Hill coefficients,dose–response curves and allosteric mechanisms

Hill coefficients (n _H) derived from four parameter logistic fits to dose–response curves were compared to calculated realistic reaction schemes and related to experimental data: (1) Hill coefficients may give information on the number of interacting sites but cannot distinguish between competitive, non-competitive or ortho-, iso-, or allosteric mechanisms. (2) For enzymatic dose–inhibition curves, Hill coefficients smaller than one do not indicate anticooperative binding but show that at least one ternary complex has enzymatic activity. (3) Hill coefficients different from one are proof for multiple ligand binding. The large variations of reported Hill coefficients corresponds to multiple allosteric binding, where induced conformational changes cause loss of the active conformation. Such a denaturation mechanism is in stark contrast to the desired specificity of drugs. The discussion is open.     

Iodine concentration of milk in a dose–response study with dairy cows and implications for consumer iodine intake

Most feed is poor in iodine and iodine supplementation of cow's diets must guarantee milk iodine concentrations for humans that contribute to prevention of the deficiency and minimize the risk of exceeding an upper limit of iodine intake. Five Holstein cows were fed four iodine doses (via Ca(ΙO₃)₂·6H₂O). In four sequential 14-d periods, doses of 0.2 (basal diet), 1.3, 5.1, and 10.1 mg iodine kg^?1 diet dry matter (DM) were administered. Samples of milk were collected during each period; blood was also sampled from each cow for each iodine dosage. In an 18-d depletion period, a non-supplemented diet was provided. Iodine was determined by inductively coupled plasma-mass spectrometry. The iodine content of milk and serum reflected the iodine dosages in feed significantly. The levels for the four doses tested in milk were 101±32, 343±109, 1215±222, and 2762±852 μg iodine kg^?1. The total amount of iodine in milk per day was 30–40% of ingested supplemental iodine. Omitting additional iodine resulted in a short-term reduction of serum and milk iodine following an exponential decay function. The iodine supplementation of 0.5–1.5 mg kg^?1 diet DM represents the requirement of the cow, resulting in 100–300 μg iodine L^?1 milk, which optimally contributes to human supply. The maximum dietary levels of former and present EU legislations (10 and 5 mg iodine kg^?1 cow feed) increase the risk of iodine excess in humans.     

Boron neutron capture therapy (BNCT) for liver metastasis in an experimental model: dose–response at five-week follow-up based on retrospective dose assessment in individual rats

Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. Employing an experimental model of liver metastases in rats, we recently demonstrated that BNCT mediated by boronophenylalanine (BPA-BNCT) at 13 Gy prescribed to tumor is therapeutically useful at 3-week follow-up. The aim of the present study was to evaluate dose–response at 5-week follow-up, based on retrospective dose assessment in individual rats. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA-BNCT (n = 19), Beam only (n = 8) and Sham (n = 7) (matched manipulation, no treatment). For each rat, neutron flux was measured in situ and boron content was measured in a pre-irradiation blood sample for retrospective individual dose assessment. For statistical analysis (ANOVA), individual data for the BPA-BNCT group were pooled according to absorbed tumor dose, BPA-BNCT I: 4.5–8.9 Gy and BPA-BNCT II: 9.2–16 Gy. At 5 weeks post-irradiation, the tumor surface area post-treatment/pre-treatment ratio was 12.2 ± 6.6 for Sham, 7.8 ± 4.1 for Beam only, 4.4 ± 5.6 for BPA-BNCT I and 0.45 ± 0.20 for BPA-BNCT II; tumor nodule weight was 750 ± 480 mg for Sham, 960 ± 620 mg for Beam only, 380 ± 720 mg for BPA-BNCT I and 7.3 ± 5.9 mg for BPA-BNCT II. The BPA-BNCT II group exhibited statistically significant tumor control with no contributory liver toxicity. Potential threshold doses for tumor response and significant tumor control were established at 6.1 and 9.2 Gy, respectively.     

