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PubMed1997

Evolutionary divergence and salinity-mediated selection in halophilic archaea.

Halophilic (literally salt-loving) archaea are a highly evolved group of organisms that are uniquely able to survive in and exploit hypersaline environments. In this review, we examine the potential interplay between fluctuations in environmental salinity and the primary sequence and tertiary structure of halophilic proteins. The proteins of halophilic archaea are highly adapted and magnificently engineered to function in an intracellular milieu that is in ionic balance with an external environment containing between 2 and 5 M inorganic salt. To understand the nature of halophilic adaptation and to visualize this interplay, the sequences of genes encoding the L11, L1, L10, and L12 proteins of the large ribosome subunit and Mn/Fe superoxide dismutase proteins from three genera of halophilic archaea have been aligned and analyzed for the presence of synonymous and nonsynonymous nucleotide substitutions. Compared to homologous eubacterial genes, these halophilic genes exhibit an inordinately high proportion of nonsynonymous nucleotide substitutions that result in amino acid replacement in the encoded proteins. More than one-third of the replacements involve acidic amino acid residues. We suggest that fluctuations in environmental salinity provide the driving force for fixation of the excessive number of nonsynonymous substitutions. Tinkering with the number, location, and arrangement of acidic and other amino acid residues influences the fitness (i.e., hydrophobicity, surface hydration, and structural stability) of the halophilic protein. Tinkering is also evident at halophilic protein positions monomorphic or polymorphic for serine; more than one-third of these positions use both the TCN and the AGY serine codons, indicating that there have been multiple nonsynonymous substitutions at these positions. Our model suggests that fluctuating environmental salinity prevents optimization of fitness for many halophilic proteins and helps to explain the unusual evolutionary divergence of their encoding genes.

Archaea↗

PubMed2003

Risk-adjusted expected return for selection decisions.

The results of genetic evaluation are predictions of breeding values for the selection candidates, and these involve uncertainty with regard to future returns from the use of those selected individuals. This uncertainty is due to differential variability in BLUP of breeding values and can be translated into risk: High fluctuations mean greater risk, which is not taken into account by just looking at expected return. In this research, the methodology of value at risk (VaR) and expected shortfall is introduced for animal breeding decisions as a means to adjust the expected return for the cost of uncertainty in prediction of breeding values. This methodology has recently received a great deal of attention from financial institutions. Given a specified probability alpha, VaR is the alpha-quantile of the distribution of economic returns. The conditional value at risk (CVaR), or expected shortfall, is the expectation of the economic returns, which are less or equal to the VaR. By subtracting the CVaR from the predicted aggregate genotype (muR), a risk-adjusted expected return (RAER) measure was obtained. The measures muR, VaR, and RAER were calculated for a data set with progeny of 161 Polled Hereford bulls belonging to a beef cattle company. The Pearson and Spearman correlations between muR and RAER were 0.89 (P < 0.001) and 0.90 (P < 0.001), respectively. Even though the latter correlation was high, some bulls ranked differently for muR compared with RAER. The Pearson correlation between muR and VaR was low (0.124) and nonsignificant (P > 0.05), whereas the correlation between VaR and RAER was -0.31 (P < 0.0001). The results indicate the need to take into account the adjustment for risk in expected return in order to alleviate the effects of possible losses when overrated animals are selected.

Algorithms↗

PubMed1979

Deterministic single-locus density-dependent selection.

Density-regulated selection is considered for a single, multiallele gene locus and separated generations. Characteristics resulting from the basic assumption that the average population fitness decreases with increasing density are derived. Under this assumption, it proves to be necessary to distinguish between regions of allelic frequencies which imply limited population growth, unlimited growth, or ultimate extinction when the population stays in the respective region. Particular attention is given to the investigation of the region of limited growth and the 'carrying capacity function' theta defined on it. Relationships between theta and the average fitness (adaptive surface) in the non-density dependent model are explained. Besides stability properties of equilibrium points, more general characteristics concerning the asymptotic behavior of population trajectories are treated. In this context, the problems of sudden loss of alleles and of population extinction as a result of large fluctuations in density are discussed.

Alleles↗

PubMed1997

Expression of the bumetanide-sensitive Na-K-Cl cotransporter BSC2 is differentially regulated by fluid mechanical and inflammatory cytokine stimuli in vascular endothelium.

