Opticin: a potent anti-angiogenic/antiproliferative agent for breast cancer therapy

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Spatial distribution of metabolites in the retina and its relevance to studies of metabolic retinal disorders

Introduction: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. Objectives: To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina. Methods: We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina. Results: Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific. Conclusions: The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity

A Family of Maximum Margin Criterion for Adaptive Learning

In recent years, pattern analysis plays an important role in data mining and recognition, and many variants have been proposed to handle complicated scenarios. In the literature, it has been quite familiar with high dimensionality of data samples, but either such characteristics or large data have become usual sense in real-world applications. In this work, an improved maximum margin criterion (MMC) method is introduced firstly. With the new definition of MMC, several variants of MMC, including random MMC, layered MMC, 2D^2 MMC, are designed to make adaptive learning applicable. Particularly, the MMC network is developed to learn deep features of images in light of simple deep networks. Experimental results on a diversity of data sets demonstrate the discriminant ability of proposed MMC methods are compenent to be adopted in complicated application scenarios.Comment: 14 page

Intravitreal administration of recombinant human opticin protects against hyperoxia-induced pre-retinal neovascularization

Opticin is an extracellular glycoprotein present in the vitreous. Its antiangiogenic properties offer the potential for therapeutic intervention in conditions such as proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the hypothesis that intravitreal administration of recombinant human opticin can safely protect against the development of pathological angiogenesis and promote its regression. We generated and purified recombinant human opticin and investigated its impact on the development and regression of pathological retinal neovascularization following intravitreal administration in murine oxygen-induced retinopathy. We also investigated its effect on normal retinal vascular development and function, following intravitreal injection in neonatal mice, by histological examination and electroretinography. In oxygen-induced retinopathy, intravitreal administration of human recombinant opticin protected against the development of retinal neovascularization to similar extent as aflibercept, which targets VEGF. Opticin also accelerated regression of established retinal neovascularization, though the effect at 18 h was less than that of aflibercept. Intravitreal administration of human recombinant opticin in neonatal mice caused no detectable perturbation of subsequent retinal vascular development or function. In summary we found that intraocular administration of recombinant human opticin protects against the development of pathological angiogenesis in mice and promotes its regression

Age and Smoking Related Changes in Metal Ion Levels in Human Lens: Implications for Cataract Formation

Age-related cataract formation is the primary cause of blindness worldwide and although treatable by surgical removal of the lens the majority of sufferers have neither the finances nor access to the medical facilities required. Therefore, a better understanding of the pathogenesis of cataract may identify new therapeutic targets to prevent or slow its progression. Cataract incidence is strongly correlated with age and cigarette smoking, factors that are often associated with accumulation of metal ions in other tissues. Therefore this study evaluated the age-related changes in 14 metal ions in 32 post mortem human lenses without known cataract from donors of 11 to 82 years of age by inductively coupled plasma mass spectrometry; smoking-related changes in 10 smokers verses 14 non-smokers were also analysed. A significant age-related increase in selenium and decrease in copper ions was observed for the first time in the lens tissue, where cadmium ion levels were also increased as has been seen previously. Aluminium and vanadium ions were found to be increased in smokers compared to non-smokers (an analysis that has only been carried out before in lenses with cataract). These changes in metal ions, i.e. that occur as a consequence of normal ageing and of smoking, could contribute to cataract formation via induction of oxidative stress pathways, modulation of extracellular matrix structure/function and cellular toxicity. Thus, this study has identified novel changes in metal ions in human lens that could potentially drive the pathology of cataract formation

