This could be analogous to the effects holding an item in working memory selleck inhibitor has in guiding attention to matching features (for review, see

Soto et al., 2008). Thus, setting voluntary attention to the task-relevant feature also selects the same feature in an image that is internally created in the absence of incoming visual signals, analogous to its effect on ‘normal’ perception when multiple features physically appear in a visual scene (Saenz et al., 2003). Our results also show that the relationship between pitch and synaesthetic objects follow the same rules as the subtle cross-modal mappings seen in non-synaesthetes: non-synaesthetic individuals tend to map high-pitched sounds with small, bright objects located high in space. This effect in non-synaesthetes has been documented using subjective report (Eitan and Timmers, 2010; Ward et al., 2006), speeded reaction time (Ben-Artzi and Marks, 1995; Evans and Treisman, 2010; Marks, 1987),

and preferential looking in infants (Walker et al., 2010). Although the implicit cross-modal Selleckchem R428 correspondences in non-synaesthetes can only be measured under specific experimental settings, whereas synaesthetes have daily conscious experiences of auditorily-induced visual percepts, there are some hints in the data that controls may be subtly affected by these mappings even when we use stimuli tailored to synaesthete experiences. For example, as Fig. 5a illustrates, controls show a pattern numerically similar to that of synaesthetes across conditions, although there are no statistically significant congruency effects in their data. Ward et al. (2006) suggest that similarities between synaesthetes and non-synaesthetes in sound–colour mappings show

that synaesthesia co-opts the neural substrates for ‘normal’ cross-modality mappings and reveals the associations in a more explicit form. Another study reporting the similarity between synaesthetes and non-synaesthetes in their mapping between luminance and numerical quantity also fits the notion that synaesthesia builds on ‘normal’ mechanisms of non-synaesthetic Bcl-w brain (Cohen Kadosh et al., 2007). We interpret our data similarly as implying a common neural/cognitive mechanism underlying both auditory–visual synaesthesia and ‘normal’ cross-modal mappings. The documentation of non-colour synaesthetic visual features is crucial for developing more comprehensive models to explain how synaesthesia relates to general aspects of cognition. Here we provide objective evidence showing that auditorily-induced synaesthetic objects with multiple features affect behaviour, as well as that attention modulates the component features of synaesthetic objects. Our findings suggest overt synaesthetic experiences induced by sounds reflect implicit cross-modal mechanisms we all share.

In summary, biglycan plays important roles in the musculoskeletal system. The fact that non-glycanated forms of biglycan are effective in ameliorating muscle defects and that it can be administered systemically makes it particularly amenable for tissue and cell therapy. Taken together, it is reasonable to conclude that biglycan holds promise as a novel therapeutic for numerous musculoskeletal diseases including low bone mass, osteoarthritis, ectopic bone formation and muscular dystrophy. The experiments described in this commentary were supported partly by the Division of Intramural Research, NIDCR of the Intramural Research Program, NIH,

DHHS. “
“Human development, like that INCB018424 clinical trial of other mammals, is critically dependent on the formation and function of the embryonic heart. Forming between 3 and 8 weeks of gestation, the heart supports

subsequent growth of the foetus and it is perhaps not surprising that disruption of either heart development or function are believed to account for up to 10% of all miscarriages. Indeed, even amongst live births, anomalies of the heart are still detected in approximately 1% of babies and their management constitutes a significant medical burden. Heart development itself is an exquisitely complex process involving the transformation of a simple, tubular ABT263 peristaltic pump into a mature, multi-chambered organ, capable of supporting separate systemic and pulmonary circulation upon birth. Understanding the complex interplay of growth, differentiation and tissue interactions and their underlying genetic programmes that drive formation of this organ is an enormous challenge for developmental biologists, but is essential if we are to unravel the environmental and genetic influences that result in congenital heart disease. Animal models provide the opportunity both to examine normal heart development

Dolutegravir chemical structure in a range of vertebrate embryos and to test the effect of experimental perturbation on heart morphogenesis or function. Structurally more similar to the human heart than that of avian or amphibian species, the mouse heart is most commonly used for studying cardiogenesis. Indeed, the past decade has witnessed a dramatic increase in our understanding of mouse heart development, driven primarily by the use of genetic manipulation. Not only has this facilitated study of the role played by individual genes in heart formation (revealing profound similarities in gene function between human and mouse counterparts), it has also provided the means to reliably distinguish the contribution of distinct cell lineages to the developing heart. As a result, the limiting factor is perhaps no longer the difficulty in establishing methods to perturb heart development; rather it is the challenge of integrating the burgeoning data from diverse studies of gene expression, cell lineage, proliferation and tissue architecture.

