Combinations of Genetic Data Present in Bipolar Patients,but Absent in Control Persons

The main objective of the study was to find combinations of genetic variants significantly associated with bipolar disorder. In a previous study of bipolar disorder, combinations of three single nucleotide polymorphism (SNP) genotypes taken from 803 SNPs were analyzed, and four clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of four SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from the new cluster and from the four previous clusters were identified in the genomes of 209 of the 607 patients in the study whereas none of the 1355 control participants had any of these combinations in their genome.     

β-Lactam and glycopeptide antibiotics: first and last line of defense?

Most infections are caused by bacteria, many of which are ever-evolving and resistant to nearly all available antibiotics. β-Lactams and glycopeptides are used to combat these infections by inhibiting bacterial cell-wall synthesis. This mechanism remains an interesting target in the search for new antibiotics in light of failed genomic approaches and the limited input of major pharmaceutical companies. Several strategies have enriched the pipeline of bacterial cell-wall inhibitors; examples include combining screening strategies with lesser-explored microbial diversity, or reinventing known scaffolds based on structure-function relationships. Drugs developed using novel strategies will contribute to the arsenal in fight against the continued emergence of bacterial resistance.     

The genetic structure of cattle populations (Bos taurus) in northern Eurasia and the neighbouring Near Eastern regions: implications for breeding strategies and conservation

We investigated the genetic structure and variation of 21 populations of cattle (Bos taurus) in northern Eurasia and the neighbouring Near Eastern regions of the Balkan, the Caucasus and Ukraine employing 30 microsatellite markers. By analyses of population relationships, as well as by a Bayesian-based clustering approach, we identified a genetic distinctness between populations of modern commercial origin and those of native origin. Our data suggested that northern European Russia represents the most heavily colonized area by modern commercial cattle. Further genetic mixture analyses based on individual assignment tests found that native Red Steppe cattle were also employed in the historical breeding practices in Eastern Europe, most probably for incorporating their strong and extensive adaptability. In analysis of molecular variance, within-population differences accounted for approximately 90% of the genetic variation. Despite some correspondence between geographical proximity and genetic similarity, genetic differentiation was observed to be significantly associated with the difference in breeding purpose among the European populations (percentage of variance among groups and significance: 2.99%, P = 0.02). Our findings give unique genetic insight into the historical patterns of cattle breeding practices in the former Soviet Union. The results identify the neighbouring Near Eastern regions such as the Balkan, the Caucasus and Ukraine, and the isolated Far Eastern Siberia as areas of 'genetic endemism', where cattle populations should be given conservation priority. The results will also be of importance for cost-effective management of their future utilization.     

Prdm9 deficiency of rat oocytes causes synapsis among non-homologous chromosomes and aneuploidy

Mammalian Genome - Aneuploidy (abnormal chromosome number) accompanies reduced ovarian function in humans and mice, but the reasons behind this concomitance remain underexplored. Some variants in...     

Terpene chemodiversity of relict conifers Picea omorika, Pinus heldreichii, and Pinus peuce, endemic to Balkan

Terpenes are often used as ecological and chemotaxonomic markers of plant species, as well as for estimation of geographic variability. Essential oils of relic and Balkan endemic/subendemic conifers, Picea omorika, Pinus heldreichii, and P. peuce, in central part of Balkan Peninsula (Serbia and Montenegro), on the level of terpene classes and common terpene compounds were investigated. In finding terpene combinations, which could show the best diversity between species and their natural populations, several statistical methods were applied. Apart from the content of different terpene classes (P. omorika has the most abundant O-containing monoterpenes and sesquiterpenes; P. heldreichii and P. peuce have the largest abundance of sesquiterpene and monoterpene hydrocarbons, resp.), the species are clearly separated according to terpene profile with 22 common compounds. But, divergences in their populations were established only in combination of several compounds (specific for each species), and they were found to be the results of geomorphologic, climatic, and genetic factors. We found similarities between investigated species and some taxa from literature with respect to terpene composition, possibly due to hybridization and phylogenetic relations. Obtained results are also important regarding to chemotaxonomy, biogeography, phylogeny, and evolution of these taxa.     

Combinations of SNPs related to signal transduction in bipolar disorder

Any given single nucleotide polymorphism (SNP) in a genome may have little or no functional impact. A biologically significant effect may possibly emerge only when a number of key SNP-related genotypes occur together in a single organism. Thus, in analysis of many SNPs in association studies of complex diseases, it may be useful to look at combinations of genotypes. Genes related to signal transmission, e.g., ion channel genes, may be of interest in this respect in the context of bipolar disorder. In the present study, we analysed 803 SNPs in 55 genes related to aspects of signal transmission and calculated all combinations of three genotypes from the 3×803 SNP genotypes for 1355 controls and 607 patients with bipolar disorder. Four clusters of patient-specific combinations were identified. Permutation tests indicated that some of these combinations might be related to bipolar disorder. The WTCCC bipolar dataset were use for replication, 469 of the 803 SNP were present in the WTCCC dataset either directly (n = 132) or by imputation (n = 337) covering 51 of our selected genes. We found three clusters of patient-specific 3×SNP combinations in the WTCCC dataset. Different SNPs were involved in the clusters in the two datasets. The present analyses of the combinations of SNP genotypes support a role for both genetic heterogeneity and interactions in the genetic architecture of bipolar disorder.     

