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PubMed1996

Boehringer Mannheim award lecture 1995. La conference Boehringer Mannheim 1995. De novo design of alpha-helical proteins: basic research to medical applications.

The two-stranded alpha-helical coiled-coil is a universal dimerization domain used by nature in a diverse group of proteins. The simplicity of the coiled-coil structure makes it an ideal model system to use in understanding the fundamentals of protein folding and stability and in testing the principles of de novo design. The issues that must be addressed in the de novo design of coiled-coils for use in research and medical applications are (i) controlling parallel versus antiparallel orientation of the polypeptide chains, (ii) controlling the number of helical strands in the assembly (iii) maximizing stability of homodimers or heterodimers in the shortest possible chain length that may require the engineering of covalent constraints, and (iv) the ability to have selective heterodimerization without homodimerization, which requires a balancing of selectivity versus affinity of the dimerization strands. Examples of our initial inroads in using this de novo design motif in various applications include: heterodimer technology for the detection and purification of recombinant peptides and proteins; a universal dimerization domain for biosensors; a two-stage targeting and delivery system; and coiled-coils as templates for combinatorial helical libraries for basic research and drug discovery and as synthetic carrier molecules. The universality of this dimerization motif in nature suggests an endless number of possibilities for its use in de novo design, limited only by the creativity of peptide-protein engineers.

Amino Acid Sequence↗
PubMed2004

Natural selection and molecular evolution in PTC, a bitter-taste receptor gene.

The ability to taste phenylthiocarbamide (PTC) is a classic phenotype that has long been known to vary in human populations. This phenotype is of genetic, epidemiologic, and evolutionary interest because the ability to taste PTC is correlated with the ability to taste other bitter substances, many of which are toxic. Thus, variation in PTC perception may reflect variation in dietary preferences throughout human history and could correlate with susceptibility to diet-related diseases in modern populations. To test R. A. Fisher's long-standing hypothesis that variability in PTC perception has been maintained by balancing natural selection, we examined patterns of DNA sequence variation in the recently identified PTC gene, which accounts for up to 85% of phenotypic variance in the trait. We analyzed the entire coding region of PTC (1,002 bp) in a sample of 330 chromosomes collected from African (n=62), Asian (n=138), European (n=110), and North American (n=20) populations by use of new statistical tests for natural selection that take into account the potentially confounding effects of human population growth. Two intermediate-frequency haplotypes corresponding to "taster" and "nontaster" phenotypes were found. These haplotypes had similar frequencies across Africa, Asia, and Europe. Genetic differentiation between the continental population samples was low (FST=0.056) in comparison with estimates based on other genes. In addition, Tajima's D and Fu and Li's D and F statistics demonstrated a significant deviation from neutrality because of an excess of intermediate-frequency variants when human population growth was taken into account (P<.01). These results combine to suggest that balancing natural selection has acted to maintain "taster" and "nontaster" alleles at the PTC locus in humans.

Alleles↗
PubMed2005

[Markers of oxidative balance and concentration of selected metals in pollinotics].