In vascular endothelium, the electroneutral Na-K-Cl cotransport system is thought to function in the maintenance of a selective permeability barrier in certain vascular beds (e.g., brain), as well as in the preservation of endothelial homeostasis in the face of fluctuating osmotic conditions that may accompany certain pathophysiological conditions (e.g., diabetes mellitus). Here we demonstrate that the gene encoding the bumetanide-sensitive cotransporter BSC2, one of the two major isoforms of Na-K-Cl cotransporters present in mammalian cells, can be differentially regulated by inflammatory cytokines and fluid mechanical forces in cultured endothelium. Interleukin-1beta and tumor necrosis factor-alpha significantly upregulate expression of BSC2 mRNA and protein in human umbilical vein endothelial cells, a response that is inhibited by pretreatment with interferon-gamma. Steady laminar fluid shear stress, at a physiologic magnitude (10 dyn/cm2), is also able to induce and maintain elevated expression of BSC2 in cultured human umbilical vein endothelial cells, while a comparable time-averaged magnitude of turbulent fluid shear stress is not. In vivo, BSC2 mRNA is upregulated after intraperitoneal administration of bacterial endotoxin (LPS) in murine lung and kidney, but not in cardiac tissue. These results provide the first experimental evidence that the BSC2 gene can be selectively regulated by different inflammatory cytokine and fluid mechanical stimuli in endothelium, and support a role for BSC2 in vascular homeostasis and inflammation.

Animals↗

PubMed1995

Linkage and the limits to natural selection.

The probability of fixation of a favorable mutation is reduced if selection at other loci causes inherited variation in fitness. A general method for calculating the fixation probability of an allele that can find itself in a variety of genetic backgrounds is applied to find the effect of substitutions, fluctuating polymorphisms, and deleterious mutations in a large population. With loose linkage, r, the effects depend on the additive genetic variance in relative fitness, var(W), and act by reducing effective population size by (N/Ne) = 1 + var(W)/2r2. However, tightly linked loci can have a substantial effect not predictable from Ne. Linked deleterious mutations reduce the fixation probability of weakly favored alleles by exp (-2U/R), where U is the total mutation rate and R is the map length in Morgans. Substitutions can cause a greater reduction: an allele with advantage s < scrit = (pi 2/6) loge (S/s) [var(W)/R] is very unlikely to be fixed. (S is the advantage of the substitution impeding fixation.) Fluctuating polymorphisms at many (n) linked loci can also have a substantial effect, reducing fixation probability by exp [square root of 2Kn var(W)/R] [K = -1/E((u-u)2/uv) depending on the frequencies (u,v) at the selected polymorphisms]. Hitchhiking due to all three kinds of selection may substantially impede adaptation that depends on weakly favored alleles.

Genetic Linkage↗

PubMed2001

Extension of the Fluctuation-Dissipation Theorem to the Physical Aging of a Model Glass-Forming Liquid.

We present evidence in favor of the possibility of treating an out-of-equilibrium supercooled simple liquid as a system in quasiequilibrium. Two different temperatures, one controlled by the external bath and one internally selected by the system, characterize the quasiequilibrium state. The value of the internal temperature is explicitly calculated within the inherent structure thermodynamic formalism. We find that the internal temperature enters the relation between the response to an external perturbation and the long-time decay of fluctuations in the liquid.

Journal Article↗

PubMed1995

Adaptive mutations in Escherichia coli as a model for the multiple mutational origins of tumors.

The cells in most tumors are found to carry multiple mutations; however, based upon mutation rates determined by fluctuation tests, the frequency of such multiple mutations should be so low that tumors are never detected within human populations. Fluctuation tests, which determine the cell-division-dependent mutation rate per cell generation in growing cells, may not be appropriate for estimating mutation rates in nondividing or very slowly dividing cells. Recent studies of time-dependent, "adaptive" mutations in nondividing populations of microorganisms suggest that similar measurements may be more appropriate to understanding the mutation origins of tumors. Here I use the ebgR and ebgA genes of Escherichia coli to measure adaptive mutation rates where multiple mutations are required for rapid growth. Mutations in either ebgA or ebgR allow very slow growth on lactulose (4-O-beta-D-galactosyl-D-fructose), with doubling times of 3.2 and 17.3 days, respectively. However, when both mutations are present, cells can grow rapidly with doubling times of 2.7 hr. I show that during prolonged (28-day) selection for growth on lactulose, the number of lactulose-utilizing mutants that accumulate is 40,000 times greater than can be accounted for on the basis of mutation rates measured by fluctuation tests, but is entirely consistent with the time-dependent adaptive mutation rates measured under the same conditions of prolonged selection.

Adaptation, Physiological↗

PubMed2003

Potential relationships between physical traits and male broiler breeder fertility.

