Simultaneous Attenuation Research Articles

Effect of lentivirus-mediated shRNA inactivation of HK1, HK2, and HK3 genes in colorectal cancer and melanoma cells.

BackgroundThe switch from oxidative phosphorylation to glycolysis in proliferating cancer cells, even under aerobic conditions, has been shown first in 1926 by Otto Warburg. Today this phenomenon is known as the “Warburg effect” and recognized as a hallmark of cancer. The metabolic shift to glycolysis is associated with the alterations in signaling pathways involved in energy metabolism, including glucose uptake and fermentation, and regulation of mitochondrial functions. Hexokinases (HKs), which catalyze the first step of glycolysis, have been identified to play a role in tumorigenesis of human colorectal cancer (CRC) and melanoma. However, the mechanism of action of HKs in the promotion of tumor growth remains unclear.ResultsThe purpose of the present study was to investigate the effect of silencing of hexokinase genes (HK1, HK2, and HK3) in colorectal cancer (HT-29, SW 480, HCT-15, RKO, and HCT 116) and melanoma (MDA-MB-435S and SK-MEL-28) cell lines using short hairpin RNA (shRNA) lentiviral vectors. shRNA lentiviral plasmid vectors pLSLP-HK1, pLSLP-HK2, and pLSLP-HK3 were constructed and then transfected separately or co-transfected into the cells. HK2 inactivation was associated with increased expression of HK1 in colorectal cancer cell lines pointing to the compensation effect. Simultaneous attenuation of HK1 and HK2 levels led to decreased cell viability. Co-transfection with shRNA vectors against HK1, HK2, and HK3 mRNAs resulted in a rapid cell death via apoptosis.ConclusionsWe have demonstrated that simultaneous inactivation of HK1 and HK2 was sufficient to decrease proliferation and viability of melanoma and colorectal cancer cells. Our results suggest that HK1 and HK2 could be the key therapeutic targets for reducing aerobic glycolysis in examined cancers.

Dynamically controllable anisotropic metamaterials with simultaneous attenuation and amplification

Anisotropic homogeneous metamaterials that are neither wholly dissipative nor wholly active at a specific frequency are permitted by classical electromagnetic theory. Well-established homogenization formalisms indicate that such a metamaterial may be realized quite simply as a random mixture of electrically small (possibly nanoscale) spheroidal particles of at least two different isotropic dielectric materials, one of which must be dissipative but the other active. The dielectric properties of this metamaterial are influenced by the volume fraction, spatial distribution, particle shape and size, and the relative permittivities of the component materials. Similar metamaterials with more complicated linear as well as nonlinear constitutive properties are possible. Dynamic control of the active component material, for example via stimulated Raman scattering, affords dynamic control of the metamaterial.

Simultaneous attenuation of pharmaceuticals, organic matter, and nutrients in wastewater effluent through managed aquifer recharge: Batch and column studies

Batch and column experiments were conducted to evaluate the removal of organic matter, nutrients, and pharmaceuticals and to identify the removal mechanisms of the target contaminants. The sands used in the experiments were obtained from the Youngsan River located in South Korea. Neutral and cationic pharmaceuticals (iopromide, estrone, and trimethoprim) were removed with efficiencies greater than 80% from different sand media during experiments, due to the effect of sorption between sand and pharmaceuticals. However, the anionic pharmaceuticals (sulfamethoxazole, ketoprofen, ibuprofen, and diclofenac) were more effectively removed by natural sand, compared to baked sand. These observations were mainly attributed to biodegradation under natural conditions of surface organic matter and ATP concentrations. The removal of organic matter and nitrogen was also found to increase under biotic conditions. Therefore, it is indicated that biodegradation plays an important role and act as major mechanisms for the removal of organic matter, nutrients, and selected pharmaceuticals during sand passage and the managed aquifer recharge, which is an effective treatment method for removing target contaminants. However, the low removal efficiencies of pharmaceuticals (e.g., carbamazepine and sulfamethoxazole) require additional processes (e.g., AOPs, NF and RO membrane), a long residence time, and long travel distance for increasing the removal efficiencies.

