Identification of a novel RPGRIP1 mutation in an Iranian family with leber congenital amaurosis by exome sequencing

Leber congenital amaurosis (LCA) is a heterogeneous, early‐onset inherited retinal dystrophy, which is associated with severe visual impairment. We aimed to determine the disease‐causing variants in Iranian LCA and evaluate the clinical implications. Clinically, a possible LCA disease was found through diagnostic imaging, such as fundus photography, autofluorescence and optical coherence tomography. All affected patients showed typical eye symptoms associated with LCA including narrow arterioles, blindness, pigmentary changes and nystagmus. Target exome sequencing was performed to analyse the proband DNA. A homozygous novel c. 2889delT  (p.P963 fs) mutation in the RPGRIP1 gene was identified, which was likely the deleterious and pathogenic mutation in the proband. Structurally, this mutation lost a retinitis pigmentosa GTPase regulator (RPGR)‐interacting domain at the C‐terminus which most likely impaired stability in the RPGRIP1 with the distribution of polarised proteins in the cilium connecting process. Sanger sequencing showed complete co‐segregation  in this pedigree. This study provides compelling evidence that the c. 2889delT  (p.P963 fs) mutation in the RPGRIP1 gene works as a pathogenic mutation that contributes to the progression of LCA.     

Nanofiber-based polyethersulfone scaffold and efficient differentiation of human induced pluripotent stem cells into osteoblastic lineage

Human induced pluripotent stem cells (iPSCs) have been shown to have promising potential for regenerative medicine and tissue engineering applications. In the present study, osteogenic differentiation of human iPSCs was evaluated on polyethersulfone (PES) nanofibrous scaffold. According to the results, higher significant expressions of common osteogenic-related genes such as runx2, collagen type I, osteocalcin and osteonectin was observed in PES seeded human iPSCs compared with control. Alizarin red staining and alkaline phosphatase activity of differentiated iPSCs demonstrated significant osteoblastic differentiation potential of these cells. In this study biocompatibility of PES nanofibrous scaffold confirmed by flattened and spreading morphology of iPSCs under osteoblastic differentiation inductive culture. Taking together, nanofiber-based PES scaffold seeded iPSCs showed the highest capacity for differentiation into osteoblasts-like cells. These cells and PES scaffold were demonstrated to have great efficiency for treatment of bone damages and lesions.     

Comparison of Mercury Contamination in Live and Dead Dolphins from a Newly Described Species,Tursiops australis

Globally it is estimated that up to 37% of all marine mammals are at a risk of extinction, due in particular to human impacts, including coastal pollution. Dolphins are known to be at risk from anthropogenic contaminants due to their longevity and high trophic position. While it is known that beach-cast animals are often high in contaminants, it has not been possible to determine whether levels may also be high in live animals from the same populations. In this paper we quantitatively assess mercury contamination in the two main populations of a newly described dolphin species from south eastern Australia, Tursiops australis. This species appear to be limited to coastal waters in close proximity to a major urban centre, and as such is likely to be vulnerable to anthropogenic pollution. For the first time, we were able to compare blubber mercury concentrations from biopsy samples of live individuals and necropsies of beach-cast animals and show that beach-cast animals were highly contaminated with mercury, at almost three times the levels found in live animals. Levels in live animals were also high, and are attributable to chronic low dose exposure to mercury from the dolphin''s diet. Measurable levels of mercury were found in a number of important prey fish species. This illustrates the potential for low dose toxins in the environment to pass through marine food webs and potentially contribute to marine mammal deaths. This study demonstrates the potential use of blubber from biopsy samples to make inferences about the health of dolphins exposed to mercury.     

A Review on the Role of Chromium Supplementation in Ruminant Nutrition—Effects on Productive Performance,Blood Metabolites,Antioxidant Status,and Immunocompetence

Interactions of arsenic with essential trace elements may result in disturbances on body homeostasis. In the present study, we aimed to investigate the effects of different arsenic compounds on micromineral content and antioxidant enzyme activities in rat liver. Male Wistar rats were randomly divided into five groups and exposed to sodium arsenite and sodium arsenate at 0.01 and 10 mg/L for 8 weeks in drinking water. The concentration of arsenic increased in the liver of all arsenic-exposed animals. The proportion of zinc and copper increased in animals exposed to 0.01 mg/L sodium arsenite. In addition, these animals presented a reduction in magnesium and sodium content. Superoxide dismutase activity decreased mainly in arsenite-exposed animals, whereas catalase activity decreased in animals exposed to 10 mg/L sodium arsenate. Further, exposure to sodium arsenate at 10 mg/L altered copper and magnesium content in the liver, and reduced total protein levels. Overall, both arsenic compounds altered the liver histology, with reduction in the proportion of cytoplasm and hepatocyte, and increased the percentage of sinusoidal capillaries and macrophages. In conclusion, our findings showed that oral exposure to arsenic compounds disturbs the trace elements balance in the liver, especially at low concentration, altering enzymatic and stereological parameters. We concluded that despite the increase in trace elements content, the antioxidant enzyme activities were downregulated and did not prevent morphological alterations in the liver of animals exposed to both arsenic compounds.     

Identification and evaluation of glutathione conjugate gamma-l-glutamyl-l-cysteine for improved drug delivery to the brain

Abstract

Glutathione (GU), an endogenous antioxidant tripeptide, is frequently transferred in the human brain through N-methyl-d-aspartate receptor (NMDAR), profusely expressed at the blood–brain barrier (BBB) junction. GU, also modifies the characteristics of tight junction proteins (occludin and claudin) at the site of BBB by depolarizing the enzyme, protein tyrosine phosphatase that manifests its usefulness for passive delivery of nanocarriers to the brain. GU, thus, represents itself as an ideal ligand for the surface decoration of nanocarriers to successfully administer them across the brain via receptor-mediated drug delivery pathway. Hence, we have employed here, in-silico approaches to identify the potential GU-like molecules, as appropriate ligand(s) for surface engineering of nanoconstruct with the purpose of attaining targeted drug delivery to the brain. Structure-based virtual screening methods was used to filter PubChem database for the identification of bioactive compounds with >95% structure similarity with GU. We have further screened the compounds against NMDAR using molecular docking approach. Top hits were selected based on their high binding affinities and selectivity towards NMDAR, and their binding pattern was analysed in detail. Finally, all atom molecular dynamics simulation for 100?ns was carried out on free NMDAR and in-presence of the selected GU-like compound, gamma-l-glutamyl-l-cysteine to evaluate complex stability and structural dynamics. In conclusion, gamma-l-glutamyl-l-cysteine may act as potential binding partner of NMDAR which can further be evaluated in drug delivery system to brain across the BBB.

Communicated by Ramaswamy H. Sarma