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PubMed2006

Why women live longer than men: sex differences in longevity.

Historically, women have lived longer than men in almost every country in the world. A similar pattern of sex differences in longevity is also found in many other species; however, it is not clear if there are more species in which females live longer or vice versa. For virtually all the primary causes of death and at virtually all ages, mortality rates are higher for men. Women do not live longer than men because they age more slowly, but because they are more robust at every age. Paradoxically, although women have lower mortality rates they have higher overall rates of physical illness than do men. Several hypotheses have been proposed for sex differences in longevity, including more active female immune functioning, the protective effect of estrogen, compensatory effects of the second X chromosome, reduction in the activity of growth hormone and the insulin-like growth factor 1 signaling cascade, and the influence of oxidative stress on aging and disease. At present, none of these hypotheses are strongly supported, although weak support is available for the oxidative stress hypothesis. With the advent of more rapid genome sequencing, molecular tools will become available for more species, thus further detailing the causes for the differences in longevity between the sexes.

Animals↗
PubMedDate not supplied

Mys, a family of mammalian transposable elements isolated by phylogenetic screening.

It has recently been demonstrated both emperically and mathematically that transposable elements may spread rapidly throughout a population once introduced even when they dramatically reduce the fitness of individuals that carry them. Such events result in pronounced differences in the phylogenetic distribution of genetic elements capable of rapid genome invasion. Using a simple and general procedure to screen the genome of the white-footed mouse Peromyscus leucopus, we have isolated a family of retrovirus-like elements which is apparently absent from the genome of the house mouse Mus domesticus. Here, we report this procedure and an analysis of the organization, phylogenetic distribution and sequence of this family of transposable elements.

Animals↗
PubMed2005

Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population.

An RNA virus population does not consist of a single genotype; rather, it is an ensemble of related sequences, termed quasispecies. Quasispecies arise from rapid genomic evolution powered by the high mutation rate of RNA viral replication. Although a high mutation rate is dangerous for a virus because it results in nonviable individuals, it has been hypothesized that high mutation rates create a 'cloud' of potentially beneficial mutations at the population level, which afford the viral quasispecies a greater probability to evolve and adapt to new environments and challenges during infection. Mathematical models predict that viral quasispecies are not simply a collection of diverse mutants but a group of interactive variants, which together contribute to the characteristics of the population. According to this view, viral populations, rather than individual variants, are the target of evolutionary selection. Here we test this hypothesis by examining the consequences of limiting genomic diversity on viral populations. We find that poliovirus carrying a high-fidelity polymerase replicates at wild-type levels but generates less genomic diversity and is unable to adapt to adverse growth conditions. In infected animals, the reduced viral diversity leads to loss of neurotropism and an attenuated pathogenic phenotype. Notably, using chemical mutagenesis to expand quasispecies diversity of the high-fidelity virus before infection restores neurotropism and pathogenesis. Analysis of viruses isolated from brain provides direct evidence for complementation between members in the quasispecies, indicating that selection indeed occurs at the population level rather than on individual variants. Our study provides direct evidence for a fundamental prediction of the quasispecies theory and establishes a link between mutation rate, population dynamics and pathogenesis.

Animals↗
PubMed1987

Translocation and amplification of an X-chromosome DNA repeat in inbred strains of mice.

A 9-kb repetitive DNA fragment (70-38) located near the centromere of the mouse X chromosome is amplified and translocated to an autosome in different inbred strains of mice. In situ hybridization and hybrid cell studies showed that probe 70-38 is located only on the X chromosome in mouse strains A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, DBA/2J and SWR/J. However, in four other mouse strains the DNA sequence is found near the centromere of an autosome in addition to the X chromosome. This autosome differs among the mouse strains (chromosome 11 in C57BL/10J or ScSn, chromosome 13 in NZB/B1NJ and chromosome 17 in SJL/J and PO). In those strains where the repeated sequence is located on an autosome, it has been amplified to about 100 copies. Restriction enzyme digestion patterns suggest a common structure for 70-38 sequences in the different strains. The changes in copy number, restriction enzyme digestion patterns, and chromosomal location of 70-38 reflect a rapid genomic evolution inbred mouse strains.

