Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model

Preeclampsia (PE) is characterized by widespread endothelial damage with hypertension, proteinuria, glomeruloendotheliosis and elevated soluble Flt-1 (sFlt-1), a natural occurring antagonist of vascular endothelial growth factor (VEGF). Cancer patients receiving anti-VEGF therapy exhibit similar symptoms. We suggested that a decrease in circulating sFlt-1 would alleviate the symptoms associated with PE. Adenoviral (Adv) overexpression of sFlt-1 induced proteinuria, caused glomerular damage and increase in blood pressure in female Balb/c mice. Circulating level of sFlt-1 above 50 ng/ml plasma induced severe vascular damage and glomerular endotheliosis. Albumin concentration in urine was elevated up to 30-fold, compared to control AdvGFP-treated animals. The threshold of kidney damage was in the range of 20-30 ng/ml sFlt-1 in plasma (8-15 ng/ml in urine). Co-administration of AdvsFlt-1 with AdvVEGF to neutralize circulating sFlt-1 resulted in more than a 70% reduction in free sFlt-1 in plasma, more than 80% reduction in urine and rescued the damaging effect of sFlt-1 on the kidneys. This demonstrates that below a critical threshold sFlt-1 fails to elicit damage to the fenestrated endothelium and that co-expression of VEGF is able to rescue effects mediated by sFlt-1 overexpression.

Theoretical study of Talbot-like bands observed using a laser diode below threshold

We report on a theoretical study of an interferometric system in which half of a collimated beam from a broadband optical source is intercepted by a glass slide, the whole beam subsequently being incident on a diffraction grating and the resulting spectrum being viewed using a linear CCD array. Using Fourier theory, we derive the expression of the intensity distribution across the CCD array. This expression is then examined for non-cavity and cavity sources for different cases determined by the direction from which the slide is inserted into the beam and the source bandwidth. The theoretical model shows that the narrower the source linewidth, the higher the deviation of the Talbot bands' visibility (as it is dependent on the path imbalance) from the previously known triangular shape. When the source is a laser diode below threshold, the structure of the CCD signal spectrum is very complex. The number of components present simultaneously increases with the number of grating lines and decreases with the laser cavity length. The model also predicts the appearance of bands in situations not usually associated with Talbot bands.

The sciatic nerve of the toad Xenopus laevis as a physiological model of the human cochlear nerve

The response of single fibres of the human cochlear nerve to electrical stimulation by a cochlear implant has previously been inferred from the response of the cochlear nerve in other mammals. These experiments are hindered by stimulus artefact and the range of stimulus currents used is therefore much less than the perceptual dynamic range (from threshold to discomfort) of human subjects. We have investigated use of the sciatic nerve of the toad Xenopus laevis as a convenient physiological model of the human cochlear nerve. Use of this completely dissected nerve reduces the problems of stimulus artefact whilst maintaining the advantages of a physiological preparation. The validity of the model was assessed by measuring the refractory periods, excitation time-constant, and relative spread of single fibres using microelectrode recording. We have also investigated the response of nerve fibres to sinusoidal stimulation. Based on these measurements, we propose that the sciatic nerve may be a suitable model of the human cochlear nerve if the timescales of stimuli are decreased by a factor of about five to compensate for the slower dynamics of the sciatic nerve and if noise is added to the stimuli to compensate for the lower internal noise of sciatic nerve fibres.

Nonlinear semi-analytical model for simulation of few-mode fiber transmission

In this letter, a nonlinear semi-analytical model (NSAM) for simulation of few-mode fiber transmission is proposed. The NSAM considers the mode mixing arising from the Kerr effect and waveguide imperfections. An analytical explanation of the model is presented, as well as simulation results for the transmission over a two mode fiber (TMF) of 112 Gb/s using coherently detected polarization multiplexed quadrature phase-shift-keying modulation. The simulations show that by transmitting over only one of the two modes on TMFs, long-haul transmission can be realized without increase of receiver complexity. For a 6000-km transmission link, a small modal dispersion penalty is observed in the linear domain, while a significant increase of the nonlinear threshold is observed due to the large core of TMF. © 2006 IEEE.

Does the Swedish Interactive Threshold Algorithm (SITA) accurately map visual field loss attributed to vigabatrin?

