bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
Authors: Weinberg Frank , Hamanaka Robert , Wheaton William W. , Weinberg Samuel , Joseph Joy , Lopez Marcos , Kalyanaraman Balaraman , Mutlu Gökhan M. , Budinger G. R. Scott , Chandel Navdeep S.
Published: April 2010

Otto Warburg's theory on the origins of cancer postulates that tumor cells have defects in mitochondrial oxidative phosphorylation and therefore rely on high levels of aerobic glycolysis as the major source of ATP to fuel cellular proliferation (the Warburg effect). This is in contrast to normal cells, which primarily utilize oxidative phosphorylation for growth and survival. Here we report that the major function of glucose metabolism for Kras-induced anchorage-independent growth, a hallmark of transformed cells, is to support the pentose phosphate pathway. The major function of glycolytic ATP is to support growth under hypoxic conditions. Glutamine conversion into the tricarboxylic acid cycle intermediate alpha-ketoglutarate through glutaminase and alanine aminotransferase is essential for Kras-induced anchorage-independent growth. Mitochondrial metabolism allows for the generation of reactive oxygen species (ROS) which are required for Kras-induced anchorage-independent growth through regulation of the ERK MAPK signaling pathway. We show that the major source of ROS generation required for anchorage-independent growth is the Q
o
site of mitochondrial complex III. Furthermore, disruption of mitochondrial function by loss of the mitochondrial transcription factor A (TFAM) gene reduced tumorigenesis in an oncogenic Kras-driven mouse model of lung cancer. These results demonstrate that mitochondrial metabolism and mitochondrial ROS generation are essential for Kras-induced cell proliferation and tumorigenesis.
GM-CSF–dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization
Authors: King Irah L. , Kroenke Mark A. , Segal Benjamin M.
Published: April 2010

Dendritic cells (DCs) play an important role in CD4+ T helper (Th) cell differentiation and in the initiation of both protective and pathogenic immunity. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a DC growth factor critical for the induction of experimental autoimmune encephalomyelitis (EAE) and other autoimmune diseases, yet its mechanism of action in vivo is not fully defined. We show that GM-CSF is directly required for the accumulation of radiosensitive dermal-derived langerin+CD103+ DCs in the skin and peripheral lymph nodes under steady-state and inflammatory conditions. Langerin+CD103+ DCs stimulated naive myelin-reactive T cells to proliferate and produce IFN-γ and IL-17. They were superior to other DC subsets in inducing expression of T-bet and promoting Th1 cell differentiation. Ablation of this subset in vivo conferred resistance to EAE. The current report reveals a previously unidentified role for GM-CSF in DC ontogeny and identifies langerin+CD103+ DCs as an important subset in CD4+ T cell–mediated autoimmune disease.
Calcineurin regulates innate antifungal immunity in neutrophils
Authors: Greenblatt Matthew B. , Aliprantis Antonios , Hu Bella , Glimcher Laurie H.
Published: April 2010

Patients taking immunosuppressive drugs, like cyclosporine A (CsA), that inhibit calcineurin are highly susceptible to disseminated fungal infections, although it is unclear how these drugs suppress resistance to these opportunistic pathogens. We show that in a mouse model of disseminated Candida albicans infection, CsA-induced susceptibility to fungal infection maps to the innate immune system. To further define the cell types targeted by CsA, we generated mice with a conditional deletion of calcineurin B (CnB) in neutrophils. These mice displayed markedly decreased resistance to infection with C. albicans, and both CnB-deficient and CsA-treated neutrophils showed a defect in the ex vivo killing of C. albicans. In response to the fungal-derived pathogen-associated molecular pattern zymosan, neutrophils lacking CnB displayed impaired up-regulation of genes (IL-10, Cox2, Egr1, and Egr2) regulated by nuclear factor of activated T cells, the best characterized CnB substrate. This activity was Myd88 independent and was reproduced by stimulation with the β(1,3) glucan curdlan, indicating that dectin-1, rather than toll-like receptors, is the upstream activator of calcineurin. Our results suggest that disseminated fungal infections seen in CsA-treated patients are not just a general consequence of systemic suppression of adaptive immunity but are, rather, a result of the specific blockade of evolutionarily conserved innate pathways for fungal resistance.
Automorphisms of hyperelliptic modular curves X0(N) in positive characteristic
Authors: Kontogeorgis Aristides , Yang Yifan
Published: April 2010

We study the automorphism groups of the reduction $X_0(N) \times \bar {\mathbb {F}}_p$ of a modular curve X0(N) over primes p∤N.
TMEM16A/Anoctamin 1 protein mediates calcium‐activated chloride currents in pulmonary arterial smooth muscle cells
Authors: Manoury Boris , Tamuleviciute Aiste , Tammaro Paolo
Published: April 2010