Animals↗
PubMed2000

MAGPIE/EGRET annotation of the 2.9-Mb Drosophila melanogaster Adh region.

Our challenge in annotating the 2.91-Mb Adh region of the Drosophila melanogaster genome was to identify genetic and genomic features automatically, completely, and precisely within a 6-week period. To do so, we augmented the MAGPIE microbial genome annotation system to handle eukaryotic genomic sequence data. The new configuration required the integration of eukaryotic gene-finding tools and DNA repeat tools into the automatic data collection module. It also required us to define in MAGPIE new strategies to combine data about eukaryotic exon predictions with functional data to refine the exon predictions. At the heart of the resulting new eukaryotic genome annotation system is a reverse comparison of public protein and complementary DNA sequences against the input genome to identify missing exons and to refine exon boundaries. The software modules that add eukaryotic genome annotation capability to MAGPIE are available as EGRET (Eukaryotic Genome Rapid Evaluation Tool).

Alcohol Dehydrogenase↗
PubMed2005

A novel representation of protein sequences for prediction of subcellular location using support vector machines.

As the number of complete genomes rapidly increases, accurate methods to automatically predict the subcellular location of proteins are increasingly useful to help their functional annotation. In order to improve the predictive accuracy of the many prediction methods developed to date, a novel representation of protein sequences is proposed. This representation involves local compositions of amino acids and twin amino acids, and local frequencies of distance between successive (basic, hydrophobic, and other) amino acids. For calculating the local features, each sequence is split into three parts: N-terminal, middle, and C-terminal. The N-terminal part is further divided into four regions to consider ambiguity in the length and position of signal sequences. We tested this representation with support vector machines on two data sets extracted from the SWISS-PROT database. Through fivefold cross-validation tests, overall accuracies of more than 87% and 91% were obtained for eukaryotic and prokaryotic proteins, respectively. It is concluded that considering the respective features in the N-terminal, middle, and C-terminal parts is helpful to predict the subcellular location.

Amino Acids, Basic↗
PubMed2006

Functional annotation prediction: all for one and one for all.

In an era of rapid genome sequencing and high-throughput technology, automatic function prediction for a novel sequence is of utter importance in bioinformatics. While automatic annotation methods based on local alignment searches can be simple and straightforward, they suffer from several drawbacks, including relatively low sensitivity and assignment of incorrect annotations that are not associated with the region of similarity. ProtoNet is a hierarchical organization of the protein sequences in the UniProt database. Although the hierarchy is constructed in an unsupervised automatic manner, it has been shown to be coherent with several biological data sources. We extend the ProtoNet system in order to assign functional annotations automatically. By leveraging on the scaffold of the hierarchical classification, the method is able to overcome some frequent annotation pitfalls.

Algorithms↗
PubMed1999

Neuropeptide gene families in the nematode Caenorhabditis elegans.

Neuropeptides have diverse roles in the function and development of the nervous system. With the completion of the sequencing of the C. elegans genome, rapid identification of nematode neuropeptide genes is possible. To date, 41 C. elegans neuropeptide genes have been identified. Of these genes, 20 genes, named flp (FMRFamide-like peptide) genes, encode FMRFamide-related proteins (FaRPs). Deletion of one of the flp genes, flp-1, results in several behavioral defects, suggesting that at least one flp gene is not functionally redundant with other flp genes. Twenty-one genes, named neuropeptide-like protein (nlp) genes, encode peptides distinct from the FaRP family. The predicted nlp-1 and nlp-2 neuropeptides have modest similarity to buccalin and myomodulin, respectively. Cellular expression patterns and genetic analysis of flp and nlp genes suggest that neuropeptides in nematodes also have widespread and varied roles in nervous system function.

