Transcriptome changes in age-related macular degeneration

Age-related macular degeneration (AMD) is a debilitating, common cause of visual impairment. While the last decade has seen great progress in understanding the pathophysiology of AMD, the molecular changes that occur in eyes with AMD are still poorly understood. In the current issue of Genome Medicine, Newman and colleagues present the first systematic transcriptional profile analysis of AMD-affected tissues, providing a comprehensive set of expression data for different regions (macula versus periphery), tissues (retina versus retinal pigment epithelium (RPE)/choroid), and disease state (control versus early or advanced AMD). Their findings will serve as a foundation for additional systems-level research into the pathogenesis of this blinding disease

The ERCC6 Gene and Age-Related Macular Degeneration

Background: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. Methodology/Principal Findings: Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P = 0.018). Conclusions/Significance: Our meta analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants

Overexpression of HTRA1 Leads to Ultrastructural Changes in the Elastic Layer of Bruch's Membrane via Cleavage of Extracellular Matrix Components

Variants in the chromosomal region 10q26 are strongly associated with an increased risk for age-related macular degeneration (AMD). Two potential AMD genes are located in this region: ARMS2 and HTRA1 (high-temperature requirement A1). Previous studies have suggested that polymorphisms in the promotor region of HTRA1 result in overexpression of HTRA1 protein. This study investigated the role of HTRA1 overexpression in the pathogenesis of AMD. Transgenic Htra1 mice overexpressing the murine protein in the retinal pigment epithelium (RPE) layer of the retina were generated and characterized by transmission electron microscopy, immunofluorescence staining and Western Blot analysis. The elastic layer of Bruch's membrane (BM) in the Htra1 transgenic mice was fragmented and less continuous than in wild type (WT) controls. Recombinant HTRA1 lacking the N-terminal domain cleaved various extracellular matrix (ECM) proteins. Subsequent Western Blot analysis revealed an overexpression of fibronectin fragments and a reduction of fibulin 5 and tropoelastin in the RPE/choroid layer in transgenic mice compared to WT. Fibulin 5 is essential for elastogenesis by promoting elastic fiber assembly and maturation. Taken together, our data implicate that HTRA1 overexpression leads to an altered elastogenesis in BM through fibulin 5 cleavage. It highlights the importance of ECM related proteins in the development of AMD and links HTRA1 to other AMD risk genes such as fibulin 5, fibulin 6, ARMS2 and TIMP3

Compositional analysis of bacterial communities in seawater, sediment, and sponges in the Misool coral reef system, Indonesia

Sponge species have been deemed high microbial abundance (HMA) or low microbial abundance (LMA) based on the composition and abundance of their microbial symbionts. In the present study, we evaluated the richness and composition of bacterial communities associated with one HMA sponge (Xestospongia testudinaria; Demospongiae: Haplosclerida: Petrosiidae), one LMA sponge (Stylissa carteri; Demospongiae: Scopalinida - Scopalinidae), and one sponge with a hitherto unknown microbial community (Aaptos suberitoides; Demospongiae: Suberitida: Suberitidae) inhabiting the Misool coral reef system in the West Papua province of Indonesia. The bacterial communities of these sponge species were also compared with seawater and sediment bacterial communities from the same coastal coral reef habitat. Using a 16S rRNA gene barcoded pyrosequencing approach, we showed that the most abundant phylum overall was Proteobacteria. The biotope (sponge species, sediment or seawater) explained almost 84% of the variation in bacterial composition with highly significant differences in composition among biotopes and a clear separation between bacterial communities from seawater and S. carteri; X. testudinaria and A. suberitoides and sediment. The Chloroflexi classes SAR202 and Anaerolineae were most abundant in A. suberitoides and X. testudinaria and both of these species shared several OTUs that were largely absent in the remaining biotopes. This suggests that A. suberitoides is a HMA sponge. Although similar, the bacterial communities of S. carteri and seawater were compositionally distinct. These results confirm compositional differences between sponge and non-sponge biotopes and between HMA and LMA sponges.publishe

Harnessing the potential of ligninolytic enzymes for lignocellulosic biomass pretreatment

Abundant lignocellulosic biomass from various industries provides a great potential feedstock for the production of value-added products such as biofuel, animal feed, and paper pulping. However, low yield of sugar obtained from lignocellulosic hydrolysate is usually due to the presence of lignin that acts as a protective barrier for cellulose and thus restricts the accessibility of the enzyme to work on the cellulosic component. This review focuses on the significance of biological pretreatment specifically using ligninolytic enzymes as an alternative method apart from the conventional physical and chemical pretreatment. Different modes of biological pretreatment are discussed in this paper which is based on (i) fungal pretreatment where fungi mycelia colonise and directly attack the substrate by releasing ligninolytic enzymes and (ii) enzymatic pretreatment using ligninolytic enzymes to counter the drawbacks of fungal pretreatment. This review also discusses the important factors of biological pretreatment using ligninolytic enzymes such as nature of the lignocellulosic biomass, pH, temperature, presence of mediator, oxygen, and surfactant during the biodelignification process

