bluuebunny/crossref_metadata_2025 huggingface dataset:
Allergy-Blocking Transmitters
Authors: Simpson Stephen J.
Published: July 2007

The endocannabinoid system performs various regulatory functions and has been implicated in a growing number of physiological roles, both in the central and peripheral nervous systems and in peripheral organs. Karsak
et al
. now find that this influence extends to regulation of allergic response. Mice lacking the two known cannabinoid receptors showed a strong tendency toward developing cutaneous contact sensitivity in response to distinct allergens. Blocking the receptors with antagonists had a similar effect, whereas absence of the gene encoding an enzyme responsible for breaking down cannabinoids increased resistance of mice to contact sensitivity. The regulation of the endocannabinoids or their receptors might be useful in treating allergies, although their role in the wider context of human allergy needs to be explored.

M. Karsak, E. Gaffal, R. Date, L. Wang-Eckhardt, J. Rehnelt, S. Petrosino, K. Starowicz, R. Steuder, E. Schlicker, B. Cravatt, R. Mechoulam, R. Buettner, S. Werner, V. Di Marzo, T. Tüting, A. Zimmer, Attenuation of allergic contact dermatitis through the endocannabinoid system.
Science
316
, 1494-1497 (2007).
[Abstract]
[Full Text]
Identifying Oncogenes
Authors: Adler Elizabeth M.
Published: July 2007

The extensive karyotypic abnormalities and genetic disruption characteristic of epithelial cancers make it difficult to pinpoint which mutations are critical to the development and maintenance of cancer. Boehm
et al.
used an integrative genomic approach to identify potential oncogenes by determining which signaling pathways downstream of oncogenic Ras contribute to cell transformation. They created 16 human embryonic kidney (HEK) cell lines that expressed single or paired combinations of mutant alleles that activated the MAPK (mitogen-activated protein kinase) or PI3K (phosphatidylinositol 3-kinase) signaling pathways and assessed their ability to recapitulate the tumorigenic phenotype of oncogenic Ras. Among these, the phenotype of a constitutively active mutant of MEK1 (a MAPK kinase) in combination with a myristoylated AKT1 mutant (myr-AKT, which constitutively activates PI3K signaling) most resembled that of oncogenic Ras. The authors then screened a library of activated kinases and identified four that could substitute for myr-AKT in eliciting an oncogenic Ras-like phenotype in combination with the
MEK1
mutant. One of these,
IKBKE
[which encodes inhibitor of κB kinase ε (IKKε)], was amplified and overexpressed in a substantial fraction of human breast cancer cells and breast cancer cell lines. Moreover, shRNA directed against
IKBKE
inhibited the proliferation and survival of breast cancer cell lines with
IKBKE
amplification. Cells expressing constitutively active
IKBKE
showed an increase in NF-κB nuclear translocation and in expression of NF-κB target genes, and inhibition of NF-κB signaling increased doubling time and suppressed colony formation in
IKBKE
-transformed HEK cells. Furthermore, IKKε was associated with NF-κB activation in breast cancer cell lines and tissue. Thus, the authors conclude that
IKBKE
is a breast cancer oncogene that may link PI3K signaling to activation of the NF-κB pathway. Agami discusses the work.

J. S. Boehm, J. J. Zhao, J. Yao, S. Y. Kim, R. Firestein, I. F. Dunn, S. K. Sjostrom, L. A. Garraway, S. Weremowicz, A. L. Richardson, H. Greulich, C. J. Stewart, L. A. Mulvey, R. R. Shen, L. Ambrogio, T. Hirozane-Kishikawa, D. E. Hill, M. Vidal, M. Meyerson, J. K. Grenier, G. Hinkle, D. E. Root, T. M. Roberts, E. S. Lander, K. Polyak, W. C. Hahn, Integrative genomic approaches identify
IKBKE
as a breast cancer oncogene.
Cell
129
, 1065−1079 (2007).
[PubMed]

R. Agami, All roads lead to ΙΚΚε.
Cell
129
, 1043-1045 (2007).
[PubMed]
Hans Brinker Meets Gap Junctions
Authors: Ray L. Bryan
Published: July 2007

Gap junction channels allow communication between adjacent cells. Hemichannels formed from connexin proteins, one in each cell membrane, come together to allow small molecules, from ions to second messengers and peptides, to pass between cells. Conductance of the channels can be modulated, and mutations in connexin26 are associated with human diseases, including hereditary deafness. Oshima
et al
. solved the electron crystallographic structure of a mutant connexin26 protein similar to the one that causes the human hearing disorder. They obtained 2D crystals and combined images of them to obtain a 3D density map showing three membranes and two sets of symmetrically related intercellular channels at a resolution of 10 Å in the membrane plane and 14.1 Å perpendicular to the membrane plane. Most striking was a prominent density right in the center of the pore, essentially plugging the pore. Although the structures do not allow tracing of the plug to connect with the primary protein sequence, the authors suspect that the plug represents one of the protein termini, probably the N terminus. The mutant used and the conditions for crystallization should yield channels in a closed conformation. Such a plug would allow conductance of each hemichannel to be independently modulated, with a conducting pore formed only when both hemichannels had their plugs deflected to the cytoplasmic side.

A. Oshima, K. Tani, Y. Hiroaki, Y. Fujiyoshi, G. E. Sosinsky, Three-dimensional structure of a human connexin26 gap junction channel reveals a plug in the vestibule.
Proc. Natl. Acad. Sci. U.S.A.
104
, 10034-10039 (2007).
[Abstract]
[Full Text]
Immunogenicity of Influenza Virus Vaccine Is Increased by Anti-Gal-Mediated Targeting to Antigen-Presenting Cells
Authors: Abdel-Motal Ussama M. , Guay Heath M. , Wigglesworth Kim , Welsh Raymond M. , Galili Uri
Published: July 2007

This study describes a method for increasing the immunogenicity of influenza virus vaccines by exploiting the natural anti-Gal antibody to effectively target vaccines to antigen-presenting cells (APC). This method is based on enzymatic engineering of carbohydrate chains on virus envelope hemagglutinin to carry the α-Gal epitope (Galα1-3Galβ1-4GlcNAc-R). This epitope interacts with anti-Gal, the most abundant antibody in humans (1% of immunoglobulins). Influenza virus vaccine expressing α-Gal epitopes is opsonized in situ by anti-Gal immunoglobulin G. The Fc portion of opsonizing anti-Gal interacts with Fcγ receptors on APC and induces effective uptake of the vaccine virus by APC. APC internalizes the opsonized virus to transport it to draining lymph nodes for stimulation of influenza virus-specific T cells, thereby eliciting a protective immune response. The efficacy of such an influenza vaccine was demonstrated in α1,3galactosyltransferase (α1,3GT) knockout mice, which produce anti-Gal, using the influenza virus strain A/Puerto Rico/8/34-H1N1 (PR8). Synthesis of α-Gal epitopes on carbohydrate chains of PR8 virus (PR8αgal) was catalyzed by recombinant α1,3GT, the glycosylation enzyme that synthesizes α-Gal epitopes in cells of nonprimate mammals. Mice immunized with PR8αgaldisplayed much higher numbers of PR8-specific CD8+and CD4+T cells (determined by intracellular cytokine staining and enzyme-linked immunospot assay) and produced anti-PR8 antibodies with much higher titers than mice immunized with PR8 lacking α-Gal epitopes. Mice immunized with PR8αgalalso displayed a much higher level of protection than PR8 immunized mice after being challenged with lethal doses of live PR8 virus. We suggest that a similar method for increasing immunogenicity may be applicable to avian influenza vaccines.
Bile Acids Promote the Expression of Hepatitis C Virus in Replicon-Harboring Cells
Authors: Chang Kyeong-Ok , George David W.
Published: July 2007

Hepatitis C virus (HCV) is a cause of chronic liver disease, with more than 170 million persistently infected individuals worldwide. Although the combination therapy of alpha interferon (IFN-α) and ribavirin is effective for chronic HCV infection, around half of all patients infected with HCV genotype 1 fail to show sustained virologic responses and remain chronically infected. Previously, we demonstrated that bile acids were essential for growth of porcine enteric calicivirus in cell culture in association with down-regulation of IFN responses. Because hepatocytes are exposed to high concentrations of bile acids in the liver, we hypothesized that bile acids have similar effects on HCV replication. We incubated HCV replicon-harboring cells (genotype 1b, Con1) in the presence of various bile acids and monitored the expression of HCV RNA and protein (NS5B). The addition of an individual bile acid (deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, or glycochenodeoxycholic acid) in the medium increased the levels of HCV RNA and proteins up to fivefold at 48 h of incubation. An antagonist of bile acid receptor farnesoid X receptor (FXR),
Z
-guggulsterone, reduced the bile acid-mediated increase of HCV RNA. When IFN (α or γ) and each bile acid were incubated together, we observed that bile acid significantly reduced the anti-HCV effect of IFN. These results indicated that bile acids are factors in the failure of IFN treatment for certain patients infected with HCV genotype 1. Our finding may also contribute to the establishment of better regimens for treatment of chronic HCV infections by including agents altering the bile acid-mediated FXR pathway.
The effect of protective headgear on head injuries and concussions in adolescent football (soccer) players
Authors: Delaney J S , Al-Kashmiri A , Drummond R , Correa J A
Published: July 2007

Objective:

To examine the effects of protective headgear in adolescent football (soccer) players.

Design:

Cross-sectional study.

Setting:

Oakville Soccer Club, Oakville, Canada.

Participants:

Football players aged 12–17 years.

Intervention:

A questionnaire examining the 2006 football season using self-reported symptoms.

Main outcome measures:

The number of concussions experienced during the current football season, the duration of symptoms, injuries to the head and face and any associated risk factors for these injuries.

Results:

In the population studied, 47.8% had experienced symptoms of a concussion during the current football year. 26.9% of athletes who wore headgear (HG) and 52.8% of those who did not wear headgear (No-HG) had concussions. Approximately 4 out of 5 athletes in each group did not realize they had suffered a concussion. More than one concussion was experienced by 50.0% of the concussed HG athletes and 69.3% of the concussed No-HG group. 23.9% of all concussed players experienced symptoms for at least 1 day or longer. Variables that increased the risk of suffering a concussion during the 2006 football year included being female and not wearing headgear. Being female and not wearing football headgear increased the risk of suffering an abrasion, laceration or contusion on areas of the head covered by football headgear.

Conclusion:

Adolescent football players experience a significant number of concussions. Being female may increase the risk of suffering a concussion and injuries on the head and face, while the use of football headgear may decrease the risk of sustaining these injuries.
Endothelin-1 blockade prevents COX2induction and TXA2production in the fructose hypertensive ratThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.
Authors: Jiang Jihong , Tran Linda , Vasudevan Harish , Xia Zhengyuan , Yuen Violet G. , McNeill John H.
Published: July 2007

Feeding rats with a high fructose diet results in insulin resistance and hypertension. Fructose-hypertensive rats (FHR) have increased vascular levels of endothelin-1 (ET-1) and thromboxane (TXA2). We have previously shown that chronic treatment with either the dual endothelin receptor blocker, bosentan, or the thromboxane synthase inhibitor, dazmegrel, prevented fructose-induced increases in blood pressure, suggesting that both ET-1 and TXA2play important roles in the development of hyperinsulinemia/insulin resistance-associated hypertension. In this study, we investigated the potential interrelationship between ET-1 and TXA2in the development of fructose-induced hypertension in vivo. Male Wistar rats were fed on a high fructose diet for 9 weeks. Either bosentan or dazmegrel treatment (daily by oral gavage) was initiated 3 weeks after the start of fructose feeding for a total duration of 6 weeks. At the end of drug treatment, blood and aorta were collected from each animal. Plasma thromboxane B2(TXB2), a stable TXA2metabolite, increased significantly in FHR and was reduced to control level by both chronic bosentan and dazmegrel treatment. Protein expression of cyclooxygenase 2 (COX2) was elevated significantly in FHR aortas and treatment with bosentan and dazmegrel corrected these changes. These results indicate that the actions of ET-1 in the aorta of FHR may be mediated through COX2-derived TXA2. Bosentan may prevent the development of hypertension in fructose-fed rats through inhibition of COX2induction and subsequently the reduction in plasma TXA2.
WIDE-BANDGAP SEMICONDUCTOR DEVICES FOR AUTOMOTIVE APPLICATIONS
Authors: Sugimoto M. , Ueda H. , Uesugi T. , kachi T.
Published: July 2007

In this paper, we discuss requirements of power devices for automotive applications, especially hybrid vehicles and the development of GaN power devices at Toyota. We fabricated AlGaN/GaN HEMTs and measured their characteristics. The maximum breakdown voltage was over 600V. The drain current with a gate width of 31mm was over 8A. A thermograph image of the HEMT under high current operation shows the AlGaN/GaN HEMT operated at more than 300°C. And we confirmed the operation of a vertical GaN device. All the results of the GaN HEMTs are really promising to realize high performance and small size inverters for future automobiles.
Electrical Comparison of Ta/Ti/Al/Mo/Au and Ti/Al/Mo/Au Ohmic Contacts on Undoped GaN HEMTs Structure with AlN Interlayer
Authors: Sun Yunju , Eastman Lester F.
Published: July 2007

A significant improvement of contact transfer resistance on undoped GaN/AlGaN/AlN (10 Å)/ GaN high electron mobility transistor (HEMT) structure was demonstrated using a Ta/Ti/Al/Mo/Au metallization scheme compared to a Ti/Al/Mo/Au metallization scheme. A contact resistance as low as 0.16 ± 0.03 ohm - mm was achieved by rapid thermal annealing of evaporated Ta (125 Å)/ Ti (150 Å)/ Al (900 Å)/ Mo (400 Å)/ Au (500 Å) metal contact at 700 °C for 1 min followed by 800 °C for 30 sec in a N 2 ambient. An excellent edge acuity was also demonstrated for the annealed Ta/Ti/Al/Mo/Au ohmic contacts.
TEMPERATURE-DEPENDENT MICROWAVE PERFORMANCE OF SB-HETEROSTRUCTURE BACKWARD DIODES FOR MILLIMETER-WAVE DETECTION
Authors: SU N. , ZHANG Z. , FAY P. , MOYER H. P. , RAJAVEL R. D. , SCHULMAN J.
Published: July 2007

The temperature dependence of heterostructure backward diodes based on the InAs/AlGaSb/GaSb material system for millimeter-wave detection has been investigated experimentally. Measured dc curvatures of 36 V-1 at 298 K and 74 V-1 at 4.2 K have been obtained. Variable-temperature on-wafer s-parameters to 110 GHz reveal that the junction capacitance of a typical 2×2 μ m 2 area device decreases from 18 fF at 298 K to 11 fF at 77 K, while the junction resistance decreases from 13.9 kΩ to 10.2 kΩ. Directly measured voltage sensitivities at 50 GHz of 3650 V/W and 7190 V/W were obtained at 298 K and 4.2 K, respectively, consistent with the expected value from measured dc curvature. A 1 dB compression point of 18.5 μW and 7.2 μW at 298 K and 77 K, respectively, was measured. A physical model based on self-consistent Poisson-Schrödinger equation solutions was obtained to explain the experimental observations, and suggests the ways to further improve the device performance.
THEORY OF THIRD SOUND AND STABILITY OF THIN 3He–4He SUPERFLUID FILMS
Authors: MILLER M. D. , KROTSCHECK E.
Published: July 2007

In this paper, we summarize the results of recent studies of third sound in thin, superfluid 3 He -4 He mixture films and the relation of the third sound spectrum to the question of the films' thermodynamic stability. We have considered films on several representative substrates: Nuclepore, glass, Li and Na . Our approach utilizes the variational, hypernetted chain/Euler-Lagrange (HNC–EL) theory as applied to inhomogeneous boson systems to calculate chemical potentials for both the 4 He superfluid film and the physisorbed 3 He . Numerical density derivatives of the chemical potentials lead to the sought-after third sound speeds. On all substrates, the third sound speeds show a series of oscillations as a function of film coverage that is driven by the layered structure of the 4 He film. We find that the effect on the third sound response of adding a small amount of 3 He to the 4 He film can depend sensitively on the particular 4 He film coverage. The third sound speed can either increase or decrease. In fact, in some regimes, the added 3 He destabilizes the film and can drive "layering transitions" leading to quite complicated geometric structures of the film in which the outermost layer consists of phase–separated regimes of 3 He and 4 He . Finally, we examine the range of applicability of the usual film–averaged hydrodynamic description. We find that at least up to film thicknesses of six liquid layers, there is no regime in which this hydrodynamic description is applicable.
LOWERING OF BOSON-FERMION SYSTEM ENERGY WITH A GAPPED COOPER RESONANT-PAIR DISPERSION RELATION
Authors: MAMEDOV T. A. , DE LLANO M.
Published: July 2007

