, CP 04510. Mexico; GDC-0449 cost 2Institut Cavanilles de Biodiversitat i Biologia Evolutiva de la Universitat de Valencia. Apartat Postal 22085, Valencia. CP 46071. España; 3Área Académica de Biología del Instituto de PFT�� Ciencias Básicas e Ingeniería. Universidad Autónoma del Estado de Hidalgo. Apartado Postal 1-69 Plaza Juárez, Pachuca de Soto, Hidalgo. CP 42001. Mexico The hardening of the cell theory during the second half of the 19th century encountered strong resistance by those that considered viruses and hypothetical organisms smaller than cells, on the one hand, and by those that

were convinced that the basic traits of life were found not in complete cells but only within protoplasm, on the other. Spanish-speaking scientists were not an exception, and some of the most distinguished members in academia became engaged in this debate. It was the case of the distinguished

Spanish histologist Santiago Ramón y Cajal, who proposed the existence of hypothetical living metastructures within nucleated cells, as part of a more comprehensive “cytocolonial theory” (Ramón y Cajal, 1989). His ideas were not accepted in his country nor in Latin America due to scientific prejudices and the prevalence of the hardened version of cell theory, and in other international academic circles probably because of language barriers. Eventually, however, as he matured Ramón y Cajal abandoned his initially enthusiastic critique of the cell theory and, by his discoveries, became one of its more important supporters (López-Piñero, 2006). López-Piñero, Ricolinostat order JM (2006)

Santiago Ramón y Cajal. Colección Biografías. Publicacions de la Universitat de Valencia and Editorial de la Universidad de Granada, Valencia. Ramón y Cajal S (1989) Recollections of my life. MIT Press, Cambridge. E-mail: ulisesi@uaeh.​edu.​mx Linear Temporality: A Cultural Perspective of the Origin of Life Ninel Valderrama-Negrn1, Sandra Ramos-Amzquita2, Sergio Ramos-Bernal3, Alicia Negron-Mendoza3 1Facultad de Filosofa y Letras; 2Facultad de Ciencias Polticas; 3Instituto de Ciencias Nucleares, Universidad Nacional Autnoma Cisplatin cost de Mexico (UNAM) Mexico, D.F. Mexico The Aristotelian paradigm of time plays an important role in Western Modernity (1453–1789), in science and in the way that Western civilization perceives the origin of life. The aim of the present paper is to analyze the philosophical basis for the origin of life in Western Modernity. Our argument takes as its point of departure the idea that the Aristotelian paradigm of linear temporality influences all aspects of life, including science, even after the outcome of the scientific method. This paradigm implies a conception of time that has as main characteristics a beginning and an end, forming the idea of linear temporality. This point of view is based on the perception of human life as finite. In addition, this temporality serves as a framework in Western thinking, which is different from that of other cultures.

In the absence of external fields, the Navitoclax mouse calculated density of states (DOS) shows a peak at the GW786034 in vivo Fermi energy, and the local density of states

(LDOS) shows that electron states are localized at the cone base. On the other hand, the symmetries observed in the LDOS at different energies allow a systematic description of the electronic structure and selection rules of optical transitions driven by polarized radiation. Unlike the nanodisk, the presence of topological disorder in nanocones involves a deviation from the electrical neutrality at the apex and at the edges. Methods In what follows, we present results for n w =0,1,2, corresponding to CND and CNCs whose disclination angles are 60° and 120°. For those systems, the s p 2 hybridization may be

neglected. The electronic wave function may be written as (2) where the |π j 〉 denotes the atomic orbitals 2p at site . Note that the CCI-779 cell line overlapping between neighboring orbitals prohibits the set |π j 〉 to be an orthogonal basis. Only in the ideal case of zero overlap s=0, the coefficients in might be considered equal to the discrete amplitude probability to find an electron at the j-th atom (described by the one electron state |Ψ〉). We use the s≠0 basis, |π j 〉, to construct the eigenvalue equation and the base to calculate the properties related to discrete positions. Of course, to relate both bases, it is Vasopressin Receptor required to know the projection. We define a N C ×N C matrix Δ (1) relating the nearest neighboring atomic sites i,j, (3) Similarly, (4) The S overlap matrix elements are then given by (5) The hopping matrix elements of the tight-binding Hamiltonian are (6) where t is the hopping energy parameter. Assuming the eigenvalue equation , the atomic matrix elements are (7) and (8) The resulting equation system may be written as a generalized eigenvalue problem , where the column vector

contains the coefficient C j , (9) The general solution may be expressed in terms of the auxiliary variables and ε(0), which satisfy (10) As also satisfies Equation (9), we obtain (11) The orthogonality condition for the electronic states (12) implies that (13) For the calculation of the DOS, we use a Lorentzian distribution (14) It is important to mention that, in ab initio calculations of carbon systems with edges, the atomic edges are passivated by hydrogen atoms. For graphene nanoribbons, the hydrogen passivation effects are better described when hybridized sigma-orbitals are considered [19]. However, for a single pi-orbital model, position-dependent hopping amplitude is usually adopted.