Genetic selection in primary broiler breeders may modify skeletal structure, possibly impeding semen transfer, and could alter the size and degree of fluctuating asymmetry (FA) of bilateral traits associated with fertility. Hence, we hypothesized specific morphometric traits could predict differential fertility. Sixty primary broiler breeder males from Strains A and B (n = 30/strain) were individually housed with an average of 10 females per male. Male fertility and sperm penetration (SP) through the perivitelline layer were estimated on fresh eggs. At 50 wk, BW, keel length (KL), posterior pelvic width and length (PPW, PPL), dorsal pelvic width and length (DPW, DPL), tarsometatarsal length and width (TL, TW), comb length and width (CL, CW), and wattle length, width, and area (WL, WW, WA) were measured. Results indicated that Strain A had smaller BW, KL, WL, WW, WA, CL, CW, PPL, DPL, and DPW. A higher degree of FA was found in Strain A TL and WL (P < 0.05), yet DPW FA was greater for Strain B (P < 0.001). In addition, DPW FA negatively correlated with Strain B fertility (r = -0.369; P < 0.01); however, other FA measurements did not correlate with estimated fertility or SP. Strain A WL correlated with SP (r = 0.383; P < 0.01) and fertility (r = 0.346; P < 0.01). Results indicate DPW alteration may impact semen transfer upon copulation, as Strain A fertility negatively correlated with DPW (r = -0.298; P < 0.05). This research provides evidence that morphometric traits might be useful to predict fertility in broiler breeders.

Animals↗

PubMed1991

Standard and controlled-release levodopa/carbidopa in patients with fluctuating Parkinson's disease on a protein redistribution diet. A preliminary report.

Ten patients with Parkinson's disease (PD) with motor fluctuations that responded to a protein redistribution diet were studied. All 10 patients were receiving standard Sinemet (levodopa/carbidopa). Five randomly selected patients were changed from standard Sinemet to a controlled-release form of Sinemet. The other five patients continued to receive standard Sinemet. To maintain the same degree of control of PD in the five patients switched to the controlled-release form of Sinemet, the daily levodopa intake increased. While receiving optimal therapy (standard Sinemet or controlled-release Sinemet) and a protein redistribution diet, all 10 patients then underwent hourly videotaping and blood sampling (for plasma levodopa levels) during 2 consecutive days. Videotapes were blindly reviewed for PD disability, dyskinesia, and the time required to walk a measured distance. Comparing the two groups, standard Sinemet with controlled-release Sinemet, respectively, mean levodopa requirements were 505 and 1895 mg, plasma levodopa levels were 6.1 and 17.6 mumol/L, and abnormal involuntary movement scale scores were 14 and 26. Their mean PD disability scores did not differ statistically or clinically. Also no statistically significant differences were noted in either their mean walking times or their mean daily dose frequencies.

Antiparkinson Agents↗

PubMed1991

Limitations of coronary angiography: an underestimated problem?

Angiographic imaging suffers from many limitations which may distort the diagnostic information obtained from coronary arteriograms. Radiographic features limiting precise coronary stenosis measurement are caused by the x-ray source, the image intensifier, and the chemical properties of the cinefilm. Biologic variations are introduced by fluctuations in angiographic contrast concentration and flow- or contrast-dependent coronary dilation. Random errors are also introduced by the selection of the radiographic projection and frame to be analyzed and the digitization of cineangiograms. These limitations and their significance in distorting quantitative information obtained from coronary angiograms are discussed in this review.

Angiography↗

PubMed1987

Spontaneous neuronal firing patterns in fetal rat cortical networks during development in vitro: a quantitative analysis.

The development of spontaneous bioelectric activity (SBA) was studied in dissociated occipital cortex cultures prepared from 19 day old rat fetuses. All cultures, recorded one per diem from 5 to 33 days in vitro (div), showed SBA. Computer analysis of 76 extracellularly recorded single unit spike trains was carried out after selection on the basis of stationarity criteria. Statistically significant developmental trends were found in (i) interspike interval dependencies and (ii) fluctuations in mean firing rate, on the order of a minute or longer. The highly dependent firing patterns, including stereotyped bursting, were present mostly in the 9-12 div group, whereas minute-to-minute fluctuations in the intensity of firing were considerably more pronounced in the oldest group (22-33 div) than in the younger cultures. In addition, firing categories defined on the basis of factor-analysis revealed that such fluctuations were almost exclusively to be found in neurons which fired in a pronounced 'burst', rather than a relatively continuous fashion. Only a few mature appearing synaptic structures were observed electron microscopically prior to 12 div, but increased steadily in number thereafter. No cultures prior to 14 div, but all cultures older than this, stained positively for the presence of glutamic acid decarboxylase. An extensive immunoreactive, putative GABAergic, network was present by three weeks in vitro.

