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PubMed2006

Disease risk analysis: A paradigm for using health-based data to inform primate conservation and public health.

Risk analysis is a multidisciplinary process used to evaluate existing knowledge in order to prioritize risks associated with the spread of disease. A principle aim of risk analysis is to facilitate the development of cost-effective management strategies. Risk analysis calls for a multidisciplinary approach to piece together and integrate the numerous factors that influence disease transmission. The seven papers included in this volume of AJP present current primatological research as viewed through the prism of risk analysis. Issues such as interspecies disease transmission, public health, and conservation of endangered species are addressed, and risk analysis is put forward as a possible paradigm to promote understanding of infectious disease and its impact on nonhuman primate and human populations.

Animals↗
PubMed2004

Are residues in a protein folding nucleus evolutionarily conserved?

Protein is the working molecule of the cell, and evolution is the hallmark of life. It is important to understand how protein folding and evolution influence each other. Several studies correlating experimental measurement of residue participation in folding nucleus and sequence conservation have reached different conclusions. These studies are based on assessment of sequence conservation at folding nucleus sites using entropy or relative entropy measurement derived from multiple sequence alignment. Here we report analysis of conservation of folding nucleus using an evolutionary model alternative to entropy-based approaches. We employ a continuous time Markov model of codon substitution to distinguish mutation fixed by evolution and mutation fixed by chance. This model takes into account bias in codon frequency, bias-favoring transition over transversion, as well as explicit phylogenetic information. We measure selection pressure using the ratio omega of synonymous versus non-synonymous substitution at individual residue site. The omega-values are estimated using the PAML method, a maximum-likelihood estimator. Our results show that there is little correlation between the extent of kinetic participation in protein folding nucleus as measured by experimental phi-value and selection pressure as measured by omega-value. In addition, two randomization tests failed to show that folding nucleus residues are significantly more conserved than the whole protein, or the median omega value of all residues in the protein. These results suggest that at the level of codon substitution, there is no indication that folding nucleus residues are significantly more conserved than other residues. We further reconstruct candidate ancestral residues of the folding nucleus and suggest possible test tube mutation studies for testing folding behavior of ancient folding nucleus.

Amino Acid Sequence↗
PubMed2006

Signatures of ecological resource availability in the animal and plant proteomes.

Although substantial and ecologically significant differences in elemental composition are well documented for whole organisms, little is known about whether such differences extend to lower levels of biological organization, such as the elemental composition of major molecules. In a proteome-scale investigation of 9 plant genomes and 9 animal genomes, we find that the nitrogen (N) content of plant proteins is lower than that in animal proteins. Furthermore, protein N content declines with the intensity of gene expression for plants, whereas the N content of animal proteins shows no consistent pattern with expression. Additional analyses indicate that the differences in N content between plant and animal proteomes and in plant proteins as a function of gene expression cannot be attributed to protein size, GC content, gene function, or amino acid properties. These patterns suggest that ecophysiological selection has operated to conserve N in plants via decreased reliance on N-rich amino acids. This inference was supported by an analysis of conserved and variable sites indicating that the N content of plant amino acids coded by variable sites is similar to that of the sites conserved between plant and animal genomes and shows no association with expression level. In contrast, in animals, the N content of amino acids coded by variable sites is significantly higher than that for conserved sites, suggesting relaxation of selective constraints for N usage in the animal lineage. This constitutes the first evidence for an influence of environmental resource availability on proteomes of multicellular organisms.

Amino Acids↗
PubMed2003

The genetic core of the universal ancestor.

Molecular analysis of conserved sequences in the ribosomal RNAs of modern organisms reveals a three-domain phylogeny that converges in a universal ancestor for all life. We used the Clusters of Orthologous Groups database and information from published genomes to search for other universally conserved genes that have the same phylogenetic pattern as ribosomal RNA, and therefore constitute the ancestral genetic core of cells. Our analyses identified a small set of genes that can be traced back to the universal ancestor and have coevolved since that time. As indicated by earlier studies, almost all of these genes are involved with the transfer of genetic information, and most of them directly interact with the ribosome. Other universal genes have either undergone lateral transfer in the past, or have diverged so much in sequence that their distant past could not be resolved. The nature of the conserved genes suggests innovations that may have been essential to the divergence of the three domains of life. The analysis also identified several genes of unknown function with phylogenies that track with the ribosomal RNA genes. The products of these genes are likely to play fundamental roles in cellular processes.

