Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup.

Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p < 0.001), and unfavourable clinical outcome (p = 0.001). Our findings are consistent with the results of the TCGA data set for the "squamous-like" subtype of bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA "squamous-like" subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies

In Vivo Time- Resolved Microtomography Reveals the Mechanics of the Blowfly Flight Motor

Dipteran flies are amongst the smallest and most agile of flying animals. Their wings are driven indirectly by large power muscles, which cause cyclical deformations of the thorax that are amplified through the intricate wing hinge. Asymmetric flight manoeuvres are controlled by 13 pairs of steering muscles acting directly on the wing articulations. Collectively the steering muscles account for <3% of total flight muscle mass, raising the question of how they can modulate the vastly greater output of the power muscles during manoeuvres. Here we present the results of a synchrotron-based study performing micrometre-resolution, time-resolved microtomography on the 145 Hz wingbeat of blowflies. These data represent the first four-dimensional visualizations of an organism's internal movements on sub-millisecond and micrometre scales. This technique allows us to visualize and measure the three-dimensional movements of five of the largest steering muscles, and to place these in the context of the deforming thoracic mechanism that the muscles actuate. Our visualizations show that the steering muscles operate through a diverse range of nonlinear mechanisms, revealing several unexpected features that could not have been identified using any other technique. The tendons of some steering muscles buckle on every wingbeat to accommodate high amplitude movements of the wing hinge. Other steering muscles absorb kinetic energy from an oscillating control linkage, which rotates at low wingbeat amplitude but translates at high wingbeat amplitude. Kinetic energy is distributed differently in these two modes of oscillation, which may play a role in asymmetric power management during flight control. Structural flexibility is known to be important to the aerodynamic efficiency of insect wings, and to the function of their indirect power muscles. We show that it is integral also to the operation of the steering muscles, and so to the functional flexibility of the insect flight motor

The G Protein Coupled Receptor 3 Is Involved in cAMP and cGMP Signaling and Maintenance of Meiotic Arrest in Porcine Oocytes

The arrest of meiotic prophase in mammalian oocytes within fully grown follicles is dependent on cyclic adenosine monophosphate (cAMP) regulation. A large part of cAMP is produced by the Gs-linked G-protein-coupled receptor (GPR) pathway. In the present study, we examined whether GPR3 is involved in the maintenance of meiotic arrest in porcine oocytes. Expression and distribution of GPR3 were examined by western blot and immunofluorescence microscopy, respectively. The results showed that GPR3 was expressed at various stages during porcine oocyte maturation. At the germinal vesicle (GV) stage, GPR3 displayed a maximal expression level, and its expression remained stable from pro-metaphase I (MI) to metaphase II (MII). Immunofluorescence staining showed that GPR3 was mainly distributed at the nuclear envelope during the GV stage and localized to the plasma membrane at pro-MI, MI and MII stages. RNA interference (RNAi) was used to knock down the GPR3 expression within oocytes. Injection of small interfering double-stranded RNA (siRNA) targeting GPR3 stimulated meiotic resumption of oocytes. On the other hand, overexpression of GPR3 inhibited meiotic maturation of porcine oocytes, which was caused by increase of cGMP and cAMP levels and inhibition of cyclin B accumulation. Furthermore, incubation of porcine oocytes with the GPR3 ligand sphingosylphosphorylcholine (SPC) inhibited oocyte maturation. We propose that GPR3 is required for maintenance of meiotic arrest in porcine oocytes through pathways involved in the regulation of cAMP and cGMP

Integrating fluctuations into distribution of resources in transportation networks

We propose a resource distribution strategy to reduce the average travel time in a transportation network given a fixed generation rate. Suppose that there are essential resources to avoid congestion in the network as well as some extra resources. The strategy distributes the essential resources by the average loads on the vertices and integrates the fluctuations of the instantaneous loads into the distribution of the extra resources. The fluctuations are calculated with the assumption of unlimited resources, where the calculation is incorporated into the calculation of the average loads without adding to the time complexity. Simulation results show that the fluctuation-integrated strategy provides shorter average travel time than a previous distribution strategy while keeping similar robustness. The strategy is especially beneficial when the extra resources are scarce and the network is heterogeneous and lowly loaded.Comment: 14 pages, 4 figure

Effect of crystalline admixtures on the self-healing capability of early-age concrete studied by means of permeability and crack closing tests

This paper analyzes the self-healing properties of early-age concretes, engineered using a crystalline admixture (4% by the weight of cement), by measuring the permeability of cracked specimens and their crack width. Two concrete classes (C30/37 and C45/55) and three healing exposure conditions have been investigated: water immersion at 15 °C, at 30 °C and wet/dry cycles. Specimens were pre-cracked at 2 days, to values of crack width in the range of 0.10 0.40 mm. The results show almost perfect healing capability for specimens healed under water at 30 °C, better than for specimens healed under water at 15 °C, while insufficient for the wet/dry exposure.Roig Flores, M.; Pirritano, F.; Serna Ros, P.; Ferrara, L. (2016). Effect of crystalline admixtures on the self-healing capability of early-age concrete studied by means of permeability and crack closing tests. Construction and Building Materials. 114:447-457. doi:10.1016/j.conbuildmat.2016.03.196S44745711

