USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

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Progressive Decrease in the Potential Usefulness of Meningococcal Serogroup B Vaccine (4CMenB, Bexsero (R)) in Gipuzkoa, Northern Spain

The effectiveness of a vaccine is determined not only by the immunogenicity of its components, but especially by how widely it covers the disease-causing strains circulating in a given region. Because vaccine coverage varies over time, this study aimed to detect possible changes that could affect vaccine protection during a specific period in a southern European region. The 4CMenB vaccine is licensed for use in Europe, Canada, and Australia and is mainly directed against Neisseria meningitidis serogroup B. This vaccine contains four main immunogenic components: three recombinant proteins, FHbp, Nhba and NadA, and an outer membrane vesicle [PorA P1.4]. The allelic distribution of FHbp, Nhba, NadA, and PorA antigens in 82 invasive isolates (B and non-B serogroups) isolated from January 2008 to December 2013 were analyzed. 4CMenB was likely protective against 61.8% and 50% of serogroup B and non-B meningococci, respectively, in the entire period, but between 2012 and 2013, the predicted protection fell below 45% (42.1% for serogroup B isolates). The observed decreasing trend in the predicted protection during the 6 years of the study (X-2 for trend = 4.68, p=0.03) coincided with a progressive decrease of several clonal complexes (e. g., cc11, cc32 and cc41/44), which had one or more antigens against which the vaccine would offer protection.

Visualization by High Resolution Immunoelectron Microscopy of the Transient Receptor Potential Vanilloid-1 at Inhibitory Synapses of the Mouse Dentate Gyrus

We have recently shown that the transient receptor potential vanilloid type 1 (TRPV1), a non-selective cation channel in the peripheral and central nervous system, is localized at postsynaptic sites of the excitatory perforant path synapses in the hippocampal dentate molecular layer (ML). In the present work, we have studied the distribution of TRPV1 at inhibitory synapses in the ML. With this aim, a preembedding immunogold method for high resolution electron microscopy was applied to mouse hippocampus. About 30% of the inhibitory synapses in the ML are TRPV1 immunopositive, which is mostly localized perisynaptically (similar to 60% of total immunoparticles) at postsynaptic dendritic membranes receiving symmetric synapses in the inner 1/3 of the layer. This TRPV1 pattern distribution is not observed in the ML of TRPV1 knock-out mice. These findings extend the knowledge of the subcellular localization of TRPV1 to inhibitory synapses of the dentate molecular layer where the channel, in addition to excitatory synapses, is present.

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-beta 3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene

Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor.

Digital Quantum Simulation of Spin Models with Circuit Quantum Electrodynamics

Systems of interacting quantum spins show a rich spectrum of quantum phases and display interesting many-body dynamics. Computing characteristics of even small systems on conventional computers poses significant challenges. A quantum simulator has the potential to outperform standard computers in calculating the evolution of complex quantum systems. Here, we perform a digital quantum simulation of the paradigmatic Heisenberg and Ising interacting spin models using a two transmon-qubit circuit quantum electrodynamics setup. We make use of the exchange interaction naturally present in the simulator to construct a digital decomposition of the model-specific evolution and extract its full dynamics. This approach is universal and efficient, employing only resources that are polynomial in the number of spins, and indicates a path towards the controlled simulation of general spin dynamics in superconducting qubit platforms.

Anisotropic expansion and SNIa: An open issue

We review the appropriateness of using SNIa observations to detect potential signatures of anisotropic expansion in the Universe. We focus on Union2 and SNLS3 SNIa datasets and use the hemispherical comparison method to detect possible anisotropic features. Unlike some previous works where nondiagonal elements of the covariance matrix were neglected, we use the full covariance matrix of the SNIa data, thus obtaining more realistic and not underestimated errors. As a matter of fact, the significance of previously claimed detections of a preferred direction in the Union2 dataset completely disappears once we include the effects of using the full covariance matrix. Moreover, we also find that such apreferred direction is aligned with the orthogonal direction of the SDSS observational plane and this suggests a clear indication that the SDSS subsample of the Union2 dataset introduces a significant bias, making the detected preferred direction unphysical. We thus find that current SNIa surveys are inappropriate to test anisotropic features due to their highly non-homogeneous angular distribution in the sky. In addition, after removal of the highest in homogeneous sub-samples, the number of SNIa is too low. Finally, we take advantage of the particular distribution of SNLS SNIa sub- sample in the SNLS3 data set, in which the observations were taken along four different directions. We fit each direction independently and find consistent results at the 1 sigma level. Although the likelihoods peak at relatively different values of Omega(m), the low number of data along each direction gives rise to large errors so that the likelihoods are sufficiently broad as to overlap within 1 sigma. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons. org/licenses/by/4.0/).