Recently, further evidence was provided for the involvement of APOBEC3B in human cancers, as its expression was elevated in tumours compared to their matched normal samples [ 88 and 89]. By comparing the substitution patterns

of all signatures with experimental data, one of the mutational signatures was associated with exposure to ultraviolet light while another with benzo[a]pyrene, a known tobacco carcinogen. The signature associated with UV-light exhibited a higher presence of CC > TT dinucleotide substitutions as well as a strand bias indicative of the formation of photodimers, which further confirmed the association. In contrast, a mutational signature associated in lung cancer exhibited predominantly C > A selleck chemical mutations with a transcriptional strand bias suggesting the formation of bulky adducts on guanine. Interestingly, this mutational signature was also associated with CC > AA dinucleotide substitutions with a strong strand

bias. Statistical tests comparing smokers with non-smokers in two cancer types (viz. lung adenocarcinoma and tumours of the head and neck) confirmed a highly significant elevation of this ‘tobacco smoking signature’ in smokers indicating that it was due to tobacco mutagens. Further statistical analysis was performed to associate mutations in genes with the presence of mutational signatures. Distinct mutational signatures Navitoclax in vitro were associated with: mutations in BRCA1/2 in breast and pancreatic cancers; failure of the DNA mismatch repair pathway (e.g. due to methylation of the MLH1 promoter) in colorectal cancers; hypermutation of the immunoglobulin gene in CLL; recurring polymerase ɛ mutations in uterine and colorectal cancers. Interestingly, the mutational signature associated with failure of DNA mismatch repair was observed in nine different cancer types. While this process was operative in ∼20% of colorectal cancers and ∼15% of uterine cancers, it was also found in at least 1% of cancer samples in another seven cancer types. Another interesting

observation was that while almost all BRCA1/2 mutants exhibit a specific mutational signature, there were also BRCA1/2 wild-type samples with high number of mutations due to this mutational process. Thus, it is possible that some BRCA1/2 wild-type samples might harbour somatic mutations or other abnormalities Urease that result in a failure of homologous repair and activation of this mutational process. Chemotherapy treatment could cause its own set of somatic mutations [24]. Examining the pre-treatment history of all 7 042 cancer samples revealed that melanomas and glioblastomas pre-treated with an alkylating agent exhibit a distinct mutational signature. The performed global analysis was able to propose an association for 11 of the 22 validated mutation signatures, while the origins and aetiology of the other 11 mutational signatures remains unknown.

On the other hand, a hypomethylation of non-coding region has been linked to chromosome instability (Watanabe and Maekawa, 2010). Genomic imprinting, a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner,

involves the methylation of the unexpressed allele (Eggermann et al., 2011). Post-translational modifications of histone tails, have been shown to be important in altering chromatin structure and therefore DNA accessibility (Kouzarides, 2007). The functional effects of such modifications depend on the specific amino acid that is modified and on the specific covalently attached group: e.g. acetylation results in the loosening of chromatin and lends itself to replication and transcription, whereas methylated histones tight DNA and

restrict access to various enzymes. Histones modifications can regulate gene GDC-0941 clinical trial expression, chromatin remodeling, cell survival and cell death (Kouzarides, 2007). microRNAs (miRNA) are single-stranded RNAs of about 21–23 nucleotides in length that are transcribed from DNA but not translated into proteins (non-coding RNAs). Their functional role 3-Methyladenine clinical trial is gene expression regulation mediated by a control of messenger RNA (mRNA) stability or translation. Mature miRNAs can be totally complementary to the mRNA: the paring between the miRNA and the mRNA leads to the mRNA degradation, therefore impairing gene expression. Otherwise miRNA can be only partially complementary to mRNA molecules: their regulatory function is thus mediated by a block in mRNA translation (Jackson and Standart, 2007 and Pillai et al., 2007). One single miRNA regulates the expression

