Current and emerging therapies for the treatment of age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in the industrialized world. In the last few decades, the mainstay of treatment for choroidal neovascularization (CNV) due to AMD has been thermal laser photocoagulation. In the last decade, photodynamic therapy with verteporfin extended treatment for more patients. While both of these treatments have prevented further vision loss in a subset of patients, improvement in visual acuity is rare. Anti-vascular endothelial growth factor A (VEGF) therapy has revolutionized the treatment of AMD-related CNV. Pegaptanib, an anti-VEGF aptamer prevents vision loss in CNV, although the performance is similar to that of photodynamic therapy. Ranibizumab, an antibody fragment and bevacizumab, a full-length humanized monoclonal antibody against VEGF have both shown promising results with improvements in visual acuity with either agent. VEGF trap, a modified soluble VEGF receptor analogue, binds VEGF more tightly than all other anti-VEGF agents and has also shown promising results in early trials. Other treatment strategies to decrease the effect of VEGF have used small interfering ribonucleic acid (RNA) to inhibit VEGF production and VEGF receptor production. Steroids, including anecortave acetate in the treatment and prevention of CNV, have shown promise in controlled trials. Receptor tyrosine kinase inhibitors, such as vatalanib, inhibit downstream effects of VEGF, and have been effective in the treatment of CNV in early studies. Squalamine lactate inhibits plasma membrane ion channels with downstream effects on VEGF, and has shown promising results with systemic administration. Other growth factors, including pigment epithelium-derived growth factor that has been administered via an adenoviral vector has shown promising initial results. In some patients ciliary neurotrophic factor is currently being studied for the inhibition of progression of geographic atrophy. Combination therapy has been investigated, and may prove to be more effective in the management of AMD-associated CNV. Ongoing and future studies will be crucial for optimizing the treatment of patients with AMD

“And it was all my choice but it didn’t feel like a choice”: a re-examination of interpretation of data using a ‘rhetoric of choice’ lens

This research aims to re-examine interpretations of data collected from second-time 2 mothers about their experiences of becoming a mother to a second child using lenses of 3 rhetoric of choice and choice feminism. The interpretations are reconsidered to identify 4 ways in which tensions between maternal status and researcher positionality have 5 influenced the ways they were reached. The paper describes two studies, each conducted 6 by one of the authors, and the interpretations of the data made at the time the research 7 was carried out. It discusses alternative interpretations and how they challenge both the 8 researcher role and theoretical explanations of gender inequity and attachment. The paper 9 concludes that feminist research can be strengthened by attending to the intersections 10 between maternal status, and positioning as feminist, woman and researche

Role of transcriptional regulation in the evolution of plant phenotype: A dynamic systems approach

© 2015 Wiley Periodicals, Inc. A growing body of evidence suggests that alterations in transcriptional regulation of genes involved in modulating development are an important part of phenotypic evolution, and this can be documented among species and within populations. While the effects of differential transcriptional regulation in organismal development have been preferentially studied in animal systems, this phenomenon has also been addressed in plants. In this review, we summarize evidence for cis-regulatory mutations, trans-regulatory changes and epigenetic modifications as molecular events underlying important phenotypic alterations, and thus shaping the evolution of plant development. We postulate that a mechanistic understanding of why such molecular alterations have a key role in development, morphology and evolution will have to rely on dynamic models of complex regulatory networks that consider the concerted action of genetic and nongenetic components, and that also incorporate the restrictions underlying the genotype to phenotype mapping process.CONACyT 180098, 180380, 167705, 152649 and PAPIIT UNAM IN203214-3, IN203113-3, IN203814-3. BFU2012–34821 (MINECO) to C.G. and an institutional grant from Fundación Ramón Aceres to CBMSOPeer Reviewe

Rescue of a porcine anellovirus (torque teno sus virus 2) from cloned genomic DNA in pigs

