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Results for “balancing selection”

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PubMed2005

Dissecting systems-wide data using mixture models: application to identify affected cellular processes.

BACKGROUND: Functional analysis of data from genome-scale experiments, such as microarrays, requires an extensive selection of differentially expressed genes. Under many conditions, the proportion of differentially expressed genes is considerable, making the selection criteria a balance between the inclusion of false positives and the exclusion of false negatives. RESULTS: We developed an analytical method to determine a p-value threshold from a microarray experiment that is dependent on the quality and design of the data set. To this aim, populations of p-values are modeled as mathematical functions in which the parameters to describe these functions are estimated in an unsupervised manner. The strength of the method is exemplified by its application to a published gene expression data set of sporadic and familial breast tumors with BRCA1 or BRCA2 mutations. CONCLUSION: We present an objective and unsupervised way to set thresholds adapted to the quality and design of the experiment. The resulting mathematical description of the data sets of genome-scale experiments enables a probabilistic approach in systems biology.

Breast Neoplasms↗

PubMed1999

The design of mineralised hard tissues for their mechanical functions.

Most hard tissues have as their primary purpose to be stiff. Outside the arthropods, mineralisation of a soft organic matrix is the almost universal method of producing high stiffness. However, stiffening brings with it the undesirable mechanical result of brittleness (lack of toughness). The mineralisation of some tissues, such as bone and dentine, can be modified rather easily, in evolutionary terms, to produce the optimum mix of stiffness with bending strength (which, except at the highest mineralisations, go together) on one hand and toughness on the other hand. However, in most other tissues, such as mollusc shell, echinoderm skeleton, brachiopod shell, barnacle shell and enamel, mineralisation is almost all-or-none, and no subtle gradations seem possible. In such cases, other features, such as architecture, must be modified to produce a useful skeleton. Not only the mechanical properties of the skeletal tissue, but its cost, mass and time taken for production will, biologists tend to assume, be balanced by natural selection to produce a satisfactory result. However, such complexity makes it difficult to be sure that we understand the extent to which mineralised skeletal materials are the best possible solution to the problems facing the animals and that we are not just telling 'Just-So' stories. Furthermore, there are some skeletal materials that do not seem to make much sense at the moment, although no doubt all will become clear eventually.

Adaptation, Physiological↗

PubMed1999

Gender and risk of autoimmune diseases: possible role of estrogenic compounds.

A striking common feature of many autoimmune diseases in humans and experimental animals, despite differences in pathology, is that females are highly susceptible to autoimmune conditions compared to males. In several animal models, estrogens promote, whereas androgens abrogate, B-cell-mediated autoimmune diseases. To understand mechanisms by which estrogens regulate autoimmunity, it is first necessary to decipher estrogen effects on the normal immune system. Estrogen treatment of nonautoimmune mice diminished lymphocyte numbers in both developmental and mature lymphoid organs. Estrogen dysregulated T- and B-cell balance by inducing selective T-cell hypoactivity and B-cell hyperactivity. Even though estrogen did not alter the relative percentages of splenic T-cell subsets, splenic lymphocytes had a reduced proliferative response to T-cell stimulants and were refractory to rescue from activation-induced apoptosis compared to cells from placebo-treated mice. In contrast, estrogen induced B-cell hyperactivity (promoted autoantibodies to double-stranded DNA and phospholipids, increased numbers of plasma cells, and increased autoantibody yield per B cell). Note that treatment of normal mice with estrogen can alter T- and B-cell regulation and overcome B-cell tolerance to result in autoimmunity in normal individuals. Could environmental estrogens promote some human autoimmune disorders? Is there a link between environmental estrogens and autoimmune disorders, especially since these disorders are reported possibly more frequently? These provocative questions warrant investigation. Our findings on immunomodulatory effects may serve as a benchmark to examine whether endocrine-disrupting chemicals will have similar immunologic effects.

Animals↗

PubMed2005

Have male and female genitalia coevolved? A phylogenetic analysis of genitalic morphology and sexual size dimorphism in web-building spiders (Araneae: Araneoidea).