Applying two-time Green-function techniques to the Friedberg-T.D. Lee phenomenological Hamiltonian of a many-fermion system, it is shown that positive-energy resonant bosonic pairs associated with four-fermion excitations above the Fermi sea are energetically lower in a ground-state that is a mixture of two coexisting and dynamically interacting many-particle subsystems: a) unpaired fermions and b) composite bosons. It is argued that an interaction between free fermions and bosons excited above the Fermi sea in the mixture, namely, the continuous processes of pair-formation from, and disintegration into, two unpaired electrons, results in a substantially lowering the total system energy. The positive-energy composite bosons begin to appear incoherently below a depairing temperature T* as their coupling- and temperature-dependent number density gradually increases from zero. This leads quite naturally to the pseudogap phenomenon observed in high-Tccuprates.
A KIRCHOFF–SOBOLEV PARAMETRIX FOR THE WAVE EQUATION AND APPLICATIONS
Authors: KLAINERMAN SERGIU , RODNIANSKI IGOR
Published: July 2007

We construct a first order, physical space, parametrix for solutions to covariant, tensorial, wave equations on a general Lorentzian manifold. The construction is entirely geometric; that is both the parametrix and the error terms generated by it have a purely geometric interpretation. In particular, when the background Lorentzian metric satisfies the Einstein vacuum equations, the error terms, generated at some point p of the space-time, depend, roughly, only on the flux of curvature passing through the boundary of the past causal domain of p. The virtues of our specific geometric construction becomes apparent in applications to realistic problems. Though our main application is to General Relativity, which we discuss in [14], another simpler application shown here is to give a gauge invariant proof of the classical regularity result of Eardley–Moncrief [4, 5] for the Yang–Mills equations in ℝ1+3.
The Thymus as an Inductive Site for T Lymphopoiesis
Authors: Ciofani Maria , Zúñiga-Pflücker Juan Carlos
Published: July 2007

Like all hematopoietic cells, T lymphocytes are derived from bone-marrow-resident stem cells. However, whereas most blood lineages are generated within the marrow, the majority of T cell development occurs in a specialized organ, the thymus. This distinction underscores the unique capacity of the thymic microenvironment to support T lineage restriction and differentiation. Although the identity of many of the contributing thymus-derived signals is well established and rooted in highly conserved pathways involving Notch, morphogenetic, and protein tyrosine kinase signals, the manner in which the ensuing cascades are integrated to orchestrate the underlying processes of T cell development remains under investigation. This review focuses on the current definition of the early stages of T cell lymphopoiesis, with an emphasis on the nature of thymus-derived signals delivered to T cell progenitors that support the commitment and differentiation of T cells toward the αβ and γδ T cell lineages.
Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes
Authors: Cho You-Ree , Kim Hyo-Jeong , Park So-Young , Ko Hwi Jin , Hong Eun-Gyoung , Higashimori Takamasa , Zhang Zhiyou , Jung Dae Young , Ola M. Shamsul , LaNoue Kathryn F. , Leiter Edward H. , Kim Jason. K.
Published: July 2007

As a new mouse model of obesity-induced diabetes generated by combining quantitative trait loci from New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/LtJ) mice, NONcNZO10/LtJ (RCS10) male mice developed type 2 diabetes characterized by maturity onset obesity, hyperglycemia, and insulin resistance. To metabolically profile the progression to diabetes in preobese and obese states, a 2-h hyperinsulinemic euglycemic clamp was performed and organ-specific changes in insulin action were assessed in awake RCS10 and NON/LtJ (control) males at 8 and 13 wk of age. Prior to development of obesity and attendant increases in hepatic lipid content, 8-wk-old RCS10 mice developed insulin resistance in liver and skeletal muscle due to significant decreases in insulin-stimulated glucose uptake and GLUT4 expression in muscle. Transition to an obese and hyperglycemic state by 13 wk of age exacerbated insulin resistance in skeletal muscle, liver, and heart associated with organ-specific increases in lipid content. Thus, this polygenic mouse model of type 2 diabetes, wherein plasma insulin is only modestly elevated and obesity develops with maturity yet insulin action and glucose metabolism in skeletal muscle and liver are reduced at an early prediabetic age, should provide new insights into the etiology of type 2 diabetes.
The role of the stretch reflex in the gastrocnemius muscle during human locomotion at various speeds
Authors: Ishikawa M. , Komi P. V.
Published: July 2007