Manifold Elastic Net: A Unified Framework for Sparse Dimension Reduction

It is difficult to find the optimal sparse solution of a manifold learning based dimensionality reduction algorithm. The lasso or the elastic net penalized manifold learning based dimensionality reduction is not directly a lasso penalized least square problem and thus the least angle regression (LARS) (Efron et al. \cite{LARS}), one of the most popular algorithms in sparse learning, cannot be applied. Therefore, most current approaches take indirect ways or have strict settings, which can be inconvenient for applications. In this paper, we proposed the manifold elastic net or MEN for short. MEN incorporates the merits of both the manifold learning based dimensionality reduction and the sparse learning based dimensionality reduction. By using a series of equivalent transformations, we show MEN is equivalent to the lasso penalized least square problem and thus LARS is adopted to obtain the optimal sparse solution of MEN. In particular, MEN has the following advantages for subsequent classification: 1) the local geometry of samples is well preserved for low dimensional data representation, 2) both the margin maximization and the classification error minimization are considered for sparse projection calculation, 3) the projection matrix of MEN improves the parsimony in computation, 4) the elastic net penalty reduces the over-fitting problem, and 5) the projection matrix of MEN can be interpreted psychologically and physiologically. Experimental evidence on face recognition over various popular datasets suggests that MEN is superior to top level dimensionality reduction algorithms.Comment: 33 pages, 12 figure

Characterization of digital medical images utilizing support vector machines

BACKGROUND: In this paper we discuss an efficient methodology for the image analysis and characterization of digital images containing skin lesions using Support Vector Machines and present the results of a preliminary study. METHODS: The methodology is based on the support vector machines algorithm for data classification and it has been applied to the problem of the recognition of malignant melanoma versus dysplastic naevus. Border and colour based features were extracted from digital images of skin lesions acquired under reproducible conditions, using basic image processing techniques. Two alternative classification methods, the statistical discriminant analysis and the application of neural networks were also applied to the same problem and the results are compared. RESULTS: The SVM (Support Vector Machines) algorithm performed quite well achieving 94.1% correct classification, which is better than the performance of the other two classification methodologies. The method of discriminant analysis classified correctly 88% of cases (71% of Malignant Melanoma and 100% of Dysplastic Naevi), while the neural networks performed approximately the same. CONCLUSION: The use of a computer-based system, like the one described in this paper, is intended to avoid human subjectivity and to perform specific tasks according to a number of criteria. However the presence of an expert dermatologist is considered necessary for the overall visual assessment of the skin lesion and the final diagnosis

Bluetongue Virus Serotype 1 Outbreak in the Basque Country (Northern Spain) 2007–2008. Data Support a Primary Vector Windborne Transport

BACKGROUND: Bluetongue (BT) is a vector-borne disease of ruminants that has expanded its traditional global distribution in the last decade. Recently, BTV-1 emerged in Southern Spain and caused several outbreaks in livestock reaching the north of the country. The aim of this paper was to review the emergence of BTV-1 in the Basque Country (Northern Spain) during 2007 and 2008 analyzing the possibility that infected Culicoides were introduced into Basque Country by winds from the infected areas of Southern Spain. METHODOLOGY/PRINCIPAL FINDINGS: We use a complex HYSPLIT (Hybrid Single-Particle Lagrangian Integrated Trajectory) model to draw wind roses and backward wind trajectories. The analysis of winds showed September 28 to October 2 as the only period for the introduction of infected midges in the Basque Country. These wind trajectories crossed through the areas affected by serotype 1 on those dates in the South of the Iberian Peninsula. Additionally meteorological data, including wind speed and humidity, and altitude along the trajectories showed suitable conditions for Culicoides survival and dispersion. CONCLUSIONS/SIGNIFICANCE: An active infection in medium-long distance regions, wind with suitable speed, altitude and trajectory, and appropriate weather can lead to outbreaks of BTV-1 by transport of Culicoides imicola, not only over the sea (as reported previously) but also over the land. This shows that an additional factor has to be taken into account for the control of the disease which is currently essentially based on the assumption that midges will only spread the virus in a series of short hops. Moreover, the epidemiological and serological data cannot rule out the involvement of other Culicoides species in the spread of the infection, especially at a local level