Contribution of zooplankton to the fishery potential of some environments

Difference in zooplankton production in estuarine, coastal and oceanic realms of the Indian Ocean has been correlated to the fishery potential of the concerned area. In the estuarine habitat the estimated rate of secondary production can not sustain a fishery of the present magnitude. Direct correlation between fish landing and zooplankton is observed in the coastal waters. Compared to coastal waters zooplankton standing stock is low in the open ocean and this low production is compensated by a wider area. The estimated fishery potential of the ocean is much more than what is being exploited.

Assessing potential of production in Lake Choghakhor

Phytoplankton productivity is the common and important factor being considered in determining the overall status of a given body of water. This is because they are found at the base of an energy or food chain, being the basic source of primary food in a given aquatic system. Hence, information on their contribution is essential in indicating how much biomass energy will be available to all other living resources in the system. Though the primary productivity of shallow lakes is characterized by mixed populations of phytoplankton and submersed aquatic vegetation in the open water. Lake Choghakhor, is a shallow lake, located in Chaharmahal-Bakhtiyari Province. This lake is the most important ecosystem in the region especially for waterfowl populations, has a recreational value and supports tourism and fisheries. During last decade Choghakhor has been influenced by some man-made impacts such as water level fluctuation, agricultural discharge and fish (Cyprinids) introduction causing a serious problem in its trophic states. So water quality for physical, chemical and biological was monitored in five sampling stations, from April 2003 to March 2004. As biological parameters we studied phytoplankton, epiphytic algae, and zooplankton and macrobenthose community structure. Chlorophyll a content for phytoplankton and epiphytes was measured to estimate production of these groups (biomass over time). Also we determined biomasses of submersed macrophytes and macrobenthose and primary production of phytoplankton (dark and light bottles technique) to estimate fish production. The results of this study showed Lake Choghakhor did not undergo stable thermal and oxygen stratification, and the lake water was mixed throughout the study (the lake mixing regime is polymictic). Now submerged plants especially Myriophyllum spicatum has covered almost the entire lake and dense macrophyte beds (Polygonom amphibium), located on the east southern end of the lake appear to act as a sink for these nutrients. Lake Choghakhor appeared to be in a macrophyte dominated clear water state with low TP (annual mean: 24± 15μg.l-1) and chlorophyll a (annual mean: 3±1.28μg.l-1) concentrations and very high Secchi depth. The grazing pressure of dominant pelagic filtering zooplankton Daphnia longespina did not seem to be significant in determining the low phytoplankton crop expressed as chlorophyll a. We expect that sequestering of nutrients by submerged plants and associated epiphytes are the dominant stabilizing mechanisms suppressing the phytoplankton crop of Lake Choghakhor.

The potential for further proliferation of water hyacinth in Lakes Victoria, Kyoga and Kwania and some urgent aspects for research

Shore environments of Lakes Victoria and Kyoga with potential for the establishment and proliferation of water hyacinth were identified. They are characterised by: (i) shelter from violent off-shore and along-the-shore wind and wave action (ii) flat or gentle slope under relatively shallow water, and (iii) a muddy bottom rich in organic matter. Such environments are strongly associated with emergent macrophytes of papyrus, Vossia sp and, at times Typha sp where Pistia stratiotes, species of ceratophyllum, myriophylum and nymphaea also occur. In Lake Kyoga association with Vossia sp facilitated establishment of water hyacinth even along wind-swept shores and promoted extension of mats of the two machrophytes into the open lake. Urgent research on water hyacinth is proposed in the areas of nutrient relations, weed biology and on its impact on the biodiversity resource, with particular emphasis on the fishery component. Findings from the research could facilitate formulation of weed control options and alternative resource management strategies. A regional approach to address the water hyacinth menace is highly recommended.

