bluuebunny/crossref_metadata_2025 huggingface dataset:
An integrated hydrologic Bayesian multimodel combination framework: Confronting input, parameter, and model structural uncertainty in hydrologic prediction
Authors: Ajami Newsha K. , Duan Qingyun , Sorooshian Soroosh
Published: January 2007

The conventional treatment of uncertainty in rainfall‐runoff modeling primarily attributes uncertainty in the input‐output representation of the model to uncertainty in the model parameters without explicitly addressing the input, output, and model structural uncertainties. This paper presents a new framework, the Integrated Bayesian Uncertainty Estimator (IBUNE), to account for the major uncertainties of hydrologic rainfall‐runoff predictions explicitly. IBUNE distinguishes between the various sources of uncertainty including parameter, input, and model structural uncertainty. An input error model in the form of a Gaussian multiplier has been introduced within IBUNE. These multipliers are assumed to be drawn from an identical distribution with an unknown mean and variance which were estimated along with other hydrological model parameters by a Monte Carlo Markov Chain (MCMC) scheme. IBUNE also includes the Bayesian model averaging (BMA) scheme which is employed to further improve the prediction skill and address model structural uncertainty using multiple model outputs. A series of case studies using three rainfall‐runoff models to predict the streamflow in the Leaf River basin, Mississippi, are used to examine the necessity and usefulness of this technique. The results suggest that ignoring either input forcings error or model structural uncertainty will lead to unrealistic model simulations and incorrect uncertainty bounds.
Anomalous rainfall and associated atmospheric circulation in the northeast Spanish Mediterranean area and its relationship to sediment fluidization events in a lake
Authors: Soler Marianna , Serra Teresa , Colomer Jordi , Romero Romualdo
Published: January 2007

Changes in the dynamics of sediment transport in a Mediterranean lake (sediment fluidization events) are linked to atmospheric circulations patterns (trough monthly precipitation). In the basins of Lake Banyoles, located in the northeast of Spain, water enters mainly through subterranean springs, and associated fluctuations in the vertical migration of sediment distribution (fluidization events) present episodic behavior as a result of episodic rainfall in the area. The initiation of the fluidization events takes place when the monthly rainfall is ∼2.7 times greater than the mean monthly rainfall of the rainiest months in the area, especially in spring (April and May), October, and December. The duration of these events is found to be well correlated with the accumulated rainfall of the preceding 10 months before the process initiation. The rainfall, in turn, is mainly associated with six atmospheric circulation patterns among the 19 fundamental circulations that emerged in an earlier study focused on significant rainfall days in Mediterranean Spain. Among them, accentuated surface lows over the northeast of Spain, general northeasterly winds by low pressure centered to the east of Balearic Islands and short baroclinic waves over the Iberian Peninsula, with easterly flows over the northeastern coast of Spain, are found the most relevant atmospheric circulations that drive heavy rainfall events.
Release of mercury from Rocky Mountain forest fires
Authors: Biswas Abir , Blum Joel D. , Klaue Bjoern , Keeler Gerald J.
Published: January 2007

Concentrations of mercury (Hg) in soil profiles and vegetation were examined in unburned areas and in areas recently burned by wildfires of low, medium, and high fire severities in western Wyoming. Paired unburned and burned sampling sites with similar tree species composition, forest stand age, climate, and geological substrate were studied. Results indicate that Hg release from forest fires is dependent on the tree species composition of the forest, which affects prefire Hg accumulation, as well as the forest fire severity. On the basis of an average of 2.7 × 106 ha of forest and shrubland burned annually in the United States we estimate that wildfires and prescribed burns in the United States release 19 to 64 × 106g of Hg annually. This represents between 13 and 42% of the estimated United States anthropogenic Hg flux of 150 × 106g.
Radiative forcing due to stratospheric water vapour from CH4 oxidation
Authors: Myhre Gunnar , Nilsen Jørgen S. , Gulstad Line , Shine Keith P. , Rognerud Bjørg , Isaksen Ivar S. A.
Published: January 2007

Here we report on estimates of the changes in stratospheric water vapour (SWV) due to methane oxidation based on observational data. Above the tropopause oxidation of methane results in a decrease in its mixing ratio with altitude and this is a major source for SWV. The vertical profile of SWV changes from methane oxidation is presented here using satellite observations of the vertical profile of methane. Trends in the SWV are shown to be small in the lower stratosphere, but can reach 0.7 ppbv at 30 km at high latitudes over the period 1950–2000. The radiative forcing for this indirect effect of methane increase over the industrial era is estimated to be slightly weaker than 0.1 Wm−2 which implies a larger contribution of water vapour to the methane global warming potential than used in recent Intergovernmental Panel on Climate Change assessments. Our estimate considers only chemical changes and not SWV of dynamical causes. Importantly, we find substantial differences in the temperature change in the stratosphere for a homogeneous change in SWV and SWV change from methane oxidation. This has implications for trend analysis of SWV and understanding and attribution of the stratospheric temperature trend.
Diurnal variability of the gyro resonance line observed with the Arecibo incoherent scatter radar at E‐ and F1‐region altitudes
Authors: Janches Diego , Nicolls Michael J.
Published: January 2007