These enzymes [8, 9] initiate an antioxidant response, which can be beneficial for cancer prevention [13]. However, the Nrf2-ARE pathway has recently been implicated in chemoresistance and the feasibility of Nrf2 inhibition as a strategy for sensitizing cells to chemotherapeutics was demonstrated [13–15]. HMOX1 upregulation has been identified in the adaphostin response in adherent cell lines, but not in hematopoietic cell line models, and it appears that adaphostin

activates a different oxidative stress response in solid tumor models than in leukemia models. Thus, we have Osimertinib cell line investigated the mechanism behind HMOX1 induction in the adaphostin-sensitive lung tumor cell line NCI-H522, and demonstrated an enhancement of adaphostin toxicity following inhibition of Nrf2 nuclear translocation with the PI3K inhibitor wortmannin. Methods Drugs and Cell Culture Adaphostin (NSC 680410) and wortmannin (NSC 221019) were obtained from the repository of the National Cancer Institute’s Developmental Therapeutics Program (Rockville, Maryland). Desferrioxamine (DFX) and N-acetyl-cysteine (NAC) were purchased from Sigma® (St. Louis, Missouri). NCI-H522, and the leukemia cell lines, (Jurkat, HL60 and K562) were obtained

from the NCI-60 Human Tumor Cell Line Screen (National Cancer Institute-Frederick, Maryland). Transcriptional Profiling: Microarray Technology Human OperonV2, 20K arrays, GS-9973 ic50 (National Cancer Institute microarray facility/Advanced Technology Center, Gaithersburg, Maryland) were utilized according to published protocols http://​madb.​nci.​nih.​gov/​. Using competitive hybridization

of treated versus untreated samples chemically coupled (-)-p-Bromotetramisole Oxalate to a Cy™3 or Cy™5 fluorescently labeled dye (Amersham Biosciences, Little Chalfont Buckinghamshire, England) and fluorescence was read on a GenePix 4100A microarray scanner purchased from Axon Instruments (Union City, California). Data was analyzed using the Axon GenePix Pro 4.1 software and data and image files were then uploaded to the National Cancer Institute/Cancer Center for Research Microarray Center mAdB Gateway for analysis and comparison of multiple arrays. Real Time RT-PCR Five hundred nanograms of total RNA for each sample was reverse transcribed using the GeneAmp® PCR System 9700 and TaqMan® Reverse Transcription Reagents kit. Quantitative real time PCR reactions were LOXO-101 concentration conducted and measured using the ABI Prism™ 7700 Sequence Detection System and TaqMan® chemistries using published primers. Samples were tested in triplicate wells for the genes of interest and for the endogenous control, 18 S.

Consequently, telomerase assays were performed and revealed telomerase activity of autonomously proliferating cells in all HBCEC populations (Fig. 2C). The human embryonic kidney (HEK) 293T cell line served as a positive control and the buffer was used as a negative control. Together, these findings suggested a sustained expression of epithelial stem cell-like markers in HBCEC paralleled by only occasional senescence and a marked telomerase activity. Individually-derived HBCEC populations from cultured breast cancer biopsies were tested for their response to distinct

chemotherapeutic compounds and combinations. Thus, HBCEC populations (39d) from tumor biopsies of a 40 year-old (Fig. 3A) and HBCEC populations #Napabucasin manufacturer randurls[1|1|,|CHEM1|]# (34d) a 63 year-old patient (Fig. 3B) were treated with 125 nM and 1 μM of Taxol, Epothilone A, Epothilone B, Epirubicin, Doxorubicin, and the combinations of Epirubicin/Taxol, Epirubicin/Epothilone A, and

