bluuebunny/crossref_metadata_2025 huggingface dataset:
“Competitive Quenching”: A Mechanism by Which Perihydroxylated Perylenequinone Photosensitizers Can Prevent Adverse Phototoxic Damage Caused by Verteporfin During Photodynamic Therapy
Authors: Lavie Gad , Barliya Tilda , Mandel Mathilda , Blank Michael , Ron Yonina , Orenstein Arie , Livnat Tami , Friedman Noga , Weiner Lev , Sheves Mordechai , Weinberger Dov
Published: July 2007

Incorporation of photodynamic therapy into clinical practice for induction of vascular photo‐occlusion highlights the need to prevent adverse phototoxicity to sensitive juxtaposed tissues, particularly in the retina. We developed a system termed “competitive quenching” to prevent adverse phototoxic damage. It involves differential compartmentalization of a photoactivator to the intravascular compartment for photoexcitation and delivery of phototoxicity to targeted vessels. A different photodynamic agent is partitioned to the extravascular retinal space to quench reactive oxygen species generated by photosensitization, thereby protecting the adjacent retinal tissues from adverse phototoxicity. The absorption spectra of quenchers must span wavelengths that are shorter and excluded from the spectral range of photoexcitation light to prevent photoactivation of the quencher. Perihydroxylated perylenequinones were found to be suitable to function as “competitive quenchers” with the prototype hypericin identified as a potent quencher. Here we examined the mechanisms operative in competitive quenching and suggest that hypericin forms a complex with verteporfin, thereby quenching singlet oxygen formation. Furthermore, we show that hypericin, with six phenolic hydroxyls, protects retinal and endothelial hybridoma cells from phototoxicity more effectively than the dimethyl tetrahydroxy helianthrone structural analog with only four such phenolic hydroxyls. The findings suggest that hydroxyl numbers contribute to the efficacy of competitive quenching.
Sporadic coordinated shifts of regional ventilation and perfusion in juvenile pigs with normal gas exchange
Authors: Robertson H. Thomas , Neradilek Blazej , Polissar Nayak L. , Glenny Robb W.
Published: July 2007

Repeated high‐resolution measurements of both regional pulmonary ventilation and regional blood flow (r) have revealed that ∼6 to 10% of the summed spatial and temporal heterogeneity can be attributed to spontaneous temporal variability. To test the hypothesis that the spontaneous temporal shifts of r and r are coordinated, 12 anaesthetized juvenile pigs had pairs of colours of aerosol and intravenous fluorescent microspheres (FMS) administered simultaneously at 20 min intervals to mark r and r. The animals were killed, the lungs inflated, air‐dried and cut into ∼2 cm3 cubes. The concentrations of FMS colours from each cube, representing r and r at every 20 min interval, were measured with a fluorescence spectrophotometer. The correlation between per‐piece temporal shifts in r and r, calculated as the mean within‐piece covariance, was positive (P < 0.001) for every temporally adjacent pair of measurements in every animal, although there were large differences in the magnitude of the mean temporal covariance among animals. The individual cubes with the most positive temporal covariance across all measurement periods usually demonstrated a large single‐interval coordinated shift of r and r, with average temporal covariance observed at the other intervals. The largest between‐interval shifts in r and r included equal proportions of coordinated increases and coordinated decreases. High‐resolution measurements of r and r acquired over 20 min intervals reveal that the overall positive correlation between temporal changes in r and r is driven by relatively infrequent large‐magnitude changes within small regions of the lung.
The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: A 4DCT based study
Authors: Yue Ning J. , Li Xiang , Beriwal Sushil , Heron Dwight E. , Sontag Marc R. , Huq M. Saiful
Published: July 2007

The question remains regarding the dosimetric impact of intrafraction motion in 3D breast treatment. This study was conducted to investigate this issue utilizing the 4DCT scan. The 4D and helical CT scan sets were acquired for 12 breast cancer patients. For each of these patients, based on the helical CT scan, a conventional 3D conformal plan was generated. The breast treatment was then simulated based on the 4DCT scan. In each phase of the 4DCT scan, dose distribution was generated with the same beam parameters as the conventional plan. A software package was developed to compute the cumulative dose distribution from all the phases. Since the intrafraction organ motion is reflected by the 4DCT images, the cumulative dose computed based on the 4DCT images should be closer to what the patient received during treatment. Various dosimetric parameters were obtained from the plan and 4D cumulative dose distribution for the target volume and heart, and were compared to deduce the motion‐induced impacts. The studies were performed for both whole breast and partial breast treatment. In the whole breast treatment, the average intrafraction motion induced changes in , , , , and of the target volume were , , , , and , respectively, with the largest values at , , , , and , respectively. Motion had little impact on the of the target volume, but its impact on the of the target volume was significant. For left breast treatment, the motion‐induced change to the heart could be negative or positive, with the largest increase at about . In partial breast treatment, the only non‐insignificant impact was in the of the CTV (ranging from to 11.7%). The results showed that the intrafraction motion may compromise target dose coverage in breast treatments and the degree of that compromise was correlated with motion magnitude. However, the dosimetric impact of the motion on the heart dose may be limited.
Investigation of the reliability, accuracy, and efficiency of gated IMRT delivery with a commercial linear accelerator
Authors: Ahunbay Ergun , Li X. Allen
Published: July 2007