In this paper, we report on observations of the diurnal variation of a resonance line that occurs near the gyro frequency as seen with the incoherent scatter radar (ISR) at the Arecibo Observatory. This gyro resonance line has rarely been observed in ISR data, but recent results, exemplified by the observations of Bhatt et al. (2006), have implied that the gyro line is a common ionospheric feature. The observations presented here were made with much better altitude resolution in comparison with previous results and represent full 24 hour coverage for several days. The data indicate that an increase in the gyro line intensity near sunrise and sunset is an everyday occurrence. As the increase in intensity is occurring at sunset, the gyro line frequency drops from the expected frequency to one near zero frequency. As the increase in intensity is occurring at sunrise, the gyro line frequency increases from near zero frequency to one near the expected gyro line frequency. This behavior of the gyro line frequency and intensity has not been observed before. We explain these results using normal Maxwellian incoherent scatter theory together with the diurnal variation of the density in the E and F1 regions. These results may explain previous observations of the gyro line made at Arecibo and suggest avenues of future research for studying this exciting feature of the incoherent scatter spectrum.
Late Cenozoic bending of the Bolivian Andes: New paleomagnetic and kinematic constraints
Authors: Barke Richard , Lamb Simon , MacNiocaill Conall
Published: January 2007

New paleomagnetic measurements of essentially undeformed Late Cenozoic volcanic rocks in the Bolivian Andes, South America, constrain rigid body rotations about vertical axes during the last ∼13 Myr on both limbs of the Bolivian orocline in the Eastern Cordillera. Thermal and alternating field demagnetization was carried out on samples from 52 sites in three major volcanic complexes: (1) 13–2 Ma Los Frailes ignimbritic volcanics, outcropping at ∼19.5°S; (2) 9–5 Ma Morococala ignimbritic volcanics, outcropping at ∼18°S; and (3) 13–5 Ma shoshonitic to acidic lavas and intrusives, outcropping at ∼17.5°S. Well‐defined magnetic components were isolated, which are interpreted to represent the Earth's magnetic field at the time of volcanic activity. The mean magnetic vector for site groupings suggests regional tectonic rotations about vertical axes, with respect to stable South America, of 10° ± 8 clockwise for the 13–2 Ma Los Frailes volcanic complex (8° ± 9° clockwise for only the Miocene (13–5 Ma) Los Frailes volcanics), and 1° ± 18° anticlockwise for the combined 13–5 Ma Morococala and Eucalyptus volcanic complexes. These data are consistent with observed shortening gradients on the eastern margin of the Bolivian Andes, in the sub‐Andean zone, suggesting rotation and shortening are synchronous. A joint inversion for both tectonic rotation and the amount of shortening, assuming a linear variation in the amount of rotation along the length of the southern limb of the Bolivian orocline, shows that rotation of the Eastern Cordillera in the last 10–15 Myr, relative to stable South America, varies from zero at the oroclinal hinge, at ∼18°S, to a maximum of ∼13.5° clockwise at ∼22°S, decreasing to zero, south of 23°S, with an average rotation in the range 5° to 10° clockwise. Concomitant with this, shortening in the sub‐Andean zone decreases from a maximum of ∼86 km at the oroclinal hinge, to ∼47 km at 22°S, and then ∼33 km at 23°S. The lack of evidence for large‐scale internal faulting in the Eastern Cordillera since ∼9 Ma suggests either bending of the Eastern Cordillera was accommodated by more distributed small‐scale faulting or that relative rotation here mainly occurred prior to ∼9 Ma. The small average rotation of the Eastern Cordillera, on the southern limb of the orocline, is consistent with only very small rotation (<10°) of the forearc region in northern Chile during the last ∼20 Myr. Rotation of the northern limb is less well constrained, but it is also likely to be small (<5°) and anticlockwise.
Anomalous diffusion in two‐dimensional Euclidean and prefractal geometrical models of heterogeneous porous media
Authors: Kim Jung‐Woo , Perfect Edmund , Choi Heechul
Published: January 2007

Disordered systems are known to induce anomalous diffusion. This phenomenon may be important for environmental applications such as contaminant transport and nutrient availability. However, few studies have investigated anomalous diffusion in this context. In particular, the relationship between pore space geometry and anomalous diffusion is not well understood. We report on numerical simulations of solute diffusion within the water‐filled pore spaces of two‐dimensional geometrical models of heterogeneous porous media. Euclidean and mass, pore, and pore‐solid prefractal lattices were used to generate random pore networks with varying porosity (ϕ) and lacunarity (L). The objectives were to investigate the effects of ϕ and L on the solute random walk dimension (dw) and to identify which of these models best represents a natural porous medium. Solute diffusion was simulated using a stochastic cellular automaton based on the “myopic ant” algorithm. Estimates of dw ≫ 2 occurred with increasing frequency as ϕ → 0, indicating scale dependency in the standard diffusion coefficient at low porosities. The relationship between dw and ϕ for the mass and pore‐solid prefractal lattices was the closest to that for natural 2‐D systems (i.e., soil thin sections). The presence of large, interconnected pore spaces (L → 1) at low porosities reduced the intensity of anomalous diffusion (dw → 2). A power law relationship based on the product of dw and L explained >96% of the total variation in ϕ regardless of the type of lattice considered. The potential predictive capability of this approach for natural porous media deserves further investigation.
Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy
Authors: Goldberg A.L.
Published: January 2007