Linear quadratic game and non-cooperative predictive methods for potential application to modelling driver-AFS interactive steering control

This paper is concerned with the modelling of strategic interactions between the human driver and the vehicle active front steering (AFS) controller in a path-following task where the two controllers hold different target paths. The work is aimed at extending the use of mathematical models in representing driver steering behaviour in complicated driving situations. Two game theoretic approaches, namely linear quadratic game and non-cooperative model predictive control (non-cooperative MPC), are used for developing the driver-AFS interactive steering control model. For each approach, the open-loop Nash steering control solution is derived; the influences of the path-following weights, preview and control horizons, driver time delay and arm neuromuscular system (NMS) dynamics are investigated, and the CPU time consumed is recorded. It is found that the two approaches give identical time histories as well as control gains, while the non-cooperative MPC method uses much less CPU time. Specifically, it is observed that the introduction of weight on the integral of vehicle lateral displacement error helps to eliminate the steady-state path-following error; the increase in preview horizon and NMS natural frequency and the decline in time delay and NMS damping ratio improve the path-following accuracy. © 2013 Copyright Taylor and Francis Group, LLC.

Open cycle thorium–uranium-fuelled nuclear energy systems

The potential for countries that currently have a nominal nuclear energy infrastructure to adopt thorium–uranium-fuelled nuclear energy systems, using a once-through ‘open’ nuclear fuel cycle, has been suggested by the International Atomic Energy Agency. This review paper highlights generation II, III and III+ nuclear energy technologies that could potentially adopt an open thorium–uranium fuel cycle and qualitatively highlights the main differences between the open thorium–uranium and open uranium fuel cycles.

Thyristors

Thyristors are usually three-terminal devices that have four layers of alternating p-type and n-type material (i.e. three p-n junctions) comprising its main power handling section. In contrast to the linear relation which exists between load and control currents in a transistor, the thyristor is bistable. The control terminal of the thyristor, called the gate (G) electrode, may be connected to an integrated and complex structure as a part of the device. Thyristors are used to approximate ideal closed (no voltage drop between anode and cathode) or open (no anode current flow) switches for control of power flow in a circuit. This differs from low-level digital switching circuits that are designed to deliver two distinct small voltage levels while conducting small currents (ideally zero). Thyristor circuits must have the capability of delivering large currents and be able to withstand large externally applied voltages. All thyristor types are controllable in switching from a forward-lockingstate (positive potential applied to the anode with respect to the cathode, with correspondingly little anode current flow) into a forward-conduction state (large forward anode current flowing, with a small anode-cathode potential drop). Most thyristors have the characteristic that after switching from a forward-blocking state into the forward-conduction state, the gate signal can be removed and the thyristor will remain in its forward-conduction mode. This property is termed "latching" and is an important distinction between thyristors and other types of power electronic devices. © 2007 Elsevier Inc. All rights reserved.

Electrical/optical dual-function redox potential transistor

We demonstrate a new type of transistors, the electrical/optical "dual-function redox-potential transistors", which is solution processable and environmentally stable. This device consists of vertically staked electrodes that act as gate, emitter and collector. It can perform as a normal transistor, whilst one electrode which is sensitised by dye enables to generate photocurrent when illuminated. Solution processable oxide-nanoparticles were used to form various functional layers, which allow an electrolyte to penetrate through and, consequently, the current between emitter and collector can be controlled by the gate potential modulated distribution of ions. The result here shows that the device performs with high ON-current under low driving voltage (<1â€...V), while the transistor performance can readily be controlled by photo-illumination. Such device with combined optical and electrical functionalities allows single device to perform the tasks that are usually done by a circuit/system with multiple optical and electrical components, and it is promising for various applications.

High-performance bowing machine tests of bowed-string transients

The development is described of a computer-controlled bowing machine that can bow a string with a range of gestures that match or exceed the capabilities of a human violinist. Example measurements of string vibration under controlled bowing conditions are shown, including a Schelleng diagram and a set of Guettler diagrams, for the open D string of a cello. For some results a rosin-coated rod was used in place of a conventional bow, to provide quantitative data for comparison with theoretical predictions. The results show qualitative consistency with the predictions of Schelleng and Guettler, but details are revealed that go beyond the limitations of existing models. © S. Hirzel Verlag · EAA.