Animals↗
PubMed2004

Navy Hearing Conservation Program: 1995-1999 retrospective analysis of threshold shifts for age, sex, and officer/enlisted status.

This study provides a cross-sectional, population-based analysis of significant threshold shifts (STS) from over 83,000 audiograms on active duty members in the Navy Hearing Conservation Program Database for 1995-1999. Crude STS rates were lower for women than men (odds ration [OR], 0.82; 95% confidence interval [CI], 0.76-0.89; p = 0.0000) and lower for officer than enlisted (OR, 0.71; 95% CI, 0.66-0.76; p = 0.000000). STS rates also increased significantly with increasing age (chi2 for trend, 134; p = 0.0000). Compared with historical information, STS rates for officers were significantly lower (OR, 0.23; 95% CI, 0.18-0.27; p = 0.00000). Adjustment by logistic regression found STS rates were lower for women (OR, 0.837; 95% CI, 0.773-0.905; p = 0.000) and officer status (OR, 0.670; 95% CI, 0.619-0.725; p = 0.0000), and increased significantly with age. These findings warrant further investigation because they have programmatic implications on Navy hearing conservation and force health protection.

Adolescent↗
PubMed2003

Genetic structure in a montane ranid frog: restricted gene flow and nuclear-mitochondrial discordance.

There is substantial debate over the criteria that should be used to group populations of a species into distinct units for conservation (e.g. evolutionarily significant units, management units, distinct population segments). However, in practice molecular genetic differentiation is often the only or main criterion used to identify such units. Most genetic studies attempting to define conservation units in animals use a single molecular marker, most often mitochondrial, and use samples from a limited number of populations throughout the species' range. Although there are many benefits to using mtDNA, certain features can cause it to show patterns of differentiation among populations that do not reflect the history of differentiation at the nuclear genome where loci controlling traits of adaptive significance presumably occur. Here we illustrate an example of such mitochondrial-nuclear discordance in a ranid frog, and show how using mtDNA or nuclear loci alone could have led to very different conservation recommendations. We also found very high genetic differentiation among populations on a local scale, and discuss the conservation implications of our results.

Alleles↗
PubMed2003

Two-dimensional gap analysis: a tool for efficient conservation planning and biodiversity policy implementation.

The maintenance of biodiversity by securing representative and well-connected habitat networks in managed landscapes requires a wise combination of protection, management, and restoration of habitats at several scales. We suggest that the integration of natural and social sciences in the form of "Two-dimensional gap analysis" is an efficient tool for the implementation of biodiversity policies. The tool links biologically relevant "horizontal" ecological issues with "vertical" issues related to institutions and other societal issues. Using forest biodiversity as an example, we illustrate how one can combine ecological and institutional aspects of biodiversity conservation, thus facilitating environmentally sustainable regional development. In particular, we use regional gap analysis for identification of focal forest types, habitat modelling for ascertaining the functional connectivity of "green infrastructures", as tools for the horizontal gap analysis. For the vertical dimension we suggest how the social sciences can be used for assessing the success in the implementation of biodiversity policies in real landscapes by identifying institutional obstacles while implementing policies. We argue that this interdisciplinary approach could be applied in a whole range of other environments including other terrestrial biota and aquatic ecosystems where functional habitat connectivity, nonlinear response to habitat loss and a multitude of economic and social interests co-occur in the same landscape.

Conservation of Natural Resources↗
PubMed2026

Proteomic Analysis of Biomineralization Proteins in the Shell Plates and Spicules of Chiton Acanthochitona rubrolineata.