Performance and nutrient utilisation of dairy cows offered silages produced from three successive harvests of either a red clover–perennial ryegrass sward or a perennial ryegrass sward

The need to reduce reliance on imported protein feeds within the UK and Ireland has stimulated interest in locally grown forage legume crops, including red clover (Trifolium pratense L.). This 13-wk study examined the performance of 28 dairy cows offered silages produced from three successive harvests (H) of either a pure grass sward (GS) receiving 315 kg N/ha per annum or a red clover–perennial ryegrass sward (RCGS) receiving 22 kg N/ha per annum. The crops of H1, H2 and H3 were wilted for 48, 72 and 72 h, respectively. Silages from H1, H2 and H3 were offered for 5, 5 and 3 wk, respectively, with cows supplemented with 8.0 kg concentrate/d throughout the experiment. Digestibility of DM and the effectively degradable protein content were lower, while protein degradability was higher, for RCGS than for GS. Silage DM intakes (DMIs) were higher for RCGS than for GS at H1 and H2, with no differences at H3. Milk yield was higher with RCGS than with GS at H3, with no differences at H1 and H2. Milk fat and milk protein contents were lower with RCGS than with GS at H3 but did not differ at H1 and H2. Faecal N/N intake was higher in the RCGS group than in the GS group at H1, with no differences at H2 and H3. Gross energy digestibility was lower for RCGS than for GS at H2. Although cow performance was higher with RCGS treatment, the responses were variable between harvests, largely reflecting the changing proportion of RC in the swards as the season progresse

Implications of various effort-sharing approaches for national carbon budgets and emission pathways

The bottom-up approach of the Nationally Determined Contributions (NDCs) in the Paris Agreement has led countries to self-determine their greenhouse gas (GHG) emission reduction targets. The planned ‘ratcheting-up’ process, which aims to ensure that the NDCs comply with the overall goal of limiting global average temperature increase to well below 2 °C or even 1.5 °C, will most likely include some evaluation of ‘fairness’ of these reduction targets. In the literature, fairness has been discussed around equity principles, for which many different effort-sharing approaches have been proposed. In this research, we analysed how country-level emission targets and carbon budgets can be derived based on such criteria. We apply novel methods directly based on the global carbon budget, and, for comparison, more commonly used methods using GHG mitigation pathways. For both, we studied the following approaches: equal cumulative per capita emissions, contraction and convergence, grandfathering, greenhouse development rights and ability to pay. As the results critically depend on parameter settings, we used the wide authorship from a range of countries included in this paper to determine default settings and sensitivity analyses. Results show that effort-sharing approaches that (i) calculate required reduction targets in carbon budgets (relative to baseline budgets) and/or (ii) take into account historical emissions when determining carbon budgets can lead to (large) negative remaining carbon budgets for developed countries. This is the case for the equal cumulative per capita approach and especially the greenhouse development rights approach. Furthermore, for developed countries, all effort-sharing approaches except grandfathering lead to more stringent budgets than cost-optimal budgets, indicating that cost-optimal approaches do not lead to outcomes that can be regarded as fair according to most effort-sharing approaches

Nutritional content of savanna plant foods: implications for browser/grazer models of ungulate diversification

Models of herbivore diversification rely heavily on adaptations that reflect the nutritional quality of foods consumed. In particular, browsers and grazers are expected to show dichotomous adaptations to deal with high quality (concentrate) browse-based and poor quality grass-based diets, respectively. In this study, we test the widespread assumption that browse represents a higher quality food source than grass. We analyzed plants from a South African savanna, collected over one dry and one wet season across several habitat types, for percent nitrogen (%N), neutral detergent fiber (NDF), acid detergent fiber (ADF), and acid detergent lignin (ADL) to compare variations in nutritional value of different food types. Results show consistently higher %N and lower NDF and ADF of tree foliage and forbs compared to monocots, but the former have consistently higher ADL, implying a higher fiber digestibility in grass compared with browse. Some fruit species have a high NDF and ADL content, implying poorer nutritional value than is commonly assumed. Our findings are in agreement with several other studies depicting relatively poor digestibility of browse (tree foliage and fruit) compared to grass. Reference to browse as high quality foods is therefore misleading, and models of herbivory that rest on this assumption require revision. The more efficient fiber digestibility recorded in grazers compared to browsers cannot be treated as an adaptation to poor quality diets, but rather to maximize benefits of higher fiber digestibility of grass. Spatio-seasonal variations in plant nutritional seem to reflect seasonal and spatial diet changes expected for grazers and intermediate (mixed) feeders. We propose that future studies require further detail on variations in diet, diet quality, and digestive efficiency to properly understand mechanisms of adaptation