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At least 109 records · Page 6Linked to original sources
PubMed2006

Natural variation in HIV infection: Monte Carlo estimates that include CD8 effector cells.

Viral load and CD4 T-cell counts in patients infected with the human immunodeficiency virus (HIV) are commonly used to guide clinical decisions regarding drug therapy or to assess therapeutic outcomes in clinical trials. However, random fluctuations in these markers of infection can obscure clinically significant change. We employ a Monte Carlo simulation to investigate contributing factors in the expected variability in CD4 T-cell count and viral load due solely to the stochastic nature of HIV infection. The simulation includes processes that contribute to the variability in HIV infection including CD4 and CD8 T-cell population dynamics as well as T-cell activation and proliferation. The simulation results may reconcile the wide range of variabilities in viral load observed in clinical studies, by quantifying correlations between viral load measurements taken days or weeks apart. The sensitivity of variability in T-cell count and viral load to changes in the lifetimes of CD4 and CD8 T-cells is investigated, as well as the effects of drug therapy.

Anti-HIV Agents↗
PubMed2005

Monte Carlo estimates of natural variation in HIV infection.

We describe a Monte Carlo simulation of the within-host dynamics of human immunodeficiency virus 1 (HIV-1). The simulation proceeds at the level of individual T-cells and virions in a small volume of plasma, thus capturing the inherent stochasticity in viral replication, mutation and T-cell infection. When cell lifetimes are distributed exponentially in the Monte Carlo approach, our simulation results are in perfect agreement with the predictions of the corresponding systems of differential equations from the literature. The Monte Carlo model, however, uniquely allows us to estimate the natural variability in important parameters such as the T-cell count, viral load, and the basic reproductive ratio, in both the presence and absence of drug therapy. The simulation also yields the probability that an infection will not become established after exposure to a viral inoculum of a given size. Finally, we extend the Monte Carlo approach to include distributions of cell lifetimes that are less-dispersed than exponential.

Anti-HIV Agents↗
PubMed2000

Natural variation in susceptibility of Listeria strains to class IIa bacteriocins.

Thirty-one Listeria strains were tested for sensitivity to four class IIa bacteriocins, namely, enterocin A, mesentericin Y105, divercin V41, and pediocin AcH, and to nisin A. Class IIa bacteriocins displayed surprisingly similar antimicrobial patterns ranging from highly susceptible to fully resistant strains, whereas nisin A showed a different pattern in which all Listeria strains were inhibited. Particularly, it was observed that the strain Listeria monocytogenes V7 could not be inhibited by any of the class lIa bacteriocins tested. These observations suggest that Listeria strains resistant to the whole range of class IIa bacteriocins may occur in natural environments, which could be of great concern with regard to the use of these peptides as food preservatives.

Bacteriocins↗
PubMed2004

Natural variation in expression of self-incompatibility in Arabidopsis thaliana: implications for the evolution of selfing.

The switch from an out-crossing to a self-fertilizing mating system is one of the most prevalent evolutionary trends in plant reproduction and is thought to have occurred repeatedly in flowering plants. However, little is known about the evolution of self-fertility and the genetic architecture of selfing. Here, we establish Arabidopsis thaliana as a model for genetic analysis of the switch to self-fertility in the crucifer family, where the ancestral out-crossing mode of mating is determined by self-incompatibility (SI), a genetic system controlled by the S locus. We show that A. thaliana ecotypes exhibit S-locus polymorphisms and differ in their ability to express the SI trait upon transformation with S-locus genes derived from the obligate out-crosser Arabidopsis lyrata. Remarkably, at least one ecotype was reverted to a stable, self-incompatible phenotype identical to that of naturally self-incompatible species. These ecotype differences are heritable and reflect the fixation in different A. thaliana populations of independent mutations that caused or enforced the switch to self-fertility. Their continued analysis promises to identify the loci that were the targets of natural selection for selfing and to contribute to a mechanistic understanding of the SI response.

Arabidopsis↗
PubMed1997

Natural variation within the principal arginine-specific protease gene, prpR1, of Porphyromonas gingivalis.