In the present study, the fascicle length ( Lfa) of the human medial gastrocnemius (MG) muscle was monitored to evaluate possible input from the short-latency stretch reflex (SLR) during the stance phase of running and to examine its timing at various running speeds. Eight subjects ran at 2.0, 3.5, 5.0, and 6.5 m/s. The Lfa was measured with the high-speed ultrasound fascicle scanning together with kinematics and myoelectrical activities. The amplitudes and onset latency of SLR activities were determined. During ground contact, the sudden MG fascicle stretch occurred during the early contact at all running speeds. This was followed by the fascicle shortening. The timing of fascicle stretch depended on running speed and type of foot contact. In slower speed conditions (2.0, 3.5, 5 m/s), the MG fascicle stretch and the corresponding SLR activities occurred during the middle of the braking phase. In fast-speed running (6.5 m/s), however, the MG fascicle stretch occurred later compared with the lower speed. The corresponding SLR activities occurred significantly later at the end of the braking phase. In addition to the clear demonstration of the different timings of SLR in MG during ground contact of running, the results imply that the role of the MG SLR during the stance phase of running can be different between fast- and slow-speed running conditions.
Evidence From Retractor Bulbi EMG for Linearized Motor Control of Conditioned Nictitating Membrane Responses
Authors: Lepora N. F. , Mavritsaki E. , Porrill J. , Yeo C. H. , Evinger C. , Dean P.
Published: July 2007

Classical conditioning of nictitating membrane (NM) responses in rabbits is a robust model learning system, and experimental evidence indicates that conditioned responses (CRs) are controlled by the cerebellum. It is unknown whether cerebellar control signals deal directly with the complex nonlinearities of the plant (blink-related muscles and peripheral tissues) or whether the plant is linearized to ensure a simple relation between cerebellar neuronal firing and CR profile. To study this question, the retractor bulbi muscle EMG was recorded with implanted electrodes during NM conditioning. Pooled activity in accessory abducens motoneurons was estimated from spike trains extracted from the EMG traces, and its temporal profile was found to have an approximately Gaussian shape with peak amplitude linearly related to CR amplitude. The relation between motoneuron activity and CR profiles was accurately fitted by a first-order linear filter, with each spike input producing an exponentially decaying impulse response with time constant of order 0.1 s. Application of this first-order plant model to CR data from other laboratories suggested that, in these cases also, motoneuron activity had a Gaussian profile, with time-of-peak close to unconditioned stimulus (US) onset and SD proportional to the interval between conditioned stimulus and US onsets. These results suggest that for conditioned NM responses the cerebellum is presented with a simplified “virtual” plant that is a linearized version of the underlying nonlinear biological system. Analysis of a detailed plant model suggests that one method for linearising the plant would be appropriate recruitment of motor units.
Emergence of Multiplicative Auditory Responses in the Midbrain of the Barn Owl
Authors: Fischer Brian J. , Peña José Luis , Konishi Masakazu
Published: July 2007

Space-specific neurons in the barn owl's auditory space map gain spatial selectivity through tuning to combinations of the interaural time difference (ITD) and interaural level difference (ILD). The combination of ITD and ILD in the subthreshold responses of space-specific neurons in the external nucleus of the inferior colliculus (ICx) is well described by a multiplication of ITD- and ILD-dependent components. It is unknown, however, how ITD and ILD are combined at the site of ITD and ILD convergence in the lateral shell of the central nucleus of the inferior colliculus (ICcl) and therefore whether ICx is the first site in the auditory pathway where multiplicative tuning to ITD- and ILD-dependent signals occurs. We used extracellular recording of single neurons to determine how ITD and ILD are combined in ICcl of the anesthetized barn owl ( Tyto alba). A comparison of additive, multiplicative, and linear-threshold models of neural responses shows that ITD and ILD are combined nonlinearly in ICcl, but the interaction of ITD and ILD is not uniformly multiplicative over the sample. A subset (61%) of the neural responses is well described by the multiplicative model, indicating that ICcl is the first site where multiplicative tuning to ITD- and ILD-dependent signals occurs. ICx, however, is the first site where multiplicative tuning is observed consistently. A network model shows that a linear combination of ICcl responses to ITD–ILD pairs is sufficient to produce the multiplicative subthreshold responses to ITD and ILD seen in ICx.
Enhancement of Arm and Leg Locomotor Coupling With Augmented Cutaneous Feedback From the Hand
Authors: Zehr E. Paul , Klimstra Marc , Dragert Katie , Barzi Yasaman , Bowden Mark G. , Javan Bahar , Phadke Chetan
Published: July 2007

Cutaneous feedback from the hand could assist with coordination between the arms and legs during locomotion. Previously we used a reduced walking model of combined arm and leg (arm&leg) cycling to examine the separate effects of rhythmic arm (arm) and leg (leg) movement. Here we use this same paradigm to test the modulation H-reflexes with and without interlimb cutaneous conditioning evoked by stimulating a nerve innervating the hand (superficial radial, SR). It was hypothesized that both arm and leg would contribute significantly to suppression of H-reflex amplitude during arm&leg. We also predicted a conservation of interlimb cutaneous conditioning during movement and an interaction between arm and leg rhythmic movement control. Subjects were seated in a recumbent arm&leg cycle ergometer and maintained a low-level soleus contraction for all tasks. H-reflex amplitude was facilitated by cutaneous conditioning evoked by stimulation of the SR nerve. H-reflex amplitudes were taken from recruitment curves and included modulation of 50% Hmax and Hmax. The suppressive effect of arm was less than that for leg and arm&leg, while suppression during leg and arm&leg were generally equivalent. For H-reflexes conditioned by cutaneous input, amplitudes during arm&leg instead were in between those for arm and leg modulation. Multiple regression analysis revealed a significant contribution for arm only in trials when SR stimulation was used to condition H-reflex amplitudes. We suggest that there is a measurable interaction between neural activity regulating arm and leg movement during locomotion that is specifically enhanced when cutaneous input from the hand is present.
O-Glycosylation Regulates LNCaP Prostate Cancer Cell Susceptibility to Apoptosis Induced by Galectin-1
Authors: Valenzuela Hector F. , Pace Karen E. , Cabrera Paula V. , White Rachel , Porvari Katja , Kaija Helena , Vihko Pirkko , Baum Linda G.
Published: July 2007

