Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α₁ subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α₁–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α₁ and β₁ subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.     

Impaired Eye Region Search Accuracy in Children with Autistic Spectrum Disorders

To explore mechanisms underlying reduced fixation of eyes in autism, children with Autistic Spectrum Disorders (ASD) and typically developing children were tested in five visual search experiments: simple color feature; color-shape conjunction; face in non-face objects; mouth region; and eye region. No group differences were found for reaction time profile shapes in any of the five experiments, suggesting intact basic search mechanics in children with ASD. Contrary to early reports in the literature, but consistent with other more recent findings, we observed no superiority for conjunction search in children with ASD. Importantly, children with ASD did show reduced accuracy for eye region search (p = .005), suggesting that eyes contribute less to high-level face representations in ASD or that there is an eye region-specific disruption to attentional processes engaged by search in ASD.     

Reactive Oxygen Species Modulate the Barrier Function of the Human Glomerular Endothelial Glycocalyx

Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S³⁵ and ³H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress.     

Persistent anthropogenic legacies structure depth dependence of regenerating rooting systems and their functions

Biotically-mediated weathering helps to shape Earth’s surface. For example, plants expend carbon (C) to mobilize nutrients in forms whose relative abundances vary with depth. It thus is likely that trees’ nutrient acquisition strategies—their investment in rooting systems and exudates—may function differently following disturbance-induced changes in depth of rooting zones and soil nutrient stocks. These changes may persist across centuries. We test the hypothesis that plant C allocation for nutrient acquisition is depth dependent as a function of rooting system development and relative abundances of organic vs. mineral nutrient stocks. We further posit that patterns of belowground C allocation to nutrient acquisition reveal anthropogenic signatures through many decades of forest regeneration. To test this idea, we examined fine root abundances and rooting system C in organic acid exudates and exo-enzymes in tandem with depth distributions of organically- and mineral-bound P stocks. Our design permitted us to estimate C tradeoffs between organic vs. mineral nutrient benefits in paired forests with many similar aboveground traits but different ages: post-agricultural mixed-pine forests and older reference hardwoods. Fine roots were more abundant throughout the upper 2 m in reference forest soils than in regenerating stands. Rooting systems in all forests exhibited depth-dependent C allocations to nutrient acquisition reflecting relative abundances of organic vs. mineral bound P stocks. Further, organic vs. mineral stocks underwent redistribution with historic land use, producing distinct ecosystem nutritional economies. In reference forests, rooting systems are allocating C to relatively deep fine roots and low-C exudation strategies that can increase mobility of mineral-bound P stocks. Regenerating forests exhibit relatively shallower fine root distributions and more diverse exudation strategies reflecting more variable nutrient stocks. We observed these disparities in rooting systems’ depth and nutritional mechanisms even though the regenerating forests have attained aboveground biomass stocks similar to those in reference hardwood forests. These distinctions offer plausible belowground mechanisms for observations of continued C sink strength in relatively old forests, and have implications for soil C fates and soil development on timescales relevant to human lifetimes. As such, depth-dependent nutrient returns on plant C investments represent a subtle but consequential signal of the Anthropocene.

     

Elaeocarpus reticulatus fruit extracts reduce viability and induce apoptosis in pancreatic cancer cells in vitro

Molecular Biology Reports - Treatment options for pancreatic cancer (PC) are severely limited due to late diagnosis, early metastasis and the inadequacy of chemotherapy and radiotherapy to combat...     

Kinetic regulation of the binding of prothrombin to phospholipid membranes

A wide range of equilibrium and kinetic constants exist for the interaction of prothrombin and other coagulation factors with various model membranes from a variety of techniques. We have investigated the interaction of prothrombin with pure dioleoylphosphatidylcholine (DOPC) membranes and dioleoylphosphatidlyserine (DOPS)-containing membranes (DOPC:DOPS, 3:1) using surface plasmon resonance (SPR, with four different model membrane presentations) in addition to isotheral titration calorimetry (ITC, with suspensions of phospholipid vesicles) and ELISA methods. Using ITC, we found a simple low-affinity interaction with DOPC:DOPS membranes with a K _D = 5.1 μM. However, ELISA methods using phospholipid bound to microtitre plates indicated a complex interaction with both DOPC:DOPS and DOPC membranes with K _D values of 20 and 58 nM, respectively. An explanation for these discrepant results was developed from SPR studies. Using SPR with low levels of immobilised DOPC:DOPS, a high-affinity interaction with a K _D of 18 nM was obtained. However, as phospholipid and prothrombin concentrations were increased, two distinct interactions could be discerned: (i) a kinetically slow, high-affinity interaction with K _D in the 10^?8 M range and (ii) a kinetically rapid, low-affinity interaction with K _D in the 10^?6 M range. This low affinity, rapidly equilibrating, interaction dominated in the presence of DOPS. Detailed SPR studies supported a heterogeneous binding model in agreement with ELISA data. The binding of prothrombin with phospholipid membranes is complex and the techniques used to measure binding will report K _D values reflecting the mixture of complexes detected. Existing data suggest that the weaker rapid interaction between prothrombin and membranes is the most important in vivo when considering the activation of prothrombin at the cell surface.     

The influence of antifouling practices on marine invasions

Vessel hull-fouling is increasingly recognised as one of the major vectors for the transfer of marine non-indigenous species. For hundreds of years, copper (Cu) has been used as a primary biocide to prevent the establishment of fouling assemblages on ships' hulls. Some non-indigenous fouling taxa continue to be transferred via hull-fouling despite the presence of Cu antifouling biocides. In addition, several of these species appear to enjoy a competitive advantage over similar native taxa within metal-polluted environments. This metal tolerance may further assist their establishment and spread in new habitats. This review synthesises existing research on the links between Cu and the invasion of fouling species, and shows that, with respect to the vector of hull-fouling, tolerance to Cu has the potential to play a role in the transfer of non-indigenous fouling organisms. Also highlighted are the future directions for research into this important nexus between industry, ecology and environmental management.     

Taxonomic status of southern South American Conepatus (Carnivora: Mephitidae)

Despite recent taxonomic evaluations of Mephitidae and North American hog‐nosed skunks, southern South American species of Conepatus have not been thoroughly examined in a systematic context. Conepatus chinga and Conepatus humboldtii were described more than 150 years ago, based on external characters such as hair coloration and size. Although historically recognized as valid species, to date no detailed systematic analysis has been performed for either of these taxa. Herein, we evaluated the taxonomic status of C. chinga and C. humboldtii within the southern part of South America using geometric morphometrics of the skull and mandible, mitochondrial DNA analysis using the cytochrome b and cytochrome oxidase c subunit I genes, and also control region and pelage pattern variation. We failed to find morphological (skull shape and pelage coloration patterns) or molecular differences between these two species; thus, we considered that the specimens assigned to C. chinga and C. humboldtii belong to the same species. Our results indicate that environmental variation seems to be responsible for shape and size variation in Conepatus skulls from southern South America. © 2013 The Linnean Society of London