RI, one of the major extracellular arginine-specific proteases of Porphyromonas gingivalis is a heterodimer composed of catalytic (alpha) and adhesin (beta) chains, encoded by the gene prpR1. The distribution of prpR1 and its variation within 43 isolates of P. gingivalis was determined. Chromosomal DNA was digested with Sma I and probed with a 32P-labeled DNA fragment from within the coding region for the alpha component of P. gingivalis W50. All isolates gave the expected 3.2 kb band, corresponding to the coding region for the alpha and beta components. The presence of a second locus (prR2) homologous to the alpha region of prpR1 was also detected. The 1.7-kb alpha coding region of prpR1 was amplified for subsequent restriction analysis. Following Taq I restriction all isolates gave identical patterns. With Rsa I, the majority of isolates (77%) could be placed into a single group. In conclusion, the prpR1 and prR2 loci are maintained in natural populations of P. gingivalis, and only minor polymorphism is detectable within the catalytic domain.

Adhesins, Bacterial↗
PubMed1987

Natural variation in passive sodium permeability in human erythrocytes.

The rate of influx of 22Na+ into human erythrocytes (RBC) varies greatly depending upon the donor. A high rate of influx may be related to a congenital predisposition to essential hypertension. In Northern Europeans, we find a threefold difference in the rate of 22Na+ influx between those with the least (LP) and most highly permeable (HP) RBC (from less than 0.15 to greater than 0.60 mmol Na+/liter RBC/hr). In order to further define determinants of these apparently hereditary differences in passive membrane Na+ transport, we identified two groups of normal laboratory and hospital personnel differing markedly (greater than twofold) in RBC 22Na+ influx rate. We find that the loop diuretics furosemide and bumetanide decrease by about 50% the influx of 22Na+ into HP RBC, but have a lesser influence on LP RBC. Impermeant polyanions such as citrate and pyrophosphate also specifically diminish 22Na+ influx into HP, but not LP, RBC. Therefore, the exaggerated 22Na+ influx into HP RBC probably occurs through a discrete pathway (perhaps via "Na/K/Cl cotransport"), which appears to be almost absent in LP RBC. The differences between HP and LP RBC most likely do not involve polymorphisms of RBC anion transport per se. The rate of RBC anion (35SO4(2-)) transport is the same in HP and LP RBC and is equally inhibited by furosemide and (to a lesser extent) bumetanide. Furthermore, the potent inhibitor of RBC anion transport, DIDS (diisothiocyanostilbene disulfonate) does not affect RBC Na+ permeability in either group. Nonetheless, the preferential reduction of Na+ permeation of HP RBC by loop diuretics may be of help in experimentally distinguishing HP from LP phenotypes. This information may be crucial in unraveling the structural basis of intrinsic differences in cell membrane Na+ permeability and their possible relationship to essential hypertension.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2002

Natural variation in baseline data: when do we call a new sample 'resistant'?

Mortality of pear psylla to amitraz was studied by means of bioassays. Variation between samples, temporal variation within the season in one orchard and spatial variation between Swiss regions were considered. Variation between samples was large enough to produce different Probit functions and LC50 values. Temporal and spatial variations were too small to indicate resistance. Prediction intervals of the pooled functions using bootstrapping were calculated to determine if future samples come from a population with decreased sensitivity. Probabilistic criteria on the population level were proposed for resistance.

Animals↗
PubMed1996

Natural variation in HIV-1 protease, Gag p7 and p6, and protease cleavage sites within gag/pol polyproteins: amino acid substitutions in the absence of protease inhibitors in mothers and children infected by human immunodeficiency virus type 1.

