Roth spots in a Rendu-Osler-Weber syndrome.

PURPOSE: To describe the molecular diagnosis and atypical ocular presentation of a patient who suffered for a Rendu-Osler-Weber syndrome associated with juvenile polyposis (JP) syndrome. METHODS: This is a case report of a patient that underwent fundus examen, brain Magnetic Resonance Imaging (MRI) and arteriography. Genetic testing was performed by next-generation-sequencing (NGS). RESULTS: A 35-year-old woman presented with right hemiplegia with right homonymous lateral hemianopia and homolateral complete sensory deficit. She also had Roth spots in her left fundus. Genetic testing revealed a pathogenic variation in the heterozygous state in the SMAD-4 gene (c.1245_1248del). CONCLUSION: Hereditary Hemorrhagic Telangiectasia (HTT) also known as Rendu-Osler-Weber syndrome is a rare autosomal dominant disease which reveals mostly with epistaxis and cutaneous telangiectasias. Our clinical case reports Roth spots in the context of HTT associated with juvenile polyposis syndrome. SMAD-4 mutation may explain the presence of a carotid-ophthalmic aneurysm which is not a lesion usually found in HTT.

Increased intravitreal glucose in rhegmatogenous retinal detachment.

PURPOSE: Altered glucose metabolism, along with low-grade inflammation, has been proposed to be involved in retinal detachment (RD)-induced cone loss. Here, we assessed intravitreal glucose and cytological profile in patients with macula-off RD. METHODS: Glucose concentration was analysed in vitreous samples from 137 non-diabetic patients undergoing vitrectomy for either primary macula-off RD (n = 73) or epiretinal membrane (ERM; n = 64). Cellularity was assessed in vitreous cytospin preparations by a semi-quantitative immunostaining approach. RESULTS: Intravitreal glucose concentration was higher in the RD group (2.28 mmol.L-1 n =73 vs 1.6 mmol.L-1 n = 64; p < 0.0001). Overall cellularity and density of macrophages were significantly higher in the vitreous of RD patients (respectively p = 0.003 and p < 0.0001). Among the RD patients, intravitreal glucose concentration correlated with macrophages density (p = 0.002): its levels remained significantly higher in eyes in which macrophages were innumerable compared to lower macrophages densities RD eyes (p = 0.0095). CONCLUSIONS: We observed a strong relationship between intravitreal glucose concentration and vitreous macrophage density. Additional indicators for vitreous glycation and low-grade inflammation should be further studied.

Preservation of exopolymeric substances in estuarine sediments.

The surface of intertidal estuarine sediments is covered with diatom biofilms excreting exopolymeric substances (EPSs) through photosynthesis. These EPSs are highly reactive and increase sediment cohesiveness notably through organo-mineral interactions. In most sedimentary environments, EPSs are partly to fully degraded by heterotrophic bacteria in the uppermost millimeters of the sediment and so they are thought to be virtually absent deeper in the sedimentary column. Here, we present the first evidence of the preservation of EPSs and EPS-mineral aggregates in a 6-m-long sedimentary core obtained from an estuarine point bar in the Gironde Estuary. EPSs were extracted from 18 depth intervals along the core, and their physicochemical properties were characterized by (i) wet chemical assays to measure the concentrations of polysaccharides and proteins, and EPS deprotonation of functional groups, (ii) acid-base titrations, and (iii) Fourier transform infrared spectroscopy. EPS-sediment complexes were also imaged using cryo-scanning electron microscopy. EPS results were analyzed in the context of sediment properties including facies, grain size, and total organic carbon, and of metabolic and enzymatic activities. Our results showed a predictable decrease in EPS concentrations (proteins and polysaccharides) and reactivity from the surface biofilm to a depth of 0.5 m, possibly linked to heterotrophic degradation. Concentrations remained relatively low down to ca. 4.3 m deep. Surprisingly, at that depth EPSs abundance was comparable to the surface and showed a downward decrease to 6.08 m. cryo-scanning electron microscopy (Cryo-SEM) showed that the EPS complexes with sediment were abundant at all studied depth and potentially protected EPSs from degradation. EPS composition did not change substantially from the surface to the bottom of the core. EPS concentrations and acidity were anti-correlated with metabolic activity, but showed no statistical correlation with grain size, TOC, depth or enzymatic activity. Maximum EPS concentrations were found at the top of tide-dominated sedimentary sequences, and very low concentrations were found in river flood-dominated sedimentary sequences. Based on this observation, we propose a scenario where biofilm development and EPS production are maximal when (i) the point bar and the intertidal areas were the most extensive, i.e., tide-dominated sequences and (ii) the tide-dominated deposit were succeeded by rapid burial beneath sediments, potentially decreasing the probability of encounter between bacterial cells and EPSs.

