Molecular dynamics studies of trinucleotide repeat DNA involved in neurodegenerative disorders.

Expansion of trinucleotide repeat DNA of the classes CAG�·CTG, CGG�·CCG and GAA�·TTC are found to be associated with several neurodegenerative disorders. Different mechanisms have been attributed to the expansion of triplets, mainly involving the formation of alternate secondary structures by such repeats. This paper reports the molecular dynamics simulation of triplet repeat DNA sequences to study the basic structural features of DNA that are responsible for the formation of structures such as hairpins and slip-strand DNA leading to expansion. All the triplet repeat sequences studied were found to be more flexible compared to the control sequence unassociated with disease. Moreover, flexibility was found to be in the order CAG�·CTG > CGG�·CCG = GAA�·TTC, the highly flexible CAG�·CTG repeat being the most common cause of neurodegenerative disorders. In another simulation, a single G�·C to T�·A mutation at the 9th position of the CAG�·CTG repeat exhibited a reduction in bending compared to the pure 15-mer CAGâ�¢CTG repeat. EPM1 dodecamer repeat associated with the pathogenesis of progressive myoclonus epilepsy was also simulated and showed flexible nature suggesting a similar expansion mechanism.

Genetic disorders and spermatogenesis.

Male infertility affects one man in twenty and a genetic basis seems likely in at least 30% of those men. Genetic regulation of fertility involves the inter-related processes of testicular development, spermatogenesis (involving germ cell mitosis, meiosis and spermatid maturation), and their endocrine and paracrine regulation. In regard to spermatogenesis, particular attention has been given to the Yq11 region, where some spermatogenesis genes ('azoospermia factors') appear to be located. Several candidate genes have been identified but have not been shown to have a defined or essential role in spermatogenesis. Microdeletions of Yq11 are found in approximately 15% of azoospermic or severely oligospermic men. The complexity of the genetic control of male fertility is demonstrated by the evidence for genes involved in spermatogenesis and sexual differentiation on the X chromosome and autosomes. Better understanding of the genetic regulation of normal spermatogenesis will provide new probes for clinical studies; however, at present the majority of spermatogenic failure remains without an identified genetic linkage. The advent of intracytoplasmic sperm injection permits fertility in many previously sterile men and presents the possibility of their transmission of infertility; appropriate counselling is required.

Neuromuscular and biomechanical factors codetermine the solution to motor redundancy in rhythmic multijoint arm movement

How the CNS deals with the issue of motor redundancy remains a central question for motor control research. Here we investigate the means by which neuromuscular and biomechanical factors interact to resolve motor redundancy in rhythmic multijoint arm movements. We used a two-df motorised robot arm to manipulate the dynamics of rhythmic flexion-extension (FE) and supination-pronation (SP) movements at the elbow-joint complex. Participants were required to produce rhythmic FE and SP movements, either in isolation, or in combination (at the phase relationship of their choice), while we recorded the activity of key bi-functional muscles. When performed in combination, most participants spontaneously produced an in-phase pattern of coordination in which flexion is synchronised with supination. The activity of the Biceps Brachii (BB), the strongest arm muscle which also has the largest moment arms in both flexion and supination was significantly higher for FE and SP performed in combination than in isolation, suggesting optimal exploitation of the mechanical advantage of this muscle. In a separate condition, participants were required to produce a rhythmic SP movement while a rhythmic FE movement was imposed by the motorised robot. Simulations based upon a musculoskeletal model of the arm demonstrated that in this context, the most efficient use of the force-velocity relationship of BB requires that an anti-phase pattern of coordination (flexion synchronized with pronation) be produced. In practice, the participants maintained the in-phase behavior, and BB activity was higher than for SP performed in isolation. This finding suggests that the neural organisation underlying the exploitation of bifunctional muscle properties, in the natural context, constrains the system to maintain the