Background: Vigabatrin (VGB) is an anti-epileptic medication which has been linked to peripheral constriction of the visual field. Documenting the natural history associated with continued VGB exposure is important when making decisions about the risk and benefits associated with the treatment. Due to its speed the Swedish Interactive Threshold Algorithm (SITA) has become the algorithm of choice when carrying out Full Threshold automated static perimetry. SITA uses prior distributions of normal and glaucomatous visual field behaviour to estimate threshold sensitivity. As the abnormal model is based on glaucomatous behaviour this algorithm has not been validated for VGB recipients. We aim to assess the clinical utility of the SITA algorithm for accurately mapping VGB attributed field loss. Methods: The sample comprised one randomly selected eye of 16 patients diagnosed with epilepsy, exposed to VGB therapy. A clinical diagnosis of VGB attributed visual field loss was documented in 44% of the group. The mean age was 39.3 years∈±∈14.5 years and the mean deviation was -4.76 dB ±4.34 dB. Each patient was examined with the Full Threshold, SITA Standard and SITA Fast algorithm. Results: SITA Standard was on average approximately twice as fast (7.6 minutes) and SITA Fast approximately 3 times as fast (4.7 minutes) as examinations completed using the Full Threshold algorithm (15.8 minutes). In the clinical environment, the visual field outcome with both SITA algorithms was equivalent to visual field examination using the Full Threshold algorithm in terms of visual inspection of the grey scale plots, defect area and defect severity. Conclusions: Our research shows that both SITA algorithms are able to accurately map visual field loss attributed to VGB. As patients diagnosed with epilepsy are often vulnerable to fatigue, the time saving offered by SITA Fast means that this algorithm has a significant advantage for use with VGB recipients.

Effect of spatial inhomogeneity of charge carrier mobility on current-voltage characteristics in organic field-effect transistors

A semi-quantitative model is put forward elucidating the role of spatial inhomogeneity of charge carrier mobility in organic field-effect transistors. The model, based on electrostatic arguments, allows estimating the effective thickness of the conducting channel and its changes in function of source-drain and gate voltages. Local mobility gradients in the direction perpendicular to the insulator/semiconductor interface translate into voltage dependences of the average carrier mobility in the channel, resulting in positive or negative deviations of current-voltage characteristics from their expected shapes. The proposed effect supplements those described in the literature, i.e., density-dependent mobility of charge carriers, short-channel effects, and contribution of contact resistance.

A template model predicts detection of sparse stimul

Contemporary models of contrast integration across space assume that pooling operates uniformly over the target region. For sparse stimuli, where high contrast regions are separated by areas containing no signal, this strategy may be sub-optimal because it pools more noise than signal as area increases. Little is known about the behaviour of human observers for detecting such stimuli. We performed an experiment in which three observers detected regular textures of various areas, and six levels of sparseness. Stimuli were regular grids of horizontal grating micropatches, each 1 cycle wide. We varied the ratio of signals (marks) to gaps (spaces), with mark:space ratios ranging from 1 : 0 (a dense texture with no spaces) to 1 : 24. To compensate for the decline in sensitivity with increasing distance from fixation, we adjusted the stimulus contrast as a function of eccentricity based on previous measurements [Baldwin, Meese & Baker, 2012, J Vis, 12(11):23]. We used the resulting area summation functions and psychometric slopes to test several filter-based models of signal combination. A MAX model failed to predict the thresholds, but did a good job on the slopes. Blanket summation of stimulus energy improved the threshold fit, but did not predict an observed slope increase with mark:space ratio. Our best model used a template matched to the sparseness of the stimulus, and pooled the squared contrast signal over space. Templates for regular patterns have also recently been proposed to explain the regular appearance of slightly irregular textures (Morgan et al, 2012, Proc R Soc B, 279, 2754–2760)

Ferroelectric-like behaviour of melanin:humidity effect on current-voltage characteristics

The influence of low vacuum on quasistatic current-voltage (I–V) dependences and the impact of wet air pulse on dynamic bipolar I-V-loops and unipolar I-V-curves of fungal melanin thin layers have been studied for the first time. The threshold hysteresis voltages of I–V dependences are near to the standard electrode potentials of anodic water decomposition. Short wet air pulse impact leads to sharp increase of the current and appearance of “hump”-like and “knee”-like features of I-V-loops and I-V-curves, respectively. By treatment of I-V-loop allowing for I-V-curve shape the maxima of displacement current are revealed. The peculiarities of I-V-characteristics were modelled by series-parallel RC-circuit with Zener diodes as nonlinear elements. As a reason of appearance of temporal polar media with reversible ferroelectric-like polarization and ionic space charge transfer is considered the water-assisted dissociation of some ionic groups of melanin monomers that significantly influences electrophysical parameters of melanin nanostructures.