Amino Acid Sequence↗
PubMed2000

A recent outbreak of human immunodeficiency virus type 1 infection in southern China was initiated by two highly homogeneous, geographically separated strains, circulating recombinant form AE and a novel BC recombinant.

New outbreaks of human immunodeficiency virus type 1 (HIV-1) among injecting drug users (IDUs) are spreading in China along heroin trafficking routes. Recently, two separate HIV-1 epidemics among IDUs were reported in Guangxi, Southern China, where partial sequencing of the env gene showed subtype C and circulating recombinant form (CRF) AE. We evaluated five virtually full-length HIV-1 genome sequences from IDUs in Guangxi to determine the genetic diversity and the presence of intersubtype recombinants. Sequence analysis showed two geographically separated, highly homogeneous HIV-1 strains. B/C intersubtype recombinants were found in three IDUs from Baise City, in a mountainous region near the Yunnan-Guangxi border. These were mostly subtype C, with portions of the capsid and reverse transcriptase (RT) genes from subtype B. The subtype B portion of the capsid was located in the N-terminal domain, which has been shown to influence virus core maturation, virus infectivity, and binding to cyclophilin A, whereas the subtype B portion of RT was located in the palm subdomain, which is the active site of the enzyme. These BC recombinants differed from a BC recombinant found in Xinjiang Province in northwestern China. CRF AE strains were found in IDUs from Nanning, the capital of Guangxi, and in IDUs from Pingxiang City near the China-Vietnam border. The AE and BC recombinants were both remarkable for their low interpatient diversity, less than 1% for the full genome. Rapid spread of HIV-1 among IDUs may foster the emergence of highly homogeneous strains, including novel recombinants in regions with multiple subtypes.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Spinal estrogen attenuates the exercise pressor reflex but has little effect on the expression of genes regulating neurotransmitters in the dorsal root ganglia.

Previously, our laboratory showed that estrogen, topically applied to the spinal cord, attenuated the exercise pressor reflex in female cats (Schmitt PM and Kaufman MP. J Appl Physiol 95: 1418-1424, 2003; 98: 633-639, 2005). The attenuation was gender specific and was in part opioid dependent. Our finding that the mu- and delta-opioid antagonist naloxone was only able to partially restore estrogen's attenuating effect on the pressor response to static contraction suggested that estrogen affected an additional pathway, involving the dorsal root ganglion (DRG). Estrogen has been described to stimulate transcription within 10 min of its application to the DRG, raising the possibility that rapid genomic effects on neurotransmitter production may have contributed to estrogen's effect on the exercise pressor reflex. This prompted us to test the hypothesis that estrogen modulated the pressor response to static contraction by influencing gene expression of the neurotransmitters released by the thin-fiber muscle afferents that evoke the exercise pressor reflex. We confirmed in decerebrated female rats that topical application of estrogen (0.01 microg/ml) to the lumbosacral spinal cord attenuated the pressor response to static muscle contraction (from 10+/-3 to 1+/-1 mmHg; P<0.05). DRG were then harvested postmortem, and changes in mRNA expression were analyzed. GeneChip analysis revealed that neither estrogen nor contraction alone changed the mRNA expression of substance P, the neurokinin-1 receptor, CGRP, NGF, the P2X3 receptor, GABAA and GABAB, the 5-HT3A and 5-HT3B receptor, N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors, opioid receptors, and opioid-like receptor. Surprisingly, however, contraction stimulated the expression of neuropeptide Y in the DRG in the presence and absence of estrogen. We conclude that estrogen does not attenuate the exercise pressor reflex through a genomic effect in the DRG.

Animals↗
PubMed2005

Replicative homeostasis: a fundamental mechanism mediating selective viral replication and escape mutation.