Latent space of a small genetic network: Geometry of dynamics and information.

The high-dimensional character of most biological systems presents genuine challenges for modeling and prediction. Here we propose a neural network-based approach for dimensionality reduction and analysis of biological gene expression data, using, as a case study, a well-known genetic network in the early Drosophila embryo, the gap gene patterning system. We build an autoencoder compressing the dynamics of spatial gap gene expression into a two-dimensional (2D) latent map. The resulting 2D dynamics suggests an almost linear model, with a small bare set of essential interactions. Maternally defined spatial modes control gap genes positioning, without the classically assumed intricate set of repressive gap gene interactions. This, surprisingly, predicts minimal changes of neighboring gap domains when knocking out gap genes, consistent with previous observations. Latent space geometries in maternal mutants are also consistent with the existence of such spatial modes. Finally, we show how positional information is well defined and interpretable as a polar angle in latent space. Our work illustrates how optimization of small neural networks on medium-sized biological datasets is sufficiently informative to capture essential underlying mechanisms of network function.

Comparing Heads-Up versus Binocular Microscope Visualization Systems in Anterior and Posterior Segment Surgeries: A Retrospective Study.

BACKGROUND: Three-dimensional (3D) visualization systems, also known as heads-up systems, are now available for eye surgery and as with every new device there is need for a specific evaluation. OBJECTIVES: The aim of this study was to compare the efficiency, surgical comfort, and safety of a 3D visualization system to a standard binocular microscope (BM) in routine ophthalmologic procedures. METHOD: After a 4-week training period, a 3D visualization system (Ngenuity, Alcon®) available in one of the Robert Debré Hospital Ophthalmology Departments' operating rooms was compared to a standard BM (OPMI LUMIRA 700, Zeiss®), in the process of a call for new device evaluation. From December 2017 to March 2018, 5 surgeons and their respective residents were asked to fill in a questionnaire for all procedures. Before the surgery, the surgeon recorded: (i) the type of surgery (cataract [PK], retinal detachment [RD], epiretinal membrane peeling [ERM], macular hole, vitreous haemorrhage [VH]), (ii) the type of visualization system chosen (3D or BM), and (iii) the estimated surgical risk (low, intermediate, or high grade). At the end of the procedure, the primary surgeon recorded the remaining parameters, including: (i) surgery duration, (ii) intraoperative complications, (iii) percentage of endoillumination for posterior segment surgeries, (iv) status of the operator (senior or resident) and operator switch if necessary (senior only, resident only, or resident with help of the senior), and rated: (i) the visual comfort (low, normal, excellent), (ii) the operative fluency (low, normal, excellent), (iii) backaches (none, low, moderate, important), and (iv) headaches (range from 0 to 10). Age and sex were collected retrospectively. The procedures performed with 3D and BM were subsequently compared using univariate (χ2, Fisher, Wilcoxon) and multivariate analysis (generalized linear model), allowing us to identify parameters independently associated with PK surgery duration. RESULTS: A total of 102 valid questionnaires, relative to 73 PK and 29 vitreoretinal procedures, respectively, were analysed. As regards PK (3D, n = 25 vs. BM, n = 48), the mean age, sex ratio, surgical risk, intraoperative complications (1/25 vs. 4/48), visual comfort, backaches, and headaches were similar between the two systems. The use of 3D allowed faster PK surgeries (16.44 ± 4.36 vs. 21.44 ± 7.50 min; p = 0.007) and slightly enhanced the operative fluency. In vitreoretinal surgeries (3D, n = 14 vs. BM, n = 15), no obvious differences between the two visualization systems were observed, although the use of the 3D system was found to slightly decrease the operative fluency. Parameters independently associated with PK surgery duration were 3D visualization (ß = -4.4 ± 1.4; p = 0.002), high preoperative surgical risk (ß = 6.2 ± 2.4; p = 0.012), intraoperative complications (ß = 8.7 ± 2.6; p = 0.001), and surgeon status (ß = -4.4 ± 1.3; p = 0.001) in univariate and multivariate analysis. CONCLUSIONS: 3D visualization can be safely used in routine practice. It slightly improves the operative fluency, allowing faster PK surgery.