Resistance to apoptosis is a critical feature of neoplastic cells. Galectin-1 is an endogenous carbohydrate-binding protein that induces death of leukemia and lymphoma cells, breast cancer cells, and the LNCaP prostate cancer cell line, but not other prostate cancer cell lines. To understand the mechanism of galectin-1 sensitivity of LNCaP cells compared with other prostate cancer cells, we characterized glycan ligands that are important for conferring galectin-1 sensitivity in these cells, and analyzed expression of glycosyltransferase genes in galectin-1–sensitive, prostate-specific antigen–positive (PSA+) LNCaP cells compared with a galectin-1–resistant PSA− LNCaP subclone. We identified one glycosyltransferase, core 2 N-acetylglucosaminyltransferase, which is down-regulated in galectin-1–resistant PSA− LNCaP cells compared with galectin-1–sensitive PSA+ LNCaP cells. Intriguingly, this is the same glycosyltransferase required for galectin-1 susceptibility of T lymphoma cells, indicating that similar O-glycan ligands on different polypeptide backbones may be common death trigger receptors recognized by galectin-1 on different types of cancer cells. Blocking O-glycan elongation by expressing α2,3-sialyltransferase 1 rendered LNCaP cells resistant to galectin-1, showing that specific O-glycans are critical for galectin-1 susceptibility. Loss of galectin-1 susceptibility and synthesis of endogenous galectin-1 has been proposed to promote tumor evasion of immune attack; we found that galectin-1–expressing prostate cancer cells killed bound T cells, whereas LNCaP cells that do not express galectin-1 did not kill T cells. Resistance to galectin-1–induced apoptosis may directly contribute to the survival of prostate cancer cells as well as promote immune evasion by the tumor. [Cancer Res 2007;67(13):6155–62]
BRCA1 Activates a G2-M Cell Cycle Checkpoint following 6-Thioguanine–Induced DNA Mismatch Damage
Authors: Yamane Kazuhiko , Schupp Jane E. , Kinsella Timothy J.
Published: July 2007

Human DNA mismatch repair (MMR) is involved in the response to certain chemotherapy drugs, including 6-thioguanine (6-TG). Consistently, MMR-deficient human tumor cells show resistance to 6-TG damage as manifested by a reduced G2-M arrest and decreased apoptosis. In this study, we investigate the role of the BRCA1 protein in modulating a 6-TG–induced MMR damage response, using an isogenic human breast cancer cell line model, including a BRCA1 mutated cell line (HCC1937) and its transfectant with a wild-type BRCA1 cDNA. The MMR proteins MSH2, MSH6, MLH1, and PMS2 are similarly detected in both cell lines. BRCA1-mutant cells are more resistant to 6-TG than BRCA1-positive cells in a clonogenic survival assay and show reduced apoptosis. Additionally, the mutated BRCA1 results in an almost complete loss of a G2-M cell cycle checkpoint response induced by 6-TG. Transfection of single specific small interfering RNAs (siRNA) against MSH2, MLH1, ATR, and Chk1 in BRCA1-positive cells markedly reduces the BRCA1-dependent G2-M checkpoint response. Interestingly, ATR and Chk1 siRNA transfection in BRCA1-positive cells shows similar levels of 6-TG cytotoxicity as the control transfectant, whereas MSH2 and MLH1 siRNA transfectants show 6-TG resistance as expected. DNA MMR processing, as measured by the number of 6-TG–induced DNA strand breaks using an alkaline comet assay (±z-VAD-fmk cotreatment) and by levels of iododeoxyuridine-DNA incorporation, is independent of BRCA1, suggesting the involvement of BRCA1 in the G2-M checkpoint response to 6-TG but not in the subsequent excision processing of 6-TG mispairs by MMR. [Cancer Res 2007;67(13):6286–92]
Amphipathic Peptide-Based Fusion Peptides and Immunoconjugates for the Targeted Ablation of Prostate Cancer Cells
Authors: Rege Kaushal , Patel Suraj J. , Megeed Zaki , Yarmush Martin L.
Published: July 2007

We describe the design, generation, and in vitro evaluation of targeted amphipathic fusion peptides and immunoconjugates for the ablation of prostate cancer cells. The overexpression of the prostate-specific membrane antigen (PSMA) was exploited as means to specifically deliver cytotoxic peptides to prostate cancer cells. Cationic amphipathic lytic peptides were chosen as cytotoxic agents due to their ability to depolarize mitochondrial membranes and induce apoptosis. Specific delivery of the lytic peptide was facilitated by PSMA-targeting peptides and antibodies. Our results indicate that although the use of PSMA-targeted peptides only modestly enhanced the cytotoxic activity of the lytic peptide, peptide-antibody conjugates were two orders of magnitude more potent than untargeted peptide. In addition to quantifying the cytotoxic activities of the individual constructs, we also investigated the mechanisms of cell death induced by the fusion peptides and immunoconjugates. Although fusion peptides induced oncotic/necrotic death in cells, treatment with immunoconjugates resulted in apoptotic death. In summary, immunoconjugates based on lytic peptides are a promising class of therapeutics for prostate cancer therapy and warrant further investigation. [Cancer Res 2007;67(13):6368–75]
EGFR Activation Results in Enhanced Cyclooxygenase-2 Expression through p38 Mitogen-Activated Protein Kinase–Dependent Activation of the Sp1/Sp3 Transcription Factors in Human Gliomas
Authors: Xu Kaiming , Shu Hui-Kuo G.
Published: July 2007

