Using a mammalian cell cycle simulation to interpret differential kinase inhibition in anti-tumour pharmaceutical development

Systems biology needs to show practical relevance to commercial biological challenges such as those of pharmaceutical development. The aim of this work is to design and validate some applications in anti-cancer therapeutic development. The test system was a group of novel cyclin-dependent kinase (CDK) inhibitors synthesised by Cyclacel Ltd. The measured in vitro IC50s of each compound were used as input data to a proprietary cell cycle model developed by Physiomics plc. The model was able to predict over three orders of magnitude the cytotoxicity of each compound without model adaptation to specific cancer cell types. This pattern matched the experimentally determined data. One class of compounds was predicted to cause an increase of the cell cycle length with a non-linear dose-response curve. Further work will use apoptosis and DNA replication simulations to look at overall cell effects.     

Hepatic stereology of Schistosomiasis mansoni infected-mice fed a high-fat diet

High-fat diets induce weight gain and fatty liver in wild-type mice. Schistosomiasis mansoni infection also promotes hepatic injury. This study was designed to quantify hepatic alterations in schistosomiasis mansoni-infected mice fed a high fat-rich chow compared to mice fed a standard rodent chow, using stereology. Female SW mice fed each either high-fat diet (29% lipids) or standard chow (12% lipids) over 8 months, and then were infected with Schistosoma mansoni cercariae. Four experimental groups were studied: infected mice fed a high-fat diet (IHFC) or standard chow (ISC), uninfected mice fed a high-fat diet (HFC) or standard chow (SC). Mice were sacrificed during early infection (9 weeks from exposure). The following hepatic biometry and the stereology parameters were determined: volume density (hepatocytes [h], sinusoids [s], steatosis [st] and hepatic fibrosis [hf]); numerical density (hepatocyte nuclei - Nv[h]); absolute number of total hepatocyte N[h], normal hepatocyte N[nh], and binucleated hepatocyte N[bh], percentage of normal hepatocyte P[nh] and binucleated hepatocyte P[bh]. IHFC and HFC groups exhibited TC, HDL-C, LDL-C, and body mass significantly greater (p < 0.05) than control group. No significant differences were found regards liver volume (p = 0.07). Significant differences were observed regards P[nh] (p = 0.0045), P[bh] (p = 0.0045), Nv[h] (p = 0.0006), N[h] (p = 0.0125), N[bh] (p = 0.0164) and N[nh] (p = 0.0078). IHFC mice group presented 29% of binucleated hepatocytes compared to HFC group (19%), ISC group (17%) and SC (6%). Volume density was significantly different between groups: Vv[h] (p = 0.0052), Vv[s] (p = 0.0025), Vv[st] (p = 0.0004), and Vv[hf] (p = 0.0007). In conclusion, schistosomiasis mansoni infection with concurrent high-fat diet promotes intensive quantitative changes in hepatic structure, contributing to an increasing on hepatic regeneration.     

Rapid detection of Clostridium botulinum toxins A, B, E, and F in clinical samples, selected food matrices, and buffer using paramagnetic bead-based electrochemiluminescence detection

Sensitive and specific electrochemiluminescence (ECL) assays were used to detect Clostridium botulinum neurotoxins serotypes A, B, E, and F in undiluted human serum, undiluted human urine, assay buffer, and selected food matrices (whole milk, apple juice, ground beef, pastry, and raw eggs). These novel assays used paramagnetic bead-based electrochemiluminescent technology in which biotinylated serotype-specific antibodies were bound to streptavidin-coated paramagnetic beads. The beads acted as the solid support and captured analyte from solution. Electrochemiluminescent detection relied on the use of ruthenium chelate-labeled anti-serotype antibodies and analysis with a BioVeris M-Series M1R analyzer. The sensitivities of the assays in clinically relevant matrices were 50 pg/ml for serotypes A and E, 100 pg/ml for serotype B, and 400 pg/ml for serotype F. The detection limits in selected food matrices ranged from 50 pg/ml for serotype A to 50 to 100 pg/ml for serotypes B, E, and F. The antibodies used for capture and detection exhibited no cross-reactivity when tested with the other serotypes. When purified native toxin was compared with toxins complexed to neurotoxin-associated proteins, no significant differences in assay response were noted for serotypes A, B, and F. Interestingly, the native form of serotype E exhibited reduced signal and limit of detection compared with the complexed form of the protein. We suspect that this difference may be due to trypsin activation of this particular serotype. The assays described in this article demonstrate limits of detection similar in range to the gold standard mouse bioassay, but with greatly reduced time to data. These rapid sensitive assays may have potential use in clinical settings, research studies, and screening of food products for botulinum toxins.     

