Outer Function Research Articles

Infliximab exerts a dose-dependent effect on retinal safety in the albino rabbit.

To assess the retinal toxicity of an intravitreal injection of infliximab, a monoclonal antibody to tumor necrosis factor α, in a rabbit model. Two groups of adult albino rabbits (n=5) received intravitreal injections of infliximab (0.1ml) in the study eye and balanced salt solution (BSS, 0.1ml) in the control eye at baseline. Group 1 was administered with 1.5mg/0.1ml, and group 2 was injected with 7.5mg/0.1ml of infliximab solution. Electroretinography (ERG) was performed at baseline and at 1, 7, 30, and 45days after the injection. Visual evoked potentials (VEPs) were recorded at 7 and 45days after the injection. After the last electrophysiological assessment, the rabbits were euthanized and retinal histopathology and immunhistochemistry for glial fibrillary acidic protein (GFAP) were performed. ERG responses demonstrated no significant deficit in retinal function in eyes injected with infliximab. Mean dark-adapted a-wave and b-wave maximal amplitude and semi-saturation constant values at baseline and throughout the 45days of follow-up after the injection indicated no remarkable difference in outer retinal function between the control and experimental eyes. VEP responses were similar at each time point (7 and 45days). No difference was seen in retinal histopathology and immunocytochemistry sections in eyes receiving the 1.5mg/0.1ml dose compared to the control eyes. However, increased GFAP labeling in retinal Müller cells was detected in rabbit eyes treated with the 7.5mg/0.1ml dose. Intravitreal injection of 1.5mg/0.1ml infliximab dose has no toxic effect on the integrity (functional or structural) of the retina in rabbits. A higher dose of 7.5mg/0.1ml may be slightly toxic as suggested by positive Müller cell GFAP expression. Additional studies of retinal toxicity at higher doses and after multiple injections are needed to establish the retinal safety of intravitreal infliximab therapy in humans.

Structural Insights into the Yersinia pestis Outer Membrane Protein Ail in Lipid Bilayers

Yersinia pestis the causative agent of plague, is highly pathogenic and poses very high risk to public health. The outer membrane protein Ail (Adhesion invasion locus) is one of the most highly expressed proteins on the cell surface of Y. pestis, and a major target for the development of medical countermeasures. Ail is essential for microbial virulence and is critical for promoting the survival of Y. pestis in serum. Structures of Ail have been determined by X-ray diffraction and solution NMR spectroscopy, but the protein's activity is influenced by the detergents in these samples, underscoring the importance of the surrounding environment for structure-activity studies. Here we describe the backbone structure of Ail, determined in lipid bilayer nanodiscs, using solution NMR spectroscopy. We also present solid-state NMR data obtained for Ail in membranes containing lipopolysaccharide (LPS), a major component of the bacterial outer membranes. The protein in lipid bilayers, adopts the same eight-stranded β-barrel fold observed in the crystalline and micellar states. The membrane composition, however, appears to have a marked effect on protein dynamics, with LPS enhancing conformational order and slowing down the 15N transverse relaxation rate. The results provide information about the way in which an outer membrane protein inserts and functions in the bacterial membrane.

Invariant subspaces generated by a single function in the Polydisk

In this study, we partially answer the question left open in Rudin's book "Function theory in polydiscs" on the structure of invariant subspaces of the Hardy space $H^2(U^n)$ on the polydisc $U^n$. We completely describe all invariant subspaces generated by a single function in the polydisc. Then, using our results, we give the unitary equivalence of this type of invariant subspace and a characterization of outer functions in $H^2(U^n)$.

Pupillary Light Reflexes in Severe Photoreceptor Blindness Isolate the Melanopic Component of Intrinsically Photosensitive Retinal Ganglion Cells.