Hepatitis C (HCV), hepatitis B (HBV), the human immunodeficiency viruses (HIV), and other viruses that replicate via RNA intermediaries, cause an enormous burden of disease and premature death worldwide. These viruses circulate within infected hosts as vast populations of closely related, but genetically diverse, molecules known as "quasispecies". The mechanism(s) by which this extreme genetic and antigenic diversity is stably maintained are unclear, but are fundamental to understanding viral persistence and pathobiology. The persistence of HCV, an RNA virus, is especially problematic and HCV stability, maintained despite rapid genomic mutation, is highly paradoxical. This paper presents the hypothesis, and evidence, that viruses capable of persistent infection autoregulate replication and the likely mechanism mediating autoregulation - Replicative Homeostasis - is described. Replicative homeostasis causes formation of stable, but highly reactive, equilibria that drive quasispecies expansion and generates escape mutation. Replicative homeostasis explains both viral kinetics and the enigma of RNA quasispecies stability and provides a rational, mechanistic basis for all observed viral behaviours and host responses. More importantly, this paradigm has specific therapeutic implication and defines, precisely, new approaches to antiviral therapy. Replicative homeostasis may also modulate cellular gene expression.

Antigens, Viral↗
PubMed2004

Design and preparation of recombinant antigens as diagnostic reagents in solid-phase immunosorbent assays.

Analysis of the humoral immune response to infectious diseases has played, and will to continue to play, a key role in their diagnosis and immune surveillance. Although rapid genome detection methodologies, such as PCR, are beginning to replace immune assays for disease diagnosis, they are not suitable for all applications, especially the surveillance of the immune status of human populations. Here we review the limitations of current conventional tools for measuring immune responses and outline principles for the design and production of novel diagnostic reagents. Methods for the production of viral diagnostic antigens by a variety of recombinant systems are described and their relative merits and disadvantages discussed. Protocols for the production of viral diagnostic antigens in eukaryotic, insect and mammalian systems are described using measles nucleocapsid antigen as a model. Indirect ELISA protocols which can differentiate immunoglobulin classes and subclasses are also described. Examples of the use of these analyses in research and surveillance are given.

Antibodies, Viral↗
PubMed2004

1alpha,25(OH)2D3 induces capacitative calcium entry involving a TRPC3 protein in skeletal muscle and osteoblastic cells.

This work describes the involvement of TRPC proteins in capacitative calcium entry (CCE) induced by 1alpha,25-dihydroxy-vitamin-D3 [1alpha,25(OH)2D3] in chick skeletal muscle and in rat osteoblast-like cells (ROS 17/2.8) and the role of the vitamin D receptor (VDR) in this non-genomic rapid response mediated by the hormone. We propose that an endogenous TRPC3 protein mediates 1alpha,25(OH)2D3 modulation of CCE in these cells, which seems to implicate VDR-TRPC3 association and the participation of an INAD-like scaffold protein.

Animals↗
PubMed2006

Rapid non-genomic vasoconstrictor actions of aldosterone in the renal microcirculation.

There is increasing evidence for the pathophysiological importance of aldosterone in renal diseases. Studies have so far demonstrated that aldosterone exerts deleterious renal effects by inducing oxidative stress, endothelial dysfunction, inflammation and fibrosis through a mineralocorticoid receptor (MR)-dependent genomic mechanisms. On the other hand, a number of recent studies provided evidence that aldosterone can act through a rapid non-genomic mechanism in cardiovascular tissues including the kidney, though the relative importance of such actions in renal diseases remains to be determined. We have recently found that physiological concentrations of aldosterone cause rapid vasoconstriction in the renal microcirculation. The vasoconstrictor actions were compatible with non-genomic; the major characteristics was its relatively early onset (apparent within 5min), which was not affected by either actinomycin D or cycloheximide (inhibitors of transcription or protein synthesis). Thus, in addition to genomic actions, such non-genomic vasoconstrictor actions in the renal microcirculation may contribute to the deleterious renal effects of aldosterone in renal diseases.