Reduced sensitivity of human immunodeficiency virus type 1 (HIV-1) to protease inhibitors is associated with multiple amino acid substitutions in the virus-encoded protease. The combination of changes that contribute to drug resistance is dependent in part upon the amino acid residues comprising protease alleles prior to drug therapy. We analyzed within peripheral blood mononuclear cells from HIV-1-infected mothers and their children viral gag/pol regions, which included p7, transframe p6/p6*, and protease coding sequences, as well as six protease cleavage sites. Sixty protease alleles from 12 individuals differed by at least 3 to as many as 10 amino acids from proteases encoded by molecular clones of HIV-1, indicating that there is no prototype or consensus wild-type HIV-1 protease sequence. Protease variants with a proline at position 63, a substitution associated with resistance to protease inhibitors, appeared in the absence of antiprotease therapy in 7 patients and were transmitted by 2 mothers to their infants. Gag p7 p6 regions were significantly more variable than protease. The p6/p6* region contained length variants and amino acid repeats in both reading frames. Five protease cleavage sites (B, D', D, E, and F) contained highly conserved amino acid sequences in individuals infected by epidemiologically distinct viruses. In contrast, C cleavage sites, localized between Gag p2 and Gag p7, displayed considerable amino acid variability, were unique among groups of infected individuals, and appeared to be related to particular protease alleles. Genetic variability in vivo in protease, in cleavage sites, and in proteins upstream of protease provides the potential to modulate enzyme activity and susceptibility to protease inhibitors.

Alleles↗
PubMed1999

Natural variation of equine infectious anemia virus Gag protein cytotoxic T lymphocyte epitopes.

Two defined cytotoxic T lymphocyte (CTL) epitopes from equine infectious anemia virus (EIAV)-infected horses, equine leukocyte alloantigen (ELA)-A5.1-restricted epitope 18a, and ELA-A9-restricted epitope 28b-1 were evaluated for conservation among three wild-type EIAV strains. Epitope 18a variation occurred in all three wild-type EIAV strains, while epitope 28b-1 varied in one strain. Further, 12% amino acid changes occurred in the Gag proteins of a recently isolated wild-type strain, documenting a much greater Gag protein variation than previously reported. Evaluation of epitope 18a among two virus isolates from sequential disease episodes in a single horse, H513 (ELA-A5.1/A8), demonstrated that no variation that affected CTL recognition occurred. H513 PBMC had CTLm to epitope 18a before the occurrence of disease episodes caused by viruses expressing epitope 18a; however, the frequencies were low (5-15/10(6) PBMC). Later in infection there was an absence of disease episodes associated with an increase in CTLm frequency to EIAV(WSU5)-infected targets, but not epitope 18a-pulsed targets. Therefore, if CTLm to EIAV epitopes were involved in maintaining the carrier state in H513, they recognized epitopes other than 18a.

Amino Acid Sequence↗
PubMed1988

Intracranial CSF volumes: natural variations and physiological changes measured by MRI.

Cranial CSF volumes, for the first time including CSF in the subarachnoid space, can be measured by Magnetic Resonance Imaging (MRI). The MRI sequence causes signal from the grey matter and white matter to cancel producing a contrast of 200: 1 between a unit of CSF and a unit of brain. We have assessed the variations between normal individuals and investigated some of the physiological factors that might influence cranial CSF volumes. Total CSF volumes were measured in 64 normal subjects, aged from 18-64 years (mean 38 years). Ventricular, cortical sulcal and posterior fossa volumes were also calculated separately. In 20 females with a normal menstrual cycle, CSF volumes were measured mid cycle and premenstrually; 10 post menopausal females and 10 males were rescanned after an interval of 2 weeks. Total cranial CSF volume were calculated before and during inhalation of 7% CO2 and before and during hyperventilation while breathing 60% O2, in 12 normal subjects. Total intracranial CSF volume ranged from 57.1-286.5 ml. Total intracranial and cortical sulcal CSF volumes increased more steeply with age than ventricular or posterior fossa CSF volumes. Males had more cranial CSF than females. Total CSF volume increased premenstrually in 19 females. Males and post-menopausal females did not have a significant change in CSF volume, on repeat examination. CO2 inhalation produced a mean increase of paCO2 of 17.2 mmHg and CSF volume decreased in all subjects (mean 9.4 ml). Cranial CSF volume increased in 11 subjects during O2 inhalation (range -0.5 to +26.7 ml mean 10.9 ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

A comparative study of the genetic bases of natural variation in tomato leaf, sepal, and petal morphology.

