Compositional nonblocking verification with always enabled events and selfloop-only events

This paper proposes to improve compositional nonblocking verification through the use of always enabled and selfloop-only events. Compositional verification involves abstraction to simplify parts of a system during verification. Normally, this abstraction is based on the set of events not used in the remainder of the system, i.e., in the part of the system not being simplified. Here, it is proposed to exploit more knowledge about the system and abstract events even though they are used in the remainder of the system. Abstraction rules from previous work are generalised, and experimental results demonstrate the applicability of the resulting algorithm to verify several industrial-scale discrete event system models, while achieving better state-space reduction than before

Extraordinary Molecular Evolution in the PRDM9 Fertility Gene

Recent work indicates that allelic incompatibility in the mouse PRDM9 (Meisetz) gene can cause hybrid male sterility, contributing to genetic isolation and potentially speciation. The only phenotype of mouse PRDM9 knockouts is a meiosis I block that causes sterility in both sexes. The PRDM9 gene encodes a protein with histone H3(K4) trimethyltransferase activity, a KRAB domain, and a DNA-binding domain consisting of multiple tandem C2H2 zinc finger (ZF) domains. We have analyzed human coding polymorphism and interspecies evolutionary changes in the PRDM9 gene. The ZF domains of PRDM9 are evolving very rapidly, with compelling evidence of positive selection in primates. Positively selected amino acids are predominantly those known to make nucleotide specific contacts in C2H2 zinc fingers. These results suggest that PRDM9 is subject to recurrent selection to change DNA-binding specificity. The human PRDM9 protein is highly polymorphic in its ZF domains and nearly all polymorphisms affect the same nucleotide contact residues that are subject to positive selection. ZF domain nucleotide sequences are strongly homogenized within species, indicating that interfinger recombination contributes to their evolution. PRDM9 has previously been assumed to be a transcription factor required to induce meiosis specific genes, a role that is inconsistent with its molecular evolution. We suggest instead that PRDM9 is involved in some aspect of centromere segregation conflict and that rapidly evolving centromeric DNA drives changes in PRDM9 DNA-binding domains

Stretching the Rules: Monocentric Chromosomes with Multiple Centromere Domains

The centromere is a functional chromosome domain that is essential for faithful chromosome segregation during cell division and that can be reliably identified by the presence of the centromere-specific histone H3 variant CenH3. In monocentric chromosomes, the centromere is characterized by a single CenH3-containing region within a morphologically distinct primary constriction. This region usually spans up to a few Mbp composed mainly of centromere-specific satellite DNA common to all chromosomes of a given species. In holocentric chromosomes, there is no primary constriction; the centromere is composed of many CenH3 loci distributed along the entire length of a chromosome. Using correlative fluorescence light microscopy and high-resolution electron microscopy, we show that pea (Pisum sativum) chromosomes exhibit remarkably long primary constrictions that contain 3-5 explicit CenH3-containing regions, a novelty in centromere organization. In addition, we estimate that the size of the chromosome segment delimited by two outermost domains varies between 69 Mbp and 107 Mbp, several factors larger than any known centromere length. These domains are almost entirely composed of repetitive DNA sequences belonging to 13 distinct families of satellite DNA and one family of centromeric retrotransposons, all of which are unevenly distributed among pea chromosomes. We present the centromeres of Pisum as novel ``meta-polycentric'' functional domains. Our results demonstrate that the organization and DNA composition of functional centromere domains can be far more complex than previously thought, do not require single repetitive elements, and do not require single centromere domains in order to segregate properly. Based on these findings, we propose Pisum as a useful model for investigation of centromere architecture and the still poorly understood role of repetitive DNA in centromere evolution, determination, and function

Losing the desire: selection can promote obligate asexuality

Whilst parthenogenesis has evolved multiple times from sexual invertebrate and vertebrate lineages, the drivers and consequences of the sex-asex transition remain mostly uncertain. A model by Stouthamer et al. recently published in BMC Evolutionary Biology shows a pathway by which obligate asexuