Harmonics added to a flickering light can upset the balance between ON and OFF pathways to produce illusory colors.

The neural signals generated by the light-sensitive photoreceptors in the human eye are substantially processed and recoded in the retina before being transmitted to the brain via the optic nerve. A key aspect of this recoding is the splitting of the signals within the two major cone-driven visual pathways into distinct ON and OFF branches that transmit information about increases and decreases in the neural signal around its mean level. While this separation is clearly important physiologically, its effect on perception is unclear. We have developed a model of the ON and OFF pathways in early color processing. Using this model as a guide, we can produce imbalances in the ON and OFF pathways by changing the shapes of time-varying stimulus waveforms and thus make reliable and predictable alterations to the perceived average color of the stimulus-although the physical mean of the waveforms does not change. The key components in the model are the early half-wave rectifying synapses that split retinal photoreceptor outputs into the ON and OFF pathways and later sigmoidal nonlinearities in each pathway. The ability to systematically vary the waveforms to change a perceptual quality by changing the balance of signals between the ON and OFF visual pathways provides a powerful psychophysical tool for disentangling and investigating the neural workings of human vision.

Delayed S-cone sensitivity losses following the onset of intense yellow backgrounds linked to the lifetime of a photobleaching product?

Thirty years ago, Mollon, Stockman, & Polden (1987) reported that after the onset of intense yellow 581-nm backgrounds, S-cone threshold rose unexpectedly for several seconds before recovering to the light-adapted steady-state value-an effect they called: "transient-tritanopia of the second kind" (TT2). Given that 581-nm lights have little direct effect on S-cones, TT2 must arise indirectly from the backgrounds' effects on the L- and M-cones. We attribute the phenomenon to the action of an unknown L- and M-cone photobleaching product, X, which acts at their outputs like an "equivalent" background light that then inhibits S-cones at a cone-opponent, second-site. The time-course of TT2 is similar in form to the lifetime of X in a two-stage, first-order biochemical reaction A→X→C with successive best-fitting time-constants of 3.09 ± 0.35 and 7.73 ± 0.70 s. Alternatively, with an additional slowly recovering exponential "restoring-force" with a best-fitting time-constant 23.94 ± 1.42 s, the two-stage best-fitting time-constants become 4.15 ± 0.62 and 6.79 ± 1.00 s. Because the time-constants are roughly independent of the background illumination, and thus the rate of photoisomerization, A→X is likely to be a reaction subsidiary to the retinoid cycle, perhaps acting as a buffer when the bleaching rate is too high. X seems to be logarithmically related to S-cone threshold, which may result from the logarithmic cone-opponent, second-site response compression after multiplicative first-site adaptation. The restoring-force may be the same cone-opponent force that sets the rate of S-cone recovery following the unusual threshold increase following the offset of dimmer yellow backgrounds, an effect known as "transient-tritanopia" (TT1).

Delayed cone-opponent signals in the luminance pathway.

Cone signals in the luminance or achromatic pathway were investigated by measuring how the perceptual timing of M- or L-cone-detected flicker depended on temporal frequency and chromatic adaptation. Relative timings were measured, as a function of temporal frequency, by superimposing M- or L-cone-isolating flicker on "equichromatic" flicker (flicker of the same wavelength as the background) and asking observers to vary contrast and phase to cancel the perception of flicker. Measurements were made in four observers on up to 35 different backgrounds varying in wavelength and radiance. Observers showed substantial perceptual delays or advances of L- and M-cone flicker that varied systematically with cone class, background wavelength, and radiance. Delays were largest for M-cone-isolating flicker. Although complex, the results can be characterised by a surprisingly simple model in which the representations of L- and M-cone flicker are comprised not only of a fast copy of the flicker signal, but also of a slow copy that is delayed by roughly 30 ms and varies in strength and sign with both background wavelength and radiance. The delays, which are too large to be due to selective cone adaptation by the chromatic backgrounds, must arise postreceptorally. Clear evidence for the slow signals can also be found in physiological measurements of horizontal and magnocellular ganglion cells, thus placing the origin of the slow signals in the retina-most likely in an extended horizontal cell network. Luminance-equated stimuli chosen to isolate chromatic channels may inadvertently generate slow signals in the luminance channel.

Linear-nonlinear models of the red-green chromatic pathway.