In an effort to better understand the dramatic differences in vegetative and floral morphology that differentiate species within the genus Lycopersicon, quantitative trait loci (QTL) for leaflet and perianth size and shape characters were mapped in an interspecific F2 population of tomato (Lycopersicon esculentum x L. pennellii). Thirty-six highly significant (P < or = 0.001) QTL were associated with 18 separate traits. QTL for correlated traits were generally not colocalized in the genome unless there was a clear codependence between the traits (e.g., organ length and area). Little or no overlap in QTL positioning between different organs was observed, suggesting that the genes determining the size and shape of leaflets, sepals, and petals are organ specific. Thus, while leaves are considered the developmental and evolutionary precursors to floral organs, genes acting late in development to determine certain aspects of morphology (namely shape and size) must have specialized to exert control over individual organs. Five of the leaflet-trait QTL map to analogous regions in the genome of eggplant, and therefore it appears there has been some conservation in the genes controlling leaf morphology within the Solanaceae.

Chromosome Mapping↗
PubMed2006

Allelic spectrum of the natural variation in CRP.

With the recent completion of the International HapMap Project, many tools are in hand for genetic association studies seeking to test the common variant/common disease hypothesis. In contrast, very few tools and resources are in place for genotype-phenotype studies hypothesizing that rare variation has a large impact on the phenotype of interest. To create these tools for rare variant/common disease studies, much interest is being generated towards investing in re-sequencing either large sample sizes of random chromosomes or smaller sample sizes of patients with extreme phenotypes. As a case study for rare variant discovery in random chromosomes, we have re-sequenced approximately 1,000 chromosomes representing diverse populations for the gene C-reactive protein (CRP). CRP is an important gene in the fields of cardiovascular and inflammation genetics, and its size (approximately 2 kb) makes it particularly amenable medical or deep re-sequencing. With these data, we explore several issues related to the present-day candidate gene association study including the benefits of complete SNP discovery, the effects of tagSNP selection across diverse populations, and completeness of dbSNP for CRP. Also, we show that while deep re-sequencing uncovers potentially medically relevant coding SNPs, these SNPs are fleetingly rare when genotyped in a population-based survey of 7,000 Americans (NHANES III). Collectively, these data suggest that several different types re-sequencing and genotyping approaches may be required to fully understand the complete spectrum of alleles that impact human phenotypes.

Alleles↗
PubMed2005

Using natural variation to investigate the function of individual amino acids in the sucrose-binding box of fructan:fructan 6G-fructosyltransferase (6G-FFT) in product formation.

Enzymes of the glycosyl hydrolase family 32 are highly similar with respect to primary sequence but catalyze divergent reactions. Previously, the importance of the conserved sucrose-binding box in determining product specificity of onion fructan:fructan 6G-fructosyltransferase (6G-FFT) was established [Ritsema et al., 2004, Plant Mol. Biol. 54: 853-863]. Onion 6G-FFT synthesizes the complex fructan neo-series inulin by transferring fructose residues to either a terminal fructose or a terminal glucose residue. In the present study we have elucidated the molecular determinants of product specificity by substitution of individual amino acids of the sucrose binding box with amino acids that are present on homologous positions in other fructosyltransferases or vacuolar invertases. Substituting the presumed nucleophile Asp85 of the beta-fructosidase motif resulted in an inactive enzyme. 6G-FFT mutants S87N and S87D did not change substrate or product specificities, whereas mutants N84Y and N84G resulted in an inactive enzyme. Most interestingly, mutants N84S, N84A, and N84Q added fructose residues preferably to a terminal fructose and hardly to the terminal glucose. This resulted in the preferential production of inulin-type fructans. Combining mutations showed that amino acid 84 determines product specificity of 6G-FFT irrespective of the amino acid at position 87.

Amino Acid Sequence↗