This review focuses on recent insights into the mechanisms and the biological functions of the proteasome. This large ATP-dependent proteolytic complex is the main site for protein degradation in mammalian cells and catalyses the rapid degradation of ubiquitinated proteins, and is the source of most antigenic peptides used by the immune system to screen for viruses and cancer. ATP is required to unfold globular proteins to open the gated channel into the 20S proteasome and to facilitate protein translation into it. Inhibitors of its proteolytic activity are widely used as research tools and have proven effective in cancer therapy.
Activated macrophages require T cells for xenograft rejection under the kidney capsule
Authors: Zhan Yifan , Brady Jamie L , Irawaty Windy , Thomas Helen E , Kay Thomas W , Lew Andrew M
Published: January 2007

Transplantation of tissues from other species has been advocated as a way to overcome the extreme shortage of human donors. Rejection, however, remains a major hurdle for clinical xenotransplantation. Although activation of macrophages by T cells is critical for the cellular rejection of xenografts, what other important interactions between these two types of cells remain less defined. When we activated macrophages of immunodeficient mice (SCID or Rag−/−) using interferon‐γ and lipopolysacharide, xenogeneic cells were rejected by activated macrophages in the peritoneal cavity (which has an abundance of resident macrophages), but were not rejected under the kidney capsule (which requires the recruitment of effectors). This difference between the two sites implies that activated macrophages are inefficient for self‐recruitment to peripheral graft sites and that T cells may still be required for the process. To test this hypothesis further, immunodeficient mice that had received xenogeneic cells were infused with peritoneal exudate cells (containing activated macrophages and activated T cells) from preimmunized immunocompetent mice. Xenogeneic cells at both the kidney capsule and peritoneal sites were rejected soon after cell transfer. However, when the exudate cells were transferred into SCID recipients that first had been injected with T cell depleting antibodies, xenograft rejection was only prominent at the peritoneal site but not kidney capsule site. These results argue that activated macrophages (as the result of T cell activation) still require T cells for xenograft rejection at peripheral sites.
ScentIndex and ScentHighlights: Productive Reading Techniques for Conceptually Reorganizing Subject Indexes and Highlighting Passages
Authors: Chi Ed H. , Hong Lichan , Heiser Julie , Card Stuart K. , Gumbrecht Michelle
Published: January 2007

A great deal of analytical work has been carried out in the context of reading, in digesting the semantics of the material, the identification of important entities, and capturing the relationship between entities. Visual analytic environments, therefore, must encompass reading tools that enable the rapid digestion of large amounts of reading material. Other than plain text search, subject indexes, and basic highlighting, tools are needed for rapid foraging of the text. In this paper, we describe a technique that presents an enhanced subject index for a book by conceptually reorganizing it to suit particular expressed user information needs. Users first enter information needs via keywords, describing the concepts they are trying to retrieve and comprehend. Then our system, called ScentIndex, computes what index entries are conceptually related, and reorganizes and displays these index entries on a single page. We provide a number of navigational cues to help users peruse over this list of index entries and find relevant passages quickly. We report some initial results in a new technique called ScentHighlights that enhances skimming activity by conceptually highlighting sentences. Both use similar techniques by computing what conceptual keywords are related to each other via word co-occurrence and spreading activation. Compared to regular reading of a paper book, our study showed that users are more efficient and more accurate in finding, comparing, and comprehending material in our system.
Ewall: A Visual Analytics Environment for Collaborative Sense-Making
Authors: Keel Paul E.
Published: January 2007

We introduce EWall, an experimental visual analytics environment for the support of remote-collaborative sense-making activities. EWall is designed to foster and support ‘ object focused thinking’, where users represent and understand information as objects, construct and recognize contextual relationships among objects, as well as communicate through objects. EWall also offers a unified infrastructure for the implementation and testing of computational agents that consolidate user contributions and manage the flow of information among users through the creation and management of a ‘ virtual transactive memory’. EWall users operate their individual graphical interfaces to collect, abstract, organize and comprehend task-relevant information relative to their areas of expertise. A first type of computational agents infers possible relationships among information items through the analysis of the spatial and temporal organization and collaborative use of information. All information items and relationships converge in a shared database. A second type of computational agents evaluates the contents of the shared database and provides individual users with a customized selection of potentially relevant information. A learning mechanism allows the computational agents to adapt to particular users and circumstances. EWall is designed to enable individual users to navigate vast amounts of shared information effectively and help remotely dispersed team members combine their contributions, work independently without diverting from common objectives, and minimize the necessary amount of verbal communication.
Off-resonance surface plasmon enhanced spontaneous emission from CdTe quantum dots
Authors: Komarala Vamsi K. , Rakovich Yury P. , Bradley A. L. , Byrne Stephen J. , Gun’ko Yurii K. , Gaponik N. , Eychmüller A.
Published: January 2007

Surface plasmon (SP) enhanced photoluminescence (PL) from CdTe quantum dots (QDs) on monolayers of Au nanoparticles is investigated under both resonant and nonresonant conditions. Enhancement of the QD PL intensity is observed when the emission spectrum is redshifted with respect to the SP absorption resonance. Coupling to the SPs results in a redshift and broadening of the PL spectrum, and an increase in the PL decay rate. The largest coupling is observed for QD monolayers with peak emission at 667nm, producing a ten fold increase in PL intensity. No change in PL intensity and decay rate is observed at the SP resonance.
Atmospheric pressure microplasma jet as a depositing tool
Authors: Benedikt J. , Focke K. , Yanguas-Gil A. , von Keudell A.
Published: January 2007