Epirubicin/Epothilone B, respectively. Similar treatments were performed with the non-metastatic breast cancer cell line MCF-7 (Fig. 4A), with the highly metastatic MDA-MB-231 cell line (Fig. 4B) and with normal post-selection HMEC of passage 16 (Fig. 5), respectively. Incubation with a single dose of 1 μM (blue bars) and 125 nM (red bars) of Taxol, epothilones or the anthracyclins and combinations for 6d were less effective as compared to a sequential incubation, selleck chemicals llc whereby the same compounds with the same concentrations of 1 μM (yellow bars) and 125 nM (turquoise bars) were replaced after 3d, resulting in a similar 6d (= 2× 3d) incubation period, respectively. Moreover, the lower concentrated drugs (125 nM) were less effective than the 1 μM dose of these compounds, respectively. In contrast, Epothilone A and B displayed different effects in both HBCEC populations. Thus, a sequential dose of these two compounds significantly increased the cytotoxicity in one population

(Fig. 3B), whereas little if any effects were observed in HBCEC from a different breast cancer patient, respectively many (Fig. 3A). Similarly, Epothilone A and B exhibited different effects on the two breast carcinoma cell lines (Fig. 4A, B). Moreover, the non-metastatic MCF-7 cell line displayed an overall increased sensitivity to the administered drugs or drug combinations as compared to the highly metastatic MDA-MB-231 cells (Fig. 4A, B). Normal post-selection HMEC (P16) demonstrated reduced cytotoxic effects of the chemotherapeutics as compared to the HBCEC cultures (Fig. 5). These differences in response to certain anti-cancer drugs could be explained by the reduced or ceased proliferative capacity of senescent post-selection HMEC (P16) in contrast to the continuous proliferation of HBCEC. Figure 3 Chemotherapeutic effects on HBCEC from breast cancer patients. HBCEC derived from a 40 year-old (HBCEC 366) (Fig. 3A) and a 63 year-old (HBCEC 367) (Fig.

Note the rare (→) positivity for CD133 (A, × 200 and B, × 400). (C) A early dysplastic lesion of colon tumorigenesis showing a marked positive immunostaining for CD133 (× 200). (D) Example of a moderately differentiated NAS adenocarcinoma displaying a diffuse staining for CD133 (× Lazertinib 200). (E and F) Examples of mucinous poorly differentiated

adenocarcinomas displaying a strong and diffuse cytoplasmic staining for CD133 with a clear immuno-negativity of nuclei (× 200 and × 550). In cancer cells the median percentage of positive cells was 5% (range 0–80; mean = 13%) and CD133 staining was not detectable in tumour cells in 30 out of 137 (22%) specimens (Figure 1C-F). When cases were stratified according with pT parameter, median percentage of positive cells was 17.5 (range 0–70; mean = 24%), 10.0 (range 0–60; mean = 16), 2.0 (range 0–65; mean = 9) and 10 (range 0–80; mean = 13) in pT1, 2, 3 and

4 tumours, respectively, and these differences were significant (p = 0.02). selleck Moreover, using the 5% positive cells as cut-off to distinguish between high (>5%) and low (≤5%) staining, high CD133 staining was detected in 9 (75%) of the 12 pT 1 cancers and in 10 (59%), 27 (36%) and 19 (58%) of the pt2, pT3 nd pT4 cancers, respectively and cross-tab selleck chemicals analysis identified a significant correlation (p = 0.02) between the two parameters (Table 2). Significance was also evident when earlier (pT1-2) tumours (66%) were compared together vs more advanced (pT3-4) (42.6%) cancers (p = 0.02). No correlation was observed with either tumour grade and N status. Table 2 CD133 expression in relation to clinical and pathological parameters in a series of 137 colon cancers   Total Low High p value     n (%) n (%)   Gender Males 78 41 (53) 37 (47)   Females 59 31 (52) 28 (48) Oxaprozin n.s. Age (yr) ≤68 73 35 (48) 38 (52)   >68 64 37 (58) 27 (42) n.s. Tumor Grading 1 9 4 (44)

