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R A Vos

Publications and source records attributed to R A Vos.

6 recordsLinked to original sources
PubMed2003

Accelerated likelihood surface exploration: the likelihood ratchet.

The existence of multiple likelihood maxima necessitates algorithms that explore a large part of the tree space. However, because of computational constraints, stepwise addition-based tree-searching methods do not allow for this exploration in reasonable time. Here, I present an algorithm that increases the speed at which the likelihood landscape can be explored. The iterative algorithm combines the computational speed of distance-based tree construction methods to arrive at approximations of the global optimum with the accuracy of optimality criterion based branch-swapping methods to improve on the result of the starting tree. The algorithm moves between local optima by iteratively perturbing the tree landscape through a process of reweighting randomly drawn samples of the underlying sequence data set. Tests on simulated and real data sets demonstrated that the optimal solution obtained using stepwise addition-based heuristic searches was found faster using the algorithm presented here. Tests on a previously published data set that established the presence of tree islands under maximum likelihood demonstrated that the algorithm identifies the same tree islands in a shorter amount of time than that needed using stepwise addition. The algorithm can be readily applied using standard software for phylogenetic inference.

Algorithms↗
PubMed1995

Impaired thyroxine and 3,5,3'-triiodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthyroidal illness.

In systemic nonthyroidal illness (NTI), peripheral production of T3 from T4 is decreased, resulting in a decreased serum T3 concentration. We investigated whether factors in serum of NTI patients may play a role in this energy-saving adaptation mechanism. Metabolism of T4 and T3 by rat hepatocytes in primary culture was measured in the presence of 10% serum of normal subjects or of patients with NTI and related to the severity of disease. Patients with NTI were grouped according to serum thyroid hormone abnormalities: group I, serum rT3, T3, and T4 normal; group III, rT3 elevated, T3 decreased, T4 normal; group IV, rT3 elevated, T3 and T4 decreased. Compared with metabolism in the presence of normal serum, metabolism of T4 and to a lesser extent of T3 was progressively decreased in the presence of serum of patients of groups I-IV. A decreased net deiodination of T4 and T3 (corrected for differences in free hormone concentration) without an increase in conjugated T4 and T3 (corrected for differences in free hormone concentration) was observed, similar to results in experiments with compounds inhibiting transport into the cells and not the metabolic processes (5' deiodination) per se. Deiodination of T4 in vitro was correlated with serum T3 concentration of the patient (r = 0.69). Serum of patients with NTI influences thyroid hormone handling by hepatocytes comparable to the effect of transport inhibitors and not to that of the 5'-deiodinase inhibitor propylthiouracil, suggesting that decreased thyroid hormone transport over the cell membrane may play a role in lowered T3 production in NTI.

Animals↗
PubMed1993

Transport and metabolism of iodothyronines in cultured human hepatocytes.

Thyroid hormone uptake into cultured human hepatocytes was studied using measurement of cell-associated radioactivity of radioiodinated thyroid hormones after 10-min incubation in culture medium with 0.5% BSA. Furthermore, 20-h incubations were performed to study transport and further intracellular metabolism. The results indicate the presence of saturable active uptake systems for T4, T3, and rT3, as addition of the unlabeled hormone (1, 5, and 2 mumol/L, respectively) to the medium resulted in a decrease in cell-associated radioactivity of 20-30%. Inhibition was also achieved after 30-min preincubation with fructose (10 mmol/L), which induces a decrease in intracellular ATP or ouabain (0.5 mmol/L), indicating energy dependence and the necessity for a sodium gradient for at least part of the transport process, respectively. After 20-h incubation, iodide production was inhibited in the presence of ouabain (0.5 mmol/L), propylthiouracil (100 mumol/L), or a monoclonal antibody (81-1A1-10; ascites dilution, 1:200) directed against thyroid hormone transport systems in rat hepatocytes. These data indicate that there is a high degree of similarity between the properties of the uptake process and subsequent conversion of thyroid hormones in human and rat hepatocytes, although the rates of uptake and conversion are lower in human hepatocytes. Furthermore, regulation of thyroid hormone uptake at the level of the plasma membrane may also be operative in human hepatocytes.

Adenosine Triphosphate↗
PubMed1993

Decreased peripheral 3,5,3'-triiodothyronine (T3) production from thyroxine (T4): a syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues.

T4, rT3, and T3 kinetic studies have been performed in a T4-substituted female who showed an increased serum T4/T3 ratio and substantially increased rT3 serum levels in the presence of normal serum thyroid hormone binding properties. The kinetic studies were performed to discriminate between T4 transport inhibition into plasma T3-producing tissues and inhibition of extrathyroidal T4 to T3 conversion. The principal findings were that both T4 and rT3 transport were inhibited into the rapid equilibrating pool (REP), which mainly consists of the liver. The plasma T3 production rate was decreased. Despite an elevated serum free T4 level, serum TSH was elevated, pointing to T4 transport inhibition at the level of the thyrotroph as well. Transport of T4 and rT3 was normal to the slowly equilibrating pool, whereas no transport inhibition of T3 was found to either pool. Because T4 into T3 conversion efficiency in the REP (the main source of plasma T3 production) was normal, it was concluded that the lowered T3 production in the subject was caused by transport inhibition of T4 into the liver. Although the occurrence of the syndrome is rare, its significance is of general importance, in that it shows that transport of thyroid hormone may vary at the tissue level. Furthermore, as T3 is the principal biologically active thyroid hormone, regulation of transport of T4 into the REP may play a (patho)physiological role in the ultimate determination of thyroid hormone activity in the tissues.

Aged↗
PubMed1992

Transport of 3,5,3'-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting.

The effects of 48-h fasting on transport of T3 and subsequent metabolism in the isolated perfused rat liver were investigated. Tracer T3 disappearance curves from the recirculating medium consisted of a fast component (FC) and a slow component (SC). Using a two-compartment model, both transport [expressed as the fractional transport rate constant from medium to liver (k21)] and disposal of T3 were calculated. After fasting, k21, total metabolism, and metabolism corrected for differences in mass transfer were diminished, pointing to both decreased transport and metabolism, presumably caused by depletion of liver ATP. Concerning transport, it was shown that only transport into the intracellular liver compartment and not transport to the extracellular liver compartment was decreased after fasting. As for metabolism, T3 glucuronidation was diminished; T3 sulfation and subsequent deiodination were not affected. All mentioned decreased parameters normalized after the addition of a combination of insulin, cortisol, and/or glucose to the medium, possibly by (partially) restoration of cellular energy stores.

Adenosine Triphosphate↗