Chitons, ancient polyplacophoran mollusks, are ideal models for studying biomineralization evolution due to their conserved morphology since the Cambrian. This study investigates the matrix proteins in shell plates and spicules of Acanthochitona rubrolineata using liquid chromatography-tandem mass spectrometry. By extracting proteins from 30 individuals and using proteomic method, we identified 26 soluble proteins and 22 insoluble proteins in the shell plates and 25 insoluble proteins, and found domains such as von Willebrand factor type A, chitin-binding, ferritin, and cadherin. These domains, prevalent in molluscan biominerals, suggest conserved roles in organic matrix formation. Despite genomic dynamism, the conservation of key domains across species highlights a core biomineralization mechanism. Notably, eight of the shell proteins and eight of the spicule proteins were homologous between A. rubrolineata and chiton Acanthopleura loochooana, indicating functional conservation. Phylogenetic analysis further supported the evolutionary significance of these domains in chitons. The study advances understanding of biomineralization in Polyplacophora, emphasizing the interplay between morphological stasis and molecular evolution.

matrix proteins↗
PubMed1991

Conservative treatment of boxer's fracture: a retrospective analysis.

To investigate the outcome of conservative treatment, with and without closed reduction, 45 patients with fractures of the fifth metacarpal neck were evaluated 1 to 5 years after the initial injury. Radiographs were then taken to compare angulation and length with the original radiographs. The range of motion of the joints of the little finger was measured and the grip strength was assessed. The effects of malrotation on cosmetic appearance were observed, as were any signs of dystrophy. Finally, the patient's subjective opinion was obtained. Disability due to the injury was found in three patients while two others had moderate symptoms during daily activities. There seems to be little indication for closed reposition or operative treatment.

Adolescent↗
PubMed2004

Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases.

Iatrogenic angiosarcomas (AS), following treatment of breast carcinomas and attributed to chronic lymphedema, were first described by Stewart and Treves. With emphasis on breast-conserving therapy combined with adjuvant radiation, a recently recognized form of cutaneous postradiation angiosarcoma of the breast (CPRASB) has emerged. To more completely characterize CPRASB, 27 cases were analyzed. Histologic features studied included pattern of growth (vasoformative, sieve-like, or solid), nuclear grade, necrosis, and mitotic rate. Clinical and follow-up information was obtained. The patients received relatively standard radiation treatment. The median interval to diagnosis of CPRASB was 59 months; 5 occurred in less than 3 years. Lymphedema was largely absent, and when present was only mild in nature. CPRASB was frequently multifocal at presentation (13 of 27). All tumors had a vasoformative pattern of growth; the majority (16 of 27) had areas with a sieve-like pattern. The solid pattern was less frequent (7 of 27). The majority had high-grade nuclear features (16 grade 3, 8 grade 2, 3 grade1). The mean mitotic rate was 9/10 HPF. Necrosis was rare (2 of 27). All were treated with wide excision or mastectomy. Follow-up was available on 22 of 27 cases (median 44 months). Fourteen experienced local recurrence and 6 had multiple recurrences. Metastasis was documented in 9 of 22 patients and involved lungs (6), contralateral breast (3), skeleton (2), lymph nodes (1), and soft tissue (1). Eight patients died of disease, 2 died with disease, 4 were alive with disease, and 8 are alive without disease. The median interval to death was 33.5 months. All 4 patients with disease have documented metastasis. CPRASB differs from Stewart-Treves AS by its shorter latency period and lack of association with lymphedema.

Aged↗
PubMed2005

Identification and analysis of alternative splicing events conserved in human and mouse.

Alternative pre-mRNA splicing affects a majority of human genes and plays important roles in development and disease. Alternative splicing (AS) events conserved since the divergence of human and mouse are likely of primary biological importance, but relatively few of such events are known. Here we describe sequence features that distinguish exons subject to evolutionarily conserved AS, which we call alternative conserved exons (ACEs), from other orthologous human/mouse exons and integrate these features into an exon classification algorithm, acescan. Genome-wide analysis of annotated orthologous human-mouse exon pairs identified approximately 2,000 predicted ACEs. Alternative splicing was verified in both human and mouse tissues by using an RT-PCR-sequencing protocol for 21 of 30 (70%) predicted ACEs tested, supporting the validity of a majority of acescan predictions. By contrast, AS was observed in mouse tissues for only 2 of 15 (13%) tested exons that had EST or cDNA evidence of AS in human but were not predicted ACEs, and AS was never observed for 11 negative control exons in human or mouse tissues. Predicted ACEs were much more likely to preserve the reading frame and less likely to disrupt protein domains than other AS events and were enriched in genes expressed in the brain and in genes involved in transcriptional regulation, RNA processing, and development. Our results also imply that the vast majority of AS events represented in the human EST database are not conserved in mouse.