Synchronization properties of networks of electrically coupled neurons in the presence of noise and heterogeneities

We investigate how synchrony can be generated or induced in networks of electrically coupled integrate-and-fire neurons subject to noisy and heterogeneous inputs. Using analytical tools, we find that in a network under constant external inputs, synchrony can appear via a Hopf bifurcation from the asynchronous state to an oscillatory state. In a homogeneous net work, in the oscillatory state all neurons fire in synchrony, while in a heterogeneous network synchrony is looser, many neurons skipping cycles of the oscillation. If the transmission of action potentials via the electrical synapses is effectively excitatory, the Hopf bifurcation is supercritical, while effectively inhibitory transmission due to pronounced hyperpolarization leads to a subcritical bifurcation. In the latter case, the network exhibits bistability between an asynchronous state and an oscillatory state where all the neurons fire in synchrony. Finally we show that for time-varying external inputs, electrical coupling enhances the synchronization in an asynchronous network via a resonance at the firing-rate frequency.

Synthesis and anti-aromatase activity of some new steroidal D-lactones

Starting from D-seco derivatives of 5-androstene 1-3, the D-homo lactones, 4 and 5, were synthesized. By the Oppenauer oxidation and/or by dehydration of 4 and 5 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil), the corresponding D-lactones 6-12 were obtained. The structures of 6 and 10 were unambiguously proved by the appropriate X-ray structural analysis. Anti-aromatase assay showed that tested compounds possess inhibition potency, however, two to four times smaller (IC50 from 0.2 to 0.7 microM, respectively) in comparison to aminoglutethimide (AG).     

A one-dimensional model of the spinal cerebrospinal-fluid compartment

Modeling of the cerebrospinal fluid (CSF) system in the spine is strongly motivated by the need to understand the origins of pathological conditions such as the emergence and growth of fluid-filled cysts in the spinal cord. In this study, a one-dimensional (1D) approximation for the flow in elastic conduits was used to formulate a model of the spinal CSF compartment. The modeling was based around a coaxial geometry in which the inner elastic cylinder represented the spinal cord, middle elastic tube represented the dura, and the outermost tube represented the vertebral column. The fluid-filled annuli between the cord and dura, and the dura and vertebral column, represented the subarachnoid and epidural spaces, respectively. The system of governing equations was constructed by applying a 1D form of mass and momentum conservation to all segments of the model. The developed 1D model was used to simulate CSF pulse excited by pressure disturbances in the subarachnoid and epidural spaces. The results were compared to those obtained from an equivalent two-dimensional finite element (FE) model which was implemented using a commercial software package. The analysis of linearized governing equations revealed the existence of three types of waves, of which the two slower waves can be clearly related to the wave modes identified in previous similar studies. The third, much faster, wave emanates directly from the vertebral column and has little effect on the deformation of the spinal cord. The results obtained from the 1D model and its FE counterpart were found to be in good general agreement even when sharp spatial gradients of the spinal cord stiffness were included; both models predicted large radial displacements of the cord at the location of an initial cyst. This study suggests that 1D modeling, which is computationally inexpensive and amenable to coupling with the models of the cranial CSF system, should be a useful approach for the analysis of some aspects of the CSF dynamics in the spine. The simulation of the CSF pulse excited by a pressure disturbance in the epidural space, points to the possibility that regions of the spinal cord with abnormally low stiffness may be prone to experiencing large strains due to coughing and sneezing.     

Targeting tumour-initiating cells with TRAIL based combination therapy ensures complete and lasting eradication of multiple myeloma tumours in vivo

Multiple myeloma (MM) remains an incurable disease despite improvements to available treatments and efforts to identify new drug targets. Consequently new approaches are urgently required. We have investigated the potential of native tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with doxorubicin, to induce apoptotic cell death in phenotypically distinct populations of myeloma cells in vitro and in vivo. The cytotoxic potential of TRAIL alone, and in combination with DOX, was assessed in vitro in purified CD138(+) and CD138(-) cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD138(-) MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD138(-) cells were shown to be more resistant to the cytotoxic activity of TRAIL than CD138(+) cells and have reduced expression of TRAIL death receptors. This resistance results in preferential killing of CD 138(+) cells during exposure of MM culture to TRAIL. Furthermore, prolonged exposure results in the appearance of TRAIL-resistant CD138(-) cells. However, when TRAIL is combined with doxorubicin, this results in complete eradication of MM cells in vivo. Most importantly, this treatment successfully eliminates CD138(-) cells implicated in tumour initiation and growth maintenance. These findings may explain the failure of current therapies and offer a promising new approach in the quest to cure MM and disseminated cancers.