An atmospheric pressure microplasma jet is developed for depositing homogeneous thin films from C2H2. The adjustment of the gas flow through the microplasma jet assures optimal flow conditions as well as minimizes deposition inside the jet. In addition, the formation of an argon boundary layer surrounding the emerging plasma beam separates the ambient atmosphere from the flow of growth precursor. Thereby the incorporation of nitrogen and oxygen from the ambient atmosphere into the deposited film is suppressed. Soft polymerlike hydrogenated amorphous carbon (a-C:H) films are deposited at the rate of a few nm/s on the area of a few square millimeters.
Control of self-collimated Bloch waves by partially flat equifrequency contours in photonic crystals
Authors: Kim Ahyoung , Chung K. B. , Wu J. W.
Published: January 2007

Self-collimation effects in photonic crystals are generally investigated by employing flat equifrequency contours. Here we report, based on a partially flat equifrequency contour inducing two different group velocity vectors, the simultaneous excitation of dual self-collimated beams and the selective excitation of either of them by varying the incident angle or the width of an input Gaussian beam. With combination of the finite-difference time-domain simulation and the Fourier analysis as well as the wave vector diagram, we analyze the refractive behaviors of these self-collimated Bloch waves.
White electroluminescence from C- and Si-rich thin silicon oxides
Authors: Jambois O. , Garrido B. , Pellegrino P. , Carreras Josep , Pérez-Rodríguez A. , Montserrat J. , Bonafos C. , BenAssayag G. , Schamm S.
Published: January 2007

White electroluminescence from carbon- and silicon-rich silicon oxide layers is reported. The films were fabricated by Si and C ion implantation at low energy in 40nm thick SiO2, followed by annealing at 1100°C. Structural and optical studies allow assigning the electroluminescence to Si nanocrystals for the red part of the spectrum, and to C-related centers for the blue and green components. The external efficiency has been estimated to 10−4%. Electrical characteristics show a Fowler-Nordheim behavior for voltages above 25V, corresponding to the onset of electroluminescence. This suggests that light emission is related to the impact ionization of radiative centers.
Detecting and assessing macrophages
in vivo
to evaluate atherosclerosis noninvasively using molecular MRI
Authors: Amirbekian Vardan , Lipinski Michael J. , Briley-Saebo Karen C. , Amirbekian Smbat , Aguinaldo Juan Gilberto S. , Weinreb David B. , Vucic Esad , Frias Juan C. , Hyafil Fabien , Mani Venkatesh , Fisher Edward A. , Fayad Zahi A.
Published: January 2007

We investigated the ability of targeted immunomicelles to detect and assess macrophages in atherosclerotic plaque using MRI
in vivo
. There is a large clinical need for a noninvasive tool to assess atherosclerosis from a molecular and cellular standpoint. Macrophages play a central role in atherosclerosis and are associated with plaques vulnerable to rupture. Therefore, macrophage scavenger receptor (MSR) was chosen as a target for molecular MRI. MSR-targeted immunomicelles, micelles, and gadolinium–diethyltriaminepentaacetic acid (DTPA) were tested in ApoE−/− and WT mice by using
in vivo
MRI. Confocal laser-scanning microscopy colocalization, macrophage immunostaining and MRI correlation, competitive inhibition, and various other analyses were performed.
In vivo
MRI revealed that at 24 h postinjection, immunomicelles provided a 79% increase in signal intensity of atherosclerotic aortas in ApoE−/− mice compared with only 34% using untargeted micelles and no enhancement using gadolinium–DTPA. Confocal laser-scanning microscopy revealed colocalization between fluorescent immunomicelles and macrophages in plaques. There was a strong correlation between macrophage content in atherosclerotic plaques and the matched
in vivo
MRI results as measured by the percent normalized enhancement ratio. Monoclonal antibodies to MSR were able to significantly hinder immunomicelles from providing contrast enhancement of atherosclerotic vessels
in vivo
. Immunomicelles provided excellent validated
in vivo
enhancement of atherosclerotic plaques. The enhancement seen is related to the macrophage content of the atherosclerotic vessel areas imaged. Immunomicelles may aid in the detection of high macrophage content associated with plaques vulnerable to rupture.
Rhomboid protease AarA mediates quorum-sensing in
Providencia stuartii
by activating TatA of the twin-arginine translocase
Authors: Stevenson Lindsay G. , Strisovsky Kvido , Clemmer Katy M. , Bhatt Shantanu , Freeman Matthew , Rather Philip N.
Published: January 2007