This work reports an investigation on the reliability, accuracy, and efficiency of gated intensity modulated radiation therapy (IMRT) delivery with a commercial linear accelerator. The dosimetry measurements of segmented multileaf collimated IMRT (SMLC‐IMRT) were performed by using radiographic films and a two‐dimensional diode array. Testing involved a series of IMRT fields from actual patients combined with some manually generated fields. To examine the delivery time, dosimetry plans of standard beamlet IMRT, direct‐aperture‐optimized (DAO) IMRT, compensator IMRT, and three‐dimensional conformal radiotherapy with wedges were delivered with and without gating. The results demonstrated that the gated SMLC‐IMRT can be reliably and accurately delivered on this type of accelerators, as long as extremely high interruption frequencies and very low number of monitor units per segment are avoided. Beam flatness exceeded 5% and monitor linearity deviated more than 3% for the gated operation with breathing cycle and 20% duty cycle with segment sizes less than . Gating does not change multi leaf collimator (MLC) positioning accuracy. The DAO IMRT is preferred for gated delivery because of its short delivery time.
Implementation of a quality assurance program for computerized treatment planning systems
Authors: Camargo Priscilla R. T. L. , Rodrigues Laura N. , Furnari Laura , Rubo Rodrigo A.
Published: July 2007

In the present investigation, the necessary tests for implementing a quality assurance program for a commercial treatment planning system (TPS), recently installed at Sao Paulo University School of Medicine Clinicas Hospital—Brazil, was established and performed in accordance with the new IAEA publication TRS 430, and with AAPM Task Group 53. The tests recommended by those documents are classified mainly into acceptance, commissioning (dosimetric and nondosimetric), periodic quality assurance, and patient specific quality assurance tests. The recommendations of both IAEA and AAPM documents are being implemented at the hospital for photon beams produced by two linear accelerators. A Farmer ionization chamber was used in a phantom with a dose rate of 320 monitor unit (MU)/min and 50 MU in the case of the dosimetric tests. The acceptance tests verified hardware, network systems integration, data transfer, and software parameters. The results obtained are in good agreement with the specifications of the manufacturer. For the commissioning dosimetric tests, the absolute dose was measured for simple geometries, such as square and rectangular fields, up to more complex geometries such as off‐axis hard wedges and for behavior in the build up region. Results were analysed by the use of confidence limit as proposed by Venselaar et al. [Radio Ther. Oncol. 60, 191–201 (2001)]. Criteria of acceptability had been applied also for the comparison between the values of MU calculated manually and MU generated by TPS. The results of the dosimetric tests show that work can be reduced by choosing to perform only those that are more crucial, such as oblique incidence, shaped fields, hard wedges, and buildup region behavior. Staff experience with the implementation of the quality assurance program for a commercial TPS is extremely useful as part of a training program.
Respiratory gating in positron emission tomography: A quantitative comparison of different gating schemes
Authors: Dawood Mohammad , Büther Florian , Lang Norbert , Schober Otmar , Schäfers Klaus P
Published: July 2007

Respiratory gating is used for reducing the effects of breathing motion in a wide range of applications from radiotherapy treatment to diagnostical imaging. Different methods are feasible for respiratory gating. In this study seven gating methods were developed and tested on positron emission tomography (PET) listmode data. The results of seven patient studies were compared quantitatively with respect to motion and noise. (1) Equal and (2) variable time‐based gating methods use only the time information of the breathing cycle to define respiratory gates. (3) Equal and (4) variable amplitude‐based gating approaches utilize the amplitude of the respiratory signal. (5) Cycle‐based amplitude gating is a combination of time and amplitude‐based techniques. A baseline correction was applied to methods (3) and (4) resulting in two new approaches: Baseline corrected (6) equal and (7) variable amplitude‐based gating. Listmode PET data from seven patients were acquired together with a respiratory signal. Images were reconstructed applying the seven gating methods. Two parameters were used to quantify the results: Motion was measured as the displacement of the heart due to respiration and noise was defined as the standard deviation of pixel intensities in a background region. The amplitude‐based approaches (3) and (4) were superior to the time‐based methods (1) and (2). The improvement in capturing the motion was more than 30% (up to 130%) in all subjects. The variable time (2) and amplitude (4) methods had a more uniform noise distribution among all respiratory gates compared to equal time (1) and amplitude (3) methods. Baseline correction did not improve the results. Out of seven different respiratory gating approaches, the variable amplitude method (4) captures the respiratory motion best while keeping a constant noise level among all respiratory phases.
Comparison of speech production in upright and supine position
Authors: Stone M. , Stock G. , Bunin K. , Kumar K. , Epstein M. , Kambhamettu C. , Li M. , Parthasarathy V. , Prince J.
Published: July 2007

Speech is usually produced in an upright sitting or standing posture. Measurements and judgments of speech may be made in conditions requiring a supine position, however. These conditions include MRI recordings, and oral procedures, such as, adjustments to dental appliances, medical and surgical procedures. It is of interest, therefore, to see whether gravity has strong or systematic effects on tongue behavior. In the present study, 13 subjects repeated several words, which contained extreme consonant and vowel tongue positions, during upright and supine condition. Ultrasound imaging provided midsagittal tongue contours, in each condition, for comparison. A neck brace was used to stabilize transducer placement and the palate was used as a physiological reference to register the data sets. Results showed a significant subject effect. In supine position the tongue was more posterior than upright for seven subjects, more anterior for two subjects and varied by phoneme for four subjects. However, there was no significant phoneme effect. The direction of change and the amount of change were not directly related. Most subjects had small upright-supine differences. The largest differences, less than 3mm on average, were in the posterior tongue.
Impedance of pistons on a two-layer medium in a planar infinite rigid baffle
Authors: Hassan Scott E.
Published: July 2007