Aldosterone↗
PubMed2002

Rapid, non-genomic actions of progesterone and estradiol on steady-state calcium and resting calcium influx in lens epithelial cells.

The effects of steroids on the steady-state intracellular [Ca(2+)] ([Ca(2+)](i)) and resting Ca(2+) influx in Fura-2-loaded bovine lens epithelial cells were examined to identify potential rapid, non-genomic actions. When administered in the presence of 1-2 mM extracellular Ca(2+) ([Ca(2+)](o)), 100 micro M progesterone produced large (up to 12-fold) and transient (5 min) increases in [Ca(2+)](i). These effects were abolished in EGTA-containing solutions, and were associated with large increases in the rate at which extracellularly administered Mn(2+) quenched the intracellular Fura signal. Lower concentrations of progesterone (10-100 micro M) produced smaller increases in [Ca(2+)](i) that were concentration dependent, and 17beta-estradiol induced large, rapid and brief increases in [Ca(2+)](i) at 100 nM and smaller oscillations in [Ca(2+)](i) at 10 nM. In cells pretreated with thapsigargin, 100 micro M progesterone produced slower increases in [Ca(2+)](i) that were maintained for several minutes. These results demonstrate rapid non-genomic actions of progesterone and estradiol on resting Ca(2+) influx and [Ca(2+)](i) that may involve specific interactions with a recently discovered steroid-binding protein in the plasma membrane of lens epithelial cells.

Animals↗
PubMed2002

Towards structural genomics of RNA: rapid NMR resonance assignment and simultaneous RNA tertiary structure determination using residual dipolar couplings.

We report a new residual dipolar couplings (RDCs) based NMR procedure for rapidly determining RNA tertiary structure demonstrated on a uniformly (15)N/(13)C-labeled 27 nt variant of the trans-activation response element (TAR) RNA from HIV-I. In this procedure, the time-consuming nuclear Overhauser enhancement (NOE)-based sequential assignment step is replaced by a fully automated RDC-based assignment strategy. This approach involves examination of all allowed sequence-specific resonance assignment permutations for best-fit agreement between measured RDCs and coordinates for sub-structures in a target RNA. Using idealized A-form geometries to model Watson-Crick helices and coordinates from a previous X-ray structure to model a hairpin loop in TAR, the best-fit RDC assignment solutions are determined very rapidly (<five minutes of computational time) and are in complete agreement with corresponding NOE-based assignments. Orientational constraints derived from RDCs are used simultaneously to assemble sub-structures into an RNA tertiary conformation. Through enhanced speeds of application and reduced reliance on chemical shift dispersion, this RDC-based approach lays the foundation for rapidly determining RNA conformations in a structural genomics context, and may increase the size limit of RNAs that can be examined by NMR.

Base Sequence↗
PubMed2001

Autographa californica baculoviruses with large genomic deletions are rapidly generated in infected insect cells.

Defective interfering baculoviruses (DIs) lack considerable portions of the genome, interfere with the replication of helper virus, and cause the so-called "passage-effect" during serial passaging in insect cells and in bioreactor configurations. We investigated their origin by (nested) PCR and demonstrated that DIs lacking approximately 43% (d43) of their DNA are present in low-passage Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV)-E2 virus stocks and in polyhedra, but not in the authentic AcMNPV isolate obtained prior to passage in cell culture. To investigate whether DIs are rapidly generated de novo in Sf21 insect cells, a genetically homogeneous AcMNPV bacmid was serially passaged, resulting in the generation of d43 DIs within two passages. AT-rich sequences of up to 66 nucleotides of partly unknown origin were found at the deletion junctions in the d43 DI genomes. These data suggest that the rapid generation of DIs is an intrinsic property of baculovirus infection in insect cell culture and involves several recombination steps.

Animals↗