Calcium‐activated chloride channels (CaCCs) play important roles in several physiological processes. In vascular smooth muscle, activation of these ion channels by agonist‐induced Ca2+ release results in membrane depolarization and vasoconstriction. The molecular identity of vascular CaCCs is not fully defined. Here we present evidence that TMEM16A (or anoctamin 1), a member of the transmembrane 16 (TMEM16) protein family, forms CaCCs in pulmonary artery smooth muscle cells (PASMCs). Patch‐clamp analysis in freshly isolated PASMCs revealed strongly outward‐rectifying, slowly activating Ca2+‐activated Cl− currents sharing a high degree of similarity with heterologous TMEM16A currents. TMEM16A mRNA was identified in rat and human pulmonary arteries and various other vascular smooth muscle cell types. Further analyses revealed that several TMEM16A splice variants were detected in rat PASMCs and that TMEM16F and TMEM16K were also expressed in these cells, while TMEM16B, TMEM16D and TMEM16E were all at least 50 times less abundantly expressed and the remaining TMEM16 family members were absent. Downregulation of TMEM16A gene expression in primary cultures of rat PASMCs, with small interfering RNAs, was accompanied by almost total loss of whole‐cell CaCC currents. Based on these results, we propose that TMEM16A is the major constituent of the vascular calcium‐activated chloride channel in rat pulmonary artery smooth muscle.
An Experimental and Computational Study of a Swirl-Stabilized Premixed Flame
Authors: De Ashoke , Zhu Shengrong , Acharya Sumanta
Published: April 2010

An unconfined strongly swirled flow is investigated for different Reynolds numbers using particle image velocimetry (PIV) and large eddy simulation (LES) with a thickened-flame (TF) model. Both reacting and nonreacting flow results are presented. In the LES-TF approach, the flame front is resolved on the computational grid through artificial thickening and the individual species transport equations are directly solved with the reaction rates specified using Arrhenius chemistry. Good agreement is found when comparing predictions with the experimental data. Also the predicted root mean square (rms) fluctuations exhibit a double-peak profile with one peak in the burnt and the other in the unburnt region. The measured and predicted heat release distributions are in qualitative agreement with each other and exhibit the highest values along the inner edge of the shear layer. The precessing vortex core (PVC) is clearly observed in both the nonreacting and reacting cases. However, it appears more axially elongated for the reacting cases and the oscillations in the PVC are damped with reactions.
Engine Rapid Shutdown: Experimental Investigation on the Cooling System Transient Response
Authors: Piccione Rocco , Bova Sergio
Published: April 2010

Experimental measurements have been taken on a production four-cylinder, multipoint (fuel) injection spark-ignition engine, 1.2 dm3 displacement with a four-valve per cylinder aluminum head, and a 60 kW at 5500 rpm rated power. The aim of the investigation was to understand the behavior of the cooling system of a small automotive engine, which was operated for a prolonged period at high speed under full or part load, then brought to idle for a short period and finally shut down. In this study, the effects of different loads, idle operation time, and lengths of the engine-radiator piping were analyzed. In particular, experimental tests were carried out with the engine running at 4000 rpm under different brake mean effective pressure values in the range 496 to 1133 kPa. In all experimental tests the engine was brought to idle in 5 s, and measurements were repeated for different values of the idle operation time ranging from 1 s to 80 s. Test data of coolant conditions and metal temperature at 26 points of the engine head and liner were recorded. The cooling circuit was instrumented with transparent tubes at the radiator inlet and photographs of the vapor phase moving to the radiator were taken during experimental tests. The volume of leaked coolant as a function of time was also measured. Additional tests were carried out to evaluate the effects of different lengths of the engine-radiator piping on the after-boiling phenomenon. Finally, in order to make the results applicable also to nonautomotive engines, measurements were repeated without the standard cabin heater and the associated piping. The investigation results show that as the engine is shut down and coolant flow stops, the head metal may be hot enough to vaporize a fraction of the coolant contained in the cylinder head passages, causing the pressure within the cooling circuit to rise above the threshold value of the radiator cap pressure valve and, consequently, an important quantity of the coolant to be expelled.
NO

x

Reduction by Air-Side Versus Fuel-Side Dilution in Hydrogen Diffusion Flame Combustors
Authors: Weiland Nathan T. , Strakey Peter A.
Published: April 2010

Lean-direct-injection (LDI) combustion is being considered at the National Energy Technology Laboratory as a means to attain low NOx emissions in a high-hydrogen gas turbine combustor. Integrated gasification combined cycle (IGCC) plant designs can create a high-hydrogen fuel using a water-gas shift reactor and subsequent CO2 separation. The IGCC’s air separation unit produces a volume of N2 roughly equivalent to the volume of H2 in the gasifier product stream, which can be used to help reduce peak flame temperatures and NOx in the diffusion flame combustor. Placement of this diluent in either the air or fuel streams is a matter of practical importance, and it has not been studied to date for LDI combustion. The current work discusses how diluent placement affects diffusion flame temperatures, residence times, and stability limits, and their resulting effects on NOx emissions. From a peak flame temperature perspective, greater NOx reduction should be attainable with fuel dilution rather than air or independent dilution in any diffusion flame combustor with excess combustion air, due to the complete utilization of the diluent as a heat sink at the flame front, although the importance of this mechanism is shown to diminish as flow conditions approach stoichiometric proportions. For simple LDI combustor designs, residence time scaling relationships yield a lower NOx production potential for fuel-side dilution due to its smaller flame size, whereas air dilution yields a larger air entrainment requirement and a subsequently larger flame, with longer residence times and higher thermal NOx generation. For more complex staged-air LDI combustor designs, the dilution of the primary combustion air at fuel-rich conditions can result in the full utilization of the diluent for reducing the peak flame temperature, while also controlling flame volume and residence time for NOx reduction purposes. However, differential diffusion of hydrogen out of a diluted hydrogen/nitrogen fuel jet can create regions of higher hydrogen content in the immediate vicinity of the fuel injection point than can be attained with the dilution of the air stream, leading to increased flame stability. By this mechanism, fuel-side dilution extends the operating envelope to areas with higher velocities in the experimental configurations tested, where faster mixing rates further reduce flame residence times and NOx emissions. Strategies for accurate computational modeling of LDI combustors’ stability characteristics are also discussed.
Lean-Burn Stationary Natural Gas Engine Operation With a Prototype Laser Spark Plug
Authors: McIntyre Dustin L. , Woodruff Steven D. , Ontko John S.
Published: April 2010

An end pumped passively Q-switched laser igniter was developed to meet the ignition system needs of large bore lean burn stationary natural gas engines. The laser spark plug used an optical fiber coupled diode pump source to axially pump a passively Q-switched Nd:YAG laser and transmit the laser pulse through a custom designed lens. The optical fiber coupled pump source permits the excitation energy to be transmitted to the spark plug at relatively low optical power, less than 250 W. The Q-switched laser then generates as much as 8 mJ of light in 2.5 ns, which is focused through an asymmetric biconvex lens to create a laser spark from a focused intensity of approximately 225 GW/cm2. A single cylinder engine fueled with either natural gas only or hydrogen augmented natural gas was operated with the laser spark plug for approximately 10 h in tests spanning 4 days. The tests were conducted with fixed engine speed, fixed boost pressure, no exhaust gas recirculation, and laser spark timing advance set at maximum brake torque timing. Engine operational and emissions data were collected and analyzed.
Material Properties’ Influence in Fuel-Coolant Interaction Codes
Authors: Uršič Mitja , Leskovar Matjaž , Mavko Borut
Published: April 2010

The melt droplets’ crust formation modeling, which is used in current fuel coolant interaction (FCI) codes, is rather basic. In the paper the development of the melt droplet heat transfer model, which enables the treatment of the material properties’ influence on the steam explosion, is presented. The model is complex enough to adequately predict the crust development during the melt droplets’ cooling in the premixing phase. At the same time the model is simple enough that it can be practically implemented into FCI codes and is thus being an optimal model for FCI applications. Fragmentation criteria are derived in order to take into account the influence of the formed crust on the steam explosion process. The derived criteria are based on experimental results and the thin plate approximation. To enable the use of the model and the fragmentation criteria in FCI codes with Eulerian formulation, adequate transport equations for model parameters are given.
Bayesian Analysis of Piping Leak Frequency Using OECD/NEA Data
Authors: Wang Min , Pandey Mahesh D. , Riznic Jovica R.
Published: April 2010

The estimation of piping failure frequency is an important task to support the probabilistic risk analysis and risk-informed in-service inspection of nuclear power plant systems. This paper describes a hierarchical or two-stage Poisson-gamma Bayesian procedure and applies this to estimate the failure frequency using the Organization for Economic Co-operation and Development/Nuclear Energy Agency pipe leakage data for the United States nuclear plants. In the first stage, a generic distribution of failure rate is developed based on the failure observations from a group of similar plants. This distribution represents the interplant (plant-to-plant) variability arising from differences in construction, operation, and maintenance conditions. In the second stage, the generic prior obtained from the first stage is updated by using the data specific to a particular plant, and thus a posterior distribution of plan specific failure rate is derived. The two-stage Bayesian procedure is able to incorporate different levels of variability in a more consistent manner.
Transient Thermal Effects and Heat Partition in Sliding Contacts
Authors: Bosman R. , de Rooij M. B.
Published: April 2010