Alternative Splicing↗
PubMed2005

Deletion of long-range sequences at Sox10 compromises developmental expression in a mouse model of Waardenburg-Shah (WS4) syndrome.

The transcription factor SOX10 is mutated in the human neurocristopathy Waardenburg-Shah syndrome (WS4), which is characterized by enteric aganglionosis and pigmentation defects. SOX10 directly regulates genes expressed in neural crest lineages, including the enteric ganglia and melanocytes. Although some SOX10 target genes have been reported, the mechanisms by which SOX10 expression is regulated remain elusive. Here, we describe a transgene-insertion mutant mouse line (Hry) that displays partial enteric aganglionosis, a loss of melanocytes, and decreased Sox10 expression in homozygous embryos. Mutation analysis of Sox10 coding sequences was negative, suggesting that non-coding regulatory sequences are disrupted. To isolate the Hry molecular defect, Sox10 genomic sequences were collected from multiple species, comparative sequence analysis was performed and software was designed (ExactPlus) to identify identical sequences shared among species. Mutation analysis of conserved sequences revealed a 15.9 kb deletion located 47.3 kb upstream of Sox10 in Hry mice. ExactPlus revealed three clusters of highly conserved sequences within the deletion, one of which shows strong enhancer potential in cultured melanocytes. These studies: (i) present a novel hypomorphic Sox10 mutation that results in a WS4-like phenotype in mice; (ii) demonstrate that a 15.9 kb deletion underlies the observed phenotype and likely removes sequences essential for Sox10 expression; (iii) combine a novel in silico method for comparative sequence analysis with in vitro functional assays to identify candidate regulatory sequences deleted in this strain. These studies will direct further analyses of Sox10 regulation and provide candidate sequences for mutation detection in WS4 patients lacking a SOX10-coding mutation.

Algorithms↗
PubMed2006

Cloning and characterisation of two natural killer enhancing factor genes (NKEF-A and NKEF-B) in pufferfish, Tetraodon nigroviridis.

Natural killer cell enhancing factor (NKEF) belongs to a highly conserved peroxiredoxin (Prx) family. Its functions are involved in immune cytotoxicity, apoptosis, cell proliferation, differentiation and antioxidant activity. In present paper, two NKEF genes, NKEF-A and NKEF-B, were isolated and characterised in spotted green pufferfish, Tetraodon nigroviridis. Comparative genomic location analysis shows conserved syntenies within the NKEF-A and NKEF-B regions between Tetraodon and human, indicating that the Tetraodon NKEF-A and NKEF-B genes are orthologs for mammalian NKEF-A and NKEF-B encoding genes, respectively. The genomic organisation of the two genes is similar in different species, containing one non-coding exon, five coding exons and five introns. The deduced amino acids of the two genes are highly homologous with mammalian NKEF-A and NKEF-B proteins, including two well conserved Val-Cys-Pro (VCP) motifs. Tissue specific expression analysis by RT-PCR reveals that both genes are globally expressed. Stimulation with LPS inhibits both NKEF-A and NKEF-B gene expression in most tissues but enhances NKEF-A and NKEF-B transcriptions in spleen. This is the first report on the existence of a NKEF-B homologue in fish.

Amino Acid Sequence↗
PubMed1984

Evaluation of industrial hearing conservation programs: a review and analysis.

In 1981, a large scale reviews of the literature concerning the effects of noise on hearing was initiated by the National Institute of Neurological and Communicative Diseases and Stroke. This review concentrated on the information published in the decade of the 1970's and underscored the importance of evaluating the effectiveness of industrial hearing conservation programs. Published information on this topic was scanty prior to 1970. Investigations of the application and utility of methods for this evaluation have only recently begun to appear in the literature. The status of evaluating hearing conservation programs is the subject of the present review. Three evaluation methods are considered in detail: use of various proposed criteria for significant threshold shift; methods used by Pell at DuPont; and more recent methods developed by Royster. The condition and availability of data do not permit selection of the optimum evaluation procedure. Systematic collection and analysis of data from industrial programs are necessary if acceptable standardized procedures for evaluation of hearing conservation programs are to be developed.