Modelling Time-Dependent Acquisition of Positional Information.

Theoretical and computational modelling are crucial to understand dynamics of embryonic development. In this tutorial chapter, we describe two models of gene networks performing time-dependent acquisition of positional information under control of a dynamic morphogen: a toy-model of a bistable gene under control of a morphogen, allowing for the numerical computation of a simple Waddington's epigenetic landscape, and a recently published model of gap genes in Tribolium under control of multiple enhancers. We present detailed commented implementations of the models using python and jupyter notebooks.

φ-evo: A program to evolve phenotypic models of biological networks.

Molecular networks are at the core of most cellular decisions, but are often difficult to comprehend. Reverse engineering of network architecture from their functions has proved fruitful to classify and predict the structure and function of molecular networks, suggesting new experimental tests and biological predictions. We present φ-evo, an open-source program to evolve in silico phenotypic networks performing a given biological function. We include implementations for evolution of biochemical adaptation, adaptive sorting for immune recognition, metazoan development (somitogenesis, hox patterning), as well as Pareto evolution. We detail the program architecture based on C, Python 3, and a Jupyter interface for project configuration and network analysis. We illustrate the predictive power of φ-evo by first recovering the asymmetrical structure of the lac operon regulation from an objective function with symmetrical constraints. Second, we use the problem of hox-like embryonic patterning to show how a single effective fitness can emerge from multi-objective (Pareto) evolution. φ-evo provides an efficient approach and user-friendly interface for the phenotypic prediction of networks and the numerical study of evolution itself.

CD160 Expression in Retinal Vessels Is Associated With Retinal Neovascular Diseases.

Purpose: Anti-angiogenic agents stand first in the treatment of neovascular diseases of the retina. CD160 appeared in several experimental studies as a marker of activated endothelial cells, suggesting it could represent a promising target for novel anti-angiogenic therapies. The aim of the present study was to assess the distribution of CD160 in the human eye, and to search for a possible correlation with retinal neovascular diseases. Methods: The physiological distribution of CD160 in the normal eye was assessed with immunolabeling in 10 human donor eyes. Then, in a retrospective cohort of 75 surgical retinal specimens, the density of CD160+ microvessels was evaluated, along with immunolabeling on serial sections against ERG (pan-endothelial cell marker), CD105 (activated endothelial cell marker), and α-SMA (pericyte cell marker). The cohort was divided into two groups: 29 patients with neovascular disease (NV+) and 46 control patients (NV-). Results: CD160 was physiologically expressed by several cell types: endothelial cells of retinal blood vessels, ganglion cells, macrophages, epithelial cells of the conjunctiva, ciliary body, and retinal pigment epithelium. In the patient cohort, the percentage of CD160+ vessels in the retina was significantly and independently higher in patients suffering from neovascular diseases (P = 0.04). On the contrary, the expression of CD105 was correlated neither with retinal neovascular diseases, nor with CD160 expression. Conclusions: CD160 was expressed in some retinal vessels in both normal and pathologic eyes. CD160 expression by endothelial cells of retinal vessels was correlated with ocular neovascular diseases. CD160 could therefore represent an interesting target for novel anti-angiogenic therapies.

Short relaxation times but long transient times in both simple and complex reaction networks.

When relaxation towards an equilibrium or steady state is exponential at large times, one usually considers that the associated relaxation time τ, i.e. the inverse of the decay rate, is the longest characteristic time in the system. However, that need not be true, other times such as the lifetime of an infinitesimal perturbation can be much longer. In the present work, we demonstrate that this paradoxical property can arise even in quite simple systems such as a linear chain of reactions obeying mass action (MA) kinetics. By mathematical analysis of simple reaction networks, we pin-point the reason why the standard relaxation time does not provide relevant information on the potentially long transient times of typical infinitesimal perturbations. Overall, we consider four characteristic times and study their behaviour in both simple linear chains and in more complex reaction networks taken from the publicly available database 'Biomodels'. In all these systems, whether involving MA rates, Michaelis-Menten reversible kinetics, or phenomenological laws for reaction rates, we find that the characteristic times corresponding to lifetimes of tracers and of concentration perturbations can be significantly longer than τ.

