The influence of ATP on the binding of aromatic amino acids to the ligand response domain of the tyrosine repressor of Haemophilus influenzae

Mitogillin and related fungal ribotoxins are small basic ribonucleolytic proteins that inhibit protein synthesis by specifically hydrolyzing a single phosphodiester bond in the universally conserved alpha-sarcin/ricin loop (SRL) of large subunit ribosomal RNAs. It was previously shown that mitogillin is a natural derivative of a T1/U2-like ribonuclease with inserted domains that are involved in target selection and specificity. Site-directed mutagenesis was used to substitute single amino acids in the previously identified functional domains Ala1-Tyr24 (B1-L1-B2 domain) and Lys106-Lys113 (L4 region). Examination of the activities of the mutants in the digestion of polyinosinic acid (a ribonuclease substrate) and specific cleavage of the SRL shows that Asn7Ala and Lys111Gln substitutions lead to altered ribonuclease activity and diminished substrate specificity consistent with the proposed functions of these domains.     

Chasing the dream: plant EST microarrays

DNA microarray technology is poised to make an important contribution to the field of plant biology. Stimulated by recent funding programs, expressed sequence tag sequencing and microarray production either has begun or is being contemplated for most economically important plant species. Although the DNA microarray technology is still being refined, the basic methods are well established. The real challenges lie in data analysis and data management. To fully realize the value of this technology, centralized databases that are capable of storing microarray expression data and managing information from a variety of sources will be needed. These information resources are under development and will help usher in a new era in plant functional genomics.     

Apparently unstable normal FMR1 alleles in nine developmentally delayed patients: implications for molecular diagnosis of the fragile X syndrome

The Fragile X syndrome is a common form of X-linked mental retardation, affecting approximately 1 in 4,000 males. Since the discovery of the FMR1 gene responsible for the syndrome, molecular, rather than cytogenetic, diagnosis of Fragile X syndrome has become the gold standard. Numerous molecular diagnostic centers worldwide use PCR and Southern blotting to characterize the size of the CGG repeats within the gene, expansion of which has been shown to be associated with the vast majority of cases of Fragile X syndrome. Instability of this repeat through successive generations has been demonstrated in many patients and has been associated with numerous factors, including repeat length and molecular structure of the repeat. Nine males with normal-size alleles that exhibit repeat length instability by the presence of a second normal length distinct band by repeated PCR analysis from peripheral lymphocytes are reported. Many hypotheses addressing the reason for this apparent instability were tested without elucidating the underlying molecular causes, including cytogenetic analysis, sequence analysis of the repeat locus, and analysis of flanking dinucleotide repeat loci. All patients exhibited a normal complement of sex chromosomes by cytogenetic and molecular analysis. These results from the widely used PCR analysis illustrate an interesting molecular phenomenon and raise many questions relating to the factors and mechanisms involved in trinucleotide instability as well as having implications for the diagnostic testing of the Fragile X syndrome.     

Stable Isotopes and Zooarchaeology at Teotihuacan,Mexico Reveal Earliest Evidence of Wild Carnivore Management in Mesoamerica

From Roman gladiatorial combat to Egyptian animal mummies, the capture and manipulation of carnivores was instrumental in helping to shape social hierarchies throughout the ancient world. This paper investigates the historical inflection point when humans began to control animals not only as alimental resources but as ritual symbols and social actors in the New World. At Teotihuacan (A.D. 1–550), one of the largest pre-Hispanic cities, animal remains were integral components of ritual caches expressing state ideology and militarism during the construction of the Moon and the Sun Pyramids. The caches contain the remains of nearly 200 carnivorous animals, human sacrificial victims and other symbolic artifacts. This paper argues the presence of skeletal pathologies of infectious disease and injuries manifest on the carnivore remains show direct evidence of captivity. Stable isotope analysis (δ¹³C and δ¹⁵N) of bones and teeth confirms that some of these carnivores were consuming high levels of C₄ foods, likely reflecting a maize-based anthropocentric food chain. These results push back the antiquity of keeping captive carnivores for ritualistic purposes nearly 1000 years before the Spanish conquistadors described Moctezuma’s zoo at the Aztec capital. Mirroring these documents the results indicate a select group of carnivores at Teotihuacan may have been fed maize-eating omnivores, such as dogs and humans. Unlike historical records, the present study provides the earliest and direct archaeological evidence for this practice in Mesoamerica. It also represents the first systematic isotopic exploration of a population of archaeological eagles (n = 24) and felids (n = 29).     

Paleomobility in the Tiwanaku Diaspora: Biogeochemical analyses at Rio Muerto,Moquegua, Peru

Paleomobility has been a key element in the study of the expansion of ancient states and empires, including the Tiwanaku polity of the South Central Andes (AD 500–1000). We present radiogenic strontium and oxygen isotope data from human burials from three cemeteries in the Tiwanaku‐affiliated Middle Horizon archaeological site complex of Rio Muerto in the Moquegua Valley of southern Peru. At Rio Muerto, archaeological human enamel and bone values range from ⁸⁷Sr/⁸⁶Sr = 0.70657–0.72018, with a mean of ⁸⁷Sr/⁸⁶Sr = 0.70804 ± 0.00207 (1σ, n = 55). For the subset of samples analyzed for oxygen isotope values (n = 48), the data ranges from δ¹⁸O_{carbonate(VSMOW)} = +18.1 to +27.0‰. When contextualized with other lines of archaeological evidence, we interpret these data as evidence for an archaeological population in which the majority of individuals had “local” origins, and were likely second‐generation, or more, immigrants from the Tiwanaku heartland in the altiplano. Based on detailed life history data, we argue a smaller number of individuals came at different ages from various regions within the Tiwanaku polity. We consider whether these individuals with isotopic values consistent with “nonlocal” geographic origins could represent first‐generation migrants, marriage exchange partners, or occupationally mobile herders, traders or other travelers. By combining isotopic life history studies with mortuary treatment data, we use a person‐centered migration history approach to state integration and expansion. Isotopic analyses of paleomobility at the Rio Muerto site complex contribute to the role of diversity in ancient states by demonstrating the range of geographic origins rather than simply colonists from the Lake Titicaca Basin. Am J Phys Anthropol 155:405–421, 2014. © 2014 Wiley Periodicals, Inc.     

Core exploration in optimization of chemokine receptor CCR4 antagonists

The design, synthesis, and SAR studies of 'core' variations led to identification of novel, selective, and potent small molecule antagonist (22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound 22 was efficacious in a murine allergic inflammation model (ED50 approximately 10 mg/kg).