Sexual size dimorphism (SSD) can strongly influence the evolution of reproductive strategies and life history. If SSD is extreme, and other characters (e.g., genitalic size) also increase with size, then functional conflicts may arise between the sexes. Spiders offer an excellent opportunity to investigate this issue because of their wide range of SSD. By using modern phylogenetic methods with 16 species of orb-weaving spiders, we provide strong evidence for the "positive genitalic divergence" model, implying that sexual genitalic dimorphism (SGD) increases as SSD increases. This pattern is supported by an evolutionary mismatch between the absolute sizes of male and female genitalia across species. Indeed, our findings reveal a dramatic reversal from male genitalia that are up to 87x larger than female genitalia in size-monomorphic species to female genitalia that are up to 2.8x larger in extremely size-dimorphic species. We infer that divergence in SGD could limit SSD both in spiders, and potentially in other taxa as well. Further, male and female body size, as well as male and female genitalia size, are decoupled evolutionarily. Finally, we show a negative scaling (hypoallometry) of male and female genitalic morphology within sexes. Evolutionary forces specific to each sex, such as larger female size (increased fecundity) or smaller male size (enhanced mate-searching ability), may be balanced by stabilizing selection on relative genitalic size.

Animals↗

PubMed2003

Role of individual ionic current systems in the SA node hypothesized by a model study.

This paper discusses the development of a cardiac sinoatrial (SA) node pacemaker model. The model successfully reconstructs the experimental action potentials at various concentrations of external Ca2+ and K+. Increasing the amplitude of L-type Ca2+ current (I(CaL)) prolongs the duration of the action potential and thereby slightly decreases the spontaneous rate. On the other hand, a negative voltage shift of I(CaL) gating by a few mV markedly increases the spontaneous rate. When the amplitude of sustained inward current (I(st)) is increased, the spontaneous rate is increased irrespective of the I(CaL) amplitude. Increasing [Ca2+](o) shortens the action potential and increases the spontaneous rate. When the spontaneous activity is stopped by decreasing I(CaL) amplitude, the resting potential is nearly constant (-35 mV) over 1-15 mM [K+](o) as observed in the experiment. This is because the conductance of the inward background non-selective cation current balances with the outward [K+](o)-dependent K+ conductance. The unique role of individual voltage- and time-dependent ion channels is clearly demonstrated and distinguished from that of the background current by calculating an instantaneous zero current potential ("lead potential") during the course of the spontaneous activity.

Action Potentials↗

PubMed2000

Inhibitors of tyrosine kinases in the treatment of psoriasis.

Psoriasis is a heterogenous skin disease, characterized by epidermal hyperproliferation, abnormal keratinization and inflammation. The heterogeneity of the disease results probably from the interaction of multiple gene abnormalities with environmental factors. The new approaches to drug design have become refocused to the emerging understanding of the role of signaling pathways in health and disease. Protein tyrosine kinases (PTKs) regulate cell proliferation, differentiation and immune processes. Uncontrolled signaling from receptor and intracellular tyrosine kinases can lead to numerous proliferative diseases: cancer, leukemia, restenosis and psoriasis. Identification of PTKs that play a key role in a defined disease can lead to a selective drug. The balance of signals which regulate the homeostasis of normal epidermis is altered in psoriasis. Several lines of evidence suggest a role for the EGF receptor system in this process. Therefore, blockers of the EGFR kinase were suggested as potent antipsoriasis agents. PTK inhibitors from the tyrphostin family were found to block EGF - dependent cell proliferation. AG 1571 (SU 5271) potently inhibits ligand-induced autophosphorylation of EGF-R, downstream signal transduction events, DNA replication and cell cycle progression at micromolar concentrations, as well as proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. AG 1571 (SU 5271) has been in clinical trials by SUGEN Inc. since early 1997. Overexpression of the EGFR is the hallmark of most epithelial cancers. Therefore one can view blockers of the EGFR kinase as becoming universal inhibitors. Tyrphostins are the first signal transduction agents to be used in the clinic. This article summarizes recent progress in the development of PTK inhibitors in the treatment of psoriasis.