In tribological applications, calculating the contact temperature between contacting surfaces makes it possible to estimate lubricant failure and effectiveness, material failure, and other phenomena. The contact temperature can be divided into two scales: the macroscopic and the microscopic scales. In this article, a semi-analytical transient temperature model is presented, which can be used at both scales. The general theory is presented here and used to calculate the contact temperatures of single micro- and macrocontacts. For the steady state situation, the results obtained are in good agreement with those found in literature. Further, it is shown that the simplification of modeling a microcontact as an equivalent square uniform heat source to simplify the calculation of the maximum temperature is justified in the fully plastic regime. The partition is calculated by setting a continuity condition on the temperature field over the contact. From the results, it can be concluded that at low sliding velocities the steady state assumption, which is often used for microcontacts, is correct. However, at higher sliding velocities, the microcontact is not in the steady state and transient calculation methods are advised.
Wear Mode Comparison of High-Performance Inconel Alloys
Authors: Fox Grant R. , Liang Hong
Published: April 2010

Inconel alloys have been used as engineering materials in high temperature and high stress applications due to their excellent mechanical properties. Tribological performances of these alloys, however, have not been conducted extensively. This is because in tribological applications, these materials have not often been utilized in friction and wear-related applications, resulting in a deficiency in the characterization of their tribomechanical properties. In the present research, we investigate the mechanisms of tribological performance of two different Inconel alloys in terms of contact pressures and sliding speeds. We studied their frictional behavior. The wear data were plotted against the pressure×velocity (PV parameter) in order to investigate the changes of surface properties and wear behaviors of the same under the influence of mechanical energy input. It was interesting to find that the wear mechanisms were influenced by the process of tribotesting. There are three competing wear mechanisms found, abrasion, adhesion, and oxidation. Each of those dominates the tribological performance under different conditions.
Ammonia Derived from Glutaminolysis Is a Diffusible Regulator of Autophagy
Authors: Eng Christina H. , Yu Ker , Lucas Judy , White Eileen , Abraham Robert T.
Published: April 2010

A volatile metabolic by-product can promote cell survival through the induction of autophagy.
UPR to TLR Connection
Authors: Gough Nancy R.
Published: April 2010

Certain pathogen-sensing receptors activate one arm of the unfolded protein response to maximize transcriptional activation of inflammatory genes.
Processing by Caspases
Authors: Foley John F.
Published: April 2010

Caspases in infected cells contribute to the presentation of viral peptides to cytotoxic T cells.
IS
Ecp1
-Mediated Transposition and Homologous Recombination Can Explain the Context of
bla
CTX-M-62
Linked to
qnrB2
Authors: Zong Zhiyong , Partridge Sally R. , Iredell Jonathan R.
Published: April 2010

bla
CTX-M-62
, a C508T variant of
bla
CTX-M-3b
, was transferred from
Klebsiella pneumoniae
JIE137 on a conjugative plasmid together with a class 1 integron containing the
dfrA12
-
gcuF
-
aadA2
cassette array, IS
CR1
, and
qnrB2
.
bla
CTX-M-62
lies between intact and rearranged copies of IS
Ecp1
in a configuration that can be explained by a combination of transposition and homologous recombination and which also illustrates the ability of IS
Ecp1
to mobilize an adjacent gene as part of transposition units of different sizes.
Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults
Authors: Kityo C. , Walker A. S. , Dickinson L. , Lutwama F. , Kayiwa J. , Ssali F. , Nalumenya R. , Tumukunde D. , Munderi P. , Reid A. , Gilks C. F. , Gibb D. M. , Khoo S.
Published: April 2010

We evaluated the pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) in Ugandan adults. The study design was a three-period crossover study (3 tablets [600 mg of lopinavir/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD];
n
= 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD;
n
= 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (
n
= 20), nevirapine (
n
= 18), and no NNRTI (
n
= 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC
0-12
) was 110.1 (34%) μg·h/liter. For efavirenz, the geometric mean lopinavir AUC
0-12
(%CV) values were 91.8 μg·h/liter (58%), 65.7 μg·h/liter (39%), and 54.0 μg·h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65;
P
= 0.002) and 0.82 (90% CI, 0.68 to 0.99;
P
= 0.09), respectively, and the apparent oral clearance (CL/
F
) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC
0-12
(%CV) values were 112.9 μg·h/liter (30%), 68.1 μg·h/liter (53%), and 61.5 μg·h/liter (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88;
P
< 0.001) and 0.90 (90% CI, 0.77 to 1.06;
P
= 0.27), respectively, and the CL/
F
was reduced by 57% and 7%, respectively. Higher values for the lopinavir concentration at 12 h (
C
12
) were observed with 3 tablets and efavirenz-nevirapine (
P
= 0.04 and
P
= 0.0005, respectively), and marginally lower
C
12
values were observed with 2 tablets and efavirenz-nevirapine (
P
= 0.08 and
P
= 0.26, respectively). These data suggest that 2 tablets of lopinavir-ritonavir BD may be inadequate when dosed with NNRTIs in Ugandan adults, and the dosage should be increased by the addition of an additional adult tablet or a half-dose tablet (100/25 mg), where available.
Modeling the astronomical
Authors: Kanipe Jeff
Published: April 2010

