Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.     

Exclusion of a luminous red giant as a companion star to the progenitor of supernova SN 2011fe

Type Ia supernovae are thought to result from a thermonuclear explosion of an accreting white dwarf in a binary system, but little is known of the precise nature of the companion star and the physical properties of the progenitor system. There are two classes of models: double-degenerate (involving two white dwarfs in a close binary system) and single-degenerate models. In the latter, the primary white dwarf accretes material from a secondary companion until conditions are such that carbon ignites, at a mass of 1.38 times the mass of the Sun. The type Ia supernova SN 2011fe was recently detected in a nearby galaxy. Here we report an analysis of archival images of the location of SN 2011fe. The luminosity of the progenitor system (especially the companion star) is 10-100 times fainter than previous limits on other type Ia supernova progenitor systems, allowing us to rule out luminous red giants and almost all helium stars as the mass-donating companion to the exploding white dwarf.     

Molecular recognition of microbial lipid-based antigens by T cells

The immune system has evolved to protect hosts from pathogens. T cells represent a critical component of the immune system by their engagement in host defence mechanisms against microbial infections. Our knowledge of the molecular recognition by T cells of pathogen-derived peptidic antigens that are presented by the major histocompatibility complex glycoproteins is now well established. However, lipids represent an additional, distinct chemical class of molecules that when presented by the family of CD1 antigen-presenting molecules can serve as antigens, and be recognized by specialized subsets of T cells leading to antigen-specific activation. Over the past decades, numerous CD1-presented self- and bacterial lipid-based antigens have been isolated and characterized. However, our understanding at the molecular level of T cell immunity to CD1 molecules presenting microbial lipid-based antigens is still largely unexplored. Here, we review the insights and the molecular basis underpinning the recognition of microbial lipid-based antigens by T cells.     

The Hill equation and the origin of quantitative pharmacology

This review addresses the 100-year-old Hill equation (published in January 22, 1910), the first formula relating the result of a reversible association (e.g., concentration of a complex, magnitude of an effect) to the variable concentration of one of the associating substances (the other being present in a constant and relatively low concentration). In addition, the Hill equation was the first (and is the simplest) quantitative receptor model in pharmacology. Although the Hill equation is an empirical receptor model (its parameters have only physico-chemical meaning for a simple ligand binding reaction), it requires only minor a priori knowledge about the mechanism of action for the investigated agonist to reliably fit concentration-response curve data and to yield useful results (in contrast to most of the advanced receptor models). Thus, the Hill equation has remained an important tool for physiological and pharmacological investigations including drug discovery, moreover it serves as a theoretical basis for the development of new pharmacological models.     

Taxonomy and variation of the Lopidea nigridia complex of western North America (Heteroptera: Miridae, Orthotylinae)

External morphological variation in the Lopidea nigridia "complex" of western North America was examined using principal component analysis and showed continuous variation among populations in most characters. External morphology did not parallel paramere structure and did not substantiate previously recognized species. There was little correlation between dorsal coloration and paramere structure. Cluster analysis (UPGMA) using paramere and color characters failed to group populations coded as the same species and also failed to group all specimens of any one population. The variation in structure of the parameres and vesicae among populations of the nigridia complex was no greater than the interpopulational variation of these structures structures in the congeneric species marginata Uhler. Lopidea nigridia Uhler is treated as a polytypic species comprising three subspecies: Lopidea nigridia nigridia Uhler, a fuscous-white form from the sagebrush steppe of the Great Basin and the chaparral of southern California; Lopidea nigridia serica Knight, a solid red form from the eastern slopes of the Rocky Mountains from Alberta to Colorado and east across the Northern Great Plains to southern Manitoba; Lopidea nigridia aculeata Van Duzee, a polymorphic form varying from solid red to fuscous red and white from the Cascade Mountains and eastern slopes of the coastal ranges of British Columbia, Washington, and Oregon, the Blue and Wallawa mountains of Oregon and Washington, and throughout the Coastal and Sierra Nevada ranges of California. The following new synonymies are created: Lopidea nigridia Uhler -- Lopidea raineri Knight, Lopidea scullent Knight, Lopidea rolfsi Knight, and Lopidea wilcoxi Knight; Lopidea nigridia aculeata Van Duzee -- Lopidea nigridia hirta Van Duzee, Lopidea usingeri Van Duzee, Lopidea discreta Van Duzee, Lopidea fallax Knight, Lopidea Yakima Knight, Lopidea audeni Knight, Lopidea eriogoni Knight, Lopidea calcaria Knight, Lopidea chamberlini Knight, Lopidea angustata Knight, Lopidea rubrofusca Knight, and Lopidea flavicostata Knight and Schaffner; Lopidea nigridia serica Knight -- Lopidea medleri Akingbohungbe.