of hundreds of different target genes, vice versa one gene can be regulated by hundreds of miRNA. MicroRNAs play a key role in diverse biological processes, including development, cell proliferation, differentiation, and apoptosis. Emerging evidence indicates that epigenetic changes are important cellular and ioxilan molecular correlates of neurodegenerative diseases resulting from chronic neurotoxic chemical exposure. Kwok et al. recognized the role of DNA methylation following environmental chemical exposure in the pathogenesis of neurodegenerative diseases. DNA methylation causes an allelic skewing in a significant proportion of genes, that is, one allele can be transcribed or expressed at a higher level than the other allele, differentiating between the maternal and paternal origin allele. This phenomenon may determine how an individual’s genotype can alter the effect an environmental factor has on their risk of developing neurodegeneration (Kanthasamy et al., 2012). Exposure to dichlorodiphenyltrichloroethane (DDT) alters the methylation pattern in the hypothalamus of young male rats: the experiment conducted by Shutoh et al. (2009) showed that 6 CpG islands (in Sst, Gal, Arf1, Ttr, Msx1 amd Grifin genes) were significantly hypomethylated compared with controls.

This development should not simply combine existing model components but rely on an innovative integrated model for both media. Existing approaches for regionalizing climate change in the North Sea/Baltic Sea area must be improved and extended. Of special interest are the effects of long-period variations of the NAO, the wind and wave statistics, the mean sea level

and the general circulation. Are storm surges becoming more dangerous? What changes can be expected with respect to the ecosystem and biodiversity? “
“One of the important issues in the marine sciences is to study the relationships between seawater constituents and their optical properties in different regions of world oceans and seas (Dera 1992, 2003). On the one hand, elementary optical processes

such as light absorption and scattering by different seawater constituents determine how check details sunlight is propagated and utilized in water, which has a great influence on the thermal regimes and states of marine ecosystems (Trenberth (ed.) 1992, Kirk 1994). On the other hand, armed with a knowledge of seawater optical properties, we may be able to identify the composition and concentrations of different seawater constituents. An understanding of the relations between these constituents and their optical properties is thus necessary for both the ecological and climate MK 1775 modelling of marine environments and also for establishing practical marine research methods. These interrelations are especially complicated with respect to oceanic shelf regions and also to enclosed and semi-enclosed seas, jointly described as case II waters

according to the classification by Morel & Prieur (1977). As opposed to open ocean waters (classified as case I waters and whose optical properties are relatively well studied), in water bodies classified as case II, both autogenic (e.g. phytoplankton and its degradation products) and allogenic (substances transported from land by rivers, or by wind, and substances resuspended from the sea bottom and eroded from shorelines) constituents may play an important role, and their concentrations may be uncorrelated with one another. For decades laboratory not biogeochemical analyses of discrete water samples collected at sea have been used to determine the types and concentrations of suspended and dissolved substances in seawater. But such analyses are usually laborious and time-consuming and so are difficult to apply on a large scale. Another widely used tool for the monitoring and research of oceans and seawaters is remote sensing (see e.g. Arst 2003). Performed from above the sea surface (from a ship, aircraft or earth satellite platform), these measurements are based on analyses of the remote sensing reflectance spectrum (one of the so-called apparent optical properties (AOPs)), also commonly referred to as ‘ocean colour’.

As described for liquid state NMR noise experiments

[6] and [9] the selleck chemicals tuning required to obtain this dip line shape may deviate from the conventional tuning optimum (CTO). This offset also does not generally coincide with the optimum determined by minimizing reflected power through an external reflection bridge. This was also the case for the triple and double resonance probes in combination with two preamplifiers, where the noise power signal exhibits a dispersive line shape at the CTO. Fig. 3 shows noise spectra of H2O at different tuning offsets obtained using the triple resonance probe connected to a high-power 1H/19F preamplifier. Note that both the observed line shape and the average (thermal) noise level are tuning-dependent. De-tuning of the other channels had no influence on the 1H noise signal. The SNTO [6], where a pure “dip” power line shape (i.e. a noise level lower than average thermal noise) was seen, was at a tuning offset of 365 kHz from the resonance frequency. This offset varies between different probes

and preamplifiers as shown in Table 1. Using a (1H/13C) double resonance MAS probe instead, surprisingly, only positive noise signals could be found within the entire tuning and matching range. We concluded that the SNTO for this probe/amplifier connection lay outside check details the range accessible by the tuning capacitors. Using a high-power (solids) low noise preamplifier, the dip tuning offset was zero. This was the case for this preamplifier with all probes used. In combination with a low-power preamplifier the shape of the tuning curve was significantly different. The pure dip signal was not found with the normal routine within the tuning ranges of both probes. De-matching had a significant influence on both the noise line shape and the average thermal noise level. In the case of the triple resonance probe, slight de-matching, in case of the double resonance