The
Providencia stuartii
AarA protein is a member of the rhomboid family of intramembrane serine proteases and is required for the production of an unknown quorum-sensing molecule. In a screen to identify rhomboid-encoding genes from
Proteus mirabilis
,
tatA
was identified as a multicopy suppressor and restored extracellular signal production as well as complementing all other phenotypes of a
Prov. stuartii aarA
mutant. TatA is a component of the twin-arginine translocase (Tat) protein secretion pathway and likely forms a secretion pore. By contrast, the native
tatA
gene of
Prov. stuartii
in multicopy did not suppress an
aarA
mutation. We find that TatA in
Prov. stuartii
has a short N-terminal extension that was atypical of TatA proteins from most other bacteria. This extension was proteolytically removed by AarA both
in vivo
and
in vitro
. A
Prov. stuartii
TatA protein missing the first 7 aa restored the ability to rescue the
aarA
-dependent phenotypes. To verify that loss of the Tat system was responsible for the various phenotypes exhibited by an
aarA
mutant, a
tatC
-null allele was constructed. The
tatC
mutant exhibited the same phenotypes as an
aarA
mutant and was epistatic to
aarA
. These data provide a molecular explanation for the requirement of AarA in quorum-sensing and uncover a function for the Tat protein export system in the production of secreted signaling molecules. Finally, TatA represents a validated natural substrate for a prokaryotic rhomboid protease.
Biomimetic amplification of nanoparticle homing to tumors
Authors: Simberg Dmitri , Duza Tasmia , Park Ji Ho , Essler Markus , Pilch Jan , Zhang Lianglin , Derfus Austin M. , Yang Meng , Hoffman Robert M. , Bhatia Sangeeta , Sailor Michael J. , Ruoslahti Erkki
Published: January 2007

Nanoparticle-based diagnostics and therapeutics hold great promise because multiple functions can be built into the particles. One such function is an ability to home to specific sites in the body. We describe here biomimetic particles that not only home to tumors, but also amplify their own homing. The system is based on a peptide that recognizes clotted plasma proteins and selectively homes to tumors, where it binds to vessel walls and tumor stroma. Iron oxide nanoparticles and liposomes coated with this tumor-homing peptide accumulate in tumor vessels, where they induce additional local clotting, thereby producing new binding sites for more particles. The system mimics platelets, which also circulate freely but accumulate at a diseased site and amplify their own accumulation at that site. The self-amplifying homing is a novel function for nanoparticles. The clotting-based amplification greatly enhances tumor imaging, and the addition of a drug carrier function to the particles is envisioned.
Magnetism of rare earth intermetallics
Authors: A Szytuła
Published: January 2007

Magnetic properties of the ternary rare earth intermetallics are discussed on example of three groups of compounds RNi2X2, RNiX2and RNiX (R-rare earth metal, TX = Si, Ge). RNi2X2compounds crystallize in a tetragonal where RNiX2and RNiX in orthorhombic structures. The magnetic phase diagrams (H, T) determined for some of these compounds. The magnetic properties are analyzed in terms of the RKKY exchange interactions and crystal electric field effects.
Increased Common Fragile Site Expression, Cell Proliferation Defects, and Apoptosis following Conditional Inactivation of MouseHus1in Primary Cultured Cells
Authors: Zhu Min , Weiss Robert S.
Published: January 2007

Targeted disruption of the mouse Hus1 cell cycle checkpoint gene results in embryonic lethality and proliferative arrest in cultured cells. To investigate the essential functions of Hus1, we developed a system for the regulated inactivation of mouse Hus1 in primary fibroblasts. Inactivation of a loxP site-flanked conditional Hus1 allele by using a cre-expressing adenovirus resulted in reduced cell doubling, cell cycle alterations, and increased apoptosis. These phenotypes were associated with a significantly increased frequency of gross chromosomal abnormalities and an S-phase–specific accumulation of phosphorylated histone H2AX, an indicator of double-stranded DNA breaks. To determine whether these chromosomal abnormalities occurred randomly or at specific genomic regions, we assessed the stability of common fragile sites, chromosomal loci that are prone to breakage in cells undergoing replication stress. Hus1 was found to be essential for fragile site stability, because spontaneous chromosomal abnormalities occurred preferentially at common fragile sites upon conditional Hus1 inactivation. Although p53 levels increased after Hus1 loss, deletion of p53 failed to rescue the cell-doubling defect or increased apoptosis in conditional Hus1 knockout cells. In summary, we propose that Hus1 loss leads to chromosomal instability during DNA replication, triggering increased apoptosis and impaired proliferation through p53-independent mechanisms.
Rb is critical in a mammalian tissue stem cell population
Authors: Wenzel Pamela L. , Wu Lizhao , de Bruin Alain , Chong Jean-Leon , Chen Wen-Yi , Dureska Geoffrey , Sites Emily , Pan Tony , Sharma Ashish , Huang Kun , Ridgway Randall , Mosaliganti Kishore , Sharp Richard , Machiraju Raghu , Saltz Joel , Yamamoto Hideyuki , Cross James C. , Robinson Michael L. , Leone Gustavo
Published: January 2007

The inactivation of the retinoblastoma (Rb) tumor suppressor gene in mice results in ectopic proliferation, apoptosis, and impaired differentiation in extraembryonic, neural, and erythroid lineages, culminating in fetal death by embryonic day 15.5 (E15.5). Here we show that the specific loss of Rb in trophoblast stem (TS) cells, but not in trophoblast derivatives, leads to an overexpansion of trophoblasts, a disruption of placental architecture, and fetal death by E15.5. Despite profound placental abnormalities, fetal tissues appeared remarkably normal, suggesting that the full manifestation of fetal phenotypes requires the loss of Rb in both extraembryonic and fetal tissues. Loss of Rb resulted in an increase of E2f3 expression, and the combined ablation of Rb and E2f3 significantly suppressed Rb mutant phenotypes. This rescue appears to be cell autonomous since the inactivation of Rb and E2f3 in TS cells restored placental development and extended the life of embryos to E17.5. Taken together, these results demonstrate that loss of Rb in TS cells is the defining event causing lethality of Rb−/− embryos and reveal the convergence of extraembryonic and fetal functions of Rb in neural and erythroid development. We conclude that the Rb pathway plays a critical role in the maintenance of a mammalian stem cell population.
labA: a novel gene required for negative feedback regulation of the cyanobacterial circadian clock protein KaiC
Authors: Taniguchi Yasuhito , Katayama Mitsunori , Ito Rie , Takai Naoki , Kondo Takao , Oyama Tokitaka
Published: January 2007

