Whole-Genome Characterization of Human and Simian Immunodeficiency Virus Intrahost Diversity by Ultradeep Pyrosequencing

Rapid evolution and high intrahost sequence diversity are hallmarks of human and simian immunodeficiency virus (HIV/SIV) infection. Minor viral variants have important implications for drug resistance, receptor tropism, and immune evasion. Here, we used ultradeep pyrosequencing to sequence complete HIV/SIV genomes, detecting variants present at a frequency as low as 1%. This approach provides a more complete characterization of the viral population than is possible with conventional methods, revealing low-level drug resistance and detecting previously hidden changes in the viral population. While this work applies pyrosequencing to immunodeficiency viruses, this approach could be applied to virtually any viral pathogen.

James Parkinson (1755-1824): A pioneer of child care

James Parkinson (1755-1824) of Parkinson's disease, is well recognized as a pioneer of clinical neurology; and is even more famous as a founder of modem palaeontology. We have reviewed from primary sources his extensive contributions to clinical child care and his pioneering advocacy for child welfare, protection and safety. His writings, outreach and advocacy for children's health characterizes him as one whose influence was an important springboard from which evolved the modern specialty of paediatrics. Parkinson was one of the first to write on child-rearing practices and in this context antedated Benjamin Spock by 150 years. Parkinson was a pioneer of child safety and the prevention of childhood trauma. He wrote of the resuscitation of near-drowned children and of first aid for injured children. This critical analysis reviews his pioneering description of child abuse and the development of post-abuse hydrocephalus. He wrote the datum description (in English) of the pathophysiology and pathology of appendicitis in children, of fatal rabies in children and highlighted the risk of death even when the biting dog was not clinically rabid. His advocacy for social reform for children's welfare was courageous and pioneering. James Parkinson, hitherto unacknowledged, was a significant founder of the evolving discipline of paediatrics and child health.

Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copperATPase

Wilson disease is an autosomal recessive copper transport disorder resulting from defective biliary excretion of copper and subsequent hepatic copper accumulation and liver failure if not treated. The disease is caused by mutations in the ATP7B (WND) gene, which is expressed predominantly in the liver and encodes a copper-transporting P-type ATPase that is structurally and functionally similar to the Menkes protein (MNK), which is defective in the X-linked copper transport disorder Menkes disease. The toxic milk (tx) mouse has a clinical phenotype similar to Wilson disease patients and, recently, the tx mutation within the murine WND homologue (Wnd) of this mouse was identified, establishing it as an animal model for Wilson disease. In this study, cDNA constructs encoding the wild-type (Wnd-wt) and mutant (Wnd-tx) Wilson proteins (Wnd) were generated and expressed in Chinese hamster ovary (CHO) cells. The fx mutation disrupted the copper-induced relocalization of Wnd in CHO cells and abrogated Wnd-mediated copper resistance of transfected CHO cells. In addition, co-localization experiments demonstrated that while Wnd and MNK are located in the trans-Golgi network in basal copper conditions, with elevated copper, these proteins are sorted to different destinations within the same cell, Ultrastructural studies showed that with elevated copper levels, Wnd accumulated in large multivesicular structures resembling late endosomes that may represent a novel compartment for copper transport. The data presented provide further support for a relationship between copper transport activity and the copper-induced relocalization response of mammalian copper ATPases, and an explanation at a molecular level for the observed phenotype of fx mice.

Correlates of adults' participation in physical activity: review and update

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James W. Gerard: His image of imperial Germany, 1913-1918

The subject of this study was a typical, if in some respects well qualified, U.S. ambassadorial appointee for his time, the early twentieth century: an attorney, judge, and politician who served competently in his one diplomatic assignment, in Berlin, before returning to private life.—Ed.