Advances in computer technology have changed the way astronomers see and study the universe.
Student and faculty attitudes and beliefs about computer science
Authors: Lewis Clayton , Jackson Michele H. , Waite William M.
Published: April 2010

The curriculum should inspire students to view CS as both accomplishment and intellectual discipline.
Nuclear Receptor Nurr1 Is Expressed In and Is Associated With Human Restenosis and Inhibits Vascular Lesion Formation In Mice Involving Inhibition of Smooth Muscle Cell Proliferation and Inflammation
Authors: Bonta Peter I. , Pols Thijs W.H. , van Tiel Claudia M. , Vos Mariska , Arkenbout E. Karin , Rohlena Jakub , Koch Karel T. , de Maat Moniek P.M. , Tanck Michael W.T. , de Winter Robbert J. , Pannekoek Hans , Biessen Erik A.L. , Bot Ilze , de Vries Carlie J.M.
Published: April 2010

Background—

Restenosis is the major drawback of percutaneous coronary interventions involving excessive activation and proliferation of vascular smooth muscle cells (SMCs). The nuclear receptor Nurr1 is an early response gene known mainly for its critical role in the development of dopamine neurons. In the present study, we investigated Nurr1 in human and experimental vascular restenosis.

Methods and Results—

In a prospective cohort of 601 patients undergoing percutaneous coronary intervention, including stent placement, we found a strong association between Nurr1 haplotypes and in-stent restenosis risk. Furthermore, Nurr1 is specifically expressed in human in-stent restenosis and induced in cultured human SMCs in response to serum or tumor necrosis factor-α. Lentivirus-mediated gain- and loss-of-function experiments in SMCs demonstrated that overexpression of Nurr1 inhibited proliferation, consistent with increased expression of the key cell-cycle inhibitor p27
Kip1
, whereas Nurr1 silencing enhanced SMC growth. The tumor necrosis factor-α–induced proinflammatory response of SMCs is inhibited by Nurr1, as reflected by reduced interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1 expression. Consistent with our in vitro data, endogenous Nurr1 reduced wire injury–induced proliferation and vascular lesion formation in carotid arteries of ApoE
−/−
mice.

Conclusion—

Nurr1 haplotypes are associated with human restenosis risk, and Nurr1 is expressed in human in-stent restenosis. In SMCs, Nurr1 inhibits proliferation and inflammatory responses, which explains the inhibition of SMC-rich lesion formation in mice. The recently identified small-molecule drugs that enhance the activity of Nurr1 reveal this nuclear receptor as an attractive novel target for (local) intervention in restenosis.
Mechanism of Improved Cardiac Function After Bone Marrow Mononuclear Cell Therapy
Authors: Yoon Chang-Hwan , Koyanagi Masamichi , Iekushi Kazuma , Seeger Florian , Urbich Carmen , Zeiher Andreas M. , Dimmeler Stefanie
Published: April 2010

Background—

Cell therapy is a promising option to improve functional recovery after ischemia. Several subsets of bone marrow–derived cells were shown to reduce infarct size and increase ejection fraction in experimental models of ischemia. The mechanisms underlying the functional improvement are diverse and have been shown to include paracrine effects of the injected cells, as well as a variable degree of differentiation to endothelial cells, pericytes, smooth muscle, and cardiac muscle.

Methods and Results—

To elucidate the true nature of such plasticity and contribution to recovery, we engineered vectors that encoded inducible suicide genes under the control of endothelium (endothelial nitric oxide synthase)-, smooth muscle (SM22α)-, and cardiomyocyte (α-MHC)-specific promoters, thereby allowing selective depletion of the individual cell lineage acquired by the transplanted undifferentiated bone marrow–derived cells. Lentivirally delivered thymidine kinase, which converts the prodrug ganciclovir into a cytotoxic agent, was used to selectively eliminate cells 2 weeks after transplantation of bone marrow mononuclear cells in an acute myocardial infarction model. We demonstrate that elimination of transplanted endothelium-committed or SM22α-expressing cells, but not cardiac-committed cells, induced a significant deterioration of ejection fraction. Moreover, elimination of endothelial nitric oxide synthase–expressing cells 2 weeks after injection reduced capillary and arteriole density.