It was reported that catalytically active metals are presented in both the soluble and insoluble fractions of ambient air pollution particles. Both catalyses generate and stimulate oxidative stress. There are very few reports on the role of oxidative stress in pollen allergy Theoretical presumptions may suggest that oxidative metabolism can be influenced by the activity of some metals and, on the other hand, pollens could be a carrier of at least catalytic amount of metals. The aim of our study was to evaluate concentrations of some metals (Cd, Cr, Pb, Ni, Mg, Zn) and compare the markers of oxidative balance expressed as malondialde-hyde (MDA) concentration, superoxide dismutase (SOD) and glutathion peroxidase (GPx) activities in the blood of patients with pollinosis. The investigation was performed on the group of 50 individuals, 34 diagnosed as pollen allergic and 16 healthy volunteers. We have found Pb blood concentration higher in pollen allergics group, but only on the verge of statistical significance (p = 0.058). No statistically significant differences in the concentrations of other examined metals between pollen allergics and controls were observed; whereas SOD activity was higher in allergics (p = 0.015), GPx activity lower in allergics (p = 0.045) and MDA concentration higher in allergics (p = 0.044). The positive linear correlations between SOD and Pb (r = 0.492; p < 0.001) as well as between Mg and MDA (r = 0.329; p = 0.02) were observed. On the basis of these results we formulated the following hypotheses, in our opinion worth further investigations: The statistically significant increase in SOD activity in the group of pollen allergics when compared to the group of controls points out the role of oxidative stress in pollen allergic persons. The statistically significant decrease in GPx activity suggests the long-lasting duration of oxidative stress in pollen allergic. The positive correlation between SOD activity and Pb level may suggest the putative role of Pb in oxidative stress. The positive correlation between Mg and MDA may suggest the presence of an additional mechanism in pollen allergy probably connected with the activation of phagocytosis by magnesium.

Adult↗
PubMed1989

Protein quality and digestible energy of selected foods determined in balance trials with rats.

Chemical analyses and balance trials with rats of 17 foods showed marked differences in protein quality. According to an in vitro procedure true protein digestibility was high (around 90%). The same was also the case for the in vivo values with the exception of two legumes, beans and chick peas, which were digested to a markedly lower degree when compared to the in vitro values. The assumed reason for this is discussed. Due to extensive differences in the amino acid composition of the 17 samples BV varied considerably with the lowest value (45.5) of rice-wheat gluten breakfast cereal. Energy digestibility was generally high. Amino acid digestibility determined in vivo followed the pattern of the corresponding protein digestibility, although marked differences occurred from one amino acid to another in the same food.

Amino Acids, Essential↗
PubMed2004

Acid-base balance during hypoxic hypometabolism: selected vertebrate strategies.

An important functional advantage of hypoxic hypometabolism is that it blunts the acid-base consequences of hypoxia. Hypoxia can lead to anaerobiosis and metabolic acidosis and, in animals that are apneic, to respiratory acidosis. A fall in blood and tissue pH is a major limiting factor in hypoxic tolerance and a variety of strategies occur in vertebrates, in concert with hypometabolism, to respond to this acid-base challenge. These include sequestering of lactic acid away from the circulating blood during the hypoxic exposure, either in underperfused tissues or in mineralized tissues, supplementing extracellular buffering by releasing bone mineral into the circulation, and utilizing alternative metabolic pathways for anaerobiosis to produce ethanol rather than lactate as the principal end-product. For submerged air-breathing ectotherms, effective cutaneous O2 and CO2 exchange can also allow an animal to avoid or minimize both anaerobiosis and respiratory acidosis. These responses serve to maintain a viable acid-base state in the body and to extend the time that the hypoxic stress can be endured.

Acclimatization↗
PubMed1994

Interhemispheric balance patterns detected by selective phonemic dichotic laterality measures in four clinical subtypes of reading-disabled children.

Identifying disabilities in word-attack, word-recognition, or reading comprehension, allowed for four categories of reading disability: (1) reading comprehension only (RC), (2) word-attack plus comprehension (WA+RC), (3) word-attack, word-recognition, and comprehension (WA+WR+RC), and (4) word-attack but not comprehension (WA-RC). Along with age-matched controls (AMC) and developmental-delay controls (DDC), the disabled were tested on a directed-attention dichotic task using consonant-vowel combinations. Laterality results for each place of articulation (i.e., bilabial, alveolar, and velar) selectively attested to greater left hemisphere involvement or engagement for the RC group and greater right hemisphere involvement or engagement for the WA+RC group. Performance of the other two disabled groups was consistent with less efficient right hemisphere involvement or callosal transfer. Implications for theory, research, and remediation are discussed.

Attention↗
PubMed2000

Balancing resources and risk: selecting home care clients in Florida's CARES program.