Multidimensional simultaneous random plus erratic noise attenuation and interpolation for seismic data by joint low-rank and sparse inversion

We have developed an efficient convex optimization strategy enabling the simultaneous attenuation of random and erratic noise with interpolation in prestack seismic data. For a particular analysis window, frequency slice spatial data were reorganized into a block Toeplitz matrix with Toeplitz blocks as in Cadzow/singular spectrum analysis methods. The signal and erratic noise were, respectively, modeled as low-rank and sparse components of this matrix, and then a joint low-rank and sparse inversion (JLRSI) enabled us to recover the low-rank signal component from noisy and incomplete data thanks to joint minimization of a nuclear norm term and an [Formula: see text]-norm term. The convex optimization framework, related to recent developments in the field of compressed sensing, enabled the formulation of a well-posed problem as well as the use of state-of-the-art algorithms. We proposed an alternating directions method of multipliers scheme associated with an efficient singular value thresholding kernel. Numerical results on field data illustrated the effectiveness of the JLRSI approach at recovering missing data and increasing the signal-to-noise ratio.

Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration

In children, neuroblastomas are the most common and deadly solid tumor. Our previous study showed that honokiol, a small-molecule polyphenol, can traverse the blood–brain barrier and kill neuroblastoma cells. In this study, we further investigated the mechanisms of honokiol-induced insults to neuroblastoma cells. Treatment of neuroblastoma neuro-2a cells with honokiol elevated the levels of microtubule-associated protein light chain 3 (LC3)-II and induced cell autophagy in time- and concentration-dependent manners. Interestingly, pretreatment with 3-methyladenine (3-MA), an inhibitor of autophagy, led to the simultaneous attenuation of honokiol-induced cell autophagy and apoptosis but did not influence cell necrosis. As to the mechanisms, exposure of neuro-2a cells to honokiol time-dependently decreased the amount of phosphatidylinositol 3-kinase (PI3K). Sequentially, honokiol downregulated phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in neuro-2a cells. Furthermore, honokiol elevated the levels of glucose-regulated protein (GpR)78, an endoplasmic reticular stress (ERS)-associated protein, and amounts of intracellular reactive oxygen species (ROS). In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular autophagy. Consequently, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2. However, pretreatment of neuro-2a cells with PD98059, an inhibitor of ERK1/2, lowered honokiol-induced autophagy. The effects of honokiol on inducing autophagy and apoptosis of neuroblastoma cells were further confirmed using mouse neuroblastoma NB41A3 cells as our experimental model. Fascinatingly, treatment of neuroblastoma neuro-2a and NB41A3 cells with honokiol for 12 h did not affect cell autophagy or apoptosis but caused significant suppression of cell migration. Taken together, this study showed that honokiol can induce autophagy of neuroblastoma cells and consequent apoptosis through activating the PI3K/Akt/mTOR and ERS/ROS/ERK1/2 signaling pathways and suppressing cell migration. Thus, honokiol has potential for treating neuroblastomas.

Abstract 3369: Nuclear hormone receptor profiling of skin cancer-associated fibroblasts for targeted pharmacological modulation of skin squamous cell carcinoma

