Biological and Pharmacokinetic Studies with β-Peptides

Interactions and cleavage reactions of β-amino acids and β-oligopeptides (up to nine residues, carrying the side chains of Ala, Val, Leu, Ile, Phe, Ser, Lys, and Hop) with biological systems, such as the most potent peptidases (pronase, proteinase K, 20S proteasome), microorganisms (Pseudomonas aeruginosa and Pseudomonas putida), and mammalian blood (intravenous application to rats) have been investigated and compared with ?-peptides. The results are: i) the three peptidases do not cleave β-peptides at all (within 24 h), and they are not inhibited by a β-peptide; ii) except for certain 3-aminobutanoic-acid (β-HAla) derivatives, neither free, nor N-acetyl-β-amino acids, nor β-peptides (offered as sole N and C source) lead to growth of the two bacteria tested; iii) two water-soluble β-heptapeptides (with Lys side chains) were shown to have elimination half-lives t1/2(β) of 3 and 10 h at 100- and 30-ng/ml levels, respectively, in the rodent blood – much larger than those of α-peptides. Thus, the preliminary results described here confirm the much greater stability of β-peptides, as compared to α-peptides, towards metabolization processes, but they also suggest that there may be interactions (by hitherto unknown mechanisms) between the worlds of α- and β-peptides

Two Alleles of NF-κB in the Sea Anemone Nematostella vectensis Are Widely Dispersed in Nature and Encode Proteins with Distinct Activities

BACKGROUND. NF-κB is an evolutionarily conserved transcription factor that controls the expression of genes involved in many key organismal processes, including innate immunity, development, and stress responses. NF-κB proteins contain a highly conserved DNA-binding/dimerization domain called the Rel homology domain. METHODS/PRINCIPAL FINDINGS. We characterized two NF-κB alleles in the sea anemone Nematostella vectensis that differ at nineteen single-nucleotide polymorphisms (SNPs). Ten of these SNPs result in amino acid substitutions, including six within the Rel homology domain. Both alleles are found in natural populations of Nematostella. The relative abundance of the two NF-κB alleles differs between populations, and departures from Hardy-Weinberg equilibrium within populations indicate that the locus may be under selection. The proteins encoded by the two Nv-NF-κB alleles have different molecular properties, in part due to a Cys/Ser polymorphism at residue 67, which resides within the DNA recognition loop. In nearly all previously characterized NF-κB proteins, the analogous residue is fixed for Cys, and conversion of human RHD proteins from Cys to Ser at this site has been shown to increase DNA-binding ability and increase resistance to inhibition by thiol-reactive compounds. However, the naturally-occurring Nematostella variant with Cys at position 67 binds DNA with a higher affinity than the Ser variant. On the other hand, the Ser variant activates transcription in reporter gene assays more effectively, and it is more resistant to inhibition by a thiol-reactive compound. Reciprocal Cys<->Ser mutations at residue 67 of the native Nv-NF-κB proteins affect DNA binding as in human NF-κB proteins, e.g., a Cys->Ser mutation increases DNA binding of the native Cys variant. CONCLUSIONS/SIGNIFICANCE. These results are the first demonstration of a naturally occurring and functionally significant polymorphism in NF-κB in any species. The functional differences between these alleles and their uneven distribution in the wild suggest that different genotypes could be favored in different environments, perhaps environments that vary in their levels of peroxides or thiol-reactive compounds.National Institutes of Health (CA047763); National Science Foundation (FP-91656101-0); Environmental Protection Agency (F5E11155); Conservation International Marine Management Area Science Program; Boston University (SPRInG grant); Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution; The Beacon Institute for Rivers and Estuaries; the J Seward Johnson Fund; Boston University (5 P42 ES07381

Reassessing the protean career concept: Empirical findings, conceptual components, and measurement

This article was published in the serial Journal of Organizational Behavior [© John Wiley & Sons, Ltd.] The definitive version is available at: http://dx.doi.org/10.1002/job.1908The protean career concept is a widely acknowledged contemporary career model, but conceptual and empirical analysis of the model is scarce. We provide an integrative literature review of empirical research and note that the research is hampered by inconsistent use of terminology and methodological limitations. First, we show that the two protean metacompetencies-adaptability and identity-have been relatively neglected as the research has evolved. Second, we describe how preexisting protean measures are limited in covering the full range of the concept. Finally, we draw on career theory to suggest four conceptual components as a basis for future model development and offer suggestions for research that tests the utility of the protean career concept in relation to other similar constructs. © 2013 John Wiley & Sons, Ltd