5 (56)   2 86 50 (58) 36 (42)   3 42 18 (43) 24 (57) n.s. pT parameter pT1 12 3 (25) 9 (75)   pT2 17 7 (41) 10 (59)   pT3 75 48 (64) 27 (36)   pT4 33 14 ( 42) 19 (58) 0.02 Nodal status Negative 76 42 (55) 34 (45)   Positive 61 30 (49) 31 (51) n.s. Tumor stage I 25 9 (36) 16 (64)   II 43 31 (72) 12 (28)   III 69 32 (46) 37 (54) 0.006 Recurrence YES 57 22 (39) 35 (61)   NOT 80 50 (62) 30 (37) 0.005 Follow-up Deceased 51 20 (39) 31 (61)   Alive 86 52 (61) 34 (39) 0.013 α-DG staining Low 68 28 (41) 40 (59)   High 69 44 (64) 25 (36) 0.006 n.s.: not significant. On the other hand, high CD133 staining was detected in 16 (64%) of the 25 stage 1, 12 (28%) of the 43 stage II and in 37 (54%) of the 69 more advanced stage 3 cancers and cross-tab analysis identified a significant correlation (p = 0.006) between the two parameters (Table 2). Significance was no longer evident when stage 1/2 cancers (41%) were compared overall with more advanced stage 3 cancers (54%) (p = 0.09) (Table 2).

References 1. Van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, et al.: Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009,56(3):430–442.PubMedCrossRef 2. Sharma S, Kelly TK, Jones PA: Epigenetics in cancer. Carcinogenesis 2010,31(1):27–36.PubMedCrossRef 3. Tao W, Hongli L, Yeshan C, Wei L, Jing Y, Gang W: Lenvatinib methylation associated inactivation of RASSF1A and its synergistic effect with activated K-Ras in nasopharyngeal carcinoma.

J Exp Clin Cancer Res 2009, 28:160.CrossRef 4. Jian Z, Yuyan W, Jianchun D, Hua B, Zhijie W, Lai W: DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor IWR-1 solubility dmso therapy in non-small cell lung cancer. J Exp Clin Cancer Res 2012, 31:80.CrossRef 5. Sánchez-Carbayo M: Hypermethylation in bladder cancer: biological pathways and translational applications. see more Tumour Biol 2012,33(22):347–361.PubMedCrossRef 6. Kim WJ, Kim YJ: Epigenetics of bladder cancer. Methods Mol Biol 2012, 863:111–118.PubMedCrossRef 7. Cabello MJ, Grau L, Franco N, Orenes E, Alvarez M, Blanca A, et al.: Multiplexed

methylation profiles of tumor suppressor genes in bladder cancer. J Mol Diagn 2011,13(1):29–40.PubMedCrossRef 8. Zuiverloon TC, Beukers W, van der Keur KA, Munoz JR, Bangma CH, Lingsma HF, et al.: A methylation assay for the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences in voided urine. BJU Int 2012,109(6):941–948.PubMedCrossRef 9. Eissa S, Swellam M, El-Khouly IM, Kassim SK, Shehata H, Mansour

A, et al.: Aberrant methylation of RARbeta2 and APC genes in voided urine as molecular markers for early detection of bilharzial and nonbilharzial bladder cancer. Cancer Epidemiol Biomarkers Prev 2011,20(8):1657–1664.PubMedCrossRef 10. Negraes PD, Favaro FP, Camargo JL, Oliveira ML, Goldberg J, Rainho CA, et al.: DNA methylation patterns in bladder cancer and washing cell sediments: a perspective for tumor recurrence detection. BMC Cancer 2008, 8:238.PubMedCrossRef 11. Hoque MO, Begum S, Brait M, Jeronimo C, Zahurak M, Ostrow KL, Rosenbaum E: Tissue inhibitor of metalloproteinases 3 promoter methylation is an independent Liothyronine Sodium prognostic factor for bladder cancer. J Urol 2008,179(2):743–747.PubMedCrossRef 12. Friedrich MG, Chandrasoma S, Siegmund KD, Weisenberger DJ, Cheng JC, Toma MI, et al.: Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma. Eur J Cancer 2005,41(17):2769–2778.PubMedCrossRef 13. Tada Y, Wada M, Taguchi K, Mochida Y, Kinugawa N, Tsuneyoshi M, et al.: The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. Cancer Res 2002,62(14):4048–4053.PubMed 14.

Finally, Anderson et al. [26]

reported a significant improvement in time among trained oarswomen for a 2,000 m row, following what is considered to be a high dose of caffeine (9 mg/kg). As suggested, the design and population of women studied in relation to caffeine supplementation is varied. In addition, there are no investigations in the available literature that report any outcomes related specifically to GANT61 mw resistance-trained females. Therefore, the purpose of this study was to determine the acute effects of caffeine supplementation on strength and muscular endurance in resistance-trained women. Methods Research Participants Fifteen resistance-trained females volunteered to serve as research participants for this investigation.