An integral transform technique is used to develop a general solution for the impedance of rigid pistons acting on a two-layer medium. The medium consists of a semi-infinite acoustic fluid on a viscoelastic thick plate in a rigid infinite baffle. The stresses acting on the planar baffle, as a result of piston motion, are determined using theory of linear elasticity and are therefore unrestricted in terms of applicable frequency range. The special case of a circular piston is considered and expressions for the self-and mutual impedances are developed and evaluated numerically. Numerical results are compared with classical piston impedance functions and finite-element model results. At low frequencies (k0a<1), the self-impedances vary significantly from the classical piston impedance functions due to the shear properties of the viscoelastic medium. In the midfrequency range (1<k0a<π) the self-impedances vary from the classical piston impedance functions for moderate viscoelastic layer thicknesses (0.5<h∕a<2). The mutual impedances associated with pistons on a two-layer medium generally exhibit an increased decay, as a function of separation distance, over the classical results.
Loudness reduction induced by a contralateral tone
Authors: Nieder Bärbel , Buus Søren , Cazals Yves , Scharf Bertram
Published: July 2007

The induced reduction in the loudness (ILR) of a weaker tone caused by a preceding stronger tone was measured with both tones in the same ear (ipsilateral ILR) and also in opposite ears (contralateral ILR). The two tones were always equal in duration and were presented repeatedly over several minutes. When the tone duration was 200ms, for 24 listeners the loudness reduction averaged 11dB under ipsilateral ILR and 6dB under contralateral ILR. When the duration was 5ms, ILR was 8dB whether ipsilateral or contralateral. For each duration, ipsilateral and contralateral ILR were strongly correlated (r around 0.80).
Influence of scattering, atmospheric refraction, and ground effect on sound propagation through a pine forest
Authors: Swearingen Michelle E. , White Michael J.
Published: July 2007

Sound propagation through a forest is affected by the microclimate in the canopy, scattering by trunks and stems, and ground reflection. Each of these effects is such a strong contributor to the attenuation of sound that mutual interactions between the phenomena could become important. A sound propagation model for use in a forest has been developed that incorporates scattering from trunks and branches and atmospheric refraction by modifying the effective wave number in the Green’s function parabolic equation model. The ground effect for a hard-backed pine straw layer is approximated as a local reaction impedance condition. Comparisons to experimental data are made for frequencies up to 4200Hz. Cumulative influences of the separate phenomena are examined. The method developed in this paper is compared to previously published methods. The overall comparison with spectral transmission data is good, suggesting that the model captures the necessary details.
The effects of high-intensity, low-frequency active sonar on rainbow trout
Authors: Popper Arthur N. , Halvorsen Michele B. , Kane Andrew , Miller Diane L. , Smith Michael E. , Song Jiakun , Stein Peter , Wysocki Lidia E.
Published: July 2007

This study investigated the effects on rainbow trout (Oncorhynchus mykiss) of exposure to high-intensity, low-frequency sonar using an element of the standard Surveillance Towed Array Sensor System Low Frequency Active (LFA) sonar source array. Effects of the LFA sonar on hearing were tested using auditory brainstem responses. Effects were also examined on inner ear morphology using scanning electron microscopy and on nonauditory tissues using general pathology and histopathology. Animals were exposed to a maximum received rms sound pressure level of 193dB re 1μPa2 for 324 or 648s, an exposure that is far in excess of any exposure a fish would normally encounter in the wild. The most significant effect was a 20-dB auditory threshold shift at 400Hz. However, the results varied with different groups of trout, suggesting developmental and/or genetic impacts on how sound exposure affects hearing. There was no fish mortality during or after exposure. Sensory tissue of the inner ears did not show morphological damage even several days post–sound exposure. Similarly, gross- and histopathology observations demonstrated no effects on nonauditory tissues.
Acoustic beam scattering and excitation of sphere resonance: Bessel beam example
Authors: Marston Philip L.
Published: July 2007

The exact partial wave series for the scattering by a sphere centered on an ideal Bessel beam was recently given by Marston [“Scattering of a Bessel beam by a sphere,” J. Acoust. Soc. Am. 121, 753–758 (2007)]. That series is applied here to solid elastic spheres in water and to an empty spherical shell in water. The examples are selected to illustrate the effect of varying the beam’s conical angle so as to modify the coupling to specific resonances in the response of each type of sphere considered. The backscattering may be reduced or increased depending on properties of the resonance and of the specular contribution. Changing the conical angle is equivalent to changing the beamwidth. Some applications of the Van de Hulst localization principle to the interpretation of the partial wave series and to the interpretation of the scattering dependence on the beam’s conical angle are discussed. Some potential applications to the analysis of the scattering by spheres of more general axisymmetric beams are noted.
Structural acoustic control of plates with variable boundary conditions: Design methodology
Authors: Sprofera Joseph D. , Cabell Randolph H. , Gibbs Gary P. , Clark Robert L.
Published: July 2007