Abstract Background: Cutaneous squamous cell carcinoma (SCC) is the second-most frequently diagnosed non-melanoma skin cancer that commonly manifests in sun-exposed areas of the skin, resulting in permanent disfigurement and potentially death when untreated. The development and malignant progression of skin SCC is dependent not only on the properties of the tumor epithelia but also the effects of the tumor stroma. Cancer associated fibroblasts (CAFs) are enriched in the stroma of skin SCC tumors and supply paracrine factors that encourage tumor growth. However, the transcription regulatory networks enabling this pro-tumor secretory phenotype of CAFs remain largely unknown. Nuclear receptors, being ligand-inducible transcription factors, are relevant therapeutic candidates for modulation of CAF-dependent SCC tumor advancement. Materials and methods: Laser capture microdissected CAFs from archived patient SCC biopsies were profiled for their expression of 48 known nuclear receptors. siRNA knockdown and overexpression of specific nuclear receptors in CAFs was performed, and their impact on the SCC transcriptome and phenotype was evaluated in a co-culture system. Co-administration of nuclear receptor ligands and conventional anticancer chemotherapeutics was also carried out in a 3D-organotypic skin tumor model to investigate synergistic and sensitizing effects on SCC. Findings and conclusions: Our study is the first to define a nuclear receptor profile for SCC CAFs, wherein the expression of 5 nuclear receptors was unchanged, 18 nuclear receptors were highly expressed and 3 nuclear receptors were lowly expressed in CAFs relative to normal fibroblasts. We showed that SCC tumor epithelia are transcriptionally and functionally sensitive to this nuclear receptor profile of CAFs. Simultaneous and differential attenuation of multiple aggressive SCC phenotypes was possible through the manipulation of specific nuclear receptor expression and activity in CAFs. Our results highlight the utility of CAF nuclear receptor profiling and a role for nuclear receptor-directed drugs in the multimodal treatment of skin SCC. Citation Format: Jeremy Soon Kiat Chan, Ming Keat Sng, Zi Qiang Teo, Nguan Soon Tan. Nuclear hormone receptor profiling of skin cancer-associated fibroblasts for targeted pharmacological modulation of skin squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3369. doi:10.1158/1538-7445.AM2015-3369

Development of the Poplar-Laccaria bicolor Ectomycorrhiza Modifies Root Auxin Metabolism, Signaling, and Response.

Root systems of host trees are known to establish ectomycorrhizae (ECM) interactions with rhizospheric fungi. This mutualistic association leads to dramatic developmental modifications in root architecture, with the formation of numerous short and swollen lateral roots ensheathed by a fungal mantle. Knowing that auxin plays a crucial role in root development, we investigated how auxin metabolism, signaling, and response are affected in poplar (Populus spp.)-Laccaria bicolor ECM roots. The plant-fungus interaction leads to the arrest of lateral root growth with simultaneous attenuation of the synthetic auxin response element DR5. Measurement of auxin-related metabolites in the free-living partners revealed that the mycelium of L. bicolor produces high concentrations of the auxin indole-3-acetic acid (IAA). Metabolic profiling showed an accumulation of IAA and changes in the indol-3-pyruvic acid-dependent IAA biosynthesis and IAA conjugation and degradation pathways during ECM formation. The global analysis of auxin response gene expression and the regulation of AUXIN SIGNALING F-BOX PROTEIN5, AUXIN/IAA, and AUXIN RESPONSE FACTOR expression in ECM roots suggested that symbiosis-dependent auxin signaling is activated during the colonization by L. bicolor. Taking all this evidence into account, we propose a model in which auxin signaling plays a crucial role in the modification of root growth during ECM formation.

Synergistic anti-tumor effect of combined inhibition of EGFR and JAK/STAT3 pathways in human ovarian cancer.

BackgroundThe EGFR signaling pathway is frequently activated in human ovarian cancer and associated with poor prognosis. However, inhibition of EGFR signaling in patients with recurrent ovarian cancer has been disappointing. It remains to be addressed whether ovarian cancer patients could benefit from targeting EGFR signaling. Here we investigated the mechanisms underlying the resistance to EGFR inhibition in ovarian cancer and developed a strategy to overcome it.ResultsWe found that treatment of human ovarian cancer cells with an EGFR inhibitor, gefitinib, resulted in increased STAT3 phosphorylation in a dose- and time-dependent manner. Inhibiting STAT3 activation with a small molecule inhibitor of JAK, an upstream kinase that phosphorylates and activates STAT3, synergistically increased the anti-tumor activity of gefitinib in vitro. Similar results were obtained when STAT3 or JAK1 expression was knocked down. In contrast, inhibiting other signaling pathways, such as AKT/mTOR, MEK or SRC, was relatively less effective. The combined treatment resulted in simultaneous attenuation of multiple survival pathways and increased inhibition of ERK pathway. In addition, the dual inhibition showed a stronger suppression of xenograft tumor growth than either single inhibition.ConclusionsOur findings demonstrate that feedback activation of STAT3 pathway might contribute to the resistance to EGFR inhibition. Combined blockade of both pathways appears to be more effective against human ovarian cancer than inhibition of each pathway alone both in vitro and in vivo. This study may provide a strategy to improve clinical benefit of targeting EGFR pathway in ovarian cancer patients.

Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells.

The unique metabolism of breast cancer cells provides interest in exploiting this phenomenon therapeutically. Metformin, a promising breast cancer therapeutic, targets complex I of the electron transport chain leading to an accumulation of reactive oxygen species (ROS) that eventually lead to cell death. Inhibition of complex I leads to lactate production, a metabolic byproduct already highly produced by reprogrammed cancer cells and associated with a poor prognosis. While metformin remains a promising cancer therapeutic, we sought a complementary agent to increase apoptotic promoting effects of metformin while attenuating lactate production possibly leading to greatly improved efficacy. Dichloroacetate (DCA) is a well-established drug used in the treatment of lactic acidosis which functions through inhibition of pyruvate dehydrogenase kinase (PDK) promoting mitochondrial metabolism. Our purpose was to examine the synergy and mechanisms by which these two drugs kill breast cancer cells. Cell lines were subjected to the indicated treatments and analyzed for cell death and various aspects of metabolism. Cell death and ROS production were analyzed using flow cytometry, Western blot analysis, and cell counting methods. Images of cells were taken with phase contrast microscopy or confocal microscopy. Metabolism of cells was analyzed using the Seahorse XF24 analyzer, lactate assays, and pH analysis. We show that when DCA and metformin are used in combination, synergistic induction of apoptosis of breast cancer cells occurs. Metformin-induced oxidative damage is enhanced by DCA through PDK1 inhibition which also diminishes metformin promoted lactate production. We demonstrate that DCA and metformin combine to synergistically induce caspase-dependent apoptosis involving oxidative damage with simultaneous attenuation of metformin promoted lactate production. Innovative combinations such as metformin and DCA show promise in expanding breast cancer therapies.

Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann-Pick C1-like 1 (NPC1L1) Gene Expression by DNA Methylation

Intestinal NPC1L1 transporter is essential for cholesterol absorption and the maintenance of cholesterol homeostasis in the body. NPC1L1 is differentially expressed along the gastrointestinal tract with very low levels in the colon as compared with the small intestine. This study was undertaken to examine whether DNA methylation was responsible for segment-specific expression of NPC1L1. Treatment of mice with 5-azacytidine (i.p.) resulted in a significant dose-dependent increase in NPC1L1 mRNA expression in the colon. The lack of expression of NPC1L1 in the normal colon was associated with high levels of methylation in the area flanking the 3-kb fragment upstream of the initiation site of the mouse NPC1L1 gene in mouse colon as analyzed by EpiTYPER® MassARRAY®. The high level of methylation in the colon was observed in specific CpG dinucleotides and was significantly decreased in response to 5-azacytidine. Similar to mouse NPC1L1, 5-azacytidine treatment also increased the level of human NPC1L1 mRNA expression in the intestinal HuTu-80 cell line in a dose- and time-dependent manner. Silencing the expression of DNA methyltransferase DNMT1, -2, -3A, and -3B alone by siRNA did not affect NPC1L1 expression in HuTu-80 cells. However, the simultaneous attenuation of DNMT1 and -3B expression caused a significant increase in NPC1L1 mRNA expression as compared with control. Also, in vitro methylation of the human NPC1L1 promoter significantly decreased NPC1L1 promoter activity in human intestinal Caco2 cells. In conclusion, our data demonstrated for the first time that DNA methylation in the promoter region of the NPC1L1 gene appears to be a major mechanism underlying differential expression of NPC1L1 along the length of the gastrointestinal tract.

Short-Term Rain Attenuation Frequency Scaling for Satellite Up-Link Power Control Applications

In this paper, a novel stochastic dynamic model for the short-term frequency scaling of rain attenuation is presented. The model captures the dynamic characteristics of the instantaneous frequency scaling factor and provides the means to incorporate them in simultaneous rain attenuation time series generation, as well as in analytical calculations. Moreover, an analytical framework is proposed for rain attenuation prediction at a given frequency based on the rain attenuation measured at another frequency. The proposed model can be used for the timely activation of an open-loop up-link power control scheme in broadband satellite communication networks operating at frequencies above 10 GHz. It is applied to simulated rain attenuation data that have been obtained using the Synthetic Storm Technique on rain rate experimental data. Finally, it is shown how the new model improves the performance of an up-link power control scheme in terms of system availability.

Small interference RNA targeting vascular endothelial growth factor gene effectively attenuates retinal neovascularization in mice model

Background The mechanism of retinal neovascularization is not understood completely. Many growth factors are involved in the process of retinal neovascularization, such as vascular endothelial growth factor (VEGF) and pigment epithelium-deprived factor (PEDF), which are the representatives of angiogenic and antiangiogenic molecules respectively. Oxygen induced retinopathy (OIR) is a useful model to investigate retinal neovascularization. The present study was conducted to investigate the feasibility of small interference RNA (siRNA) targeting VEGF gene in attenuating oxygen induced retinopathy (OIR) by regulating VEGF to PEDF ratio (VEGF/PEDF). Methods In vitro, cultured EOMA cells were transfected with VEGF-siRNA (psi-HITM/EGFP/VEGF siRNA) and LipofectamineTM 2000 for 24, 48, and 72 hours, respectively. Expression of VEGF mRNA was evaluated by real time polymerase chain reaction (PCR) and the level of VEGF protein was analyzed by Western blotting. In vivo, OIR model mice were established, the mice (C57BL/6J) received an intra-vitreal injection of 1 μl of mixture of psi-HITM/EGFP/VEGF siRNA and Lipofectamine 2000. Expressions of retinal VEGF and PEDF protein were measured by Western blotting, retinal neovascularization was observed by fluorescein angiography, and quantified. Results In vitro psi-HITM/EGFP/VEGF siRNA treatment significantly reduced VEGF mRNA and protein expression. In vivo, with decreased VEGF and VEGF-PEDF ratio, significant attenuation of neovascular tufts, avascular regions, tortuous, and dilated blood vessels were observed in the interfered animals. Conclusions VEGF plays an important role in OIR, and the transfection of VEGF-siRNA can effectively downregulate VEGF expression in vivo, accompanied by the downregulation of VEGF-PEDF ratio, and simultaneous attenuation of retinal neovascularization was also observed. These findings suggest that VEGF/PEDF may serve as a potential target in the treatment of retinal neovascularization and RNA interference targeting VEGF expression, which represents a possible therapeutic strategy.

SMICA and its emerging role as a prognostic and diagnostic indicator in systemic malignancies besides hepatocellular carcinoma

I read the recent article by Li et al.[1] with great interest. Intriguingly, emerging evidence suggests that soluble major histocompatibility complex class I–related chain A (sMICA) may be an important diagnostic and prognostic marker in a number of systemic malignancies besides hepatocellular carcinoma. For instance, higher sMICA levels are seen in oral squamous cell carcinomas of high TNM stages[2]. Thus, sMICA can be used as a diagnostic and prognostic indicator of advanced stage and especially lymph node metastasis in oral carcinomas. Tamaki et al.[3] have shown that patients with oral carcinomas with high sMICA levels (≥50 ng/L) have lower overall survival rates than do patients with low sMICA levels (<50 ng/L). sMICA may also be used as a diagnostic biomarker in pancreatic ductal adenocarcinomas. When used in conjunction with serum uric acid and sMICB, sMICA provides additional information on the prognosis of pancreatic ductal adenocarcinoma[4]. sMICA also exhibits higher specificity and sensitivity when compared with CA19-9, a known marker for pancreatic ductal adenocarcinomas. Indeed, Chung et al.[4] reported a sensitivity of 76.5% and a specificity of 91.2% for sMICA, while a sensitivity of 73.5% and a specificity of 90.9% for CA19-9. Moreover, sMICA levels were found to be closely related to distant metastasis of pancreatic cancer. Collectively, the three markers sMICA, sMICB, and CA19-9 provide more information than did CA19-9 alone. In colorectal cancer, sMICA levels alter in the advanced stages. These elevated levels may prove to be a highly sensitive marker for advanced stage colorectal cancer[5]. A close relationship exists between the TNM stage and sMICA levels in breast cancers; as with other cancers described here, breast cancers of advanced TNM stage exhibit higher sMICA levels. sMICA contributes to immunological escape of mammary neoplasms by impairing immune surveillance mediated by natural killer cells[6]. At the same time, it attenuates natural killer group 2, member D (NKG2D) expression. A simultaneous attenuation effect is seen in interferon-gamma secretion. Poorly differentiated and late-stage osteosarcomas demonstrate higher sMICA levels, making sMICA an excellent prognostic and diagnostic indicator of advanced stages in osteosarcomas[7]. sMICA is also a highly accurate independent prognostic indicator in multiple myelomas. Poor progression-free survival rates are seen in multiple myelomas with sMICA levels greater than 305 pg/mL[8]. The above examples clearly illustrate the diagnostic and prognostic significance of sMICA in systemic cancers and the need for further studies to establish similar plausible relationships in other systemic malignancies.