The mean hue of flickering waveforms comprising only the first two harmonics depends on their temporal alignment. We evaluate explanatory models of this hue-shift effect using previous data obtained using L- and M-cone-isolating stimuli together with chromatic sensitivity and hue discrimination data. The key questions concerned what type of nonlinearity produced the hue shifts, and where the nonlinearities lay with respect to the early band-pass and late low-pass temporal filters in the chromatic pathways. We developed two plausible models: (a) a slew-rate limited nonlinearity that follows both early and late filters, and (b) a half-wave rectifying nonlinearity-consistent with the splitting of the visual input into ON- and OFF-channels-that lies between the early and late filters followed by a compressive nonlinearity that lies after the late filter.

Hue shifts produced by temporal asymmetries in chromatic signals depend on the alignment of the first and second harmonics.

When M- or L-cone-isolating sawtooth waveforms flicker at frequencies between 4 and 13.3 Hz, there is a mean hue shift in the direction of the shallower sawtooth slope. Here, we investigate how this shift depends on the alignment of the first and second harmonics of sawtooth-like waveforms. Below 4 Hz, observers can follow hue variations caused by both harmonics, and reliably match reddish and greenish excursions. At higher frequencies, however, the hue variations appear as chromatic flicker superimposed on a steady light, the mean hue of which varies with second-harmonic alignment. Observers can match this mean hue against a variable-duty-cycle rectangular waveform and, separately, set the alignment at which the mean hue flips between reddish and greenish. The maximum hue shifts were approximately frequency independent and occurred when the peaks or troughs of the first and second harmonics roughly aligned at the visual input-consistent with the hue shift's being caused by an early instantaneous nonlinearity that saturates larger hue excursions. These predictions, however, ignore phase delays introduced within the chromatic pathway between its input and the nonlinearity that produces the hue shifts. If the nonlinearity follows the substantial filtering implied by the chromatic temporal contrast-sensitivity function, phase delays will alter the alignment of the first and second harmonics such that at the nonlinearity, the waveforms that produce the maximum hue shifts might well be those with the largest differences in rising and falling slopes-consistent with the hue shift's being caused by a central nonlinearity that limits the rate of hue change.

Hue shifts produced by temporal asymmetries in chromatic signals.

Observers viewed M- or L-cone-isolating stimuli and compared slowly-on and slowly-off sawtooth waveforms of the same mean chromaticity and luminance. Between 6 and 13 Hz, the mean hue of slowly-on L-cone and slowly-off M-cone sawtooth flicker appeared redder, and the mean hue of slowly-off L-cone and slowly-on M-cone sawtooth stimuli appeared greener-despite all the waveforms' having the same mean, near-yellow-appearing chromaticity. We measured the effect of the modulation depth and the slope of the sawtooth on the mean hue shifts as a function of temporal frequency. The results are complex but show that discriminability depended mainly on the second harmonic of the waveforms. We considered several models with combinations of linear and nonlinear stages. First, we considered models in which a nonlinear stage limits the rate of change of hue and restricts the steep slope of the sawtooth waveform more than its shallow slope, thus shifting the mean hue in the direction of the shallower slope (such a nonlinearity is also known as a slew-rate limit). Second, we considered saturation models in which the nonlinear stage compresses hue signals and thus shifts the mean of asymmetrical waveforms with or without differentiation before the nonlinearity. Overall, our modeling and results suggest that the hue shift occurs at some nonlinear mechanism in the chromatic pathway; and that, in terms of the Fourier components of the various waveforms, the effect of the nonlinearity depends crucially on the timing of the second harmonic relative to the first.

Modeling off-frequency binaural masking for short- and long-duration signals.

Experimental binaural masking-pattern data are presented together with model simulations for 12- and 600-ms signals. The masker was a diotic 11-Hz wide noise centered on 500 Hz. The tonal signal was presented either diotically or dichotically (180° interaural phase difference) with frequencies ranging from 400 to 600 Hz. The results and the modeling agree with previous data and hypotheses; simulations with a binaural model sensitive to monaural modulation cues show that the effect of duration on off-frequency binaural masking-level differences is mainly a result of modulation cues which are only available in the monaural detection of long signals.

[Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. / Barorezeptorakivierungstherapie bei therapierefraktärer Hypertonie: Indikation und Patientenselektion : Empfehlungen der BAT-Konsensusgruppe 2017.

Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients.

A Markov chain model for N-linked protein glycosylation--towards a low-parameter tool for model-driven glycoengineering.