probe (Fig. 4), significant de-matching (a new minimum occurred in the tuning curve) together with de-tuning Cyclin-dependent kinase 3 allowed us to find settings that gave rise to a dip line shape of the noise signal, in a trial-and-error approach. A more systematic approach is under investigation in our laboratories. Apparently there can be more than one combination of tuning and matching adjustments that yield an NMR noise dip signal, at least on some probes. The MAS tuning and matching conditions found for the H2O sample were also used for adamantane. In this case, where a dip was found by de-tuning only, the probe was tuned to the same SNTO frequency as found for H2O. If de-tuning and de-matching were necessary to find the dip, the controls were adjusted until the conventional tuning curve resembled as closely as possible the one found with H2O. In Fig. 5 pulse and noise spectra of adamantane obtained under conventional tuning (CTO) and SNTO conditions are compared.

These wells were filled with 100 μL of PRS, to which was added 10 μL of a H2O2 solution, resulting in a final concentration of H2O2 ranging from 5 to 40 μM. The subsequent rows contained 100 μL of PRS without (basal H2O2 production) or with phorbol myristate acetate Epacadostat (100 ng). After 60 min of incubation at 37 °C, the reaction was stopped by the addition of 10 μL of a 1 N NaOH solution. The hydrogen peroxide-dependent phenol red oxidation

was spectrophotometrically measured at 620 nm using a Titertek Multiscan apparatus. The concentration of H2O2 was calculated from the absorbance measurements and expressed as nanomoles of H2O2 per 2 × 105 cells. To determine the nitric oxide production, nitrite was measured in the supernatants of cultures or co-cultures based on the method described by Ding et al. (1988). At the end of the culture period, 50 or 100 μL of the supernatant was removed and incubated with an equal volume of Griess reagent (1% sulfanilamide, 0.1% naphthylene diamine dihydrochloride, 2.5% H3PO4) at room temperature for 10 min. The absorbance was determined using a Titertek Multiscan apparatus at 550 nm. The nitrite concentration was determined by using sodium nitrite as the standard. Cell-free medium contained 0.2–0.3 nmol of NO2−/well; Hydroxychloroquine price this value was determined in each experiment and subtracted from that obtained with cells. The proliferation of tumour cells was assessed

using the 3-(4,5 dimethylthiazol-2-thiazyl)-2,5-diphenyl-tetrazolium Demeclocycline bromide (MTT, Amresco®) assay, based on the method described by Mossmann (1983) and Zhong et al. (2008). Cultured and co-cultured macrophages were maintained in RPMI 1640 culture medium at 37 °C in an environment of 5% CO2 for 48 h. After this period, 30 μL of MTT solution (5 mg/mL) was added, and the cultures were incubated for 3 h at 37 °C. During the incubation, living cells convert the tetrazolium component of the dye solution into formazan crystals. The formazan crystals were dissolved by adding 100 μL of PBS containing 10% SDS and 0.01 N

HCl and incubating the mixture for 18 h at 37 °C in 5% CO2. The absorbance was read on a multiwell scanning spectrophotometer (ELISA reader) at 570 nm. The number of cells was estimated by comparison to a standard curve prepared using known numbers of fresh live cells added to the plates immediately before staining. The cytokines present in the supernatants of the cell cultures were quantified using an ELISA. Briefly, ELISA plates (Immuno Maxisorp; Nunc, NJ) were coated with mouse anti-rat monoclonal or polyclonal antibodies against IL1-β, TNF-α and IL-6 (R&D Systems, Minneapolis, MN). The plates were incubated overnight at room temperature and blocked for 1 h at room temperature on a shaker before adding the samples and standards and incubating for 2 h. Biotinylated secondary antibodies were added before 2 h of incubation, and then, peroxidase-conjugated streptavidin was added before 20 min of incubation.