A method for optimizing a structural acoustic control system subject to variations in plate boundary conditions is provided. The assumed modes method is used to build a plate model with varying levels of rotational boundary stiffness to simulate the dynamics of a plate with uncertain edge conditions. A transducer placement scoring process, involving Hankel singular values, is combined with a genetic optimization routine to find spatial locations robust to boundary condition variation. Predicted frequency response characteristics are examined, and theoretically optimized results are discussed in relation to the range of boundary conditions investigated. Modeled results indicate that it is possible to minimize the impact of uncertain boundary conditions in active structural acoustic control by optimizing the placement of transducers with respect to those uncertainties.
Two-dimensional modeling of wave propagation in materials with hysteretic nonlinearity
Authors: Vanaverbeke Sigfried , Abeele Koen Van Den
Published: July 2007

A multiscale model for the two-dimensional nonlinear wave propagation in a locally microdamaged medium is presented, and numerical simulations are analyzed in view of nondestructive testing applications. The multiscale model uses a statistical distribution of hysterons and upscales their microscopic stress-strain relations to a mesoscopic level. Macroscopic observations are then predicted by finite integration techniques. The influence of a small region with hysteretic nonlinearity on the generation of harmonics is investigated, and numerical results for different amplitudes of the input signal and different analysis techniques of the response signal are presented. Second, a study is conducted on the interaction of a Rayleigh wave with a microdamaged zone with hysteretic nonlinearity at the surface of an otherwise linear body, and the influence of the microdamaged zone on the surface wave velocity and on the generation of harmonics is examined. It is found that the effect of hysteresis on the Rayleigh wave propagation can be barely seen in the surface wave velocity measurement, but shows up nicely in the wave spectrum. The potential of a nonlinearity based depth profiling technique is explored by evaluating the nonlinear responses at different frequencies for a vertically stratified medium with spatially varying hysteresis properties.
A tool for real-time acoustic species identification of delphinid whistles
Authors: Oswald Julie N. , Rankin Shannon , Barlow Jay , Lammers Marc O.
Published: July 2007

The ability to identify delphinid vocalizations to species in real-time would be an asset during shipboard surveys. An automated system, Real-time Odontocete Call Classification Algorithm (ROCCA), is being developed to allow real-time acoustic species identification in the field. This Matlab-based tool automatically extracts ten variables (beginning, end, minimum and maximum frequencies, duration, slope of the beginning and end sweep, number of inflection points, number of steps, and presence/absence of harmonics) from whistles selected from a real-time scrolling spectrograph (ISHMAEL). It uses classification and regression tree analysis (CART) and discriminant function analysis (DFA) to identify whistles to species. Schools are classified based on running tallies of individual whistle classifications. Overall, 46% of schools were correctly classified for seven species and one genus (Tursiops truncatus, Stenella attenuata, S. longirostris, S. coeruleoalba, Steno bredanensis, Delphinus species, Pseudorca crassidens, and Globicephala macrorhynchus), with correct classification as high as 80% for some species. If classification success can be increased, this tool will provide a method for identifying schools that are difficult to approach and observe, will allow species distribution data to be collected when visual efforts are compromised, and will reduce the time necessary for post-cruise data analysis.
Comment on "The Spatial Extent of 20th-Century Warmth in the Context of the Past 1200 Years"
Authors: Bürger Gerd
Published: July 2007

Osborn and Briffa (Reports, 10 February 2006, p. 841) identified anomalous periods of warmth or cold in the Northern Hemisphere that were synchronous across 14 temperature-sensitive proxies. However, their finding that the spatial extent of 20th-century warming is exceptional ignores the effect of proxy screening on the corresponding significance levels. After appropriate correction, the significance of the 20th-century warming anomaly disappears.
Response to Comment on "Wandering Minds: The Default Network and Stimulus-Independent Thought"
Authors: Mason Malia F. , Norton Michael I. , Van Horn John D. , Wegner Daniel M. , Grafton Scott T. , Macrae C. Neil
Published: July 2007

Gilbert
et al.
suggest that activity in the default network may be due to the emergence of stimulus-oriented rather than stimulus-independent thought. Although both kinds of thought likely emerge during familiar tasks, we argue—and report data suggesting—that stimulus-independent thought dominates unconstrained cognitive periods.
The Hippocampus Review
Authors: Sejnowski Terrence J.
Published: July 2007

The Hippocampus Book
.
Per Andersen, Richard Morris, David Amaral, Tim Bliss, and John O'Keefe, Eds.
. Oxford University Press, New York, 2007. 868 pp. $125, £60. ISBN 9780195100273.

The contributors synthesize our understanding of the anatomy, physiology, and function of the hippocampus; its involvement in diseases; and its roles in cognition, memory, and behavior.
Epithelia Control Gut Inflammation
Authors: Gough Nancy R.
Published: July 2007

