MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 x 10(-23), n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.     

Gene silencing: trans-histone regulatory pathway in chromatin

The fundamental unit of eukaryotic chromatin, the nucleosome, consists of genomic DNA wrapped around the conserved histone proteins H3, H2B, H2A and H4, all of which are variously modified at their amino- and carboxy-terminal tails to influence the dynamics of chromatin structure and function -- for example, conjugation of histone H2B with ubiquitin controls the outcome of methylation at a specific lysine residue (Lys 4) on histone H3, which regulates gene silencing in the yeast Saccharomyces cerevisiae. Here we show that ubiquitination of H2B is also necessary for the methylation of Lys 79 in H3, the only modification known to occur away from the histone tails, but that not all methylated lysines in H3 are regulated by this 'trans-histone' pathway because the methylation of Lys 36 in H3 is unaffected. Given that gene silencing is regulated by the methylation of Lys 4 and Lys 79 in histone H3, we suggest that H2B ubiquitination acts as a master switch that controls the site-selective histone methylation patterns responsible for this silencing.     

Pathogenic bacteria attach to human fibronectin through a tandem beta-zipper

Staphylococcus aureus and Streptococcus pyogenes, two important human pathogens, target host fibronectin (Fn) in their adhesion to and invasion of host cells. Fibronectin-binding proteins (FnBPs), anchored in the bacterial cell wall, have multiple Fn-binding repeats in an unfolded region of the protein. The bacterium-binding site in the amino-terminal domain (1-5F1) of Fn contains five sequential Fn type 1 (F1) modules. Here we show the structure of a streptococcal (S. dysgalactiae) FnBP peptide (B3) in complex with the module pair 1F12F1. This identifies 1F1- and 2F1-binding motifs in B3 that form additional antiparallel beta-strands on sequential F1 modules-the first example of a tandem beta-zipper. Sequence analyses of larger regions of FnBPs from S. pyogenes and S. aureus reveal a repeating pattern of F1-binding motifs that match the pattern of F1 modules in 1-5F1 of Fn. In the process of Fn-mediated invasion of host cells, therefore, the bacterial proteins seem to exploit the modular structure of Fn by forming extended tandem beta-zippers. This work is a vital step forward in explaining the full mechanism of the integrin-dependent FnBP-mediated invasion of host cells.     

Methionine enkephalin as a possible neuromodulator of regional cerebral blood flow

Summary In swine, cerebral blood flow was documented by a left ventricular injection of radiolabeled 15-micron spheres. Utilizing this procedure, the effect of the putative neurotransmitter methionine-enkephalin on regional cerebral blood flow was systemically evaluated. Our results revealed that a peripheral infusion of methionine enkephalin into miniature swine significantly increased cerebral blood flow in the basal ganglia, cerebellum, pons, inferior parietal cortex, superior parietal cortex and frontal cortex. Non-significant increases were observed in the hippocampus, occipital cortex and medulla oblongata while no effect on blood flow was observed in the pituitary gland. Significance of these results reside in the potential role of methionine enkephalin as a modulator of blood flow to the brain.     

Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring C57BL mice

Summary These experiments systematically investigated ethanol preference in both the C57Bl/6N and C57Bl/6J mice utilizing three-choice 2-bottle preference test. In addition, these sublines were evaluated for whole brain methionineenkephalin levels, which were significantly lower in C57Bl/6J mice (alcohol preferring) compared to C57Bl/6N mice (alcohol non-preferring). This finding supports the involvement of the peptidyl opiates in ethanol seeking behavior.     

Methionine enkephalin as a possible neuromodulator of regional cerebral blood flow

In swine, cerebral blood flow was documented by a left ventricular injection of radiolabeled 15-micron spheres. Utilizing this procedure, the effect of the putative neurotransmitter methionine-enkephalin on regional cerebral blood flow was systemically evaluated. Our results revealed that a peripheral infusion of methionine enkephalin into miniature swine significantly increased cerebral blood flow in the basal ganglia, cerebellum, pons, inferior parietal cortex and frontal cortex. Non-significant increases were observed in the hippocampus, occipital cortex and medulla oblongata while no effect on blood flow was observed in the pituitary gland. Significance of these results in the potential role of methionine enkephalin as a modulator of blood flow to the brain.     

A giant Ordovician anomalocaridid

Anomalocaridids, giant lightly sclerotized invertebrate predators, occur in a number of exceptionally preserved early and middle Cambrian (542-501?million years ago) biotas and have come to symbolize the unfamiliar morphologies displayed by stem organisms in faunas of the Burgess Shale type. They are characterized by a pair of anterior, segmented appendages, a circlet of plates around the mouth, and an elongate segmented trunk lacking true tergites with a pair of flexible lateral lobes per segment. Disarticulated body parts, such as the anterior appendages and oral circlet, had been assigned to a range of taxonomic groups--but the discovery of complete specimens from the middle Cambrian Burgess Shale showed that these disparate elements all belong to a single kind of animal. Phylogenetic analyses support a position of anomalocaridids in the arthropod stem, as a sister group to the euarthropods. The anomalocaridids were the largest animals in Cambrian communities. The youngest unequivocal examples occur in the middle Cambrian Marjum Formation of Utah but an arthropod retaining some anomalocaridid characteristics is present in the Devonian of Germany. Here we report the post-Cambrian occurrence of anomalocaridids, from the Early Ordovician (488-472?million years ago) Fezouata Biota in southeastern Morocco, including specimens larger than any in Cambrian biotas. These giant animals were an important element of some marine communities for about 30?million years longer than previously realized. The Moroccan specimens confirm the presence of a dorsal array of flexible blades attached to a transverse rachis on the trunk segments; these blades probably functioned as gills.     

Genetic history of an archaic hominin group from Denisova Cave in Siberia

Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.