Simultaneous attenuation and scatter corrections from the projections in small animal PET imaging

Attenuation and scatter corrections are important in quantitative positron emission tomography (PET) imaging even in small animals such as mice and rats. In this work we describe a simple and efficient model to correct for both scatter and attenuation in a single operation. The model aims to solve the equation M=(A+F) P for the primaries P, corrected for attenuation and scatter, based on the measured coincidences M, the matrix of compensation for attenuation A and on the scatter fractions F issued from all emitting sources and contributing to M. The scatter functions are analytically calculated using Klein–Nishina formula, the scanner geometry and the detection efficiencies. This method was applied in measured data of line sources and hot spots phantoms as well as in rat heart and tumors and compared to Monte Carlo based simulations and to the single scatter simulation model developed by Watson et al. The corrected data showed a quantitative contrast and signal to noise ratio enhancement with respect to the uncorrected data. In terms of results, our method is comparable to that of Watson et al. The Monte Carlo simulations, where the primaries and the scattered events were separately registered, confirmed the accuracy of the new approach.

Phase‐adjusted echo time (PATE)‐averaging 1H MRS: application for improved glutamine quantification at 2.89 T

(1) H MRS investigations have reported altered glutamatergic neurotransmission in a variety of psychiatric disorders. The unraveling of glutamate from glutamine resonances is crucial for the interpretation of these observations, although this remains a challenge at clinical static magnetic field strengths. Glutamate resolution can be improved through an approach known as echo time (TE) averaging, which involves the acquisition and subsequent averaging of multiple TE steps. The process of TE averaging retains the central component of the glutamate methylene multiplet at 2.35 ppm, with the simultaneous attenuation of overlapping phase-modulated coupled resonances of glutamine and N-acetylaspartate. We have developed a novel post-processing approach, termed phase-adjusted echo time (PATE) averaging, for the retrieval of glutamine signals from a TE-averaged (1) H MRS dataset. The method works by the application of an optimal TE-specific phase term, which is derived from spectral simulation, prior to averaging over TE space. The simulation procedures and preliminary in vivo spectra acquired from the human frontal lobe at 2.89 T are presented. Three metabolite normalization schemes were developed to evaluate the frontal lobe test-retest reliability for glutamine measurement in six subjects, and the resulting values were comparable with previous reports for within-subject (9-14%) and inter-subject (14-20%) measures. Using the acquisition parameters and TE range described, glutamine quantification is possible in approximately 10 min. The post-processing methods described can also be applied retrospectively to extract glutamine and glutamate levels from previously acquired TE-averaged (1) H MRS datasets.

Review of the microstrip/negative-refractive-index transmission-line coupled-line coupler

The microstrip/negative-refractive-index transmission-line (MS/NRI-TL) coupler is constructed by edge coupling a regular microstrip line to a backward wave negative-refractive-index transmission line. This coupler is primarily operated in the complex-mode band in which the eigenmodes are characterised by simultaneous phase progression and attenuation (in a lossless structure) and is accompanied by contra-directional power flow on the two lines. The complex modes that are excited by the sources in this coupler can be controlled independently and by examining the multiple reflections of these modes between the two terminal planes, the scattering parameters of the corresponding four-port device can be derived. Under a first-order approximation, it is determined that the MS/NRI-TL coupler is capable of achieving arbitrary coupling levels (by increasing the length of the coupler) and very high directivity (by making the coupler length equal to an odd multiple of half a guided wavelength). Useful nomographs that enable the realisation of MS/NRI-TL couplers to meet arbitrary design specifications are included and several applications of the coupler are also presented.