The intestinal epithelial cells (IECs) provide a crucial barrier function preventing infection. Now these cells also are recognized as key instructors of inflammatory responses. Zaph
et al
. and Nenci
et al
. both used IEC-targeted gene knockouts in mice to show that nuclear factor κB (NF-κB) signaling in the IECs was essential for controlling infection and inflammatory responses. Zaph
et al
. knocked out IKKβ (
Ikkb
ΔIEC
mice) and Nenci
et al
. knocked out IKKγ (also known as NEMO) (NEMO
IEC-KO
mice) or both IKKα and IKKβ (IKK1/2
IEC-KO
); these kinases are involved in NF-κB activation. Zaph
et al
. studied the mouse response to
Trichuris muris
infection as a model of human nematode infections.
Trichuris
infection triggered NF-κB activation in the IECs of wild-type mice, and these mice developed a T helper 2 (T
H
2) response; produced interleukin (IL)-4, -5, and -13; and cleared the infection. In contrast, the type 2 immune response of the
Ikkb
ΔIEC
mice was impaired and the mice failed to clear the infection and developed severe intestinal inflammation with infiltration of lymphocytes, ulceration, and ultimately septicemia. This appeared to be due to decreased expression of the RNA of thymic stromal lymphopoietin (TSLP), which is encoded by an NF-κB-regulated gene. TSLP limits dendritic cell proinflammatory cytokine production, limits dendritic cell signals that trigger T
H
1 differentiation, and promotes dendritic cell signals that trigger T
H
2 cell differentiation. The NEMO
IEC-KO
and IKK1/2
IEC-KO
mice studied by Nenci
et al
. exhibited a more severe phenotype with spontaneous formation of chronic severe intestinal inflammation. This was due to the complete abrogation of NF-κB signaling in these two knockout mice strains, whereas loss of IKKβ or IKKα function alone impairs but does not eliminate NF-κB signaling. The colitis that the NEMO
IEC-KO
mice developed was prevented if the mice were also deficient in MyD88, which is an adaptor important for Toll-like receptor (TLR) signaling triggered by pathogens such as intestinal bacteria. Colitis was also prevented in the NEMO
IEC-KO
if the mice were deficient for tumor necrosis factor-α (TNF-α) receptors. This was consistent with the observation that NEMO-deficient cells are more sensitive to apoptosis caused by TNF-α. Together these two articles clearly show that the NF-κB signaling in IECs plays a crucial role in controlling inflammatory responses and fighting infection in the gut.

C. Zaph, A. E. Troy, B. C. Taylor, L. D. Berman-Booty, K. J. Guild, Y. Du, E. A. Yost, A. D. Gruber, M. J. May, F. R. Greten, L. Eckmann, M. Karin, D. Artis, Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis.
Nature
446
, 552-556 (2007).
[PubMed]

A. Nenci, C. Becker, A. Wullaert, R. Gareus, G. van Loo, S. Danese, M. Huth, A. Nikolaev, C. Neufert, B. Madison, D. Gumucio, M. F. Neurath, M. Pasparakis, Epithelial NEMO links innate immunity to chronic intestinal inflammation.
Nature
446
, 557-561 (2007).
[PubMed]
ASKing Macrophages to Promote Hair Growth
Authors: Adler Elizabeth M.
Published: July 2007

Noting that the abundance of ASK1 (apoptosis signal-regulating kinase 1, which is activated in response to inflammatory cytokines and various stresses) increases after epithelial injury in rats, Osaka
et al
. investigated its involvement in the increase in regional hair growth stimulated by skin injury in mice. Wounds in mice lacking ASK1 (

ASK1
–/–

mice) showed apparently normal re-epithelialization, but there was a marked delay in injury-induced hair regrowth. In contrast, hair follicle development in embryos and regrowth after plucking appeared normal. ASK1 is a mitogen-activated protein kinase kinase kinase (MAPKKK), and activation of its downstream targets c-Jun N-terminal kinase and p38 was reduced in

ASK1
–/–

compared with wild-type mice, as was activation of extracellular signal-regulated kinase (the latter likely through an indirect route). A combination of microarray analysis and reverse transcription polymerase chain reaction (RT-PCR) indicated that the expression of macrophage-specific markers, as well as that of macrophage-specific chemotactic and activating factors, was reduced in the wounded skin of

ASK1
–/–

animals compared with that in wild-type mice. Immunohistochemical analysis confirmed that

ASK1
–/–

mice exhibited decreased recruitment of macrophages to the wounded area. Intracutaneous transplantation of bone marrow-derived macrophages (BMDMs) from either wild-type or

ASK1
–/–

mice stimulated notable hair growth only in wild-type mice; intracutaneous transplantation of cytokine-activated BMDMs, however, stimulated marked hair growth in both wild-type and

ASK1
–/–

mice. Thus, ASK1-dependent recruitment and activation of macrophages appears to play a critical role in promoting hair growth after injury.

N. Osaka, T. Takahashi, S. Murakami, A. Matsuzawa, T. Noguchi, T. Fujiwara, H. Aburatani, K. Moriyama, K. Takeda, H. Ichijo, ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds.
J. Cell Biol.
176
, 903-909 (2007).
[Abstract]
[Full Text]
Focus Issue: Exploring New Avenues for Cancer Treatment
Authors: Adler Elizabeth M. , Gough Nancy R.
Published: July 2007

This issue of
Science
’s STKE features research into the pathophysiology of cancer cells. The featured articles describe how malignancy may arise due to the subversion of normal cellular functions, the signaling pathways involved, and new approaches to cancer therapy that involve the exploitation of oncogenic changes. The research presented provides an optimistic outlook for translating new understanding of cell signaling into novel therapies.
What Is Left Behind—Quality Control in Germ Cell Migration
Authors: Boldajipour Bijan , Raz Erez
Published: July 2007

Cell differentiation, cell proliferation, cell death, and cell migration are tightly controlled during animal development and adult homeostasis. Failure to regulate these processes can result in tumor formation and metastasis. Aberrant cells are therefore often cleared by induction of cell death. Recent work has elucidated the mechanism of elimination of mouse primordial germ cells that fail to migrate properly and highlights the similarity of this mechanism to those governing the same phenomenon in
Drosophila.
In addition, these studies underscore the different functions a single signaling pathway can have in controlling cell survival, cell proliferation, and cell migration during different phases of development.
Differential Responses to Change
Authors: Vinson Valda
Published: July 2007

Understanding how organisms respond to genetic or environmental perturbations requires quantitative measurements across multiple levels of biological information. Ishii
et al
. used a variety of technologies to measure gene expression, protein levels, metabolite concentrations, and reaction fluxes to study the response of
Escherichia coli
to growth rates and genetic deletions. Although
E. coli
responds to changes in the environment by regulating the level of enzyme expression to keep metabolite levels stable, messenger RNA and protein levels do not change in response to most gene disruptants. Instead, there are likely changes in the structure of the metabolic network that keep the levels of most metabolites stable.