PurposePupillary light reflex (PLR) is driven by outer retinal photoreceptors and by melanopsin-expressing intrinsically photosensitive retinal ganglion cells of the inner retina. To isolate the melanopic component, we studied patients with severe vision loss due to Leber congenital amaurosis (LCA) caused by gene mutations acting on the outer retina.MethodsDirect PLR was recorded in LCA patients (n = 21) with known molecular causation and severe vision loss. Standard stimuli (2.5 log scot-cd.m−2; ∼13 log quanta.cm−2.s−1; achromatic full-field) with 0.1- or 5-second duration were used in all patients. Additional recordings were performed with higher luminance (3.9 log scot-cd.m−2) in a subset of patients.ResultsThe LCA patients showed no detectable PLR to the standard stimulus with short duration. With longer-duration stimuli, a PLR was detectable in the majority (18/21) of patients. The latency of the PLR was 2.8 ± 1.3 seconds, whereas normal latency was 0.19 ± 0.02 seconds. Peak contraction amplitude in patients was 1.1 ± 0.9 mm at 6.2 ± 2.3 seconds, considerably different from normal amplitude of 4.2 ± 0.4 mm at 3.0 ± 0.4 seconds. Recordings with higher luminance demonstrated that PLRs in severe LCA could also be evoked with short-duration stimuli.ConclusionsThe PLR in severe LCA patients likely represents the activation of the melanopic circuit in isolation from rod and cone input. Knowledge of the properties of the human melanopic PLR allows not only comparison to those in animal models but also serves to define the fidelity of postretinal transmission in clinical trials targeting patients with no outer retinal function.

Seismic iterative migration velocity analysis: two strategies to update the velocity model

The objective of seismic imaging is to recover properties of the Earth from surface measurements recorded during active seismic surveys. Migration Velocity Analysis techniques aim at determining a background velocity model (smooth part of the pressure wave velocity model) using the redundancy of seismic data and consist of solving a nested optimisation problem. In the inner loop, an extended reflectivity model (detailed part of the model) is determined from recorded primary reflections through a data-fitting procedure depending on a given background model. In the outer loop, a coherency criterion defined on the extended reflectivity assesses the quality of the background model. The inner problem is usually solved with a single iteration of gradient optimisation, leading to artefacts in the velocity updates. We study the benefits of further iterating on the reflectivity in the inner loop, which also allows the introduction of multiple reflections in the procedure. We propose two strategies for the computation of the gradient of the outer objective function. In the first case, we compute the exact numerical gradient by taking care of the background dependency of all inner iterations. In the second case, we derive an approximate gradient by assuming the optimal reflectivity has been obtained. Both methods are compared on their computational merits and through simple numerical examples on 2D synthetic data sets. The examples illustrate that regularisation of the inner problem is essential to obtain coherent velocity updates. The second approach displays a smaller sensitivity to regularisation and is simpler to implement.

Normative Study of Wideband Acoustic Immittance Measures in Newborn Infants.

The purpose of this study was to describe normative aspects of wideband acoustic immittance (WAI) measures obtained from healthy White neonates. In this cross-sectional study, wideband absorbance (WBA), admittance magnitude, and admittance phase were measured under ambient pressure condition in 326 ears from 203 neonates (M age = 45.9 hr) who passed a battery of tests, including automated auditory brainstem response, high-frequency tympanometry, and distortion product otoacoustic emissions. Normative WBA data were in agreement with most previous studies. Normative data for both WBA and admittance magnitude revealed double-peaked patterns with the 1st peak at 1.25-2 kHz and the 2nd peak at 5-8 kHz, while normative admittance phase data showed 2 peaks at 0.8 and 4 kHz. There were no significant differences between ears or gender for the 3 WAI measures. Standard deviations for all 3 measures were highest at frequencies above 4 kHz. The 3 WAI measures between 1 kHz and 4 kHz may provide the most stable response of the outer and middle ear. WAI measures at frequencies above 4 kHz were more variable. The normative data established in the present study may serve as a reference for evaluating outer and middle ear function in neonates.

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia.

To establish a feasible and sensitive pupillographic protocol to assess outer and inner retinal function for the first gene therapy trial in achromatopsia patients (ACHM) with mutations in CNGA3. Twenty-seven CNGA3-ACHM patients and 22 age-matched control subjects were tested using chromatic pupillography. Three different protocols were established to assess the pupillary light reflex parameters and to create the final protocol. In the individual protocols, various stimulus parameters (i.e., intensity, duration, wavelength, adaptation states) were applied to evaluate the impact of these stimuli on the pupillary response in untreated ACHM patients. In the light-adapted conditions, CNGA3-ACHM patients showed significantly reduced maximal amplitudes compared with the control group when using a 1-second high intensity (28-lux corneal illumination) blue or red stimulus (P < 0.005). In the dark-adapted conditions, CNGA3-ACHM patients unexpectedly revealed significantly increased maximal amplitudes when stimulating with red (1 second) or blue (4 ms and 1 second) stimuli of low intensity (0.01-lux corneal illumination; P < 0.05). Pupil responses of CNGA3-ACHM patients after high intensity (28 lux) red and blue 1-second stimuli were within the normal range. Chromatic pupillography demonstrated significant reduced pupil responses to stimuli addressing primarily cone function, an increased sensitivity to rod-favoring stimuli and evidence for disinhibition of intrinsically photosensitive retinal ganglion cells in CNGA3-ACHM patients. A final protocol was established based on these findings. These conclusions may be useful for the objective assessment of efficacy gained by gene therapy or other innovative interventions in this hereditary retinal disorder.

