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.

The regulation of transcription of the gene for the tryptophan-specffic permease, mtr, was evaluated in several genetically marked Escherichia coli strains through the use of a single-copy lacZ reporter system. The expression of mtr was repressed 97-fold by tryptophan via the Trp repressor and induced 10-fold by phenylalanine or tyrosine via the Tyr repressor. By primer extension analysis two distinct mtr transcripts and their corresponding promoters were identified. One transcript was induced by the Tyr repressor. The tryptophan-dependent interaction of Trp repressor with an operator target within the mtr promoter was demonstrated by means of a restriction endonuclease protection assay.

Highly purified preparations of tip repressor (TrpR) protein derived from Escherichia coli strains that were engineered to overexpress this material were found to contain another protein, of 21 kDa. The second protein, designated WrbA [for tryptophan (W) repressor-binding protein] remained associated with its namesake through several sequential protein fractionation steps. The N-terminal amino acid sequence of the WrbA protein guided the design of two degenerate oligonucleotides that were used as probes in the cloning of the wrbA gene (198 codons). The WrbA protein, in purified form, was found by several criteria to enhance the formation and/or stability of noncovalent complexes between TrpR holorepressor and its primary operator targets. The formation of an operator-holorepressor-WrbA ternary complex was demonstrated by gel mobility-shift analysis. The WrbA protein alone does not interact with the hp operator. During the stationary phase, cells deficient in the WrbA protein were less efficient than wild type in their ability to repress the tp promoter. It is proposed that the WrbA protein functions as an accessory element in blocking TrpR-specific transcriptional processes that might be physiologically disadvantageous in the stationary phase of the bacterial life cycle.

The tdh promoter of Escherichia coli is induced sever-to eightfold when cells are grown in the presence of exogenous leucine. A scheme was devised to select mutants that exhibited high constitutive expression of the tdh promoter. The mutations in these strains were shown to lie within a previously identified gene (lrp) that encodes Lrp (leucine-responsive regulatory protein). By deletion analysis, the site of action of Lrp was localized to a 25-bp region between coordinates -69 and -44 of the tdh promoter. Disruption of a 12-bp presumptive target sequence found in this region of tdh resulted in constitutively derepressed expression from the tdh promoter. Similar DNA segments (consensus, TTTATTCtNaAT) were also identified in a number of other promoters, including each of the Lrp-regulated promoters whose nucleotide sequence is known. The sequence of the promoter region of serA, an Lrp-regulated gene, was determined. No Lrp consensus target sequence was present upstream of serA, suggesting that Lrp acts indirectly on the serA promoter. A previously described mutation in a leucine-responsive trans-acting factor, LivR (J. J. Anderson, S. C. Quay, hnd D. L. Oxender, J. Bacteriol. 126:80-90, 1976), resulted in constitutively repressed expression from the tdh promoter and constitutively induced expression from the serA promoter. The possibility that LivR and Lrp are ailelic is discussed.

The mtr gene of Escherichia coli K-12 encodes an L-tryptophan-specific permease. This gene was originally identified through the isolation of mutations in the 69-min region of the chromosome, closely linked to argG.Cells with lesions in mtr display a phenotype of 5-methyltryptophan resistance. The mtr gene was cloned by using the mini-Mu system. The amino acid sequence of Mtr (414 codons), deduced by DNA sequence analysis, was found to be 33% identical to that of another single-component transport protein, the tyrosine-specific permease, TyrP. The hydropathy plots of the two permeases were similar. Possible operator sites for the tyrosine and tryptophan repressors are situated within the region of DNA that is likely to be the mtr promoter.In Escherichia coli, the aromatic amino acids are concentrated in the cytoplasm mainly via four operationally distinguishable transport systems. These systems are a general aromatic amino acid permease, encoded by aroP, and three other transport systems specific for phenylalanine, tyrosine, and tryptophan (6). The general aromatic amino acid permease has strong affinity for the aromatic amino acids (Km for all three amino acids, 10' M), whereas the individual transport systems have a lower affinity but a higher specificity for their respective aromatic amino acids (Km for each, ca. 10-6 M). Mutations in the structural genes for each specific permease have been found (6,19,39). The genes for the general aromatic amino acid permease, aroP, and the tyrosine-specific permease, tyrP, have been cloned (10,14) and sequenced (20,43). The regulation of transcription from the tyrP and aroP promoters has been thoroughly investigated (11,23,24). AroP and TyrP are hydrophobic proteins that are associated with the cytoplasmic membrane (10, 44).The tryptophan-specific transport system is encoded by a single gene designated mtr. This gene is situated near the 69-min region of the bacterial chromosome (19), and the locus was first identified through the isolation of mutations that impart resistance to the antimetabolite 5-methyltryptophan. By P1 transduction, mtr is 60 to 80% linked to argG (19,25). Mutations in mtr result in a loss of tryptophanspecific uptake (C. Yanofsky, cited by Oxender [34]). In addition to the aroP and mtr systems for L-tryptophan uptake, a gene for a low-affinity tryptophan permease (K, 10-5 M) is situated within the tna operon (14).This report describes the cloning and structural characterization of the mtr+ gene. The cloned DNA has structural and genetic properties predicted for a segment from the 69-min region of the chromosome. Several lines of evidence support the notion that the region cloned and sequenced in this study encodes the tryptophan-specific transport protein Mtr. Structural comparisons of Mtr with the two other wellcharacterized aromatic amino acid permeases of E. coli are also presented. Preparation of mini-Mu lysates. Mini-Mu lysates were prepared as described previously (18). MC1040-2 carrying plasmid pEG5005 was used to prepare a mini-Mu lysate. Lys...