Single nucleotide RNA choreography

New structural analysis methods, and a tree formalism re-define and expand the RNA motif concept, unifying what previously appeared to be disparate groups of structures. We find RNA tetraloops at high frequencies, in new contexts, with unexpected lengths, and in novel topologies. The results, with broad implications for RNA structure in general, show that even at this most elementary level of organization, RNA tolerates astounding variation in conformation, length, sequence and context. However the variation is not random; it is well-described by four distinct modes, which are 3-2 switches (backbone topology variations), insertions, deletions and strand clips.     

Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C

Meconium ileus, intestinal obstruction in the newborn, is caused in most cases by CFTR mutations modulated by yet-unidentified modifier genes. We now show that in two unrelated consanguineous Bedouin kindreds, an autosomal-recessive phenotype of meconium ileus that is not associated with cystic fibrosis (CF) is caused by different homozygous mutations in GUCY2C, leading to a dramatic reduction or fully abrogating the enzymatic activity of the encoded guanlyl cyclase 2C. GUCY2C is a transmembrane receptor whose extracellular domain is activated by either the endogenous ligands, guanylin and related peptide uroguanylin, or by an external ligand, Escherichia coli (E. coli) heat-stable enterotoxin STa. GUCY2C is expressed in the human intestine, and the encoded protein activates the CFTR protein through local generation of cGMP. Thus, GUCY2C is a likely candidate modifier of the meconium ileus phenotype in CF. Because GUCY2C heterozygous and homozygous mutant mice are resistant to E. coli STa enterotoxin-induced diarrhea, it is plausible that GUCY2C mutations in the desert-dwelling Bedouin kindred are of selective advantage.     

Domain III of the T. thermophilus 23S rRNA folds independently to a near-native state

The three-dimensional structure of the ribosomal large subunit (LSU) reveals a single morphological element, although the 23S rRNA is contained in six secondary structure domains. Based upon maps of inter- and intra-domain interactions and proposed evolutionary pathways of development, we hypothesize that Domain III is a truly independent structural domain of the LSU. Domain III is primarily stabilized by intra-domain interactions, negligibly perturbed by inter-domain interactions, and is not penetrated by ribosomal proteins or other rRNA. We have probed the structure of Domain III rRNA alone and when contained within the intact 23S rRNA using SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension), in the absence and presence of magnesium. The combined results support the hypothesis that Domain III alone folds to a near-native state with secondary structure, intra-domain tertiary interactions, and inter-domain interactions that are independent of whether or not it is embedded in the intact 23S rRNA or within the LSU. The data presented support previous suggestions that Domain III was added relatively late in ribosomal evolution.     

H5-type influenza virus hemagglutinin is functionally recognized by the natural killer-activating receptor NKp44

Antiviral immune defenses involve natural killer (NK) cells. We previously showed that the NK-activating receptor NKp44 is involved in the functional recognition of H1-type influenza virus strains by NK cells. In the present study, we investigated the interaction of NKp44 and the hemagglutinin of a primary influenza virus H5N1 isolate. Here we show that recombinant NKp44 recognizes H5-expressing cells and specifically interacts with soluble H5 hemagglutinin. H5-pseudotyped lentiviral particles bind to NK cells expressing NKp44. Following interaction with target cells expressing H5, pseudotyped lentiviral particles, or membrane-associated H5, NK cells show NKp44-mediated induced activity. These findings indicate that NKp44-H5 interactions induce functional NK activation.     

Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean

Background

Mycobacterium tuberculosis is the principal etiologic agent of human tuberculosis. It has no environmental reservoir and is believed to have co-evolved with its host over millennia. This is supported by skeletal evidence of the disease in early humans, and inferred from M. tuberculosis genomic analysis. Direct examination of ancient human remains for M. tuberculosis biomarkers should aid our understanding of the nature of prehistoric tuberculosis and the host/pathogen relationship.