Glycosylation is a critical quality attribute of most recombinant biotherapeutics. Consequently, drug development requires careful control of glycoforms to meet bioactivity and biosafety requirements. However, glycoengineering can be extraordinarily difficult given the complex reaction networks underlying glycosylation and the vast number of different glycans that can be synthesized in a host cell. Computational modeling offers an intriguing option to rationally guide glycoengineering, but the high parametric demands of current modeling approaches pose challenges to their application. Here we present a novel low-parameter approach to describe glycosylation using flux-balance and Markov chain modeling. The model recapitulates the biological complexity of glycosylation, but does not require user-provided kinetic information. We use this method to predict and experimentally validate glycoprofiles on EPO, IgG as well as the endogenous secretome following glycosyltransferase knock-out in different Chinese hamster ovary (CHO) cell lines. Our approach offers a flexible and user-friendly platform that can serve as a basis for powerful computational engineering efforts in mammalian cell factories for biopharmaceutical production.

Endoplasmic reticulum: reduced and oxidized glutathione revisited.

The reducing power of glutathione, expressed by its reduction potential EGSH, is an accepted measure for redox conditions in a given cell compartment. In the endoplasmic reticulum (ER), EGSH is less reducing than elsewhere in the cell. However, attempts to determine EGSH(ER) have been inconsistent and based on ineligible assumptions. Using a codon-optimized and evidently glutathione-specific glutaredoxin-coupled redox-sensitive green fluorescent protein (roGFP) variant, we determined EGSH(ER) in HeLa cells as -208±4 mV (at pH 7.0). At variance with existing models, this is not oxidizing enough to maintain the known redox state of protein disulfide isomerase family enzymes. Live-cell microscopy confirmed ER hypo-oxidation upon inhibition of ER Ca(2+) import. Conversely, stressing the ER with a glycosylation inhibitor did not lead to more reducing conditions, as reported for yeast. These results, which for the first time establish the oxidative capacity of glutathione in the ER, illustrate a context-dependent interplay between ER stress and EGSH(ER). The reported development of ER-localized EGSH sensors will enable more targeted in vivo redox analyses in ER-related disorders.

The association between the regular use of preventive labour induction and improved term birth outcomes: findings of a systematic review and meta-analysis.

BACKGROUND: Despite a lack of high-quality evidence, the use of 'non-indicated' term labour induction is increasingly restricted throughout the world. OBJECTIVES: To assess published associations between the regular use of modelled risk-based 'non-indicated' term labour induction (hereinafter 'preventive induction') and rates of common adverse birth outcomes. SEARCH STRATEGY: MEDLINE and PUBMED databases were searched electronically. SELECTION CRITERIA: Studies were identified that compared term birth outcomes following either the current standard approach with its emphasis on the expectant management of intermediate-level risk or the regular use of preventive induction. DATA COLLECTION AND ANALYSIS: Four studies from four unique databases were identified. A meta-analysis was performed using STATA IC12. MAIN RESULTS: Pregnancies exposed to the regular use of preventive induction (n = 1153), as compared with pregnancies receiving the current standard approach (n = 1865), experienced a lower caesarean delivery rate (5.7% versus 14.4%; relative risk 0.39, 95% CI 0.31-0.50; I(2) P = 0.21), a lower neonatal intensive care unit admission rate (2.9% versus 6.5%; relative risk 0.45, 95% CI 0.31-0.65; I(2) P = 0.57), and a lower weighted adverse outcome index score (2.8 versus 6.1). CONCLUSIONS: The regular use of preventive induction, as compared with the current standard approach, was associated with a more favourable pattern of birth outcomes. Other recently published meta-analyses have also determined that certain types of 'non-indicated' labour induction are beneficial. Accordingly, the current broad restrictions on 'non-indicated' labour induction should be reconsidered. Adequately powered multi-site randomised clinical trials are needed to definitively study the risks and benefits of modelled risk-based 'non-indicated' (i.e. 'preventive') term labour induction.

Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy.

Restored rod visual function after gene therapy can be established unequivocally by demonstrating that, after dark adaptation, spectral sensitivity has the shape characteristic of rods and that this shape collapses to a cone-like shape before rods have recovered after an intense bleach. We used these tests to assess retinal function in eight young adults and children with early-onset severe retinal dystrophy from Phase II of a clinical gene-therapy trial for RPE65 deficiency that involved the subretinal delivery of a recombinant adeno-associated viral vector carrying RPE65. We found substantial improvements in rod sensitivity in two participants: dark-adapted spectral sensitivity was rod-like after treatment and was cone-like before rods had recovered after a bleach. After 40 min of dark adaptation, one participant showed up to 1,000-fold sensitivity improvements 4 months after treatment and the second up to 100-fold improvements 6 months after treatment. The dark-adapted spectral sensitivities of the other six participants remained cone-like and showed little improvement in sensitivity.