Enzyme Inhibitors↗

PubMed1975

Rumen bypass and protection of proteins and amino acids.

Potent rumen microbial proteases and deaminases rapidly degrade protein and amino acids which are soluble in the rumen liquid phase. Because protein sources vary in their solubility, the degree of degradation in the rumen is variable. Methods of decreasing protein and amino acid degradation in the rumen include heat treatment, chemical treatment, encapsulation, use of amino acid analogs, selective manipulation of balances of rumen metabolic pathways, and esophageal groove closure. It is important that procedures do not interfere with ruminal metabolism or post-ruminal digestion. Bypassing the rumen changes sites in the digestive tract of nutrient digestion and absorption and provides a mechanism for supplementing outflow of nutrients from the rumen. A feasible approach to production of animal protein from ruminants would be utilization of nonprotein nitrogen for rumen protein production, maximization of rumen bypass of dietary protein, and supplementation with rumen nondegradable amino acids.

Amino Acids↗

PubMed1998

Assessment of management in general practice: validation of a practice visit method.

BACKGROUND: Practice management (PM) in general practice is as yet ill-defined; a systematic description of its domain, as well as a valid method to assess it, are necessary for research and assessment. AIM: To develop and validate a method to assess PM of general practitioners (GPs) and practices. METHOD: Relevant and potentially discriminating indicators were selected from a systematic framework of 2410 elements of PM to be used in an assessment method (VIP = visit instrument PM). The method was first tested in a pilot study and, after revision, was evaluated in order to select discriminating indicators and to determine validity of dimensions (factor and reliability analysis, linear regression). RESULTS: One hundred and ten GPs were assessed with the practice visit method using 249 indicators; 208 of these discriminated sufficiently at practice level or at GP level. Factor analysis resulted in 34 dimensions and in a taxonomy of PM. Dimensions and indicators showed marked variation between GPs and practices. Training practices scored higher on five dimensions; single-handed and dispensing practices scored lower on delegated tasks, but higher on accessibility and availability. CONCLUSION: A visit method to assess PM has been developed and its validity studied systematically. The taxonomy and dimensions of PM were in line with other classifications. Selection of a balanced number of useful and relevant indicators was nevertheless difficult. The dimensions could discriminate between groups of GPs and practices, establishing the value of the method for assessment. The VIP method could be an important contribution to the introduction of continuous quality improvement in the profession.

Family Practice↗

PubMed2000

Rat cortical neuron cultures: an in vitro model for differentiating mechanisms of chemically induced neurotoxicity.

Various structurally unrelated chemicals [2,5 hexandione, acrylamide, organophosphates like mipafox, beta,beta iminodipropionnitrile (IDPN), 3-nitropropionic acid (3-NP), potassium cyanide (KCN), paraquat, and NMDA (N-methyl-D-apartic acid)] are known to cause degenerative damage of the peripheral or central nervous system. Differentiated neuronal cell cultures obtained from fetal rats have been used to differentiate the mechanisms underlying this type of neurotoxicity. Cytotoxicity as measured by a viability assay was not sensitive enough and had to be supplemented by further endpoints covering effects on cytoskeleton and on the energy state of the cells [glucose consumption, mitochondrial membrane potential and adenosine 5'-triphosphate (ATP) concentration]. Compounds like the delayed neurotoxic organophosphates, exert a selective direct effect on cytoskeleton elements in this model at concentrations distinctly below cytotoxic concentrations. Other compounds, like KCN, paraquat, and 3-NP selectively disrupt the balance between energy supply and demand of the neurons either by interacting with mitochondrial respiration or glycolysis. For these compounds cytoskeletal damage seemed to be secondary to the energy depletion. For NMDA, 2,5 hexandione and acrylamide, both mechanisms may contribute to the neuronal damage. In conclusion, primary cortical neuronal cultures of the rat are well suited to detect a neurotoxic potential and to differentiate its underlying mechanisms. Damage of the cytoskeleton may be considered as an endpoint mechanistically related to degenerative neuropathic effects.

Adenosine Triphosphate↗

PubMed2001

[Chronological structure of arterial pressure in hypertensive patients on enalapril].