Inclusion criteria stipulated DNA Synthesis inhibitor that all subjects were between the ages of 18-45 and had participated in resistance Sepantronium supplier training activities at least 3-5 days per week for the 6 month period immediately prior to enrollment in this study. Other inclusionary criteria included the ability to bench press 70% of individual body weight. All testing procedures were verbally explained in detail and subjects provided written informed consent prior to participation, in accordance with the guidelines established by the Institutional Review Board at a southeastern university. Study Protocol A double-blind, placebo-controlled, cross-over design was utilized in this investigation. Research participants were asked to attend three laboratory sessions. The first session was for familiarization, followed by two testing trials seven days apart using the same testing protocol. Either caffeine at a dose of 6 mg/kg or placebo (PL) was administered orally 60 minutes prior to testing, in randomized order (See Supplementation Protocol Section). Research participants were directed to continue the same general lifestyle patterns of exercise and nutrition intake during each seven-day period prior to the two exercise testing sessions. To verify the consistency many of diet, the subjects were directed to complete a 3-day dietary recall (two week days

and one weekend day) for each week prior to testing. The dietary intake data were analyzed using ESHA Food Processor SQL dietary analysis software (ESHA Research, Salem, OR). All research participants completed one familiarization session prior to participating in the two testing trials. During the familiarization session, the participants were instructed on proper technique and mechanics of the bench press exercise, according to the standard methods defined by Baechle and Earle [27] and the National Strength and Conditioning Association. Additionally, participants performed a series of lifts to determine their ability to bench press 70% of individual body weight. On test days, participants were asked to report to the testing laboratory in the morning after a 12-hour period without food.

The effect of grain size and grain boundary on the material’s mechanical property has been well discussed. Usually, the well-known Hall–Petch relationship is widely accepted. This relationship indicates that material strength increases with the decrease of grain size. However, for very fine nano-structured materials, this relationship may no longer hold. Yang and Vehoff [21] investigated the

dependency of hardness upon grain size in nano-indentation experiments. With the indentation depth of less than 100 nm, it is clearly revealed that the local interaction between dislocations and grain boundaries causes various hardness dependences on indentation depth. Zhang et al. [22] carried out nano-indentation experiments on copper with grain sizes from 10 to 200 nm. It was found that at short dwell times, the hardness increases S63845 chemical structure significantly with decreasing grain size. However, the difference substantially diminishes at longer times due to the rapid grain growth under the indenter. Similar reverse proportion relations between grain size and hardness are observed in indentation

experiments at micro-scale in the literature. Li and Reece [23] discovered that grain size has a significant effect on surface fatigue behavior, and increasing grain size reduces the threshold for crack nucleation. Also, Lim and Chaudhri [24] showed that in the grain size range of 15 to 520 μm, the initial higher dislocation density for smaller grains is believed to cause higher Vickers hardness. More importantly, the rapid advance of numerical simulation techniques has enabled more detailed analysis of dislocations Dorsomorphin concentration and grain boundaries in deformation of polycrystallines. For instance, with the help of MD simulation, the interaction of dislocations with a ∑ = 5(210)[001] grain boundary is analyzed, and the transmission of dislocation across the grain boundary is observed [25]. Another MD simulation study indicates that compared to bulk diamond crystal, substitution energies are found to be significantly lower for

grain Phosphatidylinositol diacylglycerol-lyase boundaries [26]. The remainder of the paper is organized as follows. In the next section, the MD model construction for nano-scale machining of polycrystalline is briefly introduced. The machining conditions for the simulation cases are also summarized. Thereafter, the simulation results of nano-scale machining are presented, in which the major observations are made regarding the effects of grain size and machining parameters. More importantly, a detailed discussion on the grain size effect is provided to reveal the governing mechanism in nano-scale machining. Finally, conclusions are drawn and future research is pointed out in the last section. Methods Simulation model construction Figure 1 shows the selleck compound overall MD simulation model constructed according to a 3D orthogonal machining configuration.

