korea. Further, whether differences exist in the relationship structures of importers when the exporters are from a similar cultures as opposed to dissimilar cultures is investigated. Results based on data from 198 Korean importers indicate that the model is supported. However, there are no differences in the relationship structures between exporters from similar and dissimilar cultures. Managerial implications, limitations, and recommendations for future research are also offered.