Anelloviruses are a group of single-stranded circular DNA viruses infecting humans and other animal species. Animal models combined with reverse genetic systems of anellovirus have not been developed. We report here the construction and initial characterization of full-length DNA clones of a porcine anellovirus, torque teno sus virus 2 (TTSuV2), in vitro and in vivo. We first demonstrated that five cell lines, including PK-15 cells, are free of TTSuV1 or TTSuV2 contamination, as determined by a real-time PCR and an immunofluorescence assay (IFA) using anti-TTSuV antibodies. Recombinant plasmids harboring monomeric or tandem-dimerized genomic DNA of TTSuV2 from the United States and Germany were constructed. Circular TTSuV2 genomic DNA with or without introduced genetic markers and tandem-dimerized TTSuV2 plasmids were transfected into PK-15 cells, respectively. Splicing of viral mRNAs was identified in transfected cells. Expression of TTSuV2-specific open reading frame 1 (ORF1) in cell nuclei, especially in nucleoli, was detected by IFA. However, evidence of productive TTSuV2 infection was not observed in 12 different cell lines transfected with the TTSuV2 DNA clones. Transfection with circular DNA from a TTSuV2 deletion mutant did not produce ORF1 protein, suggesting that the observed ORF1 expression is driven by TTSuV2 DNA replication in cells. Pigs inoculated with either the tandem-dimerized clones or circular genomic DNA of U.S. TTSuV2 developed viremia, and the introduced genetic markers were retained in viral DNA recovered from the sera of infected pigs. The availability of an infectious DNA clone of TTSuV2 will facilitate future study of porcine anellovirus pathogenesis and biology

Spatiotemporal inseparability of cortical motion mechanisms

Our broad objective is to establish the mechanisms responsible for motion selectivity in receptive fields (RFs) of striate cortical neurons in the cat, especially the order and nature of transformations leading to directional selectivity (DS). Examination of both RFs and models with briefly flashed single and double light and dark bars helps establish the advantage of 2-bar interaction-measurements for studying the separability between space and time in early filtering operations in the visual system. These early filters are usually smaller than a cortical RF, and form "subunits" of the RF that may or may not show latency variations across space. Such latency shifts define space-time inseparable subunits. We embed bars in a random "white-noise" stimulus to better explore negative response regions, and to compare linear and nonlinear measurements using the same stimulus. Two-bar interactions preserve inseparability at the expense of phase of the subunits tested. Here we develop a quantitative measure of space-time inseparability in subunits using singular value decomposition (SVD), and apply it to 2-bar subunit measurements of two competing models and of both DS simple and complex cells. SVD provides an estimate of the minimal number of temporal functions but not their actual shape. DS complex cells show evidence of multiple inseparable subunits, each with an early convergence of a small number of pre-cortical RFs with different time-course, probably only two. Subunits of DS simple cells are similar, except that noise masks possible additional temporal components. We propose a method for optimizing DS by balancing the variance in quadrature subunits. Finally, we demonstrate unforeseen consequences on separability from a common test in which only a partial superposition test is performed. Our finding of strong inseparability in cortical subunits argues against separable motion-opponent mechanisms. It also supports a nonlinear DS mechanism equivalent to the motion energy model, even in subunits of DS simple cells

Dependence of smoothness and velocity on cortical subunits

Our purpose is to discover the mechanisms responsible for smooth directional responses to moving bars in receptive fields (RFs) of striate cortical neurons in the cat, and to identify the components of the response that account for velocity selectivity. Responses across a RF to a flashing bar can reveal spatial and temporal asymmetries that agree with the preferred direction of bar movement. But here we show that linear superposition of these responses fails to explain the smoothness of the response in the preferred direction, the extent of directional selectivity (DS), and the selectivity for velocity of a moving bar. Our "white-noise" approach demonstrates that considering nonlinear interactions between pairs of positions as a bar moves through the RF is both necessary and nearly sufficient to account for these three response parameters. We offer an effective shortcut-measure of velocity selectivity that depends only on our standard measure of 2-bar interactions, the "motion kernel". To further examine the properties of this nonlinear mechanism, we compare nonlinear interactions in three dimensions between a DS neuron and a model of a single-subunit RF. Differences indicate that nonlinear interactions in real DS neurons reside in a family of overlapping subunits that are distributed across the RF. This major DS mechanism computes "motion energy", and differs little between simple and complex cortical neurons