Gene therapy for corneal dystrophies and disease, where are we?

We assess studies on vector systems for delivery of transgenes to the cornea that have been published over the last year, and summarise new work on the identification of specific transgenes for corneal diseases. Recent findings Adeno-associated viral vectors (AAV) are increasingly being successfully applied to the cornea, although transgene expression requires corneal epithelial debridement, or intrastromal injection of the vector. Gene delivery platforms based on nanoparticles of chitosan or gold also show promise. Over-expression of vasoinhibin-1 or decorin, or siRNA-mediated blockade of the cannabinoid receptor CB1, can all reduce corneal neovascularization. Over-expression of decorin or matrix metalloproteinase 14 can reduce corneal fibrosis and haze, while over-expression of c-Met accelerates epithelial wound healing. Induction of corneal endothelial cell replication by over-expression of E2F2, p16 or p21 can maintain or even increase corneal endothelial cell density in eye bank corneas. Over-expression of the anti-apoptotic transgenes Bcl-xL or p35 significantly enhances corneal endothelial cell survival and reduces apoptosis in stored human corneas. Summary Despite a wealth of information on methods for the delivery of nucleic acids to the human cornea, and ever-increasing information transgenes with substantial therapeutic potential, gene therapy for corneal disorders has yet to reach the clinic.KAW is supported by the National Health & Medical Research Council of Australia

Coupled myosin VI motors facilitate unidirectional movement on an F-actin network

A combination of experimentation and modeling reveal that multiple myosin VI molecules coordinately transport cargo over the actin filament network

The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Adaptive Evolution of the Myo6 Gene in Old World Fruit Bats (Family: Pteropodidae)

PMCID: PMC3631194This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Sex-linked mating strategies diverge with a manipulation of genital salience

Trivers (Sexual selection and the descent of man, Aldine-Atherton, Chicago, pp 136–179, 1972) proposed that evolutionary factors should favor divergent mating strategies for males versus females. Such differences may be less pronounced among human beings than other animals and social norms and sex roles are also pertinent influences. The present experiment (N = 133 college undergraduates, 74 female) sought to bypass some of these other influences. Participants were randomly assigned to a condition designed to increase attention to the genital region (a downward pointing arrow) or not (an upward pointing arrow). They then reported on their interest in short-term (e.g., a one-night stand) and long-term (e.g., a potential marital partner) mating opportunities. A theory-consistent three-way interaction occurred such that the genital salience manipulation primed a shorter-term reproductive strategy among men and a longer-term reproductive strategy among women. The results provide unique support for evolution-linked ideas about sex differences in the form of a role for bodily attention

Kinetic properties and small-molecule inhibition of human myosin-6.

Myosin-6 is an actin-based motor protein that moves its cargo towards the minus-end of actin filaments. Mutations in the gene encoding the myosin-6 heavy chain and changes in the cellular abundance of the protein have been linked to hypertrophic cardiomyopathy, neurodegenerative diseases, and cancer. Here, we present a detailed kinetic characterization of the human myosin-6 motor domain, describe the effect of 2,4,6-triiodophenol on the interaction of myosin-6 with F-actin and nucleotides, and show how addition of the drug reduces the number of myosin-6-dependent vesicle fusion events at the plasma membrane during constitutive secretion

Parental and Grandparental Ages in the Autistic Spectrum Disorders: A Birth Cohort Study

Background: A number of studies have assessed ages of parents of children with autistic spectrum disorders (ASD), and reported both maternal and paternal age effects. Here we assess relationships with grandparental ages. Methods and Findings: We compared the parental and grandparental ages of children in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC), according to their scores in regard to 4 autistic trait measures and whether they had been given a diagnosis of ASD. Mean maternal and paternal ages of ASD cases were raised, but this appears to be secondary to a maternal grandmother age effect (P = 0.006): OR = 1.66[95%CI 1.16, 2.37] for each 10-year increase in the grandmother’s age at the birth of the mother. Trait measures also revealed an association between the maternal grandmother’s age and the major autistic trait–the Coherence Scale (regression coefficient b = 0.142, [95%CI = 0.057, 0.228]P = 0.001). After allowing for confounders the effect size increased to b = 0.217[95%CI 0.125, 0.308](P,0.001) for each 10 year increase in age. Conclusions: Although the relationship between maternal grandmother’s age and ASD and a major autistic trait was unexpected, there is some biological plausibility, for the maternal side at least, given that the timing of female meiosis I permits direct effects on the grandchild’s genome during the grandmother’s pregnancy. An alternative explanation is the meiotic mismatch methylation (3 M) hypothesis, presented here for the first time. Nevertheless the findings should b

Mate Value and Self-Esteem: Evidence from Eight Cultural Groups

This paper explores self-perceived mate value (SPMV), and its association with self-esteem, in eight cultures. 1066 participants, from 8 cultural groups in 7 countries, rated themselves on 24 SPMVs and completed a measure of self-esteem. Consistent with evolutionary theory, women were more likely to emphasise their caring and passionate romantic nature. In line with previous cross-cultural research, characteristics indicating passion and romance and social attractiveness were stressed more by respondents from individualistic cultures, and those higher on self-expression (rather than survival) values; characteristics indicative of maturity and confidence were more likely to be mentioned by those from Traditional, rather than Secular, cultures. Contrary to gender role theory, societal equality had only limited interactions with sex and SPMV, with honesty of greater significance for male self-esteem in societies with unequal gender roles. These results point to the importance of cultural and environmental factors in influencing self-perceived mate qualities, and are discussed in relation to broader debates about the impact of gender role equality on sex differences in personality and mating strategies