correspondence between case reports and fatality data. These data also establish that mortality rates are not affected by epidemic phase 24. Further confirmation of these results is provided by an analysis of the Aberdeen data (N.B.M-B., P.R. and B.T.G., manuscript in preparation). Concerning infection-induced mortality rates, classic work by Butler 24 , Bartlett 25 , Creighton 5 and others indicates significant mortality due to measles and whooping cough during these periods. Estimates of case fatality rates for measles vary widely, from 1-2% in the postwar era up to 46% prewar 14,26,27 , whereas estimates for whooping cough are in the 3-15% range 24. Data analysis These time series contain a substantial annual component and are further complicated by increasing population sizes over the two periods examined. Hence, analyses of the relationship between measles and whooping cough outbreaks were carried out on de-trended data. We used three separate methods. First, Pearson correlation coefficients were estimated for data aggregated over each epidemic year (October to October). Second, we carried out a linear regression of annual counts of measles against whooping cough and used the slope as a measure of synchrony. The results of this technique were qualitatively identical to those of the Pearson correlation, so we present only those. Finally, we also used Wavelet spectra to explore phase differences between filtered time series 28,29. Further information can be found in the Supplementary Information.

Rice is the principal food for over half of the population of the world. With its genome size of 430 megabase pairs (Mb), the cultivated rice species Oryza sativa is a model plant for genome research. Here we report the sequence analysis of chromosome 4 of O. sativa, one of the first two rice chromosomes to be sequenced completely. The finished sequence spans 34.6 Mb and represents 97.3% of the chromosome. In addition, we report the longest known sequence for a plant centromere, a completely sequenced contig of 1.16 Mb corresponding to the centromeric region of chromosome 4. We predict 4,658 protein coding genes and 70 transfer RNA genes. A total of 1,681 predicted genes match available unique rice expressed sequence tags. Transposable elements have a pronounced bias towards the euchromatic regions, indicating a close correlation of their distributions to genes along the chromosome. Comparative genome analysis between cultivated rice subspecies shows that there is an overall syntenic relationship between the chromosomes and divergence at the level of single-nucleotide polymorphisms and insertions and deletions. By contrast, there is little conservation in gene order between rice and Arabidopsis.

Background: Cardiac fibroblasts (CF) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Due to the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is still missing. The purpose of this study was to define the CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate their function. Methods: Collagen1α1-GFP + CF were characterized after myocardial infarction (MI) by single-cell and bulk RNA-seq, ATAC-seq and functional assays. Swine and patient samples were studied using bulk RNA-seq. Results: We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear pro-fibrotic signature, express high levels of Collagen Triple Helix Repeat Containing 1 ( Cthrc1 ) and localize into the scar. Non-canonical TGF-β signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Moreover, the absence of CTHRC1 results in pronounced lethality due to ventricular rupture. Finally, a population of CF with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy. Conclusions: We report CF heterogeneity, their dynamics during the course of MI and redefine the CF that respond to cardiac injury and participate in myocardial remodeling. Our study identifies Cthrc1 as a novel regulator of the healing scar process, and as a target for future translational studies.

Experiments utilizing the Looptail mutant mouse, which harbors a missense mutation in the vangl2 gene, have been essential for studies of planar polarity and linking the function of the core planar cell polarity proteins to other developmental signals. Originally described as having dominant phenotypic traits, the molecular interactions underlying the Looptail mutant phenotype are unclear because Vangl2 protein levels are significantly reduced or absent from mutant tissues. Here we introduce a vangl2 knockout mouse and directly compare the severity of the knockout and Looptail mutant phenotypes by intercrossing the two lines and assaying the planar polarity of inner ear hair cells. Overall the vangl2 knockout phenotype is milder than the phenotype of compound mutants carrying both the Looptail and vangl2 knockout alleles. In compound mutants a greater number of hair cells are affected and changes in the orientation of individual hair cells are greater when quantified. We further demonstrate in a heterologous cell system that the protein encoded by the Looptail mutation (Vangl2S464N) disrupts delivery of Vangl1 and Vangl2 proteins to the cell surface as a result of oligomer formation between Vangl1 and Vangl2S464N, or Vangl2 and Vangl2S464N, coupled to the intracellular retention of Vangl2S464N. As a result, Vangl1 protein is missing from the apical cell surface of vestibular hair cells in Looptail mutants, but is retained at the apical cell surface of hair cells in vangl2 knockouts. Similarly the distribution of Prickle-like2, a putative Vangl2 interacting protein, is differentially affected in the two mutant lines. In summary, we provide evidence for a direct physical interaction between Vangl1 and Vangl2 through a combination of in vitro and in vivo approaches and propose that this interaction underlies the dominant phenotypic traits associated with the Looptail mutation.