Necessary optimality conditions and exact penalization for non-Lipschitz nonlinear programs

When the objective function is not locally Lipschitz, constraint qualifications are no longer sufficient for Karush–Kuhn–Tucker (KKT) conditions to hold at a local minimizer, let alone ensuring an exact penalization. In this paper, we extend quasi-normality and relaxed constant positive linear dependence condition to allow the non-Lipschitzness of the objective function and show that they are sufficient for KKT conditions to be necessary for optimality. Moreover, we derive exact penalization results for the following two special cases. When the non-Lipschitz term in the objective function is the sum of a composite function of a separable lower semi-continuous function with a continuous function and an indicator function of a closed subset, we show that a local minimizer of our problem is also a local minimizer of an exact penalization problem under a local error bound condition for a restricted constraint region and a suitable assumption on the outer separable function. When the non-Lipschitz term is the sum of a continuous function and an indicator function of a closed subset, we also show that our problem admits an exact penalization under an extended quasi-normality involving the coderivative of the continuous function.

Optimal Control of Conditional Value-at-Risk in Continuous Time

We consider continuous-time stochastic optimal control problems featuring conditional value-at-risk (CVaR) in the objective. The major difficulty in these problems arises from time inconsistency, which prevents us from directly using dynamic programming. To resolve this challenge, we convert to an equivalent bilevel optimization problem in which the inner optimization problem is standard stochastic control. Furthermore, we provide conditions under which the outer objective function is convex and differentiable. We compute the outer objective's value via a Hamilton--Jacobi--Bellman equation and its gradient via the viscosity solution of a linear parabolic equation, which allows us to perform gradient descent. The significance of this result is that we provide an efficient dynamic-programming-based algorithm for optimal control of CVaR without lifting the state space. To broaden the applicability of the proposed algorithm, we propose convergent approximation schemes in cases where our key assumptions do not hold and characterize relevant suboptimality bounds. In addition, we extend our method to a more general class of risk metrics, which includes mean variance and median deviation. We also demonstrate a concrete application to portfolio optimization under CVaR constraints. Our results contribute an efficient framework for solving time-inconsistent CVaR-based sequential optimization.

C-reactive protein isoforms differentially affect outer blood-retinal barrier integrity and function.

The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier (oBRB) and is the prime target of early age-related macular degeneration (AMD). C-reactive protein (CRP), a serum biomarker for chronic inflammation and AMD, presents two different isoforms, monomeric (mCRP) and pentameric (pCRP), that may have a different effect on inflammation and barrier function in the RPE. The results reported in this study suggest that mCRP but not pCRP impairs RPE functionality by increasing paracellular permeability and disrupting the tight junction proteins ZO-1 and occludin in RPE cells. Additionally, we evaluated the effect of drugs commonly used in clinical settings on mCRP-induced barrier dysfunction. We found that a corticosteroid (methylprednisolone) and an anti-VEGF agent (bevacizumab) prevented mCRP-induced ARPE-19 barrier disruption and IL-8 production. Furthermore, bevacizumab was also able to revert mCRP-induced IL-8 increase after mCRP stimulation. In conclusion, the presence of mCRP within retinal tissue may lead to disruption of the oBRB, an effect that may be modified in the presence of corticosteroids or anti-VEGF drugs.

Outer transfer functions of differential-algebraic systems

We consider differential-algebraic systems (DAEs) whose transfer function is outer : i . e ., it has full row rank and all transmission zeros lie in the closed left half complex plane. We characterize outer, with the aid of the Kronecker structure of the system pencil and the Smith–McMillan structure of the transfer function, as the following property of a behavioural stabilizable and detectable realization: each consistent initial value can be asymptotically controlled to zero while the output can be made arbitrarily small in the ℒ 2 -norm. The zero dynamics of systems with outer transfer functions are analyzed. We further show that our characterizations of outer provide a simple and very structured analysis of the linear-quadratic optimal control problem.