78, P = .038; r = 0.69, P = .042, respectively; Figures 5A and 6A). Trastuzumab has been used

in the treatment of Her-2–positive metastatic breast cancer over one decade [4], [7] and [8]. Although it has great affinity for Her-2 and low toxicity, about 70% of patients do not respond to this treatment [12]. Therefore, early identification of patients who would benefit from trastuzumab can avoid additional cost for patients [6]. Traditional imaging and fluorescent in situ hybridization have been viewed as the “gold standard” techniques for predicting the treatment response, but they are expensive and not real-time systems [4], [13] and [14]. Our study intended to investigate the usage of ultrasound molecular imaging techniques to evaluate the response to trastuzumab learn more therapy in Her-2–positive breast cancer in the tumor xenograft high throughput screening compounds model. Dynamically monitoring the tumor inner change, such as tumor cell apoptosis during treatment, could be an early indicator of breast cancer response to trastuzumab [15]. An apoptosis marker, Annexin V, has been labeled with FITC and coupled to magnetic nanoparticles to identify apoptotic

cells [22] and [24]. In addition, there were various methods to design targeted apoptosis probes to detect tumor cell apoptosis. Previous studies used biotin/streptavidin interactions to conjugate targeting ligands, such as αvβ3 integrin, P-selectin, or vascular endothelial selleck products growth receptor 2, to image tumor angiogenesis,

or to evaluate the antiangiogenic therapy response of tumors [16], [17] and [18]. In our targeted apoptosis NB design, streptavidin-based bubbles binding to biotin–Annexin V were also used to dynamically detect tumor apoptotic cells during treatment in vitro and in vivo. These targeted bubbles with nanolevel diameters (less than 600 nm) can easily pass through the gaps between the tumor’s new microvascular endothelial cells (865 ± 5.2 nm, tested in the preparatory study) to adhere to the surface of tumor apoptotic cells in our tumor xenograft model. In the imaging study, we tested signals of NBs at 60 minutes after the injection. According to previous reports [17] and [19], it would be of enough time for bubbles to bind to tumor cells through vessels. Thus, it is possible for us to use these targeted NBs to detect tumor apoptotic cells in vivo. First, for seeking the binding ability of targeted NB with targeted cells in vitro, we found that NB–Annexin V bound to trastuzumab-treated cells significantly better than to control (buffer-treated) cells, which is confirmed by DAPI-stained nucleus test and caspase-3–positive expression. After preparing the breast cancer–bearing mice, we performed ultrasound targeted imaging to assess the early response to anti–Her-2 drugs in breast cancer.

Croton is a genus included in Euphorbiaceae family which is widespread in northeastern Brazil. Its use in popular medicine is related to cancer treatment, constipation, diabetes, digestive

problems, dysentery, external wounds, fever, hypercholesterolemia, hypertension, inflammation, intestinal worms, malaria, pain, ulcers, and weight-loss.8 Previous phytochemical studies have shown that plants of this genus can produce a large number of diterpenoids,9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19 a class of natural products that exhibit a wide spectrum of important biological activities,8 which we can highlight the antimicrobial activity.20, 21 and 22 Casbane Diterpenes are a class of diterpenoids isolated from a few species of plants from Euphorbiaceae family with mainly anticancer and antibacterial activities.23, 24, 25, 26, 27, 28, 29, 30 and 31 The present study reports, for the first time, the antimicrobial

Selleck Dasatinib and antibiofilm activities of the Casbane Diterpene named 1,4-dihydroxy-2E,6E,12E-trien-5-one-casbane Vorinostat (CD) isolated from Croton nepetaefolius against oral bacteria. Stalks from C. nepetaefolius were collected in May, 2004, in Caucaia, Ceará, Brazil. The sample material was identified by Dr. Edson Paula Nunes at Prisco Bezerra Herbarium, Biology Department, Federal University of Ceará, Fortaleza, CE, Brazil, where the vouchers specimens (No. 33.582) were deposited. The bark from stalks (5.0 kg) of C. nepetaefolius was powdered