Expression of cyclooxygenase-2 (COX-2) has been linked to many cancers and may contribute to malignant phenotypes, including enhanced proliferation, angiogenesis, and resistance to cytotoxic therapies. Malignant gliomas are highly aggressive brain tumors that display many of these characteristics. One prominent molecular abnormality discovered in these astrocytic brain tumors is alteration of epidermal growth factor (EGF) receptor (EGFR) through gene amplification and/or mutation resulting in excessive signaling from this receptor. We found that EGF-mediated stimulation of EGFR tyrosine kinase in human glioma cell lines induces expression of both COX-2 mRNA and protein. The p38 mitogen-activated protein kinase (p38-MAPK) pathway was a strong downstream factor in this activation with inhibition of this pathway leading to strong suppression of COX-2 induction. The p38-MAPK pathway can activate the Sp1/Sp3 transcription factors and this seems necessary for EGFR-dependent transactivation of the COX-2 promoter. Analysis of COX-2 promoter/luciferase constructs revealed that transcriptional activation of the COX-2 promoter by EGFR requires the Sp1 binding site located at −245/−240. Furthermore, Sp1/Sp3 binding to this site in the promoter is enhanced by EGFR activation both in vitro and in vivo. Enhanced DNA binding by Sp1/Sp3 requires p38-MAPK activity and correlates with increased phosphorylation of the Sp1 transcription factor. Thus, EGFR activation in malignant gliomas can transcriptionally activate COX-2 expression in a process that requires p38-MAPK and Sp1/Sp3. Finally, treatment of glioma cell lines with prostaglandin E2, the predominant product of COX-2 activity, results in increased vascular endothelial growth factor expression, thus potentially linking elevations in COX-2 expression with tumor angiogenesis in malignant gliomas. [Cancer Res 2007;67(13):6121–9]
Are Peroxisome Proliferator-Activated Receptors Involved in Skeletal Muscle Wasting during Experimental Cancer Cachexia? Role of β2-Adrenergic Agonists
Authors: Fuster Gemma , Busquets Sílvia , Ametller Elisabet , Olivan Mireia , Almendro Vanessa , Fontes de Oliveira Cibely Cristine , Figueras Maite , López-Soriano Francisco J. , Argilés Josep M.
Published: July 2007

Implantation of the Yoshida AH-130 ascites hepatoma to rats resulted in a decrease in muscle weight 7 days after the inoculation of the tumor. These changes were associated with increases in the mRNA content for both peroxisome proliferator-activated receptor (PPAR) γ and PPARδ in skeletal muscle. The increase in gene expression for these transcription factors was related to increases in the expression of several genes involved in fatty acid transport, activation, and oxidation. Tumor burden also resulted in increases in PPARγ coactivator-1α gene expression and pyruvate dehydrogenase kinase 4. All these changes in lipid metabolism genes suggest that a metabolic shift occurs in skeletal muscle of tumor-bearing rats toward a more oxidative phenotype. Formoterol treatment to tumor-bearing rats resulted in an amelioration of all the changes observed as a result of tumor burden. Administration of this β2-adrenergic agonist also resulted in a decrease in mRNA content of muscle PPARα, PPARδ, and PPARγ, as well as in mRNA levels of many of the genes involved in both lipid and mitochondrial metabolism. All these results suggest an involvement of the different PPARs as transcription factors related with muscle wasting and also indicate that a possible mode of action of the anticachectic compound formoterol may involve a normalization of the levels of these transcription factors. [Cancer Res 2007;67(13):6512–9]
Quantitative Assessment of the p53-Mdm2 Feedback Loop Using Protein Lysate Microarrays
Authors: Ramalingam Sundhar , Honkanen Peter , Young Lynn , Shimura Tsutomu , Austin John , Steeg Patricia S. , Nishizuka Satoshi
Published: July 2007

Mathematical simulations of the p53-Mdm2 feedback loop suggest that both proteins will exhibit impulsive expression characteristics in response to high cellular stress levels. However, little quantitative experimental evaluation has been done, particularly of the phosphorylated forms. To evaluate the mathematical models experimentally, we used lysate microarrays from an isogenic pair of γ-ray–irradiated cell lysates from HCT116 (p53+/+ and p53−/−). Both p53 and Mdm2 proteins showed expected pulses in the wild type, whereas no pulses were seen in the knockout. Based on experimental observations, we determined model parameters and generated an in silico “knockout,” reflecting the experimental data, including phosphorylated proteins. [Cancer Res 2007;67(13):6247–52]
Identification of Griseofulvin as an Inhibitor of Centrosomal Clustering in a Phenotype-Based Screen
Authors: Rebacz Blanka , Larsen Thomas O. , Clausen Mads H. , Rønnest Mads H. , Löffler Harald , Ho Anthony D. , Krämer Alwin
Published: July 2007

