Functional Analysis of Alleged NOGGIN Mutation G92E Disproves Its Pathogenic Relevance

We identified an amino acid change (p.G92E) in the Bone Morphogenetic Protein antagonist NOGGIN in a 22-month-old boy who presented with a unilateral brachydactyly type B phenotype. Brachydactyly type B is a skeletal malformation that has been associated with increased Bone Morphogenetic Protein pathway activation in other patients. Previously, the amino acid change p.G92E in NOGGIN was described as causing fibrodysplasia ossificans progressiva, a rare genetic disorder characterized by limb malformations and progressive heterotopic bone formation in soft tissues that, like Brachydactyly type B, is caused by increased activation of Bone Morphogenetic Protein signaling. To determine whether G92E-NOGGIN shows impaired antagonism that could lead to increased Bone Morphogenetic Protein signaling, we performed functional assays to evaluate inhibition of BMP signaling. Interestingly, wt-NOGGIN shows different inhibition efficacies towards various Bone Morphogenetic Proteins that are known to be essential in limb development. However, comparing the biological activity of G92E-NOGGIN with wt-NOGGIN, we observed that G92E-NOGGIN inhibits activation of bone morphogenetic protein signaling with equal efficiency as wt-NOGGIN, supporting that G92E-NOGGIN does not cause pathological effects. Genetic testing of the child's parents revealed the same amino acid change in the healthy father, further supporting that p.G92E is a neutral amino acid substitution in NOGGIN. We conclude that p.G92E represents a rare polymorphism of the NOGGIN gene - causing neither brachydactyly nor fibrodysplasia ossificans progressiva. This study highlights that a given genetic variation should not be considered pathogenic unless supported by functional analyses

Bone morphogenetic proteins − 7 and − 2 in the treatment of delayed osseous union secondary to bacterial osteitis in a rat model

Background: Bone infections due to trauma and subsequent delayed or impaired fracture healing represent a great challenge in orthopedics and trauma surgery. The prevalence of such bacterial infection-related types of delayed non-union is high in complex fractures, particularly in open fractures with additional extensive soft-tissue damage. The aim of this study was to establish a rat model of delayed osseous union secondary to bacterial osteitis and investigate the impact of rhBMP-7 and rhBMP-2 on fracture healing in the situation of an ongoing infection. Methods: After randomization to four groups 72 Sprague-Dawley rats underwent a transverse fracture of the midshaft tibia stabilized by intramedullary titanium K-wires. Three groups received an intramedullary inoculation with Staphylococcus aureus (103 colony-forming units) before stabilization and the group without bacteria inoculation served as healing control. After 5 weeks, a second surgery was performed with irrigation of the medullary canal and local rhBMP-7 and rhBMP-2 treatment whereas control group and infected control group received sterile saline. After further 5 weeks rats were sacrificed and underwent biomechanical testing to assess the mechanical stability of the fractured bone. Additional micro-CT analysis, histological, and histomorphometric analysis were done to evaluate bone consolidation or delayed union, respectively, and to quantify callus formation and the mineralized area of the callus. Results: Biomechanical testing showed a significantly higher fracture torque in the non-infected control group and the infected rhBMP-7- and rhBMP-2 group compared with the infected control group (p < 0.001). RhBMP-7 and rhBMP-2 groups did not show statistically significant differences (p = 0.57). Histological findings supported improved bone-healing after rhBMP treatment but quantitative micro-CT and histomorphometric results still showed significantly more hypertrophic callus tissue in all three infected groups compared to the non-infected group. Results from a semiquantitative bone-healing-score revealed best bone-healing in the non-infected control group. The expected chronic infection was confirmed in all infected groups. Conclusions: In delayed bone healing secondary to infection rhBMP treatment promotes bone healing with no significant differences in the healing efficacy of rhBMP-2 and rhBMP-7 being noted. Further new therapeutic bone substitutes should be analyzed with the present rat model for delayed osseous union secondary to bacterial osteitis

Diastereoselective Synthesis of C60/Steroid Conjugates

The design and synthesis of fullerene–steroid hybrids by using Prato’s protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C60, thus ascertaining the proposed structures.Financial support by the Ministerio de Ciencia e Innovación (MINECO) of Spain (CTQ2011-24652, CTQ2011-27253, PIB2010JP-00196, and CSD2007-00010 projects) and CAM (Madrisolar-2) is acknowledged; A.R. thanks UCM for financial support; M.S. is indebted to Programa del Grupo Santander 2012

Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects

Cryptic dispersal of Cyanidiophytina (Rhodophyta) in non-acidic environments from Turkey

Cyanidiophytina are a group of polyextremophilic red algae with a worldwide, but discontinuous colonization. They are restricted to widely dispersed hot springs, geothermal habitats, and also some human-altered environments. Cyanidiophytina are predominant where pH is prohibitive for the majority of eukaryotes (pH 0.5-3). Turkey is characterized by areas rich in volcanic activity separated by non-volcanic areas. Here we show that Cyanidiophycean populations are present in thermal baths located around Turkey on neutral/alkaline soils. All known genera and species within Cyanidiophytina were detected in Turkey, including Galdieria phlegrea, recorded up to now only in Italian Phlegrean Fields. By phylogenetic analyses, Turkish G. sulphuraria strains are monophyletic with Italian and Icelandic strains, and with Russian G. daedala strains. G. maxima from Turkey clustered with Icelandic, Kamchatka, and Japanese populations. The discovery of Cyanidiophytina in non-acidic Turkish soils raises new questions about the ecological boundaries of these extremophilic algae. This aids in the understanding of the dispersal abilities and distribution patterns of this ecologically and evolutionarily interesting group of algae

The Epidemiology, Genetics and Future Management of Syndactyly

Syndactyly is a condition well documented in current literature due to it being the most common congenital hand defect, with a large aesthetic and functional significance

Creation of Malaysia’s Royal Belum State Park: A Case Study of Conservation in a Developing Country

The incentives for resource extraction and development make the conservation of biodiversity challenging within tropical forestlands. The 2007 establishment of the Royal Belum State Park in the Malaysian state of Perak offers lessons for creating protected areas in tropical countries where subnational governments are major forestland owners. This article elucidates the social and political forces that influenced Royal Belum’s creation. Those forces included Malaysian conservation groups’ efforts to establish the ecological uniqueness of the site and rally public support to protect it; the Perak state government, which is the landowner under Malaysia’s constitution, seeking a protection option that would minimize the economic costs to it (and perhaps generate net economic benefits); and the federal government providing a legal framework and support for park protection and ecotourism development. Successful long-run protection of Royal Belum will require action beyond simply designating the area as protected