Polymorphic Regulation of Outer Membrane Lipid A Composition.

ABSTRACTThe importance of the polymorphic-phase behavior of lipid A structural variations in determining their endotoxic activities has been recognized previously, but any potential role for lipid A polymorphism in controlling outer membrane structure and function has been largely ignored until now. In a recent article in mBio [7(5):e01532-16, https://doi.org/10.1128/mBio.01532-16], Katherine E. Bonnington and Meta J. Kuehn of Duke University’s Department of Biochemistry make a compelling case for considering how the molecular shapes of the various lipid A structural subtypes found in the outer membrane contribute to the process of outer membrane vesicle (OMV) formation.

Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental autoimmune uveitis.

To test the therapeutic effects of delayed treatment of mesenchymal stem cells (MSCs) in recurrent experimental autoimmune uveitis (rEAU). The efficacy of different regimens of MSC administration in rEAU were tested by evaluation of clinical and pathological intraocular inflammation, as well as retinal structural and functional integrity using optical coherence tomography (OCT) and electroretinogram (ERG). The retinal sections were also immunostained with antibodies to glial fibrillary acidic protein (GFAP) and rhodopsin (RHO). Delayed treatment of MSCs effectively alleviated the severity of intraocular inflammation with relative intact of outer retinal structure and function. Moreover, double therapies with longer interval led to an even better clinical evaluation, as well as a trend of decrease in relapse and amelioration of retinal function. MSC therapies also effectively reduced GFAP expression and increased RHO expression in the retina. MSC administration can effectively treat developed diseases of rEAU, and multiple therapies can provide additional therapeutic benefits.

Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity: Early Role for IL-1β

Retinopathy of prematurity (ROP), the most common cause of blindness in premature infants, has long been associated with inner retinal alterations. However, recent studies reveal outer retinal dysfunctions in patients formerly afflicted with ROP. We have recently demonstrated that choroidal involution occurs early in retinopathy. Herein, we investigated the mechanisms underlying the choroidal involution and its long-term impact on retinal function. An oxygen-induced retinopathy (OIR) model was used. Invitro and exvivo assays were applied to evaluate cytotoxic effects of IL-1β on choroidal endothelium. Electroretinogram was used to evaluate visual function. We found that proinflammatory IL-1β was markedly increased in retinal pigment epithelium (RPE)/choroid and positively correlated with choroidal degeneration in the early stages of retinopathy. IL-1β was found to be cytotoxic to choroid invitro, exvivo, and invivo. Long-term effects on choroidal involution included a hypoxic outer neuroretina, associated with a progressive loss of RPE and photoreceptors, and visual deterioration. Early inhibition of IL-1β receptor preserved choroid, decreased subretinal hypoxia, and prevented RPE/photoreceptor death, resulting in life-long improved visual function in IL-1 receptor antagonist-treated OIR animals. Together, these findings suggest a critical role for IL-1β-induced choroidal degeneration in outer retinal dysfunction. Neonatal therapy using IL-1 receptor antagonist preserves choroid and prevents protracted outer neuroretinal anomalies in OIR, suggesting IL-1β as a potential therapeutic target in ROP.

Identifying conductive conditions in neonates using wideband acoustic immittance

Wideband acoustic immittance (WAI) is an innovative method of middle ear assessment with significant advantages over currently available clinical tests. Previous large-scale studies in neonates have assessed accuracy against evoked otoacoustic emissions but further research is needed using a more stringent gold standard. The aim of this study was to evaluate the test performance of WAI in neonates against a composite reference standard consisting of distortion-product otoacoustic emissions (DPOAEs) and high-frequency tympanometry (HFT). Five hundred and five neonates were recruited from the maternity ward of the Townsville Hospital to participate in the study. DPOAEs and HFT were performed on each neonate to assess outer and middle ear function. Wideband absorbance and complex admittance (magnitude and phase) were measured from 226 to 8000 Hz in each neonate at ambient pressure using a click stimulus. Best separation between groups that passed and failed the reference standard occurred at frequencies from...