In the cyanobacterium Synechococcus elongatus PCC 7942, circadian timing is transmitted from the KaiABC-based central oscillator to the transcription factor RpaA via the KaiC-interacting histidine kinase SasA to activate transcription, thereby generating rhythmic circadian gene expression. However, KaiC can also repress circadian gene expression, including its own. The mechanism and significance of this negative feedback regulation have been unclear. Here, we report a novel gene, labA (low-amplitude and bright), that is required for negative feedback regulation of KaiC. Disruption of labA abolished transcriptional repression caused by overexpression of KaiC and elevated the trough levels of circadian gene expression, resulting in a low-amplitude phenotype. In contrast, overexpression of labA significantly lowered circadian gene expression. Furthermore, genetic analysis indicated that labA and sasA function in parallel pathways to regulate kaiBC expression, whereas rpaA functions downstream from labA for kaiBC expression. These results suggest that temporal information from the KaiABC-based oscillator diverges into a LabA-dependent negative pathway and a SasA-dependent positive pathway, and then converges onto RpaA to generate robust circadian gene expression. It is likely that quantitative information of KaiC is transmitted to RpaA through LabA, whereas SasA mediates the state of the KaiABC-based oscillator.
Design principles of the proteolytic cascade governing the σE-mediated envelope stress response in Escherichia coli: keys to graded, buffered, and rapid signal transduction
Authors: Chaba Rachna , Grigorova Irina L. , Flynn Julia M. , Baker Tania A. , Gross Carol A.
Published: January 2007

Proteolytic cascades often transduce signals between cellular compartments, but the features of these cascades that permit efficient conversion of a biological signal into a transcriptional output are not well elucidated. σE mediates an envelope stress response in Escherichia coli, and its activity is controlled by regulated degradation of RseA, a membrane-spanning anti-σ factor. Examination of the individual steps in this protease cascade reveals that the initial, signal-sensing cleavage step is rate-limiting; that multiple ATP-dependent proteases degrade the cytoplasmic fragment of RseA and that dissociation of σE from RseA is so slow that most free σE must be generated by the active degradation of RseA. As a consequence, the degradation rate of RseA is set by the amount of inducing signal, and insulated from the “load” on and activity of the cytoplasmic proteases. Additionally, changes in RseA degradation rate are rapidly reflected in altered σE activity. These design features are attractive as general components of signal transduction pathways governed by unstable negative regulators.
Does the differential cost of sons and daughters lead to sex ratio adjustment in great frigatebirds Fregataminor?
Authors: Juola Frans A. , Dearborn Donald C.
Published: January 2007

Sex allocation theory predicts that if benefits of producing sons and daughters differ and outweigh the costs of sex ratio adjustment, parents should produce more of the offspring that provide them with greater fitness. Potential benefits may be more likely to outweigh costs where sexual size dimorphism and, in birds, single‐egg clutches exist. Great frigatebirds Fregataminor are seabirds in which females are larger than males and clutch size is one egg. In our study population, sexual size dimorphism develops primarily during the period of complete juvenile dependence on parental care, consistent with a higher cost of producing daughters than sons. Over the course of the 1998 breeding season there was a shift from early season prevalence of daughters to late‐season prevalence of sons. Variation in food availability at time of egg laying, as indexed by sea surface temperature (SST), was a strong predictor of offspring sex in 1998. In contrast, SST in 2003 was not a predictor of offspring sex, nor was there a seasonal shift in the hatching sex ratio, despite a seasonal shift in SST. Besides food availability, we tested two additional factors in 2003 that could explain sex ratio adjustment in relation to the cost of reproduction. Offspring sex in 2003 was not related to natural or experimentally induced variation in maternal body condition; pre‐laying food supplements raised the body condition of females at the time of egg laying but did not affect offspring sex or egg mass. In addition, offspring sex was not predicted by the length of maternal telomere restriction fragments (TRFs), an index of age and possibly of reproductive experience. Broad confidence intervals on effect size suggest that undetected effects of maternal condition on offspring sex ratio could easily exist, but confidence intervals were narrower on the non‐significant effects of SST and TRF length on offspring sex ratio. The cause of different seasonal patterns of hatching sex ratio and different SST effects in 1998 and 2003 is unclear.
Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies
Authors: Lalazar Gadi , Rund Deborah , Shouval Daniel
Published: January 2007