Immunological synapse: a mathematical model of the bond formation process:mathematical modelling of the immature synapse

The cell:cell bond between an immune cell and an antigen presenting cell is a necessary event in the activation of the adaptive immune response. At the juncture between the cells, cell surface molecules on the opposing cells form non-covalent bonds and a distinct patterning is observed that is termed the immunological synapse. An important binding molecule in the synapse is the T-cell receptor (TCR), that is responsible for antigen recognition through its binding with a major-histocompatibility complex with bound peptide (pMHC). This bond leads to intracellular signalling events that culminate in the activation of the T-cell, and ultimately leads to the expression of the immune eector function. The temporal analysis of the TCR bonds during the formation of the immunological synapse presents a problem to biologists, due to the spatio-temporal scales (nanometers and picoseconds) that compare with experimental uncertainty limits. In this study, a linear stochastic model, derived from a nonlinear model of the synapse, is used to analyse the temporal dynamics of the bond attachments for the TCR. Mathematical analysis and numerical methods are employed to analyse the qualitative dynamics of the nonequilibrium membrane dynamics, with the specic aim of calculating the average persistence time for the TCR:pMHC bond. A single-threshold method, that has been previously used to successfully calculate the TCR:pMHC contact path sizes in the synapse, is applied to produce results for the average contact times of the TCR:pMHC bonds. This method is extended through the development of a two-threshold method, that produces results suggesting the average time persistence for the TCR:pMHC bond is in the order of 2-4 seconds, values that agree with experimental evidence for TCR signalling. The study reveals two distinct scaling regimes in the time persistent survival probability density prole of these bonds, one dominated by thermal uctuations and the other associated with the TCR signalling. Analysis of the thermal fluctuation regime reveals a minimal contribution to the average time persistence calculation, that has an important biological implication when comparing the probabilistic models to experimental evidence. In cases where only a few statistics can be gathered from experimental conditions, the results are unlikely to match the probabilistic predictions. The results also identify a rescaling relationship between the thermal noise and the bond length, suggesting a recalibration of the experimental conditions, to adhere to this scaling relationship, will enable biologists to identify the start of the signalling regime for previously unobserved receptor:ligand bonds. Also, the regime associated with TCR signalling exhibits a universal decay rate for the persistence probability, that is independent of the bond length.

Perception of global image contrast is predicted by the same spatial integration model of gain control as detection and discrimination

How are the image statistics of global image contrast computed? We answered this by using a contrast-matching task for checkerboard configurations of ‘battenberg’ micro-patterns where the contrasts and spatial spreads of interdigitated pairs of micro-patterns were adjusted independently. Test stimuli were 20 × 20 arrays with various sized cluster widths, matched to standard patterns of uniform contrast. When one of the test patterns contained a pattern with much higher contrast than the other, that determined global pattern contrast, as in a max() operation. Crucially, however, the full matching functions had a curious intermediate region where low contrast additions for one pattern to intermediate contrasts of the other caused a paradoxical reduction in perceived global contrast. None of the following models predicted this: RMS, energy, linear sum, max, Legge and Foley. However, a gain control model incorporating wide-field integration and suppression of nonlinear contrast responses predicted the results with no free parameters. This model was derived from experiments on summation of contrast at threshold, and masking and summation effects in dipper functions. Those experiments were also inconsistent with the failed models above. Thus, we conclude that our contrast gain control model (Meese & Summers, 2007) describes a fundamental operation in human contrast vision.

Light self-focusing in the atmosphere:thin window model

Ultra-high power (exceeding the self-focusing threshold by more than three orders of magnitude) light beams from ground-based laser systems may find applications in space-debris cleaning. The propagation of such powerful laser beams through the atmosphere reveals many novel interesting features compared to traditional light self-focusing. It is demonstrated here that for the relevant laser parameters, when the thickness of the atmosphere is much shorter than the focusing length (that is, of the orbit scale), the beam transit through the atmosphere in lowest order produces phase distortion only. This means that by using adaptive optics it may be possible to eliminate the impact of self-focusing in the atmosphere on the laser beam. The area of applicability of the proposed "thin window" model is broader than the specific physical problem considered here. For instance, it might find applications in femtosecond laser material processing.