Color and brightness encoded in a common L- and M-cone pathway with expansive and compressive nonlinearities.

Lights near 560 nm appear brighter when flickered, whereas lights near 520 or 650 nm appear yellower. Both effects are consistent with signal distortion within the visual pathway--brightness changes at an expansive nonlinearity, and hue shifts at a compressive one. We previously manipulated the distortion products generated by each nonlinearity to extract the temporal properties of stages of the L- and M-cone pathways that signal brightness and color before (early stages) and after (late stages) each nonlinearity. We find that the attenuation characteristics of the early and late stages are virtually identical in both pathways: The early temporal stage acts like a band-pass filter peaking at 10-15 Hz, while the late stage acts like low-pass filter with a cut-off frequency near 3 Hz. We propose a physiologically relevant model that accounts for the filter shapes and incorporates both nonlinearities within a common parvocellular pathway. The shape of the early band-pass filter is consistent with antagonism between center signals and more sluggish and delayed surround signals, while the late filter is consistent with a simple two-stage low-pass filter. Modeling suggests that the brightness change and hue shift are both initially caused by the half-wave rectification and partition of signals into ON and OFF components. However, the hue shift is probably caused by the additional effects of a later nonlinearity that compresses chromatic red and green signals. Plausible sites for the expansive half-wave rectifying nonlinearity are after surround antagonism, possibly from horizontal cells, but the compressive nonlinearity is likely to be after the late filter.

Non-constant geometric curvature for tailored spin-orbit coupling and chirality in superconductor-magnet heterostructures.

We show that tailoring the geometric curvature profile of magnets can be used for bespoke design of an effective non-relativistic spin-orbit coupling, which may be used to control proximity effects if the magnet is coupled to a superconductor. We consider proximity-coupled one-dimensional magnetic wires with variable curvatures, specifically three distinct shapes classified as J-, C-, and S-type. We demonstrate a chirality-dependent spin polarization of the superconducting correlations, and show the role of curvature in determining the ground state of mixed-chirality junctions. We speculate on how this may be implemented in novel device design, and include analysis of its usage in a spin-triplet SQUID.

A novel binaural pitch elicited by phase-modulated noise: MEG and psychophysical observations.

Binaural pitches are auditory percepts that emerge from combined inputs to the ears but that cannot be heard if the stimulus is presented to either ear alone. Here, we describe a binaural pitch that is not easily accommodated within current models of binaural processing. Convergent magnetoencephalography (MEG) and psychophysical measurements were used to characterize the pitch, heard when band-limited noise had a rapidly changing interaural phase difference. Several interesting features emerged: First, the pitch was perceptually lateralized, in agreement with the lateralization of the evoked changes in MEG spectral power, and its salience depended on dichotic binaural presentation. Second, the frequency of the pure tone that matched the binaural pitch lay within a lower spectral sideband of the phase-modulated noise and followed the frequency of that sideband when the modulation frequency or center frequency and bandwidth of the noise changed. Thus, the binaural pitch depended on the processing of binaural information in that lower sideband.

The temporal characteristics of the early and late stages of L- and M-cone pathways that signal brightness.

Flickering 560-nm light appears brighter and less saturated than steady light of the same average intensity. The changes in appearance are consistent with the visual signal's being distorted at some nonlinear site (or sites) within the visual pathway at which new temporal components, not part of the original waveform, are produced. By varying the input stimulus to manipulate these new temporal components--called distortion products--and measuring our observers' sensitivity in detecting them, we derived the temporal attenuation characteristics of the early (prenonlinearity) and late (post-nonlinearity) stages of the L- and M-cone pathway that signals brightness. We found that the early stage acts like a band-pass filter peaking at 10-15 Hz with sensitivity losses at both lower and higher frequencies, whereas the late stage acts like a two-stage low-pass filter with a corner frequency near 3 Hz. Although brightness is often associated with the fast achromatic or luminance pathway, these filter characteristics, and particularly those of the late filter, are consistent with comparable features of the L-M chromatic pathway that produce mainly chromatic distortion products (Petrova, Henning, & Stockman, 2013). A plausible site for the nonlinearity is after surround antagonism from horizontal cells. Modeling suggested the form of the nonlinearity to be initially expansive but possibly with a hard limit at the highest input levels.