The prevalence of hepatitis B virus (HBV) infection in patients with haematological malignancies is increased compared with the general population worldwide. HBV reactivation is common following chemotherapy and is associated with a high mortality despite prompt anti‐viral treatment. HBV reactivation may necessitate interruption of chemotherapy with adverse prognostic consequences for the haematological disease. Chemotherapy‐induced immune suppression may lead to increased HBV replication. Immune reconstitution within the weeks and months following recovery from chemotherapy may be associated with a flare of hepatitis B manifested by hepatocellular injury. Risk factors associated with HBV reactivation include detectable hepatitis B surface antigen (HBsAg), HBV DNA, Hepatitis B e (HBeAg) antigen, antibodies to hepatitis B core antigen (anti‐HBc), treatment with corticosteroids, young age and male gender. Lamivudine is effective during HBV reactivation due to immune suppression. Clinical trials have demonstrated that pre‐emptive antiviral treatment with lamivudine is superior to deferred treatment. Current recommendations emphasise screening for HBV infection in all haematology patients, particularly prior to chemotherapy. Patients who are HBsAg positive or HBV DNA positive should receive pre‐emptive treatment with lamivudine before chemotherapy. The duration of lamivudine treatment may be prolonged commensurate with the degree of immunosuppression. HBV naïve patients should be immunised against hepatitis B, as should haematopoietic stem cell donors. In summary, overt and occult HBV pose a serious, but preventable, threat. Pre‐treatment screening of patients at risk should be practiced diligently by all clinicians that treat patients with malignancies.
Profile of polymorphisms of drug‐metabolising enzymes and the risk of therapy‐related leukaemia
Authors: Bolufer Pascual , Collado Maria , Barragan Eva , Calasanz María‐José , Colomer Dolors , Tormo Mar , González Marcos , Brunet Salut , Batlle Montserrat , Cervera José , Sanz Miguel‐Angel
Published: January 2007

Therapy‐related acute myeloid leukaemia/myelodysplastic syndrome (t‐AML/t‐MDS) results from an impaired ability to detoxify chemotherapeutic drugs or repair drug‐induced genetic damage caused by genetic polymorphisms in enzymes involved in the metabolism of drugs. We analysed the prevalence of genetic polymorphisms of CYP1A1*2A(T6235C), CYP2E1*5B(C‐1019T), CYP3A4*1B(A‐290G), del{GSTT1}, del{GSTM1}, NQO1*2(C609T), MTHFR(C677T) and TYMS 2R/3R in 78 t‐AML/t‐MDS and 458 normal individuals (control group, CG) using real‐time and conventional polymerase chain reaction (PCR)‐based methods. The incidences of polymorphisms among t‐AML/t‐MDS patients and CG individuals were similar. However, a polymorphism profile consisting of CYP1A1*2A, del{GSTT1} and NQO1*2 strongly modified the risk of t‐AML/t‐MDS. The absence of all three polymorphisms decreased the risk of t‐AML/t‐MDS 18‐fold (odds ratio (OR) = 0·054, 95% confidence interval (CI) = 0·005–0·63, P = 0·02), whereas the presence of only NQO1*2 or all three polymorphisms enhanced the risk of t‐AML/t‐MDS (OR = 2·09, 95% CI = 1·08–4·03, P = 0·03 and OR = 18·42, 95% CI = 1·59–212·76, P = 0·02 respectively). Thus, the profiles of genetic polymorphisms of drug‐metabolising enzymes might explain the increased risk to t‐AML/t‐MDS observed in some patients treated with polychemotherapy.
A new deletion defect leading to α‐thalassaemia in a large Dutch Caucasian family
Authors: Nooitgedagt J. E. , Harteveld C. L. , Starreveld J. S. , Versteegh F. G. A. , Giordano P. C.
Published: January 2007

α‐thalassaemia is a common inherited haemoglobin disorder that can cause only mild symptoms in carriers and is often either not diagnosed or mistaken for iron deficiency anaemia in the Netherlands. Although considered rare in North‐Europeans, we also regularly observe common and rare defects in this population. It is important to be alert for the mild symptoms of these carriers because compound heterozygous and homozygous combinations can result in intermediate, severe or fatal disease in the progeny of healthy carriers. Using a new technical application, a novel α°‐thalassaemia deletion was recently detected in our laboratories in a propositus of a large Dutch Caucasian family. We report the phenotypic and molecular study of this new form of α°‐thalassaemia (called ‐ ‐OHα‐thalassaemia deletion), which was observed in 10 of the 19 individuals studied in the index family. Our results indicate that the frequency of these unsuspected α°‐thalassaemia defects is probably underestimated in the Netherlands.
The dexamethasone‐suppressed corticotropin‐releasing hormone stimulation test and the desmopressin test to distinguish Cushing's syndrome from pseudo‐Cushing's states
Authors: Pecori Giraldi Francesca , Pivonello Rosario , Ambrogio Alberto Giacinto , De Martino Maria Cristina , De Martin Martina , Scacchi Massimo , Colao Annamaria , Toja Paola Maria , Lombardi Gaetano , Cavagnini Francesco
Published: January 2007

Objective  Cushing's syndrome (CS), when fully expressed, is easily diagnosed. Mild cases, however, may require careful distinction from pseudo‐Cushing's states as may occur in depression, alcoholism, polycystic ovary disease and visceral obesity. The aim of the present study is a reappraisal of the diagnostic accuracy of the two tests most commonly used to differentiate CS from pseudo‐Cushing's: corticotropin‐releasing hormone (CRH) stimulation after low dose dexamethasone administration and desmopressin stimulation.

Design  The study population comprised 32 patients with CS and 23 with pseudo‐Cushing's evaluated retrospectively.

Methods  Urinary free cortisol (UFC), serum cortisol at midnight and after low dose dexamethasone (1 mg overnight and 2 mg over two days) were measured. Further, patients were tested with dexamethasone + CRH and desmopressin and the diagnostic performances of the two tests were compared in the entire series as well as in patients with mild hypercortisolism only (i.e. UFC < 690 nmol/24 h).