Thermoluminescence dose–response of synthesized and doped hydroxyapatite: effect of formed crystal phases

In this research work, pure and doped hydroxyapatite samples were synthesized using hydrolysis and hydrothermal methods to produce powder material. The crystal structure was carried out by producing data using the X-ray diffraction system and the Rietveld method using material analysis using diffraction software. Then the sample was irradiated with different radiation absorbed doses, and their thermoluminescence response was investigated from the dosimetry point of view. The results showed that the synthesis method, doping, and annealing temperature could significantly affect the crystal structure and thermoluminescence dosimetry response of hydroxyapatite samples, consequently. The results showed that the high-temperature annealing process and dopant could lead to the formation of the β-TCP crystal phase during or after the synthesis of hydroxyapatite, and the percentage of this formed phase increased when raising the temperature, and finally led to increase in the thermoluminescence response.     

Computational methods for evaluation of cell-based data assessment—Bioconductor

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Highlights► Bioconductor proposes more than 20 R packages for FCM analysis. ► Data infrastructure proposed by flowCore has become the standard for many packages. ► Automated gating is improving but remains an intensive field of research.     

Ionizing radiation stimulates secretion of pro-inflammatory cytokines: dose–response relationship,mechanisms and implications

In previous studies we showed a marked increase in secretion of inflammatory cytokines TNFα and interleukin (IL)-1β by mouse macrophages in response to different doses of ionizing radiation (IR). Here we show the stimulation of IL-12 and IL-18 secretion by mouse peritoneal macrophages after whole-body irradiation with exploration of the possible mechanisms and implications in cancer radiotherapy. Both low (0.075 Gy) and high (2 Gy) doses of IR were found to cause sustained stimulation of IL-12 and IL-18 secretion by mouse macrophages; this paralleled the activation of NF-κB as well as up-regulated expression of CD14 and TLR4–MD2 on the macrophage surface and MyD88 in the cytoplasm. The expression of CD14, TLR4–MD2 and MyD88 increased in a dose-dependent manner from radiation doses between 0.05 and 2 Gy. The secretion of IL-12 and IL-18 showed a dose-dependent increase from doses between 0.05 and 4 Gy. It is concluded that IR can stimulate the secretion of IL-12 and IL-18 presumably via activation of the Toll signaling pathway in macrophages. The potential harmful effect of repeated doses of radiation used in radiotherapy for certain cancers is discussed. Yu-Xing Shan and Shun-Zi Jin contributed equally to the present work.     

Effect of temperature on the dose–response curves for auxin-induced elongation growth in maize coleoptile segments

The dose–response curves for IAA-induced growth in maize coleoptile segments were studied as a function of time and temperature. In addition, the kinetics of growth rate responses at some auxin concentrations and temperatures was also compared. It was found that the dose–response curves for IAA-induced elongation growth were, independently of time and temperature, bell-shaped with an optimal concentration at 10⁻⁵ M IAA. The kinetics of IAA-induced growth rate responses depended on IAA concentration and temperature, and could be separated into two phases (biphasic reaction). The first phase (very rapid) was followed by a long lasting one (second phase), which began about 30 min after auxin addition. For coleoptile segments incubated at 30°C, the amplitudes of the first and second phase were significantly higher, when compared with 25°C, at all IAA concentrations studied. However, when coleoptile segments were incubated at 20°C, the elongation growth of coleoptile segments treated with suboptimal IAA concentrations was diminished, mainly as a result of both phases reduction. In conclusion, we propose that the shape of the dose–response curves for IAA-induced growth in maize coleoptile segments is connected with biphasic kinetic of growth rate response.     

U.S. Environmental Protection Agency's revised guidelines for carcinogen risk assessment: evaluating a postulated mode of carcinogenic action in guiding dose–response extrapolation

There are new opportunities to using data from molecular and cellular studies in order to bring together a fuller biological understanding of how chemicals induce neoplasia. In 1996, the Environmental Protection Agency (EPA) published a proposal to replace its 1986 Guidelines for Carcinogen Risk Assessment to take advantage of these new scientific advances in cancer biology. The analytical framework within the new guidelines focuses on an understanding of the mode of carcinogenic action. Mode of action data come into play in a couple of ways in these new guidelines. For example, such information can inform the dose–response relationship below the experimental observable range of tumours. Thus, mode of action data can be useful in establishing more appropriate guidance levels for environmental contaminants. It is the understanding of the biological processes that lead to tumour development along with the response data derived from experimental studies that can help discern the shape of the dose–response at low doses (linear vs. nonlinear). Because it is experimentally difficult to establish “true thresholds” from others with a nonlinear dose–response relationship, the proposed guidelines take a practical approach to depart from low-dose linear extrapolation procedures when there is sufficient experimental support for a mode of action consistent with nonlinear biological processes (e.g., tumours resulting from the disruption of normal physiological processes).     