The temporal characteristics of the early and late stages of the L- and M-cone pathways that signal color.

Flickering long-wavelength light appears more yellow than steady light of the same average intensity. The hue change is consistent with distortion of the visual signal at some nonlinear site (or sites) that produces temporal components not present in the original stimulus (known as distortion products). We extracted the temporal attenuation characteristics of the early (prenonlinearity) and late (post-nonlinearity) filter stages in the L- and M-cone chromatic pathway by varying the input stimulus to manipulate the distortion products and the measuring of the observers' sensitivity to them. The early, linear, filter stage acts like a band-pass filter peaking at 10-15 Hz with substantial sensitivity losses at both lower and higher frequencies. Its characteristics are consistent with nonlinearity being early in the visual pathway but following surround inhibition. The late stage, in contrast, acts like a low-pass filter with a cutoff frequency around 3 Hz. The response of the early stage speeds up with radiance, but the late stage does not. A plausible site for the nonlinearity, which modelling suggests may be smoothly compressive but with a hard limit at high input levels, is after surround inhibition from the horizontal cells.

Sensory thresholds obtained from MEG data: cortical psychometric functions.

Sensory sensitivity is typically measured using behavioural techniques (psychophysics), which rely on observers responding to very large numbers of stimulus presentations. Psychophysics can be problematic when working with special populations, such as children or clinical patients who may lack the compliance or cognitive skills to perform the behavioural tasks. We used an auditory gap-detection paradigm to develop an accurate measure of sensory threshold derived from passively-recorded magnetoencephalographic (MEG) data. Auditory evoked responses were elicited by silent gaps of varying durations in an on-going noise stimulus. Source modelling was used to spatially filter the MEG data and sigmoidal 'cortical psychometric functions' relating response amplitude to gap duration were obtained for each individual participant. Fitting the functions with a curve and estimating the gap duration at which the amplitude of the evoked response exceeded one standard deviation of the prestimulus brain activity provided an excellent prediction of psychophysical threshold. Accurate sensory thresholds can therefore be reliably extracted from MEG data recorded while participants listen passively to a stimulus. Because our paradigm required no behavioural task, the method is suitable for studies of populations where variations in cognitive skills or vigilance make traditional psychophysics unsuitable.

Shell-structure and pairing interaction in superheavy nuclei: rotational properties of the z=104 nucleus (256)rf.

The rotational band structure of the Z=104 nucleus (256)Rf has been observed up to a tentative spin of 20ℏ using state-of-the-art γ-ray spectroscopic techniques. This represents the first such measurement in a superheavy nucleus whose stability is entirely derived from the shell-correction energy. The observed rotational properties are compared to those of neighboring nuclei and it is shown that the kinematic and dynamic moments of inertia are sensitive to the underlying single-particle shell structure and the specific location of high-j orbitals. The moments of inertia therefore provide a sensitive test of shell structure and pairing in superheavy nuclei which is essential to ensure the validity of contemporary nuclear models in this mass region. The data obtained show that there is no deformed shell gap at Z=104, which is predicted in a number of current self-consistent mean-field models.

The effects of noise-bandwidth, noise-fringe duration, and temporal signal location on the binaural masking-level difference.

The effects of forward and backward noise fringes on binaural signal detectability were investigated. Masked thresholds for a 12-ms, 250-Hz, sinusoidal signal masked by Gaussian noise, centered at 250 Hz, with bandwidths from 3 to 201 Hz, were obtained in N(0)S(0) and N(0)S(π) configurations. The signal was (a) temporally centered in a 12-ms noise burst (no fringe), (b) presented at the start of a 600-ms noise burst (backward fringe), or (c) temporally centered in a 600-ms noise burst (forward-plus-backward fringe). For noise bandwidths between 3 and 75 Hz, detection in N(0)S(0) improved with the addition of a backward fringe, improving further with an additional forward fringe; there was little improvement in N(0)S(π). The binaural masking-level difference (BMLD) increased from 0 to 8 dB with a forward-plus-backward fringe as noise bandwidths increased to 100 Hz, increasing slightly to 10 dB at 201 Hz. This two-stage increase was less pronounced with a backward fringe. With no fringe, the BMLD was about 10-14 dB at all bandwidths. Performance appears to result from the interaction of across-time and across-frequency listening strategies and the possible effects of gain reduction and suppression, which combine in complex ways. Current binaural models are, as yet, unable to account fully for these effects.