Drugs of the future: the hormone relaxin

The peptide hormone relaxin is emerging as a multi-functional factor in a broad range of target tissues including several non-reproductive organs, in addition to its historical role as a hormone of pregnancy. This review discusses the evidence that collectively demonstrates the many diverse and vital roles of relaxin: the homeostatic role of endogenous relaxin in mammalian pregnancy and ageing; its gender-related effects; the therapeutic effects of relaxin in the treatment of fibrosis, inflammation, cardioprotection, vasodilation and wound healing (angiogenesis) amongst other pathophysiological conditions, and its potential mechanism of action. Furthermore, translational issues using experimental models (to humans) and its use in various clinical trials, are described, each with important lessons for the design of future trials involving relaxin. The diverse physiological and pathological roles for relaxin have led to the search for its significance in humans and highlight its potential as a drug of the future. Received 12 December 2006; received after revision 12 February 2007; accepted 15 March 2007     

Chronobiology of sleep in humans

Periodic circadian (24-h) cycles play an important role in daily hormonal and behavioural rhythms. Usually our sleep/wake cycle, temperature and melatonin rhythms are internally synchronized with a stable phase relationship. When there is a desynchrony between the sleep/wake cycle and circadian rhythm, sleep disorders such as advanced and delayed sleep phase syndrome can arise as well as transient chronobiologic disturbances, for example from jet lag and shift work. Appropriately timed bright light is effective in re-timing the circadian rhythm and sleep pattern to a more desired time, ameliorating these disturbances. Other less potent retiming effects may also be obtained from the judicious use of melatonin and exercise.     

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.     

The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast

The autosomal recessive disorder Shwachman-Diamond syndrome, characterized by bone marrow failure and leukemia predisposition, is caused by deficiency of the highly conserved Shwachman-Bodian-Diamond syndrome (SBDS) protein. Here, we identify the function of the yeast SBDS ortholog Sdo1, showing that it is critical for the release and recycling of the nucleolar shuttling factor Tif6 from pre-60S ribosomes, a key step in 60S maturation and translational activation of ribosomes. Using genome-wide synthetic genetic array mapping, we identified multiple TIF6 gain-of-function alleles that suppressed the pre-60S nuclear export defects and cytoplasmic mislocalization of Tif6 observed in sdo1Delta cells. Sdo1 appears to function within a pathway containing elongation factor-like 1, and together they control translational activation of ribosomes. Thus, our data link defective late 60S ribosomal subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition.     

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

Genomic analysis of Bartonella identifies type IV secretion systems as host adaptability factors

The bacterial genus Bartonella comprises 21 pathogens causing characteristic intraerythrocytic infections. Bartonella bacilliformis is a severe pathogen representing an ancestral lineage, whereas the other species are benign pathogens that evolved by radial speciation. Here, we have used comparative and functional genomics to infer pathogenicity genes specific to the radiating lineage, and we suggest that these genes may have facilitated adaptation to the host environment. We determined the complete genome sequence of Bartonella tribocorum by shotgun sequencing and functionally identified 97 pathogenicity genes by signature-tagged mutagenesis. Eighty-one pathogenicity genes belong to the core genome (1,097 genes) of the radiating lineage inferred from genome comparison of B. tribocorum, Bartonella henselae and Bartonella quintana. Sixty-six pathogenicity genes are present in B. bacilliformis, and one has been lost by deletion. The 14 pathogenicity genes specific for the radiating lineage encode two laterally acquired type IV secretion systems, suggesting that these systems have a role in host adaptability.