Selecting home care patients who would otherwise go into a nursing home always involves error: serving too many or two few. To clarify the choices program and case managers must make, we propose a risk-based alternative to current selection methods that involves scientifically-derived variable weighting and conscious choice of cut-off score for bestowing home care eligibility. We illustrate our proposal with data from Florida's Comprehensive Assessment and Review of Long-term Care Services (CARES) program. Using logistic regression we identify characteristics that distinguish clients recommended for nursing home placement from those referred to the community and use these results to estimate the risk of nursing home recommendation for each client. An approach to using these risk scores to determine eligibility is demonstrated along with assessment of the impact of alternative risk score cut-offs on denying care to as many as half or as few as 5% of clients served.

Activities of Daily Living↗
PubMed1982

[Evaluation of the health status of 2- and 4-year-old children from 3 selected regions according to balanced medical examinations].

The state of health and of general development of two and four-year-old children are presented on the bases of balance medical examinations performed in 3 centres (Integrated Health Care Centres). The methods and goals of those medical examinations are exposed. The examined population consisted of 1379 two- year-old and 1200-four-year-old children. About 26% of examined two-year-old urban children and 16% of rural ones have been qualified to active care groups. In the examined population of four-year-old children the respective values were 28% and 17%. Among 2-year-old children qualified for specialist's care, 85% have not been under such care before the balance-medical examination. In the 4-year-old group this situation was found in 70% of children. The most frequently observed deviations form the normal concerned: body build and posture, visual disorders, faulty mastication, insufficient body weight and/or height, dental caries and behaviour problems. Some differences in the health status were also found between the 3 centres. Environmental conditions such as sanitary facilities of the dwellings, overcrowding, utilities and home equipment were also analysed, and marked differences were observed between urban and rural areas. Further studies will be conducted in five more centres.

Child Health Services↗
PubMed2000

When did the human population size start increasing?

We analyze the frequency spectra of all available human nuclear sequence data sets by using a model of constant population size followed by exponential growth. Parameters of growth (more extreme than or) comparable to what has been suggested from mtDNA data can be rejected for 6 out of the 10 largest data sets. When the data are separated into African and non-African samples, a constant size no-growth model can be rejected for 4 out of 8 non-African samples. Long-term growth (i.e., starting 50-100 kya) can be rejected for 2 out of 8 African samples and 5 out of 8 non-African ones. Under more complex demographic models, including a bottleneck or population subdivision, more of the data are compatible with long-term growth. One problem with the data used here is that a subset of loci may reflect the action of natural selection as well as of demography. It remains possible that the correct demographic model is one of constant population size followed by long-term growth but that at several loci the demographic signature has been obscured by balancing or diversifying selection. However, it is not clear that the data at these loci are consistent with a simple model of balancing selection; more complicated selective alternatives cannot be tested unless they are made explicit. An alternative explanation is that population size growth is more recent (e.g., upper Paleolithic) and that some of the loci have experienced recent directional selection. Given the available data, the latter hypothesis seems more likely.

Africa↗
PubMed1984

Zinc, copper, and manganese intake and balance for adults consuming self-selected diets.

Twenty-eight adult men and women participated in a year-long study designed to determine accurately the nutrient intake of adults who lived at home and consumed self-selected diets. During four metabolic balance periods, 7 days each, corresponding to the seasons (spring, summer, fall, winter), duplicates of the diet, and all urine and feces were collected. Daily mean intakes for zinc and copper were 9.9 and 1.2 mg, respectively. These levels were less than the recommended daily intakes of 15 mg for zinc and 2 to 3 mg for copper. In contrast, the mean dietary intake of manganese was 3.0 mg/day which is within the suggested safe and adequate range of 2.5 to 5.0 mg. Metabolic balances were negative for all three elements possibly due to a reduction in food intake during the collection periods compared to the noncollection intervals. The collection of the duplicate diets apparently influenced the food intake during the collection weeks.