Postural stability during static strain before and after a submaximal aerobic bicycle test in athletes

Control of static balance was studied in wrestlers (n = 31) in the normal state and against the background of physical fatigue, i.e., before and after a bicycle PWC ₁₇₀ test, respectively. The static balance was evaluated using a Ritm force platform (Russia) during normal basic stance (BS) and static strain (half-squatting position (HS) with the eyes open). Before physical exercise, i.e., during BS, the differences in postural control of the center of pressure (CP) between athletes and control subjects (n = 40) were nonsignificant. In the HS position, both linear and angular sway velocities of CP (LSV and ASV, respectively) were significantly lower in wrestlers (p < 0.001), and these parameters were negatively correlated with the PWC ₁₇₀ index (r = −0.454 and r = −455, p < 0.001 for LSV and ASV, respectively), which suggests that up to 20% of the sway velocity variance during static strain is dependent on the working capacity of the subjects. After the PWC ₁₇₀ test, the sway velocities of CP increased in both groups during BS (p < 0.01) and HS (p < 0.001), which testifies to the important role of muscular fatigue in the decrease in postural stability in both groups. During BS, an increase in LSV and ASV was about the same in both groups; however, during HS, an increase in the sway velocities of CP after PWC ₁₇₀ was lower in wrestlers (the intergroup differences at p = 0.037 and p = 0.008 for LSV and ASV, respectively); this parameter was negatively correlated with the recovery of the heart rate (HR) after the bicycle test (r = −0.378, p < 0.001 and r = −0.265, p < 0.05 for LSV and ASV, respectively), which suggests that rapid recovery contributes to a certain extent (about 6.5–14.2%) to the postural stability during static strain of wrestlers against the background of their physical fatigue.     

Spatial variation in the fatty acid composition of elaiosomes in an ant-dispersed plant: Differences within and between individuals and populations

Euphorbia characias is a common myrmecochorous plant of the western Mediterranean Basin whose seeds are dispersed by ants following fruit explosion. The variation in elaiosomes’ fatty acid composition of this species was studied at three hierarchical levels (sub-individual, individual and population) in four populations from the Iberian Peninsula. We found that differences in fruit location on the inflorescence do not seem to influence the fatty acid composition of elaiosomes, providing to each propagule an equal chance of being dispersed. However, significant differences in elaiosome fatty acid composition between individuals and populations were found for most of the compounds identified. The content of oleic acid, a key mediator in the ant–seed interaction, differed widely between populations, probably reflecting geographic variations in co-adaptation between plants and their dispersers. The finding that the fatty acid composition of E. characias elaiosomes is distinct from that of the seed itself, but very similar to that of elaiosomes from unrelated species, reinforces the idea of convergent evolution in the chemical composition of these structures.     

Non-invasive prenatal diagnosis of single-gene disorders from maternal blood

Prenatal diagnosis (PD) is available for pregnancies at risk of monogenic disorders. However, PD requires the use of invasive obstetric techniques for fetal-sample collection and therefore, involves a risk of fetal loss. Circulating fetal DNA in the maternal bloodstream is being used to perform non-invasive prenatal diagnosis (NIPD). NIPD is a challenging discipline because of the biological features of the maternal blood sample. Maternal blood is an unequal mixture of small (and fragmented) amounts of fetal DNA within a wide background of maternal DNA. For this reason, initial NIPD studies have been based on the analysis of specific paternally inherited fetal tracts not present in the maternal genome so as to ensure their fetal origin. Following this strategy, different NIPD studies have been carried out, such as fetal-sex assessment for pregnancies at risk of X-linked disorders, RhD determination, and analysis of single-gene disorders with a paternal origin. The study of the paternal mutation can be used for fetal diagnosis of dominant disorders or to more accurately assess the risk of an affected child in case of recessive diseases. Huntington's disease, cystic fibrosis, or achondroplasia are some examples of diseases studied using NIPD. New technologies are opening NIPD to the analysis of maternally inherited fetal tracts. NIPD of trisomy 21 is the latest study derived from the use of next-generation sequencing (NGS).     