Geology and ore deposits of Atacocha district, departmento de Pasco, Peru

The Atacocha district is in central Peru between the Río Tingo and Río Huallaga north of Cerro de Pasco. Roads from Cerro de Pasco extend along both the Tingo and Huallaga, and all mines are accessible by road. The district lies on a ridge extending north from the high central plateau of Peru and is characterized by steep topography with more than 900 meters of relief. The district and the three producing lead-zinc mines in it were studied in 1952-53 by geologists of the Instituto Geológico del Perú and the U. S. Geological Survey. Bedded rocks range in age from pre-Permian to Tertiary(?). The pre-Permian rocks are exposed only on the edges of the district. The total thickness of Permian and younger rocks is estimated at 2,420 to 3,930 meters, but no complete section is exposed owing to folding and faulting. The Mesozoic section ranges from 1,400 to 2,900 meters in thickness. The Pucará formation of Late Triassic to Early Jurassic age makes up the lower two thirds of the section, and is composed of limestone with some interbedded shale. Cretaceous rocks overlie the limestone and consist of quartz sandstone overlain by basalt flows. Cretaceous limestone is found at the top of the section in two horizons separated by basalt flows. The youngest consolidated rocks are conglomerates of probable Early Tertiary age. The sedimentary rocks are dated largely by lithologic correlation; fossils were found only in the Pucara formation. Dacite of probable Tertiary age intrudes the bedded rocks. Dikes and sills are numerous and four small stocks were found. All but one stock and most of the dikes and sills are near the Atacocha fault, which may have formed a favorable zone for intrusion. The intrusives are most abundant between Milpo and Atacocha. The Atacocha fault divides the district into two structural areas. East of the fault the principal structural features are simple folds. To the west of the fault, folding is more complex and the rocks are cut by a series of northwesterly-striking faults, and a fault parallel to the Atacocha fault. The Atacocha fault, a reverse fault, dips steeply eastward, the east side having moved up and to the north relative to the west side. The history of the area between Permian and Late Cretaceous time was one of marine and continental deposition interrupted by three and perhaps four periods of uplift and erosion. No strong folding took place during this interval as the sedimentary contracts are either conformable or disconformable. Volcanic activity occurred during the Permian and again in the Cretaceous. The Andean orogeny began in Late Cretaceous time and continued through much of the Tertiary. The rocks were folded, faulted, and intruded by dacite. Subsequent to the intrusions, lead and zinc sulfides were deposited from hydrothermal solutions, possibly as a late phase of intrusive activity. The ore deposits of the district are concentrated in three areas, Milpo, Machcán, and Atacocha. Lead and zinc are the principal metals obtained, and silver is an important byproduct. More than 90,000 tons of lead and 65,000 tons of zinc have been produced since 1940, nearly all from the Atacocha mine. Galena and sphalerite are the principal ore minerals. They occur with small amounts of jamesonite and tetrahedrite-tennantite in a gangue of pyrite, calcite, clay minerals, quartz, rhodochrosite, and fluorite. Cerussite is an important lead mineral at Machcán where most of the workings are in the oxide zone. Three stages of mineralization are recognized at Atacocha: a quartz-pyrite stage, a sulfide stage, and a realgar-orpiment stage. The deposits are classified as leptothermal to mesothermal. Both replacement ore bodies and veins are found in the district. Replacement bodies are the principal source of ore at Machcán and Atacocha but are not important at Milpo. The veins at Machcán are formed by replacement, but those at Atacocha and Milpo seem to be formed by fissure filling. The most important features in localizing the ore deposits appear to have been the porphyry intrusions, the Atacocha fault, and the contact of the Mitu and Pucará formations. Nearly all the ore is found in limestone of the Pucará formation or in the overlying sandstones of the Goyllarisquisga formation. Rocks of the Mitu group and rocks younger than the Goyllarisquisga formation seem to have been unfavorable for ore deposition