34 male patients with hypertension stage I and II aged 29-52 years (mean age 40.9 +/- 6.00) having mean 24-h arterial pressure (AP) above 135/85 mm Hg in mean daytime AP above 140/90 mm Hg and heart rate maximum 80 b/m entered the study of AP chronostructure in conditions of pure background and on enalapril treatment week 4, 8 and 12. The initial dose of the drug was 5 mg. Dose selection was controlled by 24-h AP monitoring. Enalapril was shown to significantly reduce mean daytime and 24-h AP as well as hyperbaric index, chronobiological time index, variability of systolic AP. The above dose selection brought more balanced AP lowering at daytime and at night. After 11 weeks of treatment no night-peakers were registered, the number of over-dippers decreased. Circadian rhythm of some hemodynamic parameters was characterized by a significant fall of rhythm average in unchanged acrophase and circadian AP amplitude indicating physiological action of enalapril.

Adult↗

PubMed2002

[Evaluation of LDL-cholesterol measurement].

As a result of increased recognition of elevated LDL-cholesterol (LDL-C) as a risk for ischemic heart disease, the necessity for LDL-C measurement emerged in clinical laboratories. Consequently various LDL-C measurement methods were developed. The objective of the present review article is to compare and to evaluate the characteristics of various methods for LDL-C measurement. Because LDL is a particle defined by its density, ultracentrifugation method; beta-quantification is currently considered the reference method, but it is a time-consuming and expensive technique. The evaluation by Friedewald's equation is simple and applicable to the vast majority of normolipidemic samples. LDL-C measurement by electrophoresis provides an evaluation of LDL along with other lipoproteins. Homogeneous assays have the advantage of obviating the need for pretreatment of samples, and this is suitable for online performance, requiring only a few microliters of sample. Generally, there is little disagreement between methods in LDL-C data of normolipidemic samples. However, when the sample is from patients with dyslipidemia, there may be disagreement in LDL-C results between methods and the reason for this phenomena has been discussed. At the moment, the method for LDL-C measurement at each clinical laboratory has to be selected by adequately balancing demands, costs and benefits.

Arteriosclerosis↗

PubMed1992

Vasodilator therapy for acute heart failure: haemodynamic comparison of hydralazine/isosorbide, alpha-adrenoceptor blockade, and angiotensin-converting enzyme inhibition.

Haemodynamic comparison of three vasodilation regimens [intravenous (i.v.) hydralazine and isosorbide dinitrate (ISDN) combined, i.v. doxazosin, and i.v. enalaprilat] was undertaken in 36 patients with acute left ventricular (LV) failure due to recent myocardial infarction. Each regimen achieved similar reductions in pulmonary artery occluded pressure (PAOP, preload) and systemic arterial pressures (afterload), with increased cardiac and stroke volume (SV) indexes (p less than 0.01). Only the hydralazine and isosorbide combination induced resting tachycardia. Balanced vasodilatation after selective alpha-adrenoceptor blockade (doxazosin) and angiotensin-converting enzyme (ACE) inhibition (enalaprilat) without increase in heart rate (HR) suggests that these therapies may have definite haemodynamic advantages over the hydralazine/ISDN combination.

Adrenergic alpha-Antagonists↗

PubMedDate not supplied

Measurement of femoral head microcirculation by laser Doppler flowmetry.

Perfusion of the capital femoral epiphysis was measured by laser Doppler flowmetry (LDF) in a series of skeletally immature pigs. After induction of balanced general anesthesia, selective occlusion of the arterial blood supply to the hip was performed with continuous monitoring by a laser Doppler probe applied to the articular surface of the femoral head. The lateral femoral circumflex artery, a main branch of the superficial femoral artery in the pig, was largely responsible for femoral head perfusion in eight of nine pigs, according to LDF measurements. This finding was confirmed by postmortem silicone rubber injections and Spalteholz preparations of the femoral heads.

Animals↗

PubMed1982

Food use and perceived food meanings of the elderly.