Evaluation Studies as Topic↗
PubMed2006

Enhancers located within two introns of the vitamin D receptor gene mediate transcriptional autoregulation by 1,25-dihydroxyvitamin D3.

The biological actions of 1,25-(OH)2D3 are mediated by the vitamin D receptor (VDR), a protein that binds to target genes and alters their expression. 1,25-(OH)2D3 is also capable of inducing transcription of the VDR gene itself. In the present study, we explored both the capacity of 1,25-(OH)2D3 to induce VDR gene expression in bone cells and the mechanism instrumental to this up-regulation. After establishing the ability of 1,25-(OH)2D3 to stimulate VDR mRNA up-regulation both in bone in vivo and in osteoblastic cells, we screened the mouse VDR gene locus from 20 kb upstream of the gene's transcriptional start site (TSS) to 10 kb downstream of the final exon to identify VDR binding sites using chromatin immunoprecipitation-DNA microarray (ChIP-chip) analysis. Three conserved regions were identified 20, 27, and 29 kb downstream of the TSS. VDR binding to these sites in response to 1,25-(OH)2D3 was confirmed by ChIP analysis and was accompanied by differential localization of retinoid X receptor, histone acetylation, and RNA polymerase II recruitment. One of these regions was able to confer 1,25-(OH)2D3 regulation to downstream promoters, thereby permitting identification and characterization of the regulatory element located within. Importantly, a highly conserved region within the human VDR gene analogous to that discovered in the mouse was also capable of mediating 1,25-(OH)2D3 response. Our results demonstrate that 1,25-(OH)2D3 and its receptor autoregulate the expression of the VDR gene. The location of these regulatory regions and their apparent distances from the TSS are consistent with new findings suggesting the emerging relevance of distant enhancers.

Acetylation↗
PubMed2006

Deciphering function and mechanism of calcium-binding proteins from their evolutionary imprints.

Calcium-binding proteins regulate ion metabolism and vital signalling pathways in all living organisms. Our aim is to rationalize the molecular basis of their function by studying their evolution using computational biology techniques. Phylogenetic analysis is of primary importance for classifying cognate orthologs; profile hidden Markov models (HMM) of individual subfamilies discern functionally relevant sites by conservation probability analysis; and 3-dimensional structures display the integral protein in context. The major classifications of calcium-binding proteins, viz. EF-hand, C2 and ANX, exhibit structural diversity in their HMM fingerprints at the subfamily level, with functional consequences for protein conformation, exposure of receptor interaction sites and/or binding to membrane phospholipids. Calmodulin, S100 and annexin families were characterized in Petromyzon marinus (sea lamprey) to document genome duplication and gene creation events during the key evolutionary transition to primitive vertebrates. Novel annexins from diverse organisms revealed calcium-binding domains with accessory structural features that define their unique molecular fingerprints, protein interactivity and functional specificity. These include the first single-domain, bacterial annexin in Cytophaga hutchinsonii, the 21 tetrad annexins from the unicellular protist Giardia intestinalis, an ancestor to land plant annexins from the green alga Ostreococcus lucimarinus, invertebrate octad annexins and a critical polymorphism in human ANXA7. Receptor docking models supported the hypothesis of a potential interaction between annexin and C2 domains as a propitious mechanism for ensuring membrane translocation during signal transduction.

Amino Acid Sequence↗
PubMed1985

Conservation laryngeal surgery. A critical analysis.

Three hundred forty-two cases of laryngeal cancer were treated at the University of Michigan, Ann Arbor. One hundred ten supraglottic cancers and 150 glottic cancers were studied in depth. Conservation surgery was performed on 63 patients. Determinate two-year disease-free survival for glottic cancer was 90% in those irradiated primarily, 83% for those treated with vertical hemilaryngectomy, and 58% in the group that had total laryngectomy. Supraglottic cancers had a determinate survival rate at two years of 62% for those irradiated primarily, 80% for those treated with a supraglottic laryngectomy, and 62% when total laryngectomy was required. The cost of preserving the respiratory and sphincteric functions of the larynx in some cases amounted to the morbidity associated with a protracted hospital stay, altered deglutition, instances of a weak but functional voice, and the possibility of a permanent tracheostomy. Despite high recurrence rates of 30% to 40%, the overall determinate survival with salvage was an acceptable 80% for the conservation surgery group.

Adult↗