Conclusions—

This study demonstrates that elimination of bone marrow mononuclear cells reexpressing endothelial nitric oxide synthase particularly induced a deterioration of cardiac function, which indicates a functional contribution of the vascular cell fate decision of human bone marrow–derived mononuclear cells in vivo.
Mechanism of formation of atoll garnet during high-pressure metamorphism
Authors: Faryad S. W. , Klápová H. , Nosál L.
Published: April 2010

Atoll garnet has been found in metabasites and quartz- and mica-rich rocks that have experienced low- to medium-temperature, high-pressure eclogite facies metamorphism in the Krušné Hory (Erzgebirge). They occur in several localities but are restricted to thin, texturally distinct zones, even on a thin-section scale. The mechanism of atoll garnet formation is documented by a series of micrographs and compositional maps and profiles of atoll garnet in combination with textural relations to other phases in the rocks. The core of full garnet or its relics in the atoll garnet have larger Ca and Fe, but smaller Mg contents, compared with the thin rim (ring). In addition to quartz, Na-Ca amphibole and phengite, the atoll cores are filled by a new garnet that has a composition similar to the outer rim. Formation of the atoll garnet is interpreted as resulting from fluid infiltration and element exchange between the garnet core and matrix, a process facilitated by a temperature increase during eclogite facies metamorphism. In addition to fluid access, the primary textures, mainly grain size, were also effective for the atoll garnet formation. Small grain fractions with thin rims were easily infiltrated by fluid, which used the short distance for element exchange between core and matrix. The core garnet was gradually dissolved and replaced by new garnet having the same crystallographic orientation as the rim or relics in the core.
Propionibacterium acnes infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells
Authors: Drott Johanna B , Alexeyev Oleg , Bergström Patrik , Elgh Fredrik , Olsson Jan
Published: April 2010

Background

The immune stimulating bacterium Propionibacterium acnes is a frequent colonizer of benign and malignant prostate tissue. To understand the pathogenesis of the earliest phase of this infection, we examined the P. acnes triggered immune response in cultivated prostate epithelial cells.

Results

Prostate epithelial cells are triggered to secrete IL-6, IL-8 and GM-CSF when infected with P. acnes. The secretion of cytokines is accompanied by NFκB related upregulation of the secreted cytokines as well as several components of the TLR2-NFκB signaling pathway.

Conclusions

P. acnes has potential to trigger a strong immune reaction in the prostate glandular epithelium. Upon infection of prostate via the retrograde urethral route, the induced inflammatory reaction might facilitate bacterial colonization deeper in the prostate tissue where persistent inflammation may impact the development of prostate diseases as hyperplasia and/or malignancy.
Anti-proliferative effect of extremely low frequency electromagnetic field on preneoplastic lesions formation in the rat liver
Authors: Jiménez-García Mónica Noemí , Arellanes-Robledo Jaime , Aparicio-Bautista Diana Ivette , Rodríguez-Segura Miguel Ángel , Villa-Treviño Saúl , Godina-Nava Juan José
Published: April 2010

Background

Recently, extremely low frequency electromagnetic fields (ELF-EMF) have been studied with great interest due to their possible effects on human health. In this study, we evaluated the effect of 4.5 mT - 120 Hz ELF-EMF on the development of preneoplastic lesions in experimental hepatocarcinogenesis.

Methods

Male Fischer-344 rats were subjected to the modified resistant hepatocyte model and were exposed to 4.5 mT - 120 Hz ELF-EMF. The effects of the ELF-EMF on hepatocarcinogenesis, apoptosis, proliferation and cell cycle progression were evaluated by histochemical, TUNEL assay, caspase 3 levels, immunohistochemical and western blot analyses.

Results

The application of the ELF-EMF resulted in a decrease of more than 50% of the number and the area of γ-glutamyl transpeptidase-positive preneoplastic lesions (P = 0.01 and P = 0.03, respectively) and glutathione S-transferase placental expression (P = 0.01). The number of TUNEL-positive cells and the cleaved caspase 3 levels were unaffected; however, the proliferating cell nuclear antigen, Ki-67, and cyclin D1 expression decreased significantly (P ≤ 0.03), as compared to the sham-exposure group.

Conclusion

The application of 4.5 mT - 120 Hz ELF-EMF inhibits preneoplastic lesions chemically induced in the rat liver through the reduction of cell proliferation, without altering the apoptosis process.
Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells
Authors: Chen Mengqian , Feuerstein Michael A. , Levina Elina , Baghel Prateek S. , Carkner Richard D. , Tanner Matthew J. , Shtutman Michael , Vacherot Francis , Terry Stéphane , de la Taille Alexandre , Buttyan Ralph
Published: April 2010

Background

Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.

Results

Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.