Food use frequency and food perception analyses were used to assess food use patterns of non-institutionalized, subjectively healthy seniors, aged 65 to 77 years and living alone. The majority of the sample maintained variety and nutritional balance in food selection; the women showed greater use several items, particularly fruits and vegetables. Tea, whole wheat bread, eggs, coffee, potatoes, margarine, carrots, and orange juice ranked highest in the core food list. Perceived taste and health beliefs were strong motives in food selection.

Age Factors↗

PubMed1995

[Swollen ear canal, not always innocent].

A swollen ear canal: not to be underestimated. The role of radiology in three patients with problems due to unaccomplished otitis externa is discussed. The choice between CT scanning and MRI in selected cases is balanced.

Aged↗

PubMed1993

Selection on maternal and neonate size at birth.

Neonatal size is an important factor in determining the survivorship of infants within the first month of life. Because maternal size has an influence on neonatal size, selection should operate on those characters correlated with birth weight and gestational age, including maternal prepregnancy weight, height, and age. In the present study we use a path-analysis approach to examine the operation of selection on both neonatal and maternal size. We found that neonatal survivorship depends not only on the size of the infant at birth but also on a negative allometric relationship between the size of the neonate and the size of the mother. Thus, although the size of the mother has no direct effect on neonatal mortality, the mothers of surviving infants tend to be smaller relative to the size of their neonate. This may provide a mechanism whereby selection maintains a balance between maternal size and neonate size.

Adult↗

PubMed1996

Isolation and characterization of the basal cell membranes of the human term placenta.

A relatively simple and rapid method is described for the isolation of basal cell membranes (BCM) from the human placenta at term which showed considerable improvement in the yield, purity and membrane characteristics as compared to the earlier described methods. The method is based on thorough washings of the syncytium in balanced salt solution, selective grinding, hypotonic lysis, sonication, incubation with EDTA and then more conventional differential centrifugation and ultracentrifugation. The isolated material showed smooth surfaced vesicular structure of various sizes as revealed by both positive and negative staining and transmission electron microscopic analysis. The membrane was highly enriched in Na+/K+, Ca2+ and Mg2+ dependent ATPase activities while the cross contamination with brush border surfaces was low as revealed by the marker enzyme assays specific for the brush border membrane (BBM) such as the disaccharide hydrolases, aminopeptidase and alkaline phosphatase. The membrane showed a relatively low lipid/protein ratio and the lipid composition represented by a variety of phospholipids (phosphatidyl choline, phosphatidyl ethanolamine, sphingomyelin, phosphatidyl inositol and phosphatidyl serine), neutral lipids (cholesterol, triacyl glycerol, free fatty acids) and glycosphingolipids (ganglioside, cerebroside and sulfatide). It also contained plasmalogens. On SDS-PAGE analysis and Coomassie blue staining reaction, the isolated membrane showed 14 major bands with as many minor ones with a molecular weight ranging between 30-110 kDa.

Adenosine Triphosphatases↗

PubMed2001

A chromosomal region promoting outcrossing in a conifer.

Prefertilization mechanisms influencing selfing rates are thought to be absent in conifers. Outcrossing in conifers is promoted via an embryo-lethal system, but the genetic mechanism is poorly understood. This study is the first experimental profile of the genetic mechanism promoting outcrossing in conifers. Molecular dissection of a Pinus taeda L. selfed pedigree detected a chromosomal region identified as PtTX3020-RPtest9. Within this region, a semilethal factor was tightly linked (r = 0.0076) to a polymorphic expressed sequence tag (EST). The linkage group flanking the lethal factor showed strong heterozygote advantage. Using genotypic frequencies for the linkage group, three hypotheses about the semilethal factor could be tested: (1) the presence of a balanced lethal system, i.e., a lethal factor present in each of the two marker intervals; (2) gametic selection operative prior to fertilization; and (3) a stage-specific lethal factor. Selection acted via the embryo-lethal system. No support for a genetic mechanism operating prior to fertilization was found. The semilethal factor exerted no effect after embryo maturity. The genetic mechanism promoting outcrossing in P. taeda L. appears to have a balancing selection system due to either pseudo-overdominance or true overdominance.

Alleles↗