Adult↗
PubMed2005

Direct and correlated responses to artificial selection on male mating frequency in the stalk-eyed fly Cyrtodiopsis dalmanni.

Traditionally it was thought that fitness-related traits such as male mating frequency, with a history of strong directional selection, should have little additive genetic variance and thus respond asymmetrically to bidirectional artificial selection. However, recent findings and theory suggest that a balance between selection for increased male mating frequency and opposing selection pressures on physiologically linked traits will cause male mating frequency to have high additive genetic variation and hence respond symmetrically to selection. We tested these hypotheses in the stalk-eyed fly, Cyrtodiopsis dalmanni, in which males hold harems comprising many females and so have the opportunity to mate at extremely high frequencies. We subjected male stalk-eyed flies to artificial selection for increased ('high') and decreased ('low') mating frequency in the presence of ecologically realistic, high numbers of females. High line males mated significantly more often than control or low line males. The direct response to selection was approximately symmetric in the high and low lines, revealing high additive genetic variation for, and no significant genetic constraints on, increased male mating frequency in C. dalmanni. In order to investigate trade-offs that might constrain male mating frequency under natural conditions we examined correlated responses to artificial selection. We measured accessory gland length, testis length and eyespan after 7 and 14 generations of selection. High line males had significantly larger accessory glands than low line males. No consistent correlated responses to selection were found in testis length or eyespan. Our results suggest that costs associated with the production and maintenance of large accessory glands, although yet to be identified, are likely to be a major constraint on mating frequency in natural populations of C. dalmanni.

Animals↗
PubMed2006

Mean field theory for a balanced hypercolumn model of orientation selectivity in primary visual cortex.

We present a complete mean field theory for a balanced state of a simple model of an orientation hypercolumn, with a numerical procedure for solving the mean-field equations quantitatively. With our treatment, one can determine self-consistently both the firing rates and the firing correlations, without being restricted to specific neuron models. Here, we solve the mean-field equations numerically for integrate-and-fire neurons. Several known key properties of orientation selective cortical neurons emerge naturally from the description: Irregular firing with statistics close to - but not restricted to - Poisson statistics; an almost linear gain function (firing frequency as a function of stimulus contrast) of the neurons within the network; and a contrast-invariant tuning width of the neuronal firing. We find that the irregularity in firing depends sensitively on synaptic strengths. If the Fano factor is considerably larger (smaller) than 1 at some stimulus orientation, then it is also larger (resp. maller) than 1 for all other stimulus orientations that elicit firing. We also find that the tuning of the noise in the input current is the same as the tuning of the external input, while that for the mean input current depends on both the external input and the intracortical connectivity.

Action Potentials↗
PubMed2004

Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents.

Duloxetine, a selective but balanced serotonergic and noradrenergic reuptake inhibitor, was evaluated in the acute nociceptive pain models of tail flick and hot plate in mice and in the persistent and/or inflammatory pain models of acetic acid-induced writhing in mice, carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats, and capsaicin-induced mechanical allodynia in rats. In acute pain models, duloxetine had no significant effect on response latency in the mouse tail-flick test but produced modest increases in response latencies in the mouse hot plate test. Morphine produced dose-related analgesic effects in both the mouse tail-flick and hot plate tests. In models of inflammatory and/or persistent pain, duloxetine, morphine, and ibuprofen produced dose-related decreases in acetic acid-induced writhing in mice. Duloxetine, ibuprofen, and gabapentin also produced dose-dependent reversals of both thermal hyperalgesia and mechanical allodynia produced by carrageenan in rats. In addition, both duloxetine and morphine produced a significant reduction of capsaicin-induced mechanical allodynia in rats. Duloxetine and gabapentin were without substantial effect on the Rotorod test in mice, whereas morphine and ibuprofen produced a significant impairment. Our data indicate that duloxetine may be efficacious in the treatment of persistent and/or inflammatory pain states at doses that have modest or no effect on acute nociception or motor performance.

Adrenergic Uptake Inhibitors↗