Action Potentials↗

PubMed1976

Effects of unstirred layers or transport number discontinuities on the transient and steady-state current-voltage relationships of membranes.

The effects of current-induced electrolyte accumulation and depletion on the electrical properties of a two-layered membrane system have been examined. The membrane consisted of a charged, ion permselective layer and an uncharged, non-selective layer. The model was designed to reveal the properties of membranes possessing long pores with ionic charges at one end or of ion-selective membranes bounded by highly unstirred aqueous layers. Electrolyte concentration profiles in the inert layer and their time-dependent changes were obtained from solutions of the diffusion equation under the condition of constant current. The profiles were then used to calculate the voltage developed across the membrane at various times after the current is switched on. The theoretical results are presented in the form of i-V curves with reduced coordinates that can be used to obtain time-current-voltage relationships for membranes of the type considered having any thickness of the non-selective layer and bathed in any concentration of any 1:1 electrolyte. Experimental results on a model composite membrane were in good agreement with calculations that assume that ion transport occurs only under the influence of electrical potential and concentration gradients, suggesting that in such systems, the combined effects of convection, osmosis, electro-osmosis, and concentration-dependence of diffusion coefficients, activity coefficients, and transference numbers are small. Voltage fluctuations in the form of periodic spikes were observed experimentally at the limiting current density (the current density at which the electrolyte concentration at one surface of the selective layer goes to 0). These phenomena were not seen when the current was in the direction leading to accumulation of electrolyte in the non-selective (unstirred) layer. Such composite membranes can exhibit S-shaped and N-shaped i-V curves under ramp-voltage and ramp-current clamps, respectively.

Diffusion↗

PubMed1991

Characterization of proline-containing right-handed alpha-helix by molecular dynamics studies.

Proline residues play a special role in shaping the secondary and tertiary structures of proteins. Many of these aspects have been studied in great detail. Current interest lies in elucidating the structure of right-handed alpha-helical fragments which contain proline in the middle of the helix. Such structures play an important role in membrane proteins and in the tight packing of globular proteins. Analysis of several crystal structures and energy minimization using flexible geometry have elucidated the nature of the bend produced by proline in the right-handed alpha-helical structure. Molecular dynamics (MD) simulation studies are ideally suited to characterize rigidity or flexibility in different parts of the molecule and can also give an idea of various conformations of the molecule which can exist at a given temperature. Hence, MD studies on Ace-(Ala)6-Pro-(Ala)3-NHMe have been carried out for 100 ps after equilibration and the resulting trajectories have been analyzed. Information regarding the average values, r.m.s. fluctuations of internal parameters and the time spent in different conformations are discussed. Energy minimization has been carried out on selected MD simulated points in order to analyze the characteristics of different conformations.

Journal Article↗

PubMed2006

Sex-specific densities of estrogen receptors alpha and beta in the subnuclei of the nucleus tractus solitarius, hypoglossal nucleus and dorsal vagal motor nucleus weanling rats.

In rats ventilatory responses to N-methyl-d-aspartate (NMDA) receptor modulation are sexually dimorphic and may be altered by manipulating brain levels of estrogen receptors. Here we used image analysis and immunohistochemistry in weanling male and female rats to quantitate areas and densities of ER alpha and ER beta-positive neurons within medullary regions associated with cardiopulmonary regulation including the hypoglossal nucleus, subnuclei of the nucleus of the solitary tract (NTS), and the dorsal motor nucleus of the vagus. Weanling rats were selected because ventilation, metabolic rate, and body and brain weights are comparable at this age and there are no large fluctuations in plasma hormone levels. Females, relative to males, had smaller areas in the A2 region and parts of the NTS. Counts and densities for ER alpha were greater in females than males in almost all regions studied. In contrast sex differences in ER beta were found in fewer nuclei, but in those higher counts and densities were noted in females. In general, ER beta-positive neurons in the brainstem regions examined were less prevalent than ER alpha neurons. Thus, in weanling rats sex affected ER alpha and ER beta neuronal densities in brainstem regions associated with cardiopulmonary regulation that may be responsible for sex differences in control of breathing.

Analysis of Variance↗

PubMed2006

Circadian and ultradian influences on dreaming: a dual rhythm model.