and solubilized with ethanol (10 L × 3, at room temperature). The solvent was removed under reduced pressure to form an EtOH extract. The EtOH extract (58.2 g) was fractionated coarsely in a silica gel column, eluted with hexane (fractions 1–15), hexane/EtOAc 1:1 (fractions 16–25), EtOAc (fractions 26–40), and EtOH (fractions 41–48), affording a total of 48 fractions of 100 mL each. Resveratrol The hexane fractions (22.5 g) were pooled and fractionated in a silica gel column using hexane (fractions 1′–10′), hexane/EtOAc 1:1 (fractions 11′–16′), EtOAc (fractions 17′–21′) and EtOH (fractions 22′–25′), providing 25 fractions of 100 mL each. Fractions 11′–16′ (14.0 g), obtained with hexane/EtOAc (1:1), were fractionated coarsely in a silica gel column eluted with hexane (fraction 1″), hexane/EtOAc 9:1 (fractions 2″–5″), 8:2 (fractions 6″–15″), 7:3 (fractions 16″–32″), EtOAc (fraction 33″), providing 33 fractions of 100 mL each. Fractions 10″–13″, obtained with hexane/EtOAc (8:2), yielded a diterpene named 1,4-dihydroxy-2E,6E,12E-trien-5-one-casbane (CD) (3.0 g, 0.06%) ( Fig. 1). The CD was solubilized in MiLi-Rios water and dimethylsulfoxide (DMSO) which were diluted in culture medium reaching a maximum concentration of 1% (v/v). This percentage of DMSO does not show interference on microbial growth (data not shown). 1,4-dihydroxy-2E,6E,12E-trien-5-one-casbane (CD). Green oil I.R. (KBr, cm−1): 3400, 2920, 1660, 1618, 1020, 756. 1H NMR: 0.99 (s, 3H-16), 1.

1H NMR spectra were registered on a Bruker (Rheinstetten, Germany) DRX-500 instrument operating at 500.13 MHz for 1H observations using a Broadband Inverse (BBI) microprobe maintained at 298 K. Suppression of the H2O signal was obtained using pre-saturation experiment (pulse program zgcppr). In this case, 1H NMR spectra were

digitized into 16K data points over a spectral width of 20 ppm with an acquisition time of 1.8 s. An additional relaxation delay of 10 s was included, making a total recycling time of 11.8 s. A 90° pulse was used with 32 scans. Spectra were Fourier transformed applying a line broadening apodization function of 2.0 Hz. Double suppression of the DMSO and the residual H2O signals was obtained using pre-saturation experiment (pulse program Wetdc). JAK inhibitor In this

case, 1H NMR spectra were digitized into 32 K data points over a spectral width Bleomycin of 15 ppm with an acquisition time of 1.1 s. An additional relaxation delay of 5 s was included, making a total recycling time of 6.1 s. A 90° pulse was used with 8 scans. Spectra were Fourier transformed applying a line broadening apodization function of 1.0 Hz. All NMR spectra were processed in Bruker TopSpin 1.3. Chemical shifts are referenced to the internal standard TSP at 0.0 ppm present in each sample at the concentration of 0.58 mM. All spectra were manually phased and baseline corrected. Normalized dose–response curves of single chemicals and binary mixtures were fitted to sigmoidal shape curves with values between 0 and 1 (0–100%) by using five different theoretical models. Subsequently the two 4-Aminobutyrate aminotransferase classical approaches to mixtures

study, CA and IA, have been applied to each of the used theoretical models to compare calculated and experimental results from binary mixtures dose–response curves. Several models have been proposed in literature (Backhaus et al., 2004), of which we applied: – Weibull (W): equation(1) f(x)=exp[−exp(θ1+θ2log10 x)]f(x)=exp[−exp(θ1+θ2log10 x)]- Box–Cox transformed Weibull (BCW): equation(2) f(x)=exp−expθ1+θ2xθ3−1θ3- logit (L): equation(3) f(x)=1−11+exp(−θ1−θ2log10x)- Generalized logit (GL): equation(4) f(x)=1−1[1+exp(−θ1−θ2log10x)]θ3- Morgan-Mercier Flodin (MMF): equation(5) f(x)=11+θ1 xθ3where θ1, θ2,and θ3 are parameters of the equations. Eqs. (1), (2), (3), (4) and (5) only consider one type of effect, i.e. the response (the mean firing rate) decreases as the dose increases. However, in some cases, we could observe a bi-phasic behavior: an excitatory effect at low concentrations followed by an inhibitory effect at higher concentrations. In this case, it is possible to use a function developed by Beckon et al. (2008), which has the following form: equation(6) f(x)=11+(εup/x)βup11+(εdn/x)βdnwith βup > 0 and βdn < 0. Following Beckon et al. (2008) the β-values represent the steepness, whereas ɛ-values represent the dose at the mid-point of the rising and of the falling respectively.