A new pliopithecid genus (primates: Pliopithecoidea) from Castell de Barberà (Vallès-Penedès Basin, Catalonia, Spain)

Barberapithecus huerzeleri gen. et sp. nov. (Primates, Pliopithecidae) is erected on the basis of material from Castell de Barberà (Middle to Late Miocene, ca. 11.2-10.5 Ma), in the Vallès-Penedès Basin (Catalonia, Spain), including: 15 teeth (representing most of the permanent dentition) from a single female individual (holotype); an isolated P/3 (paratype); and a male C1/ (referred to the hypodigm). Previously, this material had been only partially figured and described, being attributed to Pliopithecus or to a new taxon with possible crouzeliine affinities. The erection of a new genus is justified by several autapomorphic features, such as markedly buccolingually compressed and mesiodistally elongated C1/, extremely buccolingually compressed, and mesiodistally oriented C/1 main cusp, P/4 with a large trigonid subequal to the talonid, very large distal foveae on the M/1 and especially the M/2, and lower molars with a quadrangular central fovea and a mesially situated entoconid. These features are associated with a set of crouzeliine synapomorphies, such as buccolingually compressed and peripheralized cusps, well-developed crests, large and well-defined occlusal foveae, upper molars with long preprotocrista, short hypoparacrista, somewhat distally situated protocone and short distal fovea, distinct P/3 metaconid, well-developed P/4 premetacristid, and relatively narrow lower molars with a reduced entoconid. Although more primitive, Barberapithecus resembles Anapithecus in some derived features. Both taxa are included into a new tribe (Anapithecini), together with other crouzeliines except Plesiopliopithecus (tribe Crouzeliini). The retention of primitive, pliopithecine-like features in Barberapithecus suggests that anapithecins might have evolved from a Pliopithecus ancestor, so that as currently conceived the Crouzeliinae might be polyphyletic.     

Brief communication: Paleobiological inferences on the locomotor repertoire of extinct hominoids based on femoral neck cortical thickness: The fossil great ape hispanopithecus laietanus as a test-case study

The relationship between femoral neck superior and inferior cortical thickness in primates is related to locomotor behavior. This relationship has been employed to infer bipedalism in fossil hominins, although bipeds share the same pattern of generalized quadrupeds, where the superior cortex is thinner than the inferior one. In contrast, knuckle‐walkers and specialized suspensory taxa display a more homogeneous distribution of cortical bone. These different patterns, probably related to the range of movement at the hip joint and concomitant differences in the load stresses at the femoral neck, are very promising for making locomotor inferences in extinct primates. To evaluate the utility of this feature in the fossil record, we relied on computed tomography applied to the femur of the Late Miocene hominoid Hispanopithecus laietanus as a test‐case study. Both an orthograde body plan and orang‐like suspensory adaptations had been previously documented for this taxon on different anatomical grounds, leading to the hypothesis that this fossil ape should display a modern ape‐like distribution of femoral neck cortical thickness. This is confirmed by the results of this study, leading to the conclusion that Hispanopithecus represents the oldest evidence of a homogeneous cortical bone distribution in the hominoid fossil record. Our results therefore strengthen the utility of femoral neck cortical thickness for making paleobiological inferences on the locomotor repertoire of fossil primates. This feature would be particularly useful for assessing the degree of orthograde arboreal locomotor behaviors vs. terrestrial bipedalism in putative early hominins. Am J PhyAnthropol 2012. © Wiley Periodicals, Inc.