Minimizing Compositions of Functions Using Proximity Algorithms with Application in Image Deblurring

We consider minimization of functions that are compositions of functions having closed-form proximity operators with linear transforms. A wide range of image processing problems including image deblurring can be formulated in this way. We develop proximity algorithms based on the fixed point characterization of the solution to the minimization problems . We further refine the proposed algorithms when the outer functions of the composed objective functions are separable. The convergence analysis of the developed algorithms is established. Numerical experiments in comparison with the well-known Chambolle-Pock algorithm and Zhang-Burger-Osher scheme for image deblurring are given to demonstrate that the proposed algorithms are efficient and robust.

Unconventional high-Tc superconductivity in fullerides.

A3C60 molecular superconductors share a common electronic phase diagram with unconventional high-temperature superconductors such as the cuprates: superconductivity emerges from an antiferromagnetic strongly correlated Mott-insulating state upon tuning a parameter such as pressure (bandwidth control) accompanied by a dome-shaped dependence of the critical temperature, Tc However, unlike atom-based superconductors, the parent state from which superconductivity emerges solely by changing an electronic parameter-the overlap between the outer wave functions of the constituent molecules-is controlled by the C60 (3-) molecular electronic structure via the on-molecule Jahn-Teller effect influence of molecular geometry and spin state. Destruction of the parent Mott-Jahn-Teller state through chemical or physical pressurization yields an unconventional Jahn-Teller metal, where quasi-localized and itinerant electron behaviours coexist. Localized features gradually disappear with lattice contraction and conventional Fermi liquid behaviour is recovered. The nature of the underlying (correlated versus weak-coupling Bardeen-Cooper-Schrieffer theory) s-wave superconducting states mirrors the unconventional/conventional metal dichotomy: the highest superconducting critical temperature occurs at the crossover between Jahn-Teller and Fermi liquid metal when the Jahn-Teller distortion melts.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'.

Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.

PurposeTo assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.MethodsAlbino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections.ResultsA five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice.ConclusionsIntraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

Composite electron propagator methods for calculating ionization energies.

Accurate ionization energies of molecules may be determined efficiently with composite electron-propagator (CEP) techniques. These methods estimate the results of a calculation with an advanced correlation method and a large basis set by performing a series of more tractable calculations in which large basis sets are used with simpler approximations and small basis sets are paired with more demanding correlation techniques. The performance of several CEP methods, in which diagonal, second-order electron propagator results with large basis sets are combined with higher-order results obtained with smaller basis sets, has been tested for the ionization energies of closed-shell molecules from the G2 set. Useful compromises of accuracy and computational efficiency employ complete-basis-set extrapolation for second-order results and small basis sets in third-order, partial third-order, renormalized partial-third order, or outer valence Green's function calculations. Analysis of results for vertical as well as adiabatic ionization energies leads to specific recommendations on the best use of regular and composite methods. Results for 22 organic molecules of interest in the design of photovoltaic devices, benzo[a]pyrene, Mg-octaethylporphyrin, and C60 illustrate the capabilities of CEP methods for calculations on large molecules.

A Transposon Screen Identifies Genetic Determinants of Vibrio cholerae Resistance to High-Molecular-Weight Antibiotics

Gram-negative bacteria are notoriously resistant to a variety of high-molecular-weight antibiotics due to the limited permeability of their outer membrane (OM). The basis of OM barrier function and the genetic factors required for its maintenance remain incompletely understood. Here, we employed transposon insertion sequencing to identify genes required for Vibrio cholerae resistance to vancomycin and bacitracin, antibiotics that are thought to be too large to efficiently penetrate the OM. The screen yielded several genes whose protein products are predicted to participate in processes important for OM barrier functions and for biofilm formation. In addition, we identified a novel factor, designated vigA (for vancomycin inhibits growth), that has not previously been characterized or linked to outer membrane function. The vigA open reading frame (ORF) codes for an inner membrane protein, and in its absence, cells became highly sensitive to glycopeptide antibiotics (vancomycin and ramoplanin) and bacitracin but not to other large antibiotics or detergents. In contrast to wild-type (WT) cells, the vigA mutant was stained with fluorescent vancomycin. These observations suggest that VigA specifically prevents the periplasmic accumulation of certain large antibiotics without exerting a general role in the maintenance of OM integrity. We also observed marked interspecies variability in the susceptibilities of Gram-negative pathogens to glycopeptides and bacitracin. Collectively, our findings suggest that the OM barrier is not absolute but rather depends on specific OM-antibiotic interactions.