Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer

Purpose: DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer. Methods: Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3. Results: DDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P<0.001) and breast cancer (HR 2.39, P=0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P=0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal. Conclusion: Overall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types

Microscopic quantum point contact formation as the electromigration mechanism in granular superconductor nanowires

Granular aluminium is a high kinetic inductance thin film superconductor which, when formed into nanowires can undergo an intrinsic electromigration process. We use a combination of experimental and computational approaches to investigate the role of grain morphology and distribution in granular aluminium thin films, when formed into nanowire constrictions. Treating the granular aluminium film as a network of randomly distributed resistors with parameters motivated by the film microstructure allows us to model the electrical characteristics of the nanowires. This model provides estimates of the dependence of sheet resistance on grain size and distribution, and the resulting device to device variation for superconducting nanowires. By fabricating a series of different length nanowires, we study the electromigration process as a function of applied current, and then compare directly to the results of our computational model. In doing so we show that the electromigration is driven by the formation of quantum point contacts between metallic aluminium grains.Comment: 11 pages, 11 figure

Microscopic quantum point contact formation as the electromigration mechanism in granular superconductor nanowires

Granular aluminium is a high kinetic inductance thin film superconductor which, when formed into nanowires can undergo an intrinsic electromigration process. We use a combination of experimental and computational approaches to investigate the role of grain morphology and distribution in granular aluminium thin films, when formed into nanowire constrictions. Treating the granular aluminium film as a network of randomly distributed resistors with parameters motivated by the film microstructure allows us to model the electrical characteristics of the nanowires. This model provides estimates of the dependence of sheet resistance on grain size and distribution, and the resulting device to device variation for superconducting nanowires. By fabricating a series of different length nanowires, we study the electromigration process as a function of applied current, and then compare directly to the results of our computational model. In doing so we show that the electromigration is driven by the formation of quantum point contacts between metallic aluminium grains

Rabi oscillations in a superconducting nanowire circuit

We investigate the circuit quantum electrodynamics of anharmonic superconducting nanowire oscillators. The sample circuit consists of a capacitively shunted nanowire with a width of about 20 nm and a varying length up to 350 nm, capacitively coupled to an on-chip resonator. By applying microwave pulses we observe Rabi oscillations, measure coherence times and the anharmonicity of the circuit. Despite the very compact design, simple top-down fabrication and high degree of disorder in the oxidized (granular) aluminum material used, we observe lifetimes in the microsecond range

Acute Moraxella catarrhalis Airway Infection of Chronically Smoke-Exposed Mice Increases Mechanisms of Emphysema Development : A Pilot Study

In chronic obstructive pulmonary disease (COPD), acute exacerbations and emphysema development are characteristics for disease pathology. COPD is complicated by infectious exacerbations with acute worsening of respiratory symptoms with Moraxella catarrhalis as one of the most frequent pathogens. Although cigarette smoke (CS) is the primary risk factor, additional molecular mechanisms for emphysema development induced by bacterial infections are incompletely understood. We investigated the impact of M. catarrhalis on emphysema development in CS exposed mice and asked whether an additional infection would induce a solubilization of pro-apoptotic and proinflammatory endothelial monocyte-activating-protein-2 (EMAPII) to exert its activities in the pulmonary microvasculature and other parts of the lungs not exposed directly to CS. Mice were exposed to smoke (6 or 9 months) and/or infected with M. catarrhalis. Lungs, bronchoalveolar lavage fluid (BALF), and plasma were analyzed. CS exposure reduced ciliated area, caused rarefaction of the lungs, and induced apoptosis. EMAPII was increased independent of prior smoke exposure in BALF of infected mice. Importantly, acute M. catarrhalis infection increased release of matrixmetalloproteases-9 and -12, which are involved in emphysema development and comprise a mechanism of EMAPII release. Our data suggest that acute M. catarrhalis infection represents an independent risk factor for emphysema development in smoke-exposed mice

A multi-center blinded study on the efficiency of phenotypic screening methods to detect glycopeptide intermediately susceptible Staphylococcus aureus (GISA) and heterogeneous GISA (h-GISA)

Contains fulltext : 52338.pdf (publisher's version ) (Open Access)BACKGROUNDS: To determine the true incidence of hGISA/GISA and its consequent clinical impact, methods must be defined that will reliably and reproducibly discriminate these resistant phenotypes from vancomycin susceptible S. aureus (VSSA). METHODS: This study assessed and compared the ability of eight Dutch laboratories under blinded conditions to discriminate VSSA from hGISA/GISA phenotypes and the intra- and inter-laboratory reproducibility of agar screening plates and the Etest method. A total of 25 blinded and unique strains (10 VSSA, 9 hGISA and 6 GISA) were categorized by the PAP-AUC method and PFGE typed to eliminate clonal duplication. All strains were deliberately added in quadruplets to evaluate intra-laboratory variability and reproducibility of the methods. Strains were tested using three agar screening methods, Brain Heart Infusion agar (BHI) + 6 microg/ml vancomycin, Mueller Hinton agar (MH) + 5 microg/ml vancomycin and MH + 5 microg/ml teicoplanin) and the Etest macromethod using a 2 McFarland inoculum. RESULTS AND DISCUSSION: The ability to detect the hGISA/GISA phenotypes varied significantly between methods and phenotypes. BHI vancomycin and MH vancomycin agar screens lacked the ability to detect hGISA. The MH teicoplanin agar screen was more sensitive but still inferior to Etest that had a sensitivity of 98.5% and 99.5%, for hGISA and GISA, respectively. Intra- and inter-laboratory reproducibility varied between methods with poorest performance seen with BHI vancomycin. CONCLUSION: This is the first multi-center blinded study to be undertaken evaluating various methods to detect GISA and hGISA. These data showed that the ability of clinical laboratories to detect GISA and hGISA varied considerably, and that screening plates with vancomycin have a poor performance in detecting hGISA

Emergence of Tuning to Natural Stimulus Statistics along the Central Auditory Pathway

We have previously shown that neurons in primary auditory cortex (A1) of anaesthetized (ketamine/medetomidine) ferrets respond more strongly and reliably to dynamic stimuli whose statistics follow "natural" 1/f dynamics than to stimuli exhibiting pitch and amplitude modulations that are faster (1/f(0.5)) or slower (1/f(2)) than 1/f. To investigate where along the central auditory pathway this 1/f-modulation tuning arises, we have now characterized responses of neurons in the central nucleus of the inferior colliculus (ICC) and the ventral division of the mediate geniculate nucleus of the thalamus (MGV) to 1/f(gamma) distributed stimuli with gamma varying between 0.5 and 2.8. We found that, while the great majority of neurons recorded from the ICC showed a strong preference for the most rapidly varying (1/f(0.5) distributed) stimuli, responses from MGV neurons did not exhibit marked or systematic preferences for any particular gamma exponent. Only in A1 did a majority of neurons respond with higher firing rates to stimuli in which gamma takes values near 1. These results indicate that 1/f tuning emerges at forebrain levels of the ascending auditory pathway

Development of outdoor luminescence imaging for drone-based PV array inspection

This work has the goal to perform outdoor defect detection imaging that will be used in a fast, accurate and automatic drone-based survey system for PV power plants. The imaging development focuses on techniques that do not require electrical contact, permitting automatic drone inspections to be perform quicker and with less manpower. The final inspection method will combine several techniques such as, infrared (IR), electroluminescence (EL), photoluminescence (PL), and visual imaging. Solar plant inspection in the future can be restricted only by imaging speed requirements, allowing an entire new perspective in large-scale PV inspection