Methodology/Principal Findings

We used conventional PCR to examine bone samples with typical tuberculosis lesions from a woman and infant, who were buried together in the now submerged site of Atlit-Yam in the Eastern Mediterranean, dating from 9250-8160 years ago. Rigorous precautions were taken to prevent contamination, and independent centers were used to confirm authenticity of findings. DNA from five M tuberculosis genetic loci was detected and had characteristics consistent with extant genetic lineages. High performance liquid chromatography was used as an independent method of verification and it directly detected mycolic acid lipid biomarkers, specific for the M. tuberculosis complex.

Conclusions/Significance

Human tuberculosis was confirmed by morphological and molecular methods in a population living in one of the first villages with evidence of agriculture and animal domestication. The widespread use of animals was not a source of infection but may have supported a denser human population that facilitated transmission of the tubercle bacillus. The similarity of the M. tuberculosis genetic signature with those of today gives support to the theory of a long-term co-existence of host and pathogen.     

The dermatoglyphic characteristics of two isolated Bedouin groups from South Sinai

The dermatoglyphics of the Muzeina and Gebeliya Bedouin tribes, two small biologically isolated populations, leading a similar nomadic life under the specific conditions of the Sinai desert, were studied. The differences found between the studied samples concern particularly the frequencies of palmar and finger pattern types. These differences are in agreement with data on the origin of the tribes, a Negro and/or European admixture being evident in the Gebeliya dermatoglyphics. The coefficients of variation for some quantitative dermatoglyphic traits, presumably with a polygenic determination, are lower in the Muzeina than in the Gebeliya sample. Isolation and consanguinity may exert their influence on the dermatoglyphic traits influencing the frequencies of the corresponding genes.     

The living and the dead: How do taphonomic processes modify relative abundance and skeletal completeness of freshwater fish?

This study is designed to determine the extent to which taphonomic processes alter the taxonomic composition of fish remains in lacustrine sediments. We wish to explore information loss in a bone assemblage relative to the original, living community. We examined fish bone assemblages from lacustrine sediments along the southern shore of Lake Kinneret (Sea of Galilee) and compared them to modern living communities. For this purpose we randomly selected 24 squares, each 0.5 m² in size, and excavated them to a depth of 30–50 cm. Three lithofacies were recovered, spanning the past 1500 years (unccorected for reservoir age). The fish remains include 5037 bones and 758 scales, of which 1566 bones were identified to taxonomic group. The list of identified species was compared with the list of indigenous species known to live in Lake Kinneret in general and in a similar sandy habitat in particular. The proportion of skeletal elements found was compared with the proportion known in a complete fish. Our study indicates that differences exist between the three lithofacies in species diversity and composition, skeletal element richness, completeness, and relative abundance. In addition, the bones exhibit a clumped distribution pattern, regardless of depositional depth. From a taphonomic and paleoecological perspective, our findings demonstrate that fish remains retrieved from lacustrine sediments do not represent the composition and diversity of species as in the recent fish community.     

A study of extracellular matrix-cell adhesion peptidic epitopes related to human serum amyloid A (SAA)

Summary Serum amyloid A (SAA), an acute-phase protein, exists normally in the serum while complexed with high-density lipoprotein 3 (SAA-HDL₃). Its levels increase markedly during inflammatory diseases. The pentapeptide Tyr-Ile-Gly-Ser-Asp (YIGSR-like) and the tripeptide Arg-Gly-Asn (RGD-like), related to the cell adhesion domains of laminin and fibronectin, respectively, exist in SAA within close proximity (YIGSDKYFHARGNY; amino acid residues 29–42). A structure-function study of linear and head-to-tail cyclic peptides, related to the amino acid residues 29–42) and 70–76 (GRGAEDS) of human SAA, was performed in order to evaluate their ability to inhibit adhesion of human T-lymphocytes to surfaces coated with extracellular matrix purified from bovine corneal cells.