N. Ishii, K. Nakahigashi, T. Baba, M. Robert, T. Soga, A. Kanai, T. Hirasawa, M. Naba, K. Hirai, A. Hoque, P. Y. Ho, Y. Kakazu, K. Sugawara, S. Igarashi, S. Harada, T. Masuda, N. Sugiyama, T. Togashi, M. Hasegawa, Y. Takai, K. Yugi, K. Arakawa, N. Iwata, Y. Toya, Y. Nakayama, T. Nishioka, K. Shimizu, H. Mori, M. Tomita, Multiple high-throughput analyses monitor the response of
E. coli
to perturbations.
Science
316
, 593-597 (2007).
[Abstract]
[Full Text]

U. Sauer, M. Heinemann, N. Zamboni, Getting closer to the whole picture.
Science
316
, 550-551 (2007).
[Summary]
[Full Text]
GPCR Versus Cytokine Receptor: Is One As Good As the Other?
Authors: Foley John F.
Published: July 2007

Th17 cells are a distinct lineage of CD4
+
T helper (Th) cells that produce the cytokines IL-17 (interleukin-17) and IL-22 and are important in fighting infection but are also involved in mediating autoimmune disorders. The generation of Th17 cells is dependent on IL-6 and transforming growth factor-β (TGF-β), together with either IL-1 or tumor necrosis factor-α. It is unclear whether IL-23 is necessary for Th17 cell development. Liao
et al
. examined the effect of sphingosine 1-phosphate (S1P) on the generation of Th17 cells. S1P, acting through its G protein-coupled receptor S1P
1
, is known to affect the trafficking and proliferation of T cells. This group has previously shown that stimulation of transgenic CD4
+
T cells expressing increased amounts of S1P
1
results in the production of more Th17 cells than does stimulation of control cells. In the current study, the authors demonstrated that the addition of S1P to cultures of mouse splenic CD4
+
T cells (maintained in the absence of IL-23) that were activated by stimulation of the T cell antigen receptor in the presence of IL-6, IL-1, and TGF-β resulted in the production of more IL-17 protein and a higher percentage of Th17 cells than in cultures that lacked S1P. A selective agonist of S1P
1
, SEW2871, had the same effect. Separate activation cultures containing optimal concentrations of either S1P or IL-23 produced similar numbers of Th17 cells. S1P treatment suppressed the production of interferon-γ and IL-4, the signature cytokines of Th1 and Th2 cells, respectively. The effect of S1P on the generation of Th17 cells was blocked by inhibitors of phosphoinositide 3-kinase and nuclear factor κB. Finally, the immunosuppressive agent FTY720, which can down-regulate S1P
1
, inhibited S1P-mediated generation of Th17 cells. These results show that S1P can substitute for IL-23 in the development of Th17 cells and suggest that part of the immunosuppressive effect of FTY720 may be due to the inhibition of Th17 cell development.

J.-J. Liao, M.-C. Huang, E. J. Goetzl, Cutting edge: Alternative signaling of Th17 cell development by sphingosine 1-phosphate.
J. Immunol.
178
, 5425-5428 (2007).
[PubMed]
Micromanaging the Immune System
Authors: Simpson Stephen
Published: July 2007

MicroRNAs (miRNAs) are abundant small RNA species that have emerged as key regulators in many biological processes. Rodriguez
et al
. observed that mice deficient in miRNA-155 develop spontaneous inflammation of the lungs and have accompanying defects in antigen presentation as well as in T cell and B cell function. Exploring the same miRNA, Thai
et al
. observed a similar T and B cell deficiency that resulted in a suboptimal response of the germinal center, which is needed for T cell-mediated antibody production. Although both studies provide some evidence for how this miRNA mediates its effects, the next important step will be to identify the precise mechanism and critical target genes involved.

A. Rodriguez, E. Vigorito, S. Clare, M. V. Warren, P. Couttet, D. R. Soond, S. van Dongen, R. J. Grocock, P. P. Das, E. A. Miska, D. Vetrie, K. Okkenhaug, A. J. Enright, G. Dougan, M. Turner, A. Bradley, Requirement of
bic/microRNA-155
for normal immune function.
Science
316
, 608-611 (2007).
[Abstract]
[Full Text]

T.-H. Thai, D. P. Calado, S. Casola, K. M. Ansel, C. Xiao, Y. Xue, A. Murphy, D. Frendewey, D. Valenzuela, J. L. Kutok, M. Schmidt-Supprian, N. Rajewsky, G. Yancopoulos, A. Rao, K. Rajewsky, Regulation of the germinal center response by microRNA-155.
Science
316
, 604-608 (2007).
[Abstract]
[Full Text]
Life Without Dynamin
Authors: Hurtley Stella M.
Published: July 2007

Dynamin 1 is a neuron-specific guanosine triphosphatase involved in the endocytic recycling of synaptic vesicle membranes. Ferguson
et al
. created genetically engineered mice lacking dynamin 1 and found, surprisingly, that they contained functional synapses and had limited postnatal viability. However, the synapses of these dynamin 1 knockouts contained branched, tubular plasma membrane invaginations capped by clathrin-coated pits, consistent with dynamin 1’s proposed role in clathrin-coated vesicle scission. Also, after strong stimulation, synaptic vesicle endocytosis was severely impaired but could resume efficiently upon stimulus termination. This finding reveals the existence of a dynamin 1-independent mechanism that can support limited synaptic vesicle endocytosis.