A major drawback of cancer chemotherapy is the lack of tumor-specific targets which would allow for the selective eradication of malignant cells without affecting healthy tissues. In contrast with normal cells, most tumor cells contain multiple centrosomes, associated with the formation of multipolar mitotic spindles and chromosome segregation defects. Many tumor cells regain mitotic stability after clonal selection by the coalescence of multiple centrosomes into two functional spindle poles. To overcome the limitations of current cancer treatments, we have developed a cell-based screening strategy to identify small molecules that inhibit centrosomal clustering and thus force tumor cells with supernumerary centrosomes to undergo multipolar mitoses, and subsequently, apoptosis. Using a chemotaxonomic selection of fungi from a large culture collection, a relatively small but diverse natural product extract library was generated. Screening of this compound library led to the identification of griseofulvin, which induced multipolar spindles by inhibition of centrosome coalescence, mitotic arrest, and subsequent cell death in tumor cell lines but not in diploid fibroblasts and keratinocytes with a normal centrosome content. The inhibition of centrosome clustering by griseofulvin was not restricted to mitotic cells but did occur during interphase as well. Whereas the formation of multipolar spindles was dynein-independent, depolymerization of interphase microtubules seemed to be mechanistically involved in centrosomal declustering. In summary, by taking advantage of the tumor-specific phenotype of centrosomal clustering, we have developed a screening strategy that might lead to the identification of drugs which selectively target tumor cells and spare healthy tissues. [Cancer Res 2007;67(13):6342–50]
Immunotherapy against APP β-Secretase Cleavage Site Improves Cognitive Function and Reduces Neuroinflammation in Tg2576 Mice without a Significant Effect on Brain Aβ Levels
Authors: Rakover Idan , Arbel Michal , Solomon Beka
Published: July 2007

Background/Objectives: Active and passive immunization methodologies against amyloid-β (Aβ) are employed to clear and reduce cerebral Aβtowards treatment of Alzheimer’s disease (AD) patients. The therapeutic potential of these antibodies in AD patients is limited because of adverse inflammatory reactions and cerebral hemorrhage, which are associated with the treatment. We propose a novel approach to inhibit Aβ production via antibodies against the β-secretase cleavage site of the amyloid precursor protein (APP). Such an approach limits APP processing by β-secretase, mainly through the endocytic pathway, and overcomes some of the limitations of BACE inhibition. Anti-APP β-site antibodies, tested in a cellular model expressing wild-type APP, were found to bind full-length APP, internalize into the cells and interfere with BACE activity, inhibiting both intra- and extracellular Aβ peptide formation. Methods: We investigated the effect of anti-β-site antibodies in an AD animal model regarding antibody efficacy, as well as possible adverse effects in the brain and periphery that may result from antibody treatment. Results/Conclusions: Here, we show that long-term systemic administration of anti-APP β-site antibodies to Tg2576 transgenic mice improved mouse cognitive functions associated with a reduction in both brain inflammation and the incidence of microhemorrhage. Furthermore, antibody treatment did not induce any peripheral autoimmunity responses. In spite of the beneficial effects observed in antibody-treated mice, brain Aβ levels were not altered as a result of antibody treatment.
Late Dietary Intervention Limits Benefits of Soy Protein or Flax Oil in Experimental Polycystic Kidney Disease
Authors: Sankaran Deepa , Bankovic-Calic Neda , Cahill Leah , Yu-Chen Peng Claudia , Ogborn Malcolm R , Aukema Harold M.
Published: July 2007

Background/Aims: Dietary soy protein and flax oil retard kidney disease progression when initiated in the early stages of disease in several experimental models, including the Han:SPRD-cy rat. However, individuals with kidney disease often do not become aware of their condition until injury to the kidney is extensive. The objective of this study was to determine whether initiating these interventions in established disease would alter further progression of renal injury. Methods: Two-month-old adult male Han:SPRD-cy rats were given either a flax oil diet (7% flax oil), a soy protein diet (20% soy protein) or a control diet (7% corn oil, 20% casein) for 4 months. Renal disease progression was assessed by examining morphological, immunohistochemical and biochemical parameters. Results: Compared to controls, there was 21–24% less staining of proliferating cells, 21–24% less oxidative damage and 13–15% less renal inflammation in kidneys from rats given dietary soy protein and flax oil. Renal cystic growth and fibrosis and serum creatinine levels were not altered by these dietary treatments. Conclusions: Late intervention with dietary soy protein and flax oil reduces some disease-associated pathologies in established renal disease in Han:SPRD-cy rats. The potential benefits of the antioxidant and anti-inflammatory effects on ultimate renal disease outcome in the long term remains to be determined.
Lactate and Glycerol Released to the Intestinal Lumen Reflect Mucosal Injury and Permeability Changes Caused by Strangulation Obstruction
Authors: Juel I.S. , Solligård E. , Skogvoll E. , Aadahl P. , Grønbech J.E.
Published: July 2007

Background: The present study evaluates whether microdialysis of glycerol and lactate reflects mucosal injury and permeability changes after strangulation obstruction of the pig small intestine. Methods: Strangulation obstruction was induced by tightening a rubber band around a small bowel loop until its venous pressure increased to a level just below diastolic aortic pressure (partial strangulation), or further until cessation of flow in the main feeding artery (total strangulation). Mucosal injury and permeability of marker molecules from blood to lumen and vice versa was compared to release of glycerol and lactate to the intestinal lumen. Results: Mucosal injury, hyperpermeability, and release of glycerol were more pronounced after total than after partial strangulation. In animals with partial strangulation there was a complete restitution of the surface epithelium, and luminal glycerol and lumen-to-blood permeability of polyethylene glycol 4000 remained low. Such animals showed a sustained elevation of lactate and blood-to-lumen permeability of fluorescein isothiocyanate dextran after 2 h of partial strangulation, but a decline to baseline levels of these parameters in animals with 1 h partial strangulation. Conclusion: Microdialysis of lactate and glycerol in the intestinal lumen may be used to assess structural and functional changes of the intestinal mucosa after strangulation obstruction.