Conclusions

Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.
Effects of dietary sodium on performance, flight and compensation strategies in the cotton bollworm, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae)
Authors: Xiao Kai , Shen Ke , Zhong Jian-Feng , Li Guo-Qing
Published: April 2010

Background

Sodium is critical for many physiological functions in insects. Herbivorous insects should expend considerable energy to compensate for sodium deficiency due to low sodium concentration in most inland plants upon which they feed. However, sodium compensation behaviors such as mud-puddling have been observed in some species but not in others. We expect that there may be other sodium compensation strategies in insects. Here, we select a rarely mud-puddling insect species, the cotton boll worm, Helicoverpa armigera, and determine the effects of dietary sodium on performance and flight, and examine their means of sodium compensation.

Results

When freshly hatched H. armigera neonates were cultured on one of three diets differing in sodium contents (diet A, B and C with a high, middle and low sodium concentrations, respectively), the larvae on diet C grew larger, had a higher mortality rate and a shorter development period than those on diet A and B. The larvae previously fed from 1st to 3rd instar on diet C consumed more subsequent diet when they were transferred to diet A or C at 4th instar, comparing to those previously fed on diet A. Moreover, any 4th-instar larvae on diet C consumed a greater amount of food than those on diet A, no matter which diet the larvae had previously ingested from 1st to 3rd instar. Moths from diet A and B flew more rapidly than those from diet C, with similar sugar and lipid utilization rates among the three test groups. When a 5th-instar cannibal from diet A, B or C and a 5th-instar victim from diet A were housed together, many more cannibals from diet C ate their victims. When a victim from diet A, B or C was provided, a cannibal from diet C was more likely to eat the victim from diet A. When newly emerged moths had been exposed to 3% sodium chloride solution for all scotophase period, the average weight increase (proxy for sodium solution intake) for moths from diet A was lower than those from diet B or C.

Conclusion

Sodium-deficient diet resulted in rapid growth and development of H. armigera larvae, decreased larvae survival, and reduced flight speed of H. armigera adults. To compensate for sodium deficiency, H. armigera ingested a large quantity of larval food, increased larval cannibalism incidence and harvested sodium during the adult stage.
A preliminary result of three-dimensional microarray technology to gene analysis with endoscopic ultrasound-guided fine-needle aspiration specimens and pancreatic juices
Authors: Nonogaki Koji , Itoh Akihiro , Kawashima Hiroki , Ohno Eizaburo , Ishikawa Takuya , Matsubara Hiroshi , Itoh Yuya , Nakamura Yosuke , Nakamura Masanao , Miyahara Ryoji , Ohmiya Naoki , Ishigami Masatoshi , Katano Yoshiaki , Goto Hidemi , Hirooka Yoshiki
Published: April 2010

Background

Analysis of gene expression and gene mutation may add information to be different from ordinary pathological tissue diagnosis. Since samples obtained endoscopically are very small, it is desired that more sensitive technology is developed for gene analysis. We investigated whether gene expression and gene mutation analysis by newly developed ultra-sensitive three-dimensional (3D) microarray is possible using small amount samples from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens and pancreatic juices.

Methods

Small amount samples from 17 EUS-FNA specimens and 16 pancreatic juices were obtained. After nucleic acid extraction, the samples were amplified with labeling and analyzed by the 3D microarray.

Results

The analyzable rate with the microarray was 46% (6/13) in EUS-FNA specimens of RNAlater® storage, and RNA degradations were observed in all the samples of frozen storage. In pancreatic juices, the analyzable rate was 67% (4/6) in frozen storage samples and 20% (2/10) in RNAlater® storage. EUS-FNA specimens were classified into cancer and non-cancer by gene expression analysis and K-ras codon 12 mutations were also detected using the 3D microarray.

Conclusions

Gene analysis from small amount samples obtained endoscopically was possible by newly developed 3D microarray technology. High quality RNA from EUS-FNA samples were obtained and remained in good condition only using RNA stabilizer. In contrast, high quality RNA from pancreatic juice samples were obtained only in frozen storage without RNA stabilizer.
Re-inspiration of CO2 from ventilator circuit: effects of circuit flushing and aspiration of dead space up to high respiratory rate
Authors: De Robertis Edoardo , Uttman Leif , Jonson Björn
Published: April 2010

Introduction

Dead space negatively influences carbon dioxide (CO2) elimination, particularly at high respiratory rates (RR) used at low tidal volume ventilation in acute respiratory distress syndrome (ARDS). Aspiration of dead space (ASPIDS), a known method for dead space reduction, comprises two mechanisms activated during late expiration: aspiration of gas from the tip of the tracheal tube and gas injection through the inspiratory line - circuit flushing. The objective was to study the efficiency of circuit flushing alone and of ASPIDS at wide combinations of RR and tidal volume (VT) in anaesthetized pigs. The hypothesis was tested that circuit flushing and ASPIDS are particularly efficient at high RR.