S. M. Ferguson, G. Brasnjo, M. Hayashi, M. Wölfel, C. Collesi, S. Giovedi, A. Raimondi, L.-W. Gong, P. Ariel, S. Paradise, E. O’Toole, R. Flavell, O. Cremona, G. Miesenböck, T. A. Ryan, P. De Camilli, A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis.
Science
316
, 570-574 (2007).
[Abstract]
[Full Text]

P. J. Robinson, How to fill a synapse.
Science
316
, 551-553 (2007).
[Summary]
[Full Text]
Adapting the Adaptor
Authors: Simpson Stephen
Published: July 2007

Adaptor proteins connect the proteins involved in multiple cell signaling pathways. In T cells, the adaptor protein ADAP regulates certain signals from the T cell receptor (TCR) that influence the function of integrin adhesion receptors. Medeiros
et al
. found that ADAP also associates directly with another adaptor, CARMA1, a membrane-associated protein that couples TCR signaling to the activation of the core transcription factor NF-κB. This association involved the assembly of a multiprotein complex that failed to form in the absence of ADAP and corresponded with impaired NF-κB activity. The study introduces a key new step in regulating the pathway that connects TCR activation with the transcriptional response to infection.

R. B. Medeiros, B. J. Burbach, K. L. Mueller, R. Srivastava, J. J. Moon, S. Highfill, E. J. Peterson, Y. Shimizu, Regulation of NF-κB activation in T cells via association of the adapter proteins ADAP and CARMA1.
Science
316
, 754-758 (2007).
[Abstract]
[Full Text]
Extrasynaptic NMDA Receptors Reshape Gene Ranks
Authors: Medina Igor
Published: July 2007

The
N
-methyl-D-aspartate (NMDA) subtype of glutamate receptors (NMDAR) plays a key role in the control of neuronal plasticity and cell survival by modifying the activity of different signaling pathways and numerous genes. However, it remains unclear how the activation of this one class of glutamate receptors can lead to different functional consequences, such as enhancement of neuronal survival or induction of neuronal death. Recent work further refines the hypothesis that synaptic and extrasynaptic NMDARs have distinct roles in neuronal survival and death by showing that these two subpopulations of NMDARs differentially modify whole-genome activity.
Sharing the PDGF Receptor
Authors: Gough Nancy R.
Published: July 2007

Ball
et al
. report that both vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) stimulate migration and proliferation of human adult mesenchymal stem cells (from bone marrow) and human dermal fibroblasts. Surprisingly, these two cell types lacked any detectable VEGF receptors (VEGFRs)--no transcripts were detected by reverse transcription polymerase chain reaction, and no proteins were detected by fluorescence-activated cell sorting. Experiments with function-blocking antibodies, selective pharmacological receptor tyrosine kinase inhibitors, or short-interfering RNAs indicated that VEGF signaled through the PDGF receptors PDGFRα and PDGFRβ. Analysis of receptor tyrosine kinase phosphorylation in response to VEGF using an array of 42 specific antibodies showed that VEGF stimulated the phosphorylation of PDGFRα and PDGFRβ, as well as stimulating the phosphorylation of the epidermal growth factor receptor, EphA7, and of Ax1. The stimulation of PDGFRs by VEGF appeared to be direct, because VEGF did not stimulate production of PDGF, and chemical cross-linking studies showed that VEGF bound to PDGFRα and PDGFRβ. Pretreatment of cells with VEGF inhibited the migration of the cells toward PDGF, which suggests that VEGF may attenuate responses to PDGF. Thus, VEGF targets are not limited to cells expressing VEGFRs.

S. G. Ball, C. A. Shuttleworth, C. M. Kielty, Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
J. Cell Biol.
177
, 489-500 (2007).
[Abstract]
[Full Text]
Glial Fiber Optics
Authors: Gough Nancy R.
Published: July 2007

Specialized glial cells called Müller cells support the function and survival of retina neurons. Franze
et al
. show that these cells also have special optical properties that allow them to pass light to the retina. Because of these properties, the light scattering, refraction, and reflection that would be expected based on the inverted structure of the eye and the need for the light to pass through multiple layers of tissue to reach the retina, are minimized. Light transmission and reflection microscopy of the inner retina (without the photoreceptor cells) revealed that light was transmitted to discrete points, and
z
-axis reconstruction revealed the presence of "tubes" that transmitted the light most effectively with minimal light scattering. These tubes corresponded to the Müller cells, and dissociated Müller cells exhibited higher refractive index than retinal neurons, which would be consistent with minimizing light loss through the length of the cell. Optical engineers use waveguide characteristic frequency (the
V
parameter) as a measure of the light guidance through a propagating model, and this is the most applicable model for the Müller cells because of their complex morphology. Calculations of the
V
parameter for Müller cells indicate that these cells could function as waveguides for visible light. Indeed, Müller cells efficiently transmitted light when placed in a modified dual-beam laser trap (the cells were aligned along their length between two optical fibers, thus allowing light to transmit from one fiber, through the cell to the other fiber).

