AIMS: Penetrance and phenotypic expressivity of cardiomyopathies are modulated by modifier genes both in model systems and patients. We aimed to dissect the disease-modifying mechanisms by examining genome-wide gene expression in a new set of mouse (Mus musculus) congenic strains. METHODS AND RESULTS: Mutant alleles of the genes calsarcin-1 (Myoz2), sarcoglycan-delta (Sgcd), and muscle LIM protein (Csrp2) were each transferred onto inbred strain backgrounds C57BL/6, C3H/He, 129S1/Sv, and FVB/N, respectively. At 9-10 weeks of age, left ventricular pump function (fractional shortening, FS) was determined by echocardiography in non-sedated congenic animals. Gene expression was then analysed in myocardial tissue using the Affymetrix Mouse 430.2 microarray platform. Variance stabilization, linear mixed-effects modelling, correlations, gene functional classification, and pathway analysis were conducted using the standard software. Strain background FVB/N appeared to protect against the consequences of gene inactivation. Sgcd-deficient congenics showed normal FS, which was consistent with their hypertrophic cardiomyopathy phenotype. Animals with other allele/background combinations developed an impaired ventricular pump function (FS <65%). Gender did not influence FS significantly, yet it determined the sets of genes that were differentially expressed in mice with low FS. In particular, genes encoding the elements of the ubiquitin-proteasome system (UPS) were strongly correlated with the cardiac impairment (absolute Spearman r≥ 0.7) in both males and females. CONCLUSION: Gene expression profiling in a novel set of congenic strains revealed an association between the UPS and myocardial contractile function, indicating that the UPS may be an important modifier of phenotypic variability in cardiomyopathies.
Cardiovascular Research (2012) 94(1): 87-95

Guinea-pigs were infected subcutaneously or by respiratory challenge with plasmid-containing (pPst+pCad+pFra+) Yersinia pestis strain 358 and its pPst-pCad+pFra+, pPst+pCad+pFra- and pPst- pCad+pFra- derivatives, grown in vitro at 28°C or at 37°C. Lack of plasmid pPst did not lead to an increase in LD50 with either route of challenge. When the virulence of the four Y. pestis strains grown at the two temperatures was compared, the LD50 values of those grown at 37°C were lower. Respiratory challenge with cultures grown at 37°C mimics the man-to-man pneumonic plague cycle. The average LD50 values decreased c. two-fold and 10-fold for pPst+ and pPst- Y. pestis variants, respectively. The data suggest that historical epidemic outbreaks of pneumonic plague in the human population residing in the Caucasus region where there are natural plague foci in common voles may have been caused by pPst- Y. pestis strains.
J. Med. Microbiol. 1996; 45 (6): 440-444.