Loss-of-function mutations in the CFH gene affecting alternatively encoded Factor H-like 1 protein cause dominant early-onset macular drusen

Purpose: To characterise the molecular mechanism underpinning early-onset macular drusen (EOMD), a phenotypically severe sub-type of age-related macular degeneration (AMD), in a sub-group of patients. Design: Multi-centre case series, in vitro experimentation and retrospective analysis of previously reported variants. Participants: Seven families with apparently autosomal dominant EOMD. Methods: Patients underwent comprehensive ophthalmic assessment. Affected individuals from families A, B and E underwent whole exome sequencing. The probands from families C, D, F and G underwent Sanger sequencing analysis of the Complement Factor H (CFH) gene. Mutant recombinant Factor H Like-1 (FHL-1) proteins were expressed in HEK293 cells to assess the impact on FHL-1 expression and function. Previously reported EOMD-causing variants in CFH were reviewed. Main Outcome Measures: Detailed clinical phenotypes, genomic findings, in vitro characterization of mutation effect on protein function, and postulation of the pathomechanism underpinning EOMD. Results: All affected participants presented with bilateral drusen. The earliest reported age of onset was 16 years with a median of 46 years). Ultra-rare (MAF ≤0.0001) CFH variants were identified as the cause of disease in each family: CFH c.1243del, p.(Ala415ProfsTer39) het; c.350+1G>T het; c.619+1G>A het, c.380G>A, p.(Arg127His) het; c.694C>T p.(Arg232Ter)het [identified in two unrelated families in this cohort]; and c.1291T>A, p.(Cys431Ser). All mutations affect complement control protein domains (CCP) 2-7, thus are predicted to impact both FHL-1, the predominant isoform in Bruch’s membrane(BrM) of the macula, and FH. In vitro analysis of recombinant proteins FHL-1R127H, FHL-1A415f/s and FHL-1C431S demonstrated that they are not secreted and thus are loss-of-function. Intra-cellular expression of mutant proteins was low, suggesting they may be rapidly degraded due to protein unfolding or instability. Review of 29 previously reported EOMD-causing mutations found that 75.8% (22/29) of impact FHL-1 and FH. In total, 86.2% (25/29) EOMD-associated variants cause haploinsufficiency of FH/FHL-1. Conclusions: EOMD is an under-recognised, phenotypically severe sub-type of AMD. We propose that haploinsufficiency of FHL-1, the main regulator of the complement pathway in BrM, where drusen develop, is an important mechanism underpinning the development of EOMD in a number of cases. Understanding the molecular basis of EOMD will shed light on AMD pathogenesis given their pathological similarities

Speaker Sex Perception from Spontaneous and Volitional Nonverbal Vocalizations.

In two experiments, we explore how speaker sex recognition is affected by vocal flexibility, introduced by volitional and spontaneous vocalizations. In Experiment 1, participants judged speaker sex from two spontaneous vocalizations, laughter and crying, and volitionally produced vowels. Striking effects of speaker sex emerged: For male vocalizations, listeners' performance was significantly impaired for spontaneous vocalizations (laughter and crying) compared to a volitional baseline (repeated vowels), a pattern that was also reflected in longer reaction times for spontaneous vocalizations. Further, performance was less accurate for laughter than crying. For female vocalizations, a different pattern emerged. In Experiment 2, we largely replicated the findings of Experiment 1 using spontaneous laughter, volitional laughter and (volitional) vowels: here, performance for male vocalizations was impaired for spontaneous laughter compared to both volitional laughter and vowels, providing further evidence that differences in volitional control over vocal production may modulate our ability to accurately perceive speaker sex from vocal signals. For both experiments, acoustic analyses showed relationships between stimulus fundamental frequency (F0) and the participants' responses. The higher the F0 of a vocal signal, the more likely listeners were to perceive a vocalization as being produced by a female speaker, an effect that was more pronounced for vocalizations produced by males. We discuss the results in terms of the availability of salient acoustic cues across different vocalizations