Point mutated caveolin-3 form (P104L) impairs myoblast differentiation via Akt and p38 signalling reduction, leading to an immature cell signature

Unbalanced levels of caveolin-3 (Cav3) are involved in muscular disorders. In the present study we show that differentiation of immortalized myoblasts is affected by either lack or overexpression of Cav3. Nevertheless, depletion of Cav3 induced by delivery of the dominant-negative Cav3 (P104L) form elicited a more severe phenotype, characterized by the simultaneous attenuation of the Akt and p38 signalling networks, leading to an immature cell and molecular signature. Accordingly, differentiation of myoblasts harbouring Cav3 (P104L) was improved by countering the reduced Akt and p38 signalling network via administration of IGF-1 or trichostatin A. Furthermore, loss of Cav3 correlated with a deregulation of the TGF-β-induced Smad2 and Erk1/2 pathways, confirming that Cav3 controls TGF-β signalling at the plasma membrane. Overall, these data suggest that loss of Cav3, primarily causing attenuation of both Akt and p38 pathways, contributes to impair myoblast fusion.

Die Abklärung des akuten Thoraxschmerzes mit der Computertomographie

Acute chest pain is a common symptom but triage decisions in these patients remain a challenge. Patient's history, cardiac enzyme levels, or electrocardiograms often are unspecific. Nowadays, multidetector-row computed tomography (CT) currently represents the imaging modality of choice for diagnosing or excluding pulmonary embolism (PE) or acute aortic syndrome (AAS). Furthermore, recent studies have demonstrated advantages for non-invasive imaging of the coronary arteries by CT. The so called triple rule-out CT allows the depiction of the pulmonary arteries, the thoracic aorta, and the coronary arteries within a single examination with a simultaneous attenuation of these three vessel territories. This enables the detection of life-threatening such as PE, AAS and ACS, as well as of non-life-threatening diseases causing acute chest pain.

Multi-frequency disturbance rejection via blending control technique for hard disk drives

This paper is concerned with the rejection of multiple narrowband disturbances in hard disk drives (HDDs). Inspired by a control blending idea, the multi-frequency disturbance rejection is formulated as a blending control problem. Each disturbance rejection is accomplished by using the H 2 optimal control method. Based on all H 2 optimal controllers, the blending technique is applied to yield a single controller which is capable of achieving rejection of all disturbances. Rejections of two and three disturbances for a 1.8-inch HDD VCM actuator are taken as application examples in the paper. Simulation and experimental results show that the ultimate controller results in a simultaneous attenuation of disturbances with frequencies higher or lower than the closed-loop system bandwidth. Moreover, the method turns out to be able to lift phase and thus prevent phase margin loss when it is used to deal with disturbances near bandwidth.

Clinical and experimental aspects of Adreno‐muscarinic synergy in the bladder base and prostate

Recent clinical trials have shown that combination therapy using an alpha-receptor antagonist and an antimuscarinic is more effective than either agent alone in improving quality of life and objective urodynamic variables in men with bladder outflow obstruction. There appear to be no negative effects on bladder function. The mode of action of this combination is unknown but presumed to be an antimuscarinic reduction in detrusor overactivity and the alpha-receptor antagonist reduced outflow tract resistance. We have shown with in vitro experiments that in smooth muscles influencing outflow tract resistance (prostate, trigone) there is a profound contractile synergy between adrenergic and muscarinic pathways. We propose the hypothesis that both arms of the combination therapy reduce contractile tone of the outflow tract and that their simultaneous attenuation has a disproportionately large effect on outflow tract resistance. Our data from trigone muscle suggest that adrenergic and muscarinic receptor activation increase the intracellular [Ca(2+)] but the adrenergic pathway also operates through Ca(2+)-sensitisation of the contractile apparatus, primarily through a PKC-dependent pathway.