The dual rhythm model of dreaming states that, under high sensory thresholds, heightened general cortical activation common to both REM/NREM and circadian-driven activation cycles sums to produce the main characteristics of dreaming. In addition, the unique pattern of regional brain activation characteristic of REM sleep amplifies the emotional intensity of the dream. Subjects were awakened from REM and NREM sleep once near the nadir of the core body temperature rhythm, where circadian-driven cortical activation was assumed to be low, and again in the late morning, where this activation was presumed to be high. As predicted, changes in the central characteristics of dream reports mirrored REM/NREM and circadian-driven fluctuations in general activation, while at the same time, the regional activation pattern unique to REM sleep amplified dream emotionality selectively in REM reports.

Activity Cycles↗

PubMed1981

Diffusion coefficients of hemoglobin by intensity fluctuation spectroscopy: effects of varying pH and ionic strength.

Measurements of the mutual diffusion coefficients (D) of the liganded human hemoglobins (Hb) oxy-HbA and oxy-HbS were performed as a function of Hb concentration (CHb), pH, and ionic strength (tau) by intensity fluctuation spectroscopy (IFS). Average diffusion coefficients, (D), and normalized variances, ((D/(D) - 1)2), were recorded. Results are reported and select features are discussed quantitatively. (a) for tau = 0.15 M, the shape of the (d) vs. CHb curve is found to vary with pH. We developed a precise description of this effect in the form of an algebraic relationship between (D), CHb, and Z, the titration charge. (b) only slight differences between the (D) values of oxy-HbS and oxy-HbA are observed, at tau = 0.15 M, for CHb Less Than or Equal To 10 g%. These differences are explained by the theory of part a. (c) No evidence of aggregation is found in solutions of oxy-HbA or oxy-HbS, at tau = 0.15 M, for CHb Less Than or Equal To 10 g%. (d) Indications of aggregation appear in oxy-HbA solutions at very low concentrations of salt. An estimate is made of the extent of aggregation, and the average radius of a cluster is determined.

Diffusion↗

PubMedDate not supplied

Publication speed in analytical chemistry journals.

Variations of the time elapsing between submission or acceptance and publication ("lapse time") of papers have been studied for 10 major analytical chemistry journals, for the 1985-1999 period. The time from receipt of all manuscripts up to their publication and the period between their acceptance and their publication were analyzed in four selected years: 1985, 1990, 1995, and 1999. The majority of the investigated journals showed good average performance with sometimes disturbing fluctuations. Talanta has not been able to catch up with the rest, while the Analyst has recently become clear leader in publication speed.

Journal Article↗

PubMed1998

[Determining visual acuity using European normal values: scientific principles and possibilities for automatic measurement].

PSYCHOMETRIC FUNCTION: According to the European standard EN ISO 8596 the Landolt-C in 8 different orientations has to be used to measure visual acuity. With decreasing size of the Landolt-C the hit rate declines from 100% to the chance level of 12.5%. This gradual transition is described by the "psychometric function". The steepest point of the psychometric function is in the middle between 100 and 12.5, i.e., at 56.25%. This point of the psychometric function (approximated by 5 of 8 Landolt-Cs) has been selected as the threshold for visual acuity, because it is there that the visual acuity is influenced least by (incidental) fluctuations. The subject has to answer by forced choice; a response like "I cannot detect anything" is not acceptable. "NORMAL" VISUAL ACUITY: Cannot be assigned to a certain value, like 1.0 or 6/6. With the standard test procedure, visually healthy, young subjects achieve a visual acuity of about 2.0 or 12/6, while in senior subjects 0.5 (3/6) may be "normal". AVERAGING VISUAL ACUITY: Logarithmic, not arithmetic, scaling of visual acuity approximates the perceptual metric. Consequently, visual acuity values may not be averaged arithmetically. Instead, three steps are required: all values have to be converted to logarithms, then averaged, and finally the average can be reconverted. Geometric averaging is equivalent. "MINIMUM ANGLE OF RESOLUTION" NOT NECESSARY: MAR is the reciprocal of visual acuity. In many studies, clinical outcome has been assessed using log(MAR). Though statistically correct, this term is unnecessary, as log(acuity) has identical statistical properties. Furthermore, log(MAR) is contra-intuitive as its value becomes smaller when vision improves. COMPUTER-ASSISTED INSTRUMENTATION: Facilitates complying with the EN ISO 8596. For instance, the Freiburg Visual Acuity Test relieves the examiner from observing whether 5 responses have been correct, and that not more than 8 tests are given per level.

Europe↗