Interacting loci cause severe iris atrophy and glaucoma in DBA/2J mice

Glaucomas are a major cause of blindness. Visual loss typically involves retinal ganglion cell death and optic nerve atrophy subsequent to a pathologic elevation of intraocular pressure (IOP). Some human glaucomas are associated with anterior segment abnormalities such as pigment dispersion syndrome (PDS) and iris atrophy with associated synechiae. The primary causes of these abnormalities are unknown, and their aetiology is poorly understood. We recently characterized a mouse strain (DBA/2J) that develops glaucoma subsequent to anterior segment changes including pigment dispersion and iris atrophy. Using crosses between mouse strains DBA/2J (D2) and C57BL/6J (B6), we now show there are two chromosomal regions that contribute to the anterior segment changes and glaucoma. Progeny homozygous for the D2 allele of one locus on chromosome 6 (called ipd) develop an iris pigment dispersion phenotype similar to human PDS. ipd resides on a region of mouse chromosome 6 with conserved synteny to a region of human chromosome 7q that is associated with human PDS. Progeny homozygous for the D2 allele of a different locus on chromosome 4 (called isa) develop an iris stromal atrophy phenotype (ISA). The Tyrpl gene is a candidate for isa and likely causes ISA via a mechanism involving pigment production. Progeny homozygous for the D2 alleles of both ipd and isa develop an earlier onset and more severe disease involving pigment dispersion and iris stromal atrophy.     

Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development.

Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects. Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate-transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. Previous experiments have identified a folate-binding protein (Folbp1) that functions as a membrane receptor to mediate the high-affinity internalization and delivery of folate to the cytoplasm of the cell. In vitro, this receptor facilitates the accumulation of cellular folate a thousand-fold relative to the media, suggesting that it may be essential in cytoplasmic folate delivery in vivo. The importance of an adequate intracellular folate pool for normal embryogenesis has long been recognized in humans and experimental animals. To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice. We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly. Folbp2-/- embryos developed normally, but Folbp1-/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10. Supplementing pregnant Folbp1+/- dams with folinic acid reversed this phenotype in nullizygous pups. Our results suggest that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homologue (FOLR1) of Folbp1 may contribute to similar defects in humans.     

Effects of environmental temperature-humidity and cage density on body weight and behavior in mice

Zusammenfassung Es wurden Mäuse des C3H/HeJ-Stammes nach Entwöhnung bis zum Alter von 125 Tagen unter verschiedenen Umweltbedingungen wie Temperatur, relative Luftfeuchtigkeit und Käfigdichte aufgezogen. Je höher Temperatur, relative Luftfeuchtigkeit und je grösser die Käfigdichte, um so grösser waren die Körpergewichtsverluste. Umwelttemperatur, Feuchtigkeit und Käfigdichte beeinflussten zusammen das Überleben der Mäuse nach Schwimmen.     

Abrupt changes in the Asian southwest monsoon during the Holocene and their links to the North Atlantic Ocean

During the last ice age, the Indian Ocean southwest monsoon exhibited abrupt changes that were closely correlated with millennial-scale climate events in the North Atlantic region, suggesting a mechanistic link. In the Holocene epoch, which had a more stable climate, the amplitude of abrupt changes in North Atlantic climate was much smaller, and it has been unclear whether these changes are related to monsoon variability. Here we present a continuous record of centennial-scale monsoon variability throughout the Holocene from rapidly accumulating and minimally bioturbated sediments in the anoxic Arabian Sea. Our monsoon proxy record reveals several intervals of weak summer monsoon that coincide with cold periods documented in the North Atlantic region--including the most recent climate changes from the Medieval Warm Period to the Little Ice Age and then to the present. We therefore suggest that the link between North Atlantic climate and the Asian monsoon is a persistent aspect of global climate.     

Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation

Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems. Staphylococcus aureus, an important human pathogen implicated in sepsis and endocarditis, secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting. Here we present the 2.2 A crystal structures of human alpha-thrombin and prethrombin-2 bound to a fully active staphylocoagulase variant. The cofactor consists of two domains, each with three-helix bundles; this is a novel fold that is distinct from known serine proteinase activators, particularly the streptococcal plasminogen activator streptokinase. The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors. Kinetic studies confirm the importance of isoleucine 1 and valine 2 at the amino terminus of staphylocoagulase for zymogen activation. In addition to making contacts with the 148 loop and (pro)exosite I of prethrombin-2, staphylocoagulase inserts its N-terminal peptide into the activation pocket of bound prethrombin-2, allosterically inducing functional catalytic machinery. These investigations demonstrate unambiguously the validity of the zymogen-activation mechanism known as 'molecular sexuality'.     

Suppression of carcinogen-induced rat mammary tumor formation by Actinomycin D

Zusammenfassung Sprague-Dawley-Ratten, die eine kombinierte Belastung mit 7,12-Dimethylbenz()anthrazen und Aktinomyzin D überleben, weisen eine drastisch erniedrigte tastbare Tumorinzidenz auf. Kontrolltiere erhielten nur das Karzinogen.