Statistical methods for temporal and space–time analysis of community composition data

This review focuses on the analysis of temporal beta diversity, which is the variation in community composition along time in a study area. Temporal beta diversity is measured by the variance of the multivariate community composition time series and that variance can be partitioned using appropriate statistical methods. Some of these methods are classical, such as simple or canonical ordination, whereas others are recent, including the methods of temporal eigenfunction analysis developed for multiscale exploration (i.e. addressing several scales of variation) of univariate or multivariate response data, reviewed, to our knowledge for the first time in this review. These methods are illustrated with ecological data from 13 years of benthic surveys in Chesapeake Bay, USA. The following methods are applied to the Chesapeake data: distance-based Moran''s eigenvector maps, asymmetric eigenvector maps, scalogram, variation partitioning, multivariate correlogram, multivariate regression tree, and two-way MANOVA to study temporal and space–time variability. Local (temporal) contributions to beta diversity (LCBD indices) are computed and analysed graphically and by regression against environmental variables, and the role of species in determining the LCBD values is analysed by correlation analysis. A tutorial detailing the analyses in the R language is provided in an appendix.     

Structure–property relation and relevance of beam theories for microtubules: a coupled molecular and continuum mechanics study

Quasi-one-dimensional microtubules (MTs) in cells enjoy high axial rigidity but large transverse flexibility due to the inter-protofilament (PF) sliding. This study aims to explore the structure–property relation for MTs and examine the relevance of the beam theories to their unique features. A molecular structural mechanics (MSM) model was used to identify the origin of the inter-PF sliding and its role in bending and vibration of MTs. The beam models were then fitted to the MSM to reveal how they cope with the distinct mechanical responses induced by the inter-PF sliding. Clear evidence showed that the inter-PF sliding is due to the soft inter-PF bonds and leads to the length-dependent bending stiffness. The Euler beam theory is found to adequately describe MT deformation when the inter-PF sliding is largely prohibited. Nevertheless, neither shear deformation nor the nonlocal effect considered in the ‘more accurate’ beam theories can fully capture the effect of the inter-PF sliding. This reflects the distinct deformation mechanisms between an MT and its equivalent continuous body.     

Effect of inorganic salts and glucose additives on dose–response,melting point and mass density of genipin gel dosimeters

Genipin gel dosimeters are hydrogels infused with a radiation-sensitive material which yield dosimetric information in three dimensions (3D). The effect of inorganic salts and glucose on the visible absorption dose–response, melting points and mass density of genipin gel dosimeters has been experimentally evaluated using 6-MV LINAC photons. As a result, the addition of glucose with optimum concentration of 10% (w/w) was found to improve the thermal stability of the genipin gel and increase its melting point (T_m) by 6 °C accompanied by a slight decrease of dose–response. Furthermore, glucose helps to adjust the gel mass density to obtain the desired tissue-equivalent properties. A drop of T_m was observed when salts were used as additives. As the salt concentration increased, gel T_m decreased. The mass density and melting point of the genipin gel could be adjusted using different amounts of glucose that improved the genipin gel suitability for 3D dose measurements without introducing additional toxicity to the final gel.     

Radiation risk estimates after radiotherapy: application of the organ equivalent dose concept to plateau dose–response relationships

Estimates of secondary cancer risk after radiotherapy are becoming more important for comparative treatment planning. Modern treatment planning systems provide accurate three-dimensional (3D) dose distributions for each individual patient. The dose distributions can be converted into organ equivalent doses to describe radiation-induced cancer after radiotherapy (OED_rad-ther) in the irradiated organs. The OED_rad-ther concept assumes that any two dose distributions in an organ are equivalent if they cause the same radiation-induced cancer risk. In this work, this concept is applied to dose–response relationships, which are leveling off at high dose. The organ-dependent operational parameter of this dose–response relationship was estimated by analyzing secondary cancer incidence data of patients with Hodgkin’s disease. The dose distributions of a typical radiotherapy treatment plan for treating Hodgkin’s disease was reconstructed. Dose distributions were calculated in individual organs from which cancer incidence data were available. The model parameter was obtained by comparing dose and cancer incidence rates for the individual organs.     

