Conformational entropy in molecular recognition by proteins

Molecular recognition by proteins is fundamental to almost every biological process, particularly the protein associations underlying cellular signal transduction. Understanding the basis for protein-protein interactions requires the full characterization of the thermodynamics of their association. Historically it has been virtually impossible to experimentally estimate changes in protein conformational entropy, a potentially important component of the free energy of protein association. However, nuclear magnetic resonance spectroscopy has emerged as a powerful tool for characterizing the dynamics of proteins. Here we employ changes in conformational dynamics as a proxy for corresponding changes in conformational entropy. We find that the change in internal dynamics of the protein calmodulin varies significantly on binding a variety of target domains. Surprisingly, the apparent change in the corresponding conformational entropy is linearly related to the change in the overall binding entropy. This indicates that changes in protein conformational entropy can contribute significantly to the free energy of protein-ligand association.     

Comparative genome sequencing of Escherichia coli allows observation of bacterial evolution on a laboratory timescale

We applied whole-genome resequencing of Escherichia coli to monitor the acquisition and fixation of mutations that conveyed a selective growth advantage during adaptation to a glycerol-based growth medium. We identified 13 different de novo mutations in five different E. coli strains and monitored their fixation over a 44-d period of adaptation. We obtained proof that the observed spontaneous mutations were responsible for improved fitness by creating single, double and triple site-directed mutants that had growth rates matching those of the evolved strains. The success of this new genome-scale approach indicates that real-time evolution studies will now be practical in a wide variety of contexts.     

A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.     

DNA hypomethylation in the origin and pathogenesis of human diseases

The pathogenesis of any given human disease is a complex multifactorial process characterized by many biologically significant and interdependent alterations. One of these changes, specific to a wide range of human pathologies, is DNA hypomethylation. DNA hypomethylation signifies one of the major DNA methylation states that refers to a relative decrease from the “normal” methylation level. It is clear that disease by itself can induce hypomethylation of DNA; however, a decrease in DNA methylation can also have an impact on the predisposition to pathological states and disease development. This review presents evidence suggesting the involvement of DNA hypomethylation in the pathogenesis of several major human pathologies, including cancer, atherosclerosis, Alzheimer’s disease, and psychiatric disorders. The views expressed in this paper do not necessarily represent those of the US Food and Drug Administration.     

Lime in the Early Bleaching Industry of Britain 1633-1828: Its Prohibition and Repeal

This essay describes the background and possible reasons for legal intervention in the use of lime in the early bleaching industry and draws on the Statutes at Large and other Acts of Parliament as primary sources. The developing chemical knowledge that may have contributed to the later Acts of repeal is also considered in some detail. The earliest noted prohibition was in 1633 and the years 1823, 1825, and 1828 were important repeal dates. No related legislation later than 1828 has been found. During the period from 1633 to 1828 there were many renewals and modifications to existing laws concerning linen and hempen manufacture; several of these contained subsections regarding bleaching. The considerable number of such Acts may account for the apparent confusion shown by earlier authors on this subject. Furthermore, the various Acts passed by the Irish House of Commons over its lifetime from 1400 to 1800, with its many interruptions, were published in a limited number of editions and are consequently held by few libraries. Ireland instituted its own laws and it was only after the Act of Union in 1800 that matters were dealt with by Westminster. Indeed, earlier historians have not always appreciated that, at certain periods of the history of the United Kingdom, Ireland and Scotland (as well as England) had their own separate parliaments.     

Density, distribution, and habitat of Flammulated Owls in Idaho

From 1990 to 1992 we surveyed for Flammulated Owls ( Otus flammeolus ) in 3 areas in Idaho: Salmon National Forest (SNF), Payette National Forest and adjacent Hells Canyon National Recreation Area (PNF-HCNRA), and Nez Perce National Forest (NPNF). We also collected and summarized information on all historic and modern records of Flammulated Owls in Idaho. Flammulated Owls were detected on 65% of 68 routes (2-16 km in length) surveyed at densities ranging from 0.04 to 1.25 singing males/40 ha. Owls were detected on survey routes as early as 10 May and as late as 23 July. Mean percent canopy cover estimated at owl locations on the PNF-HCNRA and NPNF study sites ranged from 52% to 64%, while shrub cover ranged from 16% to 21% and ground cover was 39% to 49%. Our surveys and summary of distributional records indicated that Flammulated Owls occur throughout the montane forests of Idaho in old or mature stands of open ponderosa pine ( Pinus ponderosa ), Douglas-fir ( Pseudotsuga menziesii ), and stands co-dominated by those 2 species. Fire suppression and timber harvest activity in ponderosa pine forests represent 2 main threats to the species' future security in Idaho. More research on the effects of various silvicultural treatments on Flammulated Owl populations is warranted.     