The structural appearance of adhesive discs is essentially identical, not only for different G. lamblia assemblages but also for other species such as G. muris [37, 39, 40]. Immunofluorescence assays using anti-β giardin mAb and confocal microscopy showed that βAZD1080 order -giardin localized in the ventral disc of WB permeabilized trophozoites (Figure 3A). We have extended the analysis to other Assemblages A isolates (WB clone A6 and Portland-1) and we found no

differences with the localization seen in WB 1267 trophozoites (data not shown). The distinctive fluorescence intensity detected at the margins of the ventral disc has been previously reported in Giardia trophozoites transfected with GFP-tagged β-giardin or using polyclonal Emricasan chemical structure antibodies [41, 42]. Some authors have suggested that β-giardin also localizes in the median body selleck chemicals of WB trophozoites [43]. However, we did not observe any labeling of the median body, although a large population of trophozoites was analyzed. These differences in localization may suggest that it could

be modified, taking into account that Palm et al. found three isoforms of this protein in a proteomic assay [23]. Interestingly, the immunolocalization of β-giardin at the ventral disc in GS trophozoites was rather different, with β-giardin being specifically organized into a radial array that surrounded the half ring of the ventral Arachidonate 15-lipoxygenase disc, resembling a horseshoe (Figure 3B). Also, at the center of the ventral disc, an asymmetrical grid could be observed. Figure 3 Immunolocalization

of β-giardin in WB and GS trophozoites. Reactivity of 12G5 mAb on WB and GS Giardia trophozoites was determined by indirect immunofluorescence in permeabilized trophozoites. (A) Upper panel: immunofluorescence assays showing the labelling in the ventral disc of the trophozoites. Lower panels: high magnification showing the immunostaining in the ventral disc of WB trophozoites, with more intensity on the margins. (B) Upper panel: immunofluorescence of β-giardin in GS trophozoites. Lower panels: high magnification showing immunofluorescence specifically organized into a radial array surrounding the half ring of the ventral disc and also at the centre of it. Scale bar: 10 μm. The singular localization of β-giardin in WB and GS trophozoites was unexpected, considering that the amino acid sequence of β-giardin is 100% identical in the two assemblages (Additional File 1). Complementary assays utilizing non-permeabilized WB or GS trophozoites showed no fluorescence, showing intracellular β-giardin localization. Related to this, in studies performed on G. muris trophozoites, β-giardin was described as a surface protein, based on surface protein biotinilation assays [44].

Fig. 4 The spatial distribution CH5424802 manufacturer of pharmacophore LY3039478 molecular weight properties on a background of compound I X-ray diffraction structure.

A green square depicts the plane of a phenyl ring (Color figure online) Fig. 5 The spatial distribution of pharmacophore properties on a background of compound II X-ray diffraction structure. A green square depicts the plane of a phenyl ring (Color figure online) Fig. 6 The spatial distribution of pharmacophore properties of D2 receptor ligands. A green square depicts the plane of a phenyl ring. The yellow sphere stands for hydrophobic—aliphatic property (Color figure online) Table 2 Pharmacophore properties of compound I and II Pharmacophore feature/property Compound I Compound II

Positive ionization (red) Nitrogen atom Nitrogen atom Hydrogen bond acceptor (HBA, green) Carbonyl group of amide bond Carbonyl group of amide bond Aromatic ring (orange) Benzene ring substituted with methoxy group Benzene ring substituted with two methoxy groups Hydrophobic, aromatic (pale blue) Furane ring Furane ring Hydrophobic, aliphatic (ultramarine) One methyl Cell Cycle inhibitor group in methoxy moiety attached to the benzene ring Two methyl groups in methoxy moieties attached to the benzene ring The geometry of a spatial distribution of pharmacophore properties in obtained models is an exact reflection of the X-ray diffraction structure of compounds I and II (Table 3). It is worthy to note that in spite of the high similarity of chemical structures of these compounds, that their conformations significantly differ each from other. Consequently, Endonuclease these differences distinctly appear in pharmacophore models. Obviously, it should be taken into account some flexibility of the spatial pharmacophore geometry and possibility of its change during docking of studied compounds to particular receptors. However, such changes are often possible only to small degree or impossible at all on account

of the high energetic rotation barriers. In this context, the presence of two separate aliphatic—hydrophobic centers in pharmacophore of compound II takes on a special importance for explanation of very high affinity of this compound, in contrast to compound I, for D2 receptor. It is likely that just second methoxy group in compound II molecule underlies its high binding to D2 receptor while the same group do not affect the affinity of compound II to 5-HT1A and 5-HT2A receptors. The comparative analysis of the D2 receptor ligand pharmacophore (Fig. 6) and pharmacophores of compounds I and II also leads to the same conclusion (Figs. 4 and 5). The pharmacophore of D2 ligand quite well matches the pharmacophore of compound II but does not the pharmacophore of compound I (c.f. Fig. 7).