The TGF-beta superfamily comprises a number of functionally diverse growth factors/signalling molecules (1) which elicit their response upon binding to serine-threonine kinase receptors (2). We recently reported the isolation and characterization of two new members of the family, designated cartilage-derived morphogenetic protein (CDMP) 1 and 2 (ref. 3) which are closely related to the sub-family of bone morphogenetic proteins. CDMP-1 is predominantly expressed at sites of skeletal morphogenesis (3), and we now show that a mutation in hCDMP-1 is associated with a recessive human chondrodysplasia (acromesomelic chondrodysplasia, Hunter-Thompson type (4,5)). The disorder, characterized by skeletal abnormalities restricted to the limbs andlimb joints, is phenotypically similar to murine brachypodism (bp) which is due to mutations in growth/differentiation factor-5 (Gdf-5) (6), the mouse homologue of hCDMP-1. Affected individuals are homozygous for a 22-bp (tandem-duplication) frameshift mutation in the mature region of CDMP-1. The resulting phenotype provides direct evidence for the involvement of CDMP-1 in human skeletal development and represents the first human disorder attributable to a mutation in a TGF-beta superfamily member.

BackgroundSeveral factors have been shown to influence semen parameters, one of which is sexual abstinence; a clinical criteria included in the semen evaluation to provide maximum sperm quality. The aim of the present study was to assess the effect of a daily ejaculation frequency on conventional and functional semen parameters.MethodsSemen samples were collected daily over a period of two weeks of which every second sample per person was processed and analyzed according to the World Health Organization guidelines. Furthermore, mitochondrial function, intracellular reactive oxygen species production and sperm DNA fragmentation were evaluated by flow cytometry.ResultsTotal sperm count and seminal volume per ejaculation declined and remained decreased for the duration of the daily ejaculation period. However, conventional parameters such as sperm concentration, motility, progressive motility, morphology, vitality and functional parameters such as sperm plasma membrane integrity, mitochondrial membrane potential and DNA fragmentation was not significantly affected and remained similar to the initial measurement throughout the daily ejaculation period. Despite intra- and inter individual variations, the average values of the basic semen parameters remained above the WHO (2010) reference values throughout the daily ejaculation period. Interestingly, a decreasing trend in intracellular ROS production was observed, although statistically not significant.ConclusionsThe study shows that an extended 2 week period of daily ejaculation does not have major clinical effects on conventional and functional seminal parameters.

Familial clustering and linkage disequilibrium studies suggest that genetic factors predispose to vitiligo, although a clear transmission pattern and cosegregation of vitiligo with specific mutations have not been demonstrated. We collected pedigree data on vitiligo from a set of 56 multigeneration families belonging to the Paisa community from Antioquia, Colombia, with the goal of applying the unified model of complex segregation and linkage disequilibrium analyses to test the hypotheses of the existence of a major gene predisposing to vitiligo and that allelic or haplotype polymorphisms of microsatellite loci at 6p21.3-21.4 spanning HLA (D6S276, D6S265, D6S273, and D6S291) are associated with this predisposition. Minimum sibship sample size to discriminate dominant and recessive inheritance models was largely accomplished. Between the 15 models of complex segregation used, the one that best fitted the data was that of a major dominant gene and the existence of strong environmental effects acting on the recessive genotype. The penetrance and risk estimations discriminated two sets of vitiligo patients: those with early onset of vitiligo cosegregating with a dominant mode of inheritance without environmental effects, and those with late onset of vitiligo cosegregating with the recessive genotype and being influenced by environmental effects. After establishing the normal distribution of allelic frequencies and performing multiple comparisons correction, the linkage disequilibrium analysis suggested that a major genetic factor could be located at 6p21.3-21.4, because we detected significant case-control differences for allele 122 at D6S265 (Pc=0.0264) and significant linkage disequilibrium between loci D6S276 and D6S273 in the cases but not in the controls. We cannot explain these results as a consequence of evolutionary forces or as genetic stratification acting differentially on cases and controls, because there was neither deviation from the Hardy-Weinberg expectations nor genetic subdivision between cases and controls, as θ (non-biased F ST ) was not significantly different from 0.

Male infertility can be responsible for up to 20% of the cases attending fertility consultation facilities; nonetheless, the underlying molecular mechanisms that could explain it are still elusive. Therefore, we aimed to evaluate conventional and functional parameters of semen samples from patients who presented with male infertility of unknown origin. Conventional semen parameters and functional parameters (i.e. intracellular reactive oxygen species production, mitochondrial membrane potential, sperm chromatin structure assay, sperm membrane lipid peroxidation and antioxidant capacity of seminal plasma) were evaluated on semen samples from 54 healthy donors, 23 patients with idiopathic infertility and 34 fertile controls. No significant differences were observed in the conventional seminal parameters between the fertile and infertile men. However, increased intracellular reactive oxygen species (ROS) production and DNA fragmentation were observed in the infertile patients compared to the fertile group. Alterations in intracellular ROS production and DNA fragmentation could be associated with male idiopathic infertility. These parameters could eventually distinguish both groups more accurately than the conventional parameters. Our current results are encouraging, and the efficacy of these parameters in the clinical settings needs to be further assessed to establish their predictive potential as a marker of unexplained male infertility.

Reactive oxygen and nitrogen species damage cellular macromolecules including DNA. Cells have a robust base excision repair pathway to deal with this damage in both nuclear and mitochondrial genomes. However, mitochondria lack nucleotide excision repair. Evidence suggests that chronic oxidative stress can induce protective pathways lowering genotoxicity. Understanding oxidant injury to DNA and its repair is critical for our understanding the pathophysiology of a wide range of human disorders.

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BackgroundIn recent years, the idea of a highly immunogenic protein-based vaccine to combat Streptococcus pneumoniae and its severe invasive infectious diseases has gained considerable interest. However, the target proteins to be included in a vaccine formulation have to accomplish several genetic and immunological characteristics, (such as conservation, distribution, immunogenicity and protective effect), in order to ensure its suitability and effectiveness. This study aimed to get comprehensive insights into the genomic organization, population distribution and genetic conservation of all pneumococcal surface-exposed proteins, genetic regulators and other virulence factors, whose important function and role in pathogenesis has been demonstrated or hypothesized.ResultsAfter retrieving the complete set of DNA and protein sequences reported in the databases GenBank, KEGG, VFDB, P2CS and Uniprot for pneumococcal strains whose genomes have been fully sequenced and annotated, a comprehensive bioinformatic analysis and systematic comparison has been performed for each virulence factor, stand-alone regulator and two-component regulatory system (TCS) encoded in the pan-genome of S. pneumoniae. A total of 25 S. pneumoniae strains, representing different pneumococcal phylogenetic lineages and serotypes, were considered. A set of 92 different genes and proteins were identified, classified and studied to construct a pan-genomic variability map (variome) for S. pneumoniae. Both, pneumococcal virulence factors and regulatory genes, were well-distributed in the pneumococcal genome and exhibited a conserved feature of genome organization, where replication and transcription are co-oriented. The analysis of the population distribution for each gene and protein showed that 49 of them are part of the core genome in pneumococci, while 43 belong to the accessory-genome. Estimating the genetic variability revealed that pneumolysin, enolase and Usp45 (SP_2216 in S. p. TIGR4) are the pneumococcal virulence factors with the highest conservation, while TCS08, TCS05, and TCS02 represent the most conserved pneumococcal genetic regulators.ConclusionsThe results identified well-distributed and highly conserved pneumococcal virulence factors as well as regulators, representing promising candidates for a new generation of serotype-independent protein-based vaccine(s) to combat pneumococcal infections.

Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.