Methods

In Part 1 of the study, RR and VT were, with a computer-controlled ventilator, modified for one breath at a time without changing minute ventilation. Proximal dead space in a y-piece and ventilator tubing (VDaw, prox) was measured. In part two, changes in CO2 partial pressure (PaCO2) during prolonged periods of circuit flushing and ASPIDS were studied at RR 20, 40 and 60 minutes-1.

Results

In Part 1, VDaw, prox was 7.6 ± 0.5% of VT at RR 10 minutes-1 and 16 ± 2.5% at RR 60 minutes-1. In Part 2, circuit flushing reduced PaCO2 by 20% at RR 40 minutes-1 and by 26% at RR 60 minutes-1. ASPIDS reduced PaCO2 by 33% at RR 40 minutes-1 and by 41% at RR 60 minutes-1.

Conclusions

At high RR, re-breathing of CO2 from the y-piece and tubing becomes important. Circuit flushing and ASPIDS, which significantly reduce tubing dead space and PaCO2, merit further clinical studies.
Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer
Authors: Krop Ian E. , Beeram Muralidhar , Modi Shanu , Jones Suzanne F. , Holden Scott N. , Yu Wei , Girish Sandhya , Tibbitts Jay , Yi Joo-Hee , Sliwkowski Mark X. , Jacobson Fred , Lutzker Stuart G. , Burris Howard A.
Published: April 2010

Purpose

Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer.

Patients and Methods

Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods.

Results

Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade ≤ 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade > 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%.

Conclusion

At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.
A Comparison of Percutaneous Radiofrequency Trigeminal Neurolysis and Microvascular Decompression of the Trigeminal Nerve for the Treatment of Tic Douloureux
Authors: Apfelbaum Ronald I.
Published: April 2010

In a 36-month period, 103 consecutive patients have been treated for classical trigeminal neuralgia with either percutaneous radiofrequency trigeminal neurolysis (PTN) (48 patients) or microvascular decompression (MVD) via a suboccipital craniectomy (55 patients). The results of these two procedures are tabulated, emphasizing especially the complications that have occurred with each. Successful initial relief of pain was achieved in 88% of the patients with PTN and 96% of the patients with MVD. Two significant complications occurred in the former group. Severe recurrences have occurred to date in 13% of the patients with PTN and in 5% of those with MVD. It is concluded that both procedures are effective, but that microvascular decompression offers the advantage of avoiding sensory loss and associated dysesthetic sensations. Follow-up is too short to conclude that MVD is a curative procedure, but the early results are very encouraging.
Compartmentalized organization: a common and required feature of stem cell niches?
Authors: Greco Valentina , Guo Shangqin
Published: April 2010

A key question in the stem cell field is how to balance the slow cycling of stem cells with active organ growth. Recent studies of the hair follicle stem cell niche have shown that this can be achieved by organizing the stem cell niche into two compartments: one that engages in immediate, rapid new growth and one that contributes later to long-term growth that fuels hair regeneration. Based on these and other recent findings, we propose that several other adult stem cell niches, including those in the blood, intestine and brain, have a similar bi-compartmental organization and that stem cells might work cooperatively with their progeny to sustain tissue regeneration.
Maternal activation of gap genes in the hover flyEpisyrphus
Authors: Lemke Steffen , Busch Stephanie E. , Antonopoulos Dionysios A. , Meyer Folker , Domanus Marc H. , Schmidt-Ott Urs
Published: April 2010

The metameric organization of the insect body plan is initiated with the activation of gap genes, a set of transcription-factor-encoding genes that are zygotically expressed in broad and partially overlapping domains along the anteroposterior (AP) axis of the early embryo. The spatial pattern of gap gene expression domains along the AP axis is generally conserved, but the maternal genes that regulate their expression are not. Building on the comprehensive knowledge of maternal gap gene activation in Drosophila, we used loss- and gain-of-function experiments in the hover fly Episyrphus balteatus (Syrphidae) to address the question of how the maternal regulation of gap genes evolved. We find that, in Episyrphus, a highly diverged bicoid ortholog is solely responsible for the AP polarity of the embryo. Episyrphus bicoid represses anterior zygotic expression of caudal and activates the anterior and central gap genes orthodenticle, hunchback and Krüppel. In bicoid-deficient Episyrphus embryos, nanos is insufficient to generate morphological asymmetry along the AP axis. Furthermore, we find that torso transiently regulates anterior repression of caudal and is required for the activation of orthodenticle, whereas all posterior gap gene domains of knirps, giant, hunchback, tailless and huckebein depend on caudal. We conclude that all maternal coordinate genes have altered their specific functions during the radiation of higher flies (Cyclorrhapha).