The higher plant Arabidopsis thaliana (Arabidopsis) is an important model for identifying plant genes and determining their function. To assist biological investigations and to define chromosome structure, a coordinated effort to sequence the Arabidopsis genome was initiated in late 1996. Here we report one of the first milestones of this project, the sequence of chromosome 4. Analysis of 17.38 megabases of unique sequence, representing about 17% of the genome, reveals 3,744 protein coding genes, 81 transfer RNAs and numerous repeat elements. Heterochromatic regions surrounding the putative centromere, which has not yet been completely sequenced, are characterized by an increased frequency of a variety of repeats, new repeats, reduced recombination, lowered gene density and lowered gene expression. Roughly 60% of the predicted protein-coding genes have been functionally characterized on the basis of their homology to known genes. Many genes encode predicted proteins that are homologous to human and Caenorhabditis elegans proteins.

Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.

Parental questionnaires are inexpensive alternatives to standardized testing for outcome measurement. The Parent Report of Children's Abilities has previously been revised (PARCA-R) and validated for use with very-preterm infants at 2 years of age. This study revalidated the PARCA-R for assessing cognition in a larger and more inclusive sample of preterm infants. One hundred and sixty-four children (82 males, 82 females) of <32 weeks' gestation (median 29wks, interquartile range [IQR] 28-30wks); and median birthweight 1200g (IQR 925-1463g) were evaluated using the Mental Development Index (MDI) of the Bayley Scales of Infant Development -2nd edition (BSID-II) at 2 years' corrected age. Parents completed the PARCA-R questionnaire. Significant correlations between PARCA-R Parent Report Composite (PRC) scores and MDI scores (r=0.77, 95% confidence interval [CI] 0.69-0.82, p<0.01) demonstrated concurrent validity. A receiver operating characteristic-determined PRC cut-off of <44 had optimal discriminatory power (area under curve 0.92) for identifying MDI <70, with 85% sensitivity (95% CI 0.58-0.96), 87% specificity (95% CI 0.81-0.92), 98% negative predictive value (95% CI 0.95-1), and 37% positive predictive value (95% CI 0.22-0.54). The PARCA-R has good concurrent validity and diagnostic utility for identifying cognitive delay in verypreterm infants at 2 years of age. It is useful for outcome measurement, developmental screening, and facilitating parental involvement at follow-up.

Around 15 million children are born preterm (<37 weeks of gestation) every year. Of these, 15% or 2.25 million are born very preterm (VP; <32 weeks of gestation). Here, the developmental outcomes of VP babies in diverse domains from motor, cognitive, and social function to mental health and well-being throughout childhood and adolescence are reviewed. Their life course adaptation in terms of romantic relationships, employment, and quality of life into adulthood is also considered. Some adverse effects reduce as individuals age, and others remain remarkably stable from childhood into adulthood. We argue that to advance understanding of developmental mechanisms and direct resources for intervention more effectively, social factors need to be assessed more comprehensively, and genetically sensitive designs should be considered with neuroimaging integrated to test alternative developmental models. As current evidence is based almost exclusively on studies from high-income countries, research from low- and middle-income countries is urgently needed.

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During the preparation of the manuscript, the mice in Figure 2 were incorrectly identified as having been infected with S. mansoni. The correct legend for Figure The JCI regrets the error.

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