Comparison of dose response functions for EBT3 model GafChromic™ film dosimetry system

ObjectiveDifferent dose response functions of EBT3 model GafChromic™ film dosimetry system have been compared in terms of sensitivity as well as uncertainty vs. error analysis. We also made an assessment of the necessity of scanning film pieces before and after irradiation.MethodsPieces of EBT3 film model were irradiated to different dose values in Solid Water (SW) phantom. Based on images scanned in both reflection and transmission mode before and after irradiation, twelve different response functions were calculated. For every response function, a reference radiochromic film dosimetry system was established by generating calibration curve and by performing the error vs. uncertainty analysis.ResultsResponse functions using pixel values from the green channel demonstrated the highest sensitivity in both transmission and reflection mode. All functions were successfully fitted with rational functional form, and provided an overall one-sigma uncertainty of better than 2% for doses above 2 Gy. Use of pre-scanned images to calculate response functions resulted in negligible improvement in dose measurement accuracy.ConclusionAlthough reflection scanning mode provides higher sensitivity and could lead to a more widespread use of radiochromic film dosimetry, it has fairly limited dose range and slightly increased uncertainty when compared to transmission scan based response functions. Double-scanning technique, either in transmission or reflection mode, shows negligible improvement in dose accuracy as well as a negligible increase in dose uncertainty. Normalized pixel value of the images scanned in transmission mode shows linear response in a dose range of up to 11 Gy.     

Dose–response and threshold effects in cytotoxicity and apoptosis

Cell death can occur as an active, programmed event in response to cytotoxic injury or to endogenous growth limiting factors; the latter serve to maintain homeostasis of cell number in tissues. Cells seem to use different pathways for programmed death, as reflected by their different morphology and different biochemistry. Severe cell damage leading to incapacitation of essential cell functions such as ATP synthesis or the maintenance of membrane potential may lead to “necrosis”. In any event, the incidence and rate of cell death increase with increasing signal intensity. Cytotoxic injury requires a certain number of primary insults; cell death will therefore occur only beyond a definable threshold. Growth factor control of cell death is receptor-mediated with dose–response relations including threshold phenomena follow the general principles of receptor kinetics. The occurrence of programmed cell death during the stages of carcinogenesis introduces a reversible component into this disease. Therefore, there may exist thresholds of dose or durations of exposure to certain carcinogens below which irreversible disease is not generated.     

Dose–response assessment of metal toxicity upon indigenous Thiobacillus thiooxidans BC1

This study provides a first attempt from a toxicological perspective to put forward, in general terms and explanations, the toxicity series of Cd(II), Cu(II) and Zn(II) to Thiobacillus thiooxidans BC1. Sulphur oxidation and sulphuric acid production are strongly related to microbial growth at pH less than 4. Dose–response analysis on chronic and acute toxicity (e.g. EC₂₀, median effective dose EC₅₀ and slope factor B) of divalent cadmium, copper and zinc cations suggests a toxicity series of Cu>Cd>>Zn to T. thiooxidans BC1. Zn(II) is termed non-toxic and the maximum treatment concentrations of Cd(II) and Cu(II) are approximately 300, 400 mg/l, respectively. This assessment clearly indicates viable operation ranges of metal bioleaching for mine wastewater treatment, suggesting a technological feasibility of biotreatment using acidophilic thiobacilli T. thiooxidans BC1.     

An integrated modelling approach for R5–X4 mutation and HAART therapy assessment

We have modelled the within-patient evolutionary process during HIV infection using different methodologies. New viral strains arise during the course of HIV infection. These multiple strains of the virus are able to use different coreceptors, in particular the CCR5 and the CXCR4 (R5 and X4 phenotypes, respectively) influence the progression of the disease to the AIDS phase. We present a model of HIV early infection and CTLs response which describes the dynamics of R5 quasispecies, specifying the R5 to X4 switch and the effects of the immune response. We illustrate the dynamics of HIV multiple strains in the presence of multidrug HAART therapy. The HAART combined with X4 strain blocker drugs might help to reduce infectivity and lead to slower progression of the disease. On the methodology side, our model represents a paradigm of integrating formal methods and mathematical models as a general framework to study HIV multiple strains during disease progression, and it will inch towards providing help in selecting among vaccines and drug therapies. The results presented here are one of the rare cases of methodological cross comparison (stochastic and deterministic) and a novel implementation of model checking in therapy validation.