Has your ancient stamp been regummed with synthetic glue? A FT-NIR and FT-Raman study.

The potential of FT-NIR and FT-Raman spectroscopies to characterise the gum applied on the backside of ancient stamps was investigated for the first time. This represents a very critical issue for the collectors' market, since gum conditions heavily influence stamp quotations, and fraudulent application of synthetic gum onto damaged stamp backsides to increase their desirability is a well-documented practice. Spectral data were processed by exploratory pattern recognition tools. In particular, application of principal component analysis (PCA) revealed that both of the spectroscopic techniques provide information useful to characterise stamp gum. Examination of PCA loadings and their chemical interpretation confirmed the robustness of the outcomes. Fusion of FT-NIR and FT-Raman spectral data was performed, following both a low-level and a mid-level procedure. The results were critically compared with those obtained separately for the two spectroscopic techniques.

Network function shapes network structure: the case of the Arabidopsis flower organ specification genetic network.

The reconstruction of many biological networks has allowed detailed studies of their structural properties. Several features exhibited by these networks have been interpreted to be the result of evolutionary dynamics. For instance the degree distributions may follow from a preferential attachment of new genes to older ones during evolution. Here we argue that even in the absence of any evolutionary dynamics, the presence of atypical features may follow from the fact that the network implements certain functions. To examine this network function shapes network structure scenario, we focus on the Arabidopsis genetic network controlling early flower organogenesis in which gene expression dynamics has been modelled using a Boolean framework. Specifically, for a system with 15 master genes, the phenotype consists of 10 experimentally determined steady-state expression patterns, considered here as the functional constraints on the network. The space of genetic networks satisfying these constraints is sometimes referred to as the neutral or genotype network. We sample this space using Markov Chain Monte Carlo which allows us to demonstrate how the functional (phenotypic) constraints shape the gene network structure. We find that this shaping is strongest for the edge (interaction) usage, with effects that are functionally interpretable. In contrast, higher order features such as degree assortativity and network motifs are hardly shaped by the phenotypic constraints.

Short-time growth of a Kardar-Parisi-Zhang interface with flat initial conditions.

The short-time behavior of the (1+1)-dimensional Kardar-Parisi-Zhang (KPZ) growth equation with a flat initial condition is obtained from the exact expressions for the moments of the partition function of a directed polymer with one end point free and the other fixed. From these expressions, the short-time expansions of the lowest cumulants of the KPZ height field are exactly derived. The results for these two classes of cumulants are checked in high-precision lattice numerical simulations. The short-time limit considered here is relevant for the study of the interface growth in the large-diffusivity or weak-noise limit and describes the universal crossover between the Edwards-Wilkinson and the KPZ universality classes for an initially flat interface.

Efficient gene targeting mediated by a lentiviral vector-associated meganuclease.

Gene targeting can be achieved with lentiviral vectors delivering donor sequences along with a nuclease that creates a locus-specific double-strand break (DSB). Therapeutic applications of this system would require an appropriate control of the amount of endonuclease delivered to the target cells, and potentially toxic sustained expression must be avoided. Here, we show that the nuclease can be transferred into cells as a protein associated with a lentiviral vector particle. I-SceI, a prototypic meganuclease from yeast, was incorporated into the virions as a fusion with Vpr, an HIV accessory protein. Integration-deficient lentiviral vectors containing the donor sequences and the I-SceI fusion protein were tested in reporter cells in which targeting events were scored by the repair of a puromycin resistance gene. Molecular analysis of the targeted locus indicated a 2-fold higher frequency of the expected recombination event when the nuclease was delivered as a protein rather than encoded by a separate vector. In both systems, a proportion of clones displayed multiple integrated copies of the donor sequences, either as tandems at the targeted locus or at unrelated loci. These integration patterns were dependent upon the mode of meganuclease delivery, suggesting distinct recombination processes.