K. Franze, J. Grosche, S. N. Skatchkov, S. Schinkinger, C. Foja, D. Schild, O. Uckermann, K. Travis, A. Reichenbach, J. Guck, Müller cells are living optical fibers in the vertebrate retina.
Proc. Natl. Acad. Sci. U.S.A.
104
, 8287-8292 (2007).
[Abstract]
[Full Text]
Smart Drugs, Smarter Tumors
Authors: Kiberstis Paula A.
Published: July 2007

A promising class of "smart" cancer drugs work by inhibiting specific tyrosine kinases linked to uncontrolled growth. Gefitinib and erlotinib, drugs that target the kinase activity of the epidermal growth factor receptor (EGFR), can be very effective when initially administered to lung cancer patients whose tumors contain activating mutations in the
EGFR
gene. Almost inevitably, however, these tumors develop resistance to the drugs and begin to regrow. Engelman
et al
. find that drug resistance in a subset of these tumors is caused by amplification of the
MET
oncogene, an event that in turn activates, via a different route, the same cellular signaling pathway originally activated by the mutant EGFR.

J. A. Engelman, K. Zajnullahu, T. Mitsudomi, Y. Song, C. Hyland, J. O. Park, N. Lindeman, C.-M. Gale, X. Zhao, J. Christensen, T. Kosaka, A. J. Holmes, A. M. Rogers, F. Cappuzzo, T. Mok, C. Lee, B. E. Johnson, L. C. Cantley, P. A. Jänne,
MET
Amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
Science
316
, 1039-1043 (2007).
[Abstract]
[Full Text]
Diet of Worms
Authors: Adler Elizabeth M. , Foley John F.
Published: July 2007

In many organisms, dietary restriction leads to an increased life span and a delay in various conditions associated with aging. Panowski
et al
. found that, unlike wild-type worms,
Caenorhabditis elegans
in which the
pha-4
gene was inactivated failed to live longer under conditions in which the concentration of bacteria they were fed was limited. The effect on life span of
pha-4
, which encodes a transcription factor implicated in foregut development that has a sequence similar to that of the mammalian Foxa transcription factors, was specifically related to dietary restriction. Loss of
pha-4
had no effect on longevity associated with decreased insulin and insulin-like growth factor signaling, nor did it affect longevity associated with decreased activity of the mitochondrial electron transport chain. Moreover, the effect of pha-4 on longevity was independent of its role in foregut development. Real-time polymerase chain reaction studies determined that the abundance of PHA-4 mRNA was increased in response to dietary restriction. The authors created 11 individual
C. elegans
lines with increased abundance of PHA-4 and found a statistically significant increase in the longevity of nine of these lines. A restrictive diet resulted in the increased abundance of several mitochondrial superoxide dismutases, enzymes important in protecting cells from the oxidative damage that can cause aging. Expression of the genes for these enzymes was decreased in the absence of
pha-4
. In another study, Bishop and Guarente found that mutant
C. elegans
lacking another transcription factor, SKN-1, had a decreased life span. SKN-1 is important in development, particularly in the intestine. The authors found that, similar to PHA-4, lack of SKN-1 prevented dietary-restriction-induced longevity. Lack of SKN-1 also had no effect on longevity associated with decreased insulin and insulin-like growth factor signaling. As well as being present in the intestine, SKN-1 is found in two sensory neurons (known as ASI neurons) in the head of
C. elegans
, and the authors found that it was this neuronal-associated SKN-1 that was responsible for mediating longevity. The abundance of SKN-1 in the ASI neurons was increased in
C. elegans
that had a restricted diet, compared with that in nonrestricted worms. The authors proposed that the increased abundance of SKN-1 causes the ASI neurons to release a hormonal signal that increases the rate of respiration of cells in the peripheral tissues, leading to longevity. The implications of these two studies are discussed by Antebi.

S. H. Panowski, S. Wolff, H. Aguilaniu, J. Durieux, A. Dillin, PHA-4/Foxa mediates diet-restriction-induced longevity of
C. elegans
.
Nature
447
, 550-555 (2007).
[PubMed]

N. A. Bishop, L. Guarente, Two neurons mediate diet-restriction-induced longevity in
C. elegans
.
Nature
447
, 545-549 (2007).
[PubMed]

A. Antebi, When less is more.
Nature
447
, 536-537 (2007).
[PubMed]
Let the RNA Do Its Business
Authors: Hurtley Stella M.
Published: July 2007

Viruses need to ensure that infected cells survive long enough to allow the production of progeny. Reeves
et al
. now show that human cytomegalovirus uses an unusual strategy to this end--an abundant noncoding RNA specifically interferes with an apoptotic trigger in the mitochondrion. In cells in which apoptosis has been triggered, the RNA binds to an enzyme in the mitochondrion and helps to maintain functional mitochondria, which prolongs the life of the infected cells. This mechanism obviates the need for the virus to translate a protein product to perform this function and may thus exploit the infected cell’s resources more effectively.

M. B. Reeves, A. A. Davies, B. P. McSharry, G. W. Wilkinson, J. H. Sinclair, Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death.
Science
316
, 1345-1348 (2007).
[Abstract]
[Full Text]