Results  As expected, measurement of UFC, assessment of cortisol rhythmicity and inhibition after 1 mg/2 mg dexamethasone failed to clearly classify patients with pseudo‐Cushing's. Administration of CRH following 2‐mg dexamethasone achieved 100% sensitivity but 62·5% specificity. Conversely, desmopressin testing correctly classified all but two patients with pseudo‐Cushing's (90% specificity) with 81·5% sensitivity. Diagnostic accuracy was comparable in the subgroup with mild hypercortisolism (21 CS, all 23 pseudo‐Cushing's patients). Desmopressin offered an incremental diagnostic effectiveness of 35·8/million inhabitants compared with dexamethasone + CRH as a second‐line test.

Conclusions  Neither of the two tests guarantees absolute diagnostic accuracy. The specificity of dexamethasone + CRH is less brilliant than previously reported and appears to be inferior to desmopressin stimulation. The greatest diagnostic effectiveness results from the low‐dose dexamethasone test combined with the desmopressin test. Skilful use of dynamic testing and balanced clinical judgement are necessary to distinguish between Cushing's syndrome and pseudo‐Cushing's.
Effects of rosiglitazone and metformin on inflammatory markers and adipokines: decrease in interleukin‐18 is an independent factor for the improvement of homeostasis model assessment‐beta in type 2 diabetes mellitus
Authors: Kim Hyeong Jin , Kang Eun Seok , Kim Dae Jung , Kim So Hun , Ahn Chul Woo , Cha Bong Soo , Nam Moonsuk , Chung Choon Hee , Lee Kwan Woo , Nam Chung Mo , Lee Hyun Chul
Published: January 2007

Objective  We examined the individual pharmacological effects of the addition of rosiglitazone and metformin to glimepiride on inflammatory markers and adipokines in patients with type 2 diabetes mellitus. We analysed the relationships between these variables, the measurements of insulin sensitivity and β‐cell function in patients treated with rosiglitazone plus glimepiride.

Design and patients  One hundred twenty (120) patients with type 2 diabetes mellitus were randomized and treated with glimepiride plus rosiglitazone or glimepiride plus metformin for 12 weeks. The plasma concentrations of the inflammatory markers and adipokines were measured at baseline and after 12 weeks.

Measurements  Markers of insulin sensitivity and β‐cell function were determined by the quantitative insulin sensitivity check index (QUICKI) and the homeostasis model assessment of β‐cell function (HOMA‐β), respectively. Plasma concentrations of adiponectin were measured by radioimmunoassay. Plasma concentrations of resistin, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6) and interleukin‐18 (IL‐18) were measured using ELISA.

Results  Improvements in fasting insulin level, QUICKI and HOMA‐β were noted in the rosiglitazone‐treated group. Only the QUICKI value improved in the metformin‐treated group. Adiponectin concentrations significantly increased in the rosiglitazone‐treated group after 12 weeks. Significant decreases in resistin, C‐reactive protein, TNF‐α, IL‐6 and IL‐18 were seen in the rosiglitazone‐treated patients but not in the metformin‐treated patients. The independent risk factor for the HOMA‐β change according to stepwise multivariate regression analysis was a change in IL‐18.

Conclusions  Rosiglitazone, but not metformin, improved the plasma concentrations of inflammatory markers and adipokines in patients with type 2 diabetes mellitus. A decrease in IL‐18 is an independent factor for the improvement of HOMA‐β in type 2 diabetes mellitus.
Central pulse wave velocity is responsible for increased brachial‐ankle pulse wave velocity in subclinical hypothyroidism
Authors: Nagasaki Toshiki , Inaba Masaaki , Kumeda Yasuro , Hiura Yoshikazu , Yamada Shinsuke , Shirakawa Kumi , Ishimura Eiji , Nishizawa Yoshiki
Published: January 2007

Objective  Subclinical hypothyroidism affects 5–15% of the general population, and is associated with increased morbidity from cardiovascular disease. We recently reported a significant increase in brachial‐ankle pulse wave velocity (baPWV), a parameter of arterial stiffening and an independent predictor for the presence of cardiovascular disease, in subclinical hypothyroidism. The current study was performed to assess which arterial segment is responsible for enhanced baPWV in subclinical hypothyroidism.

Patients and methods  Central PWV (PWV in heart‐femoral segments), peripheral PWV (PWV in femoral‐ankle segments), and baPWV were measured in subclinical hypothyroid patients and normal subjects.

Results  Central PWV, baPWV, and peripheral PWV were significantly higher in subclinical hypothyroid patients than in normal subjects. BaPWV was significantly and positively correlated with central and peripheral PWV in both groups. However, a significant and positive correlation between central and peripheral PWV in normal subjects was not found in subclinical hypothyroid patients. Moreover, stepwise regression analysis showed that the association of central PWV with baPWV was stronger than that of peripheral PWV, whereas in normal subjects central PWV was not associated with baPWV.

Conclusions  Our results demonstrate that central and peripheral PWV are significantly higher in subclinical hypothyroid patients, and that the increase in baPWV depends more strongly on central PWV than on peripheral PWV in these patients. This suggests that increased elastic arterial stiffening of the aorta, rather than of peripheral muscular arteries, might be more responsible for increased general arterial stiffening in subclinical hypothyroid patients.