Coordinated optimization of visual cortical maps (I) Symmetry-based analysis

In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of OP columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about an hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference.Comment: 90 pages, 16 figure

Correlation of the score for subjective pain with physical disability, clinical and radiographic scores in recent onset rheumatoid arthritis

BACKGROUND: To analyse the relationship between subjective pain score and other measures of clinical, radiographic and functional status; in particular Larsen radiographic scores and Health Assessment Questionnaire (HAQ); in patients with severe rheumatoid arthritis (RA) with a disease duration of less than 3 years. METHODS: In this cross sectional study of 105 patients with RA (76 women, 29 men: mean age 50.93; mean disease duration 15.86 months; 71% rheumatoid factor positive) subjective pain was assessed according to the Visual Analog Scale (VAS). Correlation coefficients between pain score and disease activity measures (patients' global assessment of disease by VAS, number of tender and swollen joints, morning stiffness, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] and titre of rheumatoid factor, radiographic evaluations (Larsen-Dale scores for radiographic damage of the small joints of the hands, wrist and feet), disability measures (health assessment questionnaire [HAQ]), and demographic variables were calculated; hierarchical regression analysis was done with subjective pain score as the dependent variable. RESULTS: The Spearman's correlation coefficient comparing subjective pain and HAQ was 0.421 (p < 0.001), between subjective pain and global assessment of disease and morning stiffness was 0.573 (p < 0.001) and 0.427 (p < 0.001) respectively, and between pain and number of tender and swollen joints 0.037 and 0.050 respectively (p > 0.05). In regression analysis, global assessment of disease by patients explained 32.8% of the variation in pain intensity score, morning stiffness 10.7%, CRP 4.0%, HAQ 3.8% and Larsen-Dale scores explained 2.1%; other variables were not significant in the model. CONCLUSIONS: Pain scores of patients with early severe rheumatoid arthritis are correlated at higher levels with patients' global assessment of disease and with morning stiffness rather than with radiographic or other clinical variables such as number of tender and swollen joints

Coordinated optimization of visual cortical maps (II) Numerical studies

It is an attractive hypothesis that the spatial structure of visual cortical architecture can be explained by the coordinated optimization of multiple visual cortical maps representing orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we defined a class of analytically tractable coordinated optimization models and solved representative examples in which a spatially complex organization of the orientation preference map is induced by inter-map interactions. We found that attractor solutions near symmetry breaking threshold predict a highly ordered map layout and require a substantial OD bias for OP pinwheel stabilization. Here we examine in numerical simulations whether such models exhibit biologically more realistic spatially irregular solutions at a finite distance from threshold and when transients towards attractor states are considered. We also examine whether model behavior qualitatively changes when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. Our numerical results support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the spatially irregular architecture of the visual cortex. We discuss several alternative scenarios and additional factors that may improve the agreement between model solutions and biological observations.Comment: 55 pages, 11 figures. arXiv admin note: substantial text overlap with arXiv:1102.335

Conservation of pattern as a tool for inference on spatial snapshots in ecological data

As climate change and other anthropogenic factors increase the uncertainty of vegetation ecosystem persistence, the ability to rapidly assess their dynamics is paramount. Vegetation and sessile communities form a variety of striking regular spatial patterns such as stripes, spots and labyrinths, that have been used as indicators of ecosystem current state, through qualitative analysis of simple models. Here we describe a new method for rigorous quantitative estimation of biological parameters from a single spatial snapshot. We formulate a synthetic likelihood through consideration of the expected change in the correlation structure of the spatial pattern. This then allows Bayesian inference to be performed on the model parameters, which includes providing parameter uncertainty. The method was validated against simulated data and then applied to real data in the form of aerial photographs of seagrass banding. The inferred parameters were found to be able to reproduce similar patterns to those observed and able to detect strength of spatial competition, competition-induced mortality and the local range of reproduction. This technique points to a way of performing rapid inference of spatial competition and ecological stability from a single spatial snapshots of sessile communities

Evidence for 'critical slowing down' in seagrass:a stress gradient experiment at the southern limit of its range

The theory of critical slowing down, i.e. the increasing recovery times of complex systems close to tipping points, has been proposed as an early warning signal for collapse. Empirical evidence for the reality of such warning signals is still rare in ecology. We studied this on Zostera noltii intertidal seagrass meadows at their southern range limit, the Banc d'Arguin, Mauritania. We analyse the environmental covariates of recovery rates using structural equation modelling (SEM), based on an experiment in which we assessed whether recovery after disturbances (i.e. seagrass & infauna removal) depends on stress intensity (increasing with elevation) and disturbance patch size (1 m(2) vs. 9 m(2)). The SEM analyses revealed that higher biofilm density and sediment accretion best explained seagrass recovery rates. Experimental disturbances were followed by slow rates of recovery, regrowth occurring mainly in the coolest months of the year. Macrofauna recolonisation lagged behind seagrass recovery. Overall, the recovery rate was six times slower in the high intertidal zone than in the low zone. The large disturbances in the low zone recovered faster than the small ones in the high zone. This provides empirical evidence for critical slowing down with increasing desiccation stress in an intertidal seagrass system