Aspects of Sacramento pikeminnow biology in nearshore habitats of the Sacramento-San Joaquin Delta, California

We documented distribution, relative abundance, diet composition, and body condition of Sacramento pikeminnow Ptychocheilus grandis during 2001 and 2003 at 5 sites in the Sacramento-San Joaquin Delta, California. Sacramento pikeminnow densities in nearshore habitats were higher in 2003 than 2001. In both years, spatial distribution of beach seine densities was similar. There were no significant differences in density among sampling sites except for the southernmost site where the catch was near zero. Based on rotary screw-trap data from a 6th site, we found relative abundance of Sacramento pikeminnow entering the Delta via an artificial floodplain was positively correlated with flow. Most individuals collected using all 3 gear types were age 1 or older, and appeared to grow quickly based on data from previous studies. Sacramento pikeminnow had diverse diets composed of freshwater and estuarine invertebrate and fish taxa. Incidence of piscivory was only 2% of the diet of individuals P. oregonensis , but in seeming contrast to endangered Colorado pikeminnow P. lucius , the present study showed that Sacramento pikeminnow can be successful in altered habitats. Sacramento pikeminnow; Ptychocheilus grandis; Sacramento-San Joaquin Delta; habitat use; diet composition; condition factor; Cyprinidae.     

Forest health impacts of bark beetles, dwarf mistletoe, and blister rust in a Lake Tahoe Basin mixed conifer stand

Interactions between forest health variables and mensurational characteristics in an uneven-aged eastern Sierra Nevada mixed conifer stand were examined. The stand was located in the Lake Tahoe Basin on a site featuring a coarsely textured granitic soil and numerous rock outcrops. Its composition was dominated by California white fir ( Abies concolor var. lowiana [Gord.] Lemm.), with Jeffrey pine ( Pinus jeffreyi Grev. & Balf.) and sugar pine ( Pinus lambertiana Dougl.) less prominent and incense-cedar ( Libocedrus decurrens Torr.) and mountain alder ( Alnus tenuifolia Nutt.) the most minor constituents. The majority of saplings and seedlings were white fir. The stand exhibited no evidence that its development had been influenced by fire and, overall, it consisted of numerous small trees accruing little radial growth. Nearly one-quarter of all standing stems pole size or larger were dead, with mortality concentrated in white fir. Forestfloor fuel accumulations were excessive, and coarse debris was especially prominent. A fir engraver beetle ( Scolytus ventralis LeConte) epidemic in white fir contrasted against apparent endemic population levels of the Jeffrey pine ( Dendroctonus jeffreyi Hopkins) and red turpentine ( Dendroctonus valens LeConte) beetles in Jeffrey pine and of the mountain pine beetle ( Dendroctonus ponderosae Hopkins) in sugar pine. The severity of fir engraver attack on white fir was weakly related to overall tree size and to the proportion of composition consisting of this host species, while in Jeffrey pine and sugar pine, bark beetle attacks were strongly correlated with the individual proportions of these 2 hosts. Across all species, basal area explained a substantial proportion of the variation in overall attack severity. We found light infestations of true fir dwarf mistletoe ( Arceuthobium abietinum Engelm. ex Munz f. sp. concoloris ) in white fir and western dwarf mistletoe ( Arceuthobium campylopodum Engelm.) in Jeffrey pine, plus an early stage of infection by the white pine blister rust ( Cronartium ribicola J.C. Fischer) in sugar pine. Collectively, this case study characterized and quantified many of the conditions, symptoms, and causative agents inherent in a decadent mixed conifer stand in the eastern Sierra Nevada.     

Correlation of histochemical and physiological properties of muscle units in the striped skunk

Summary Single motor units in striped skunk medial gastrocnemias were isolated and physiologically characterized. Individual muscle unit fibres tagged by glycogen depletion were analyzed histochemically and found to have histochemical profiles consistently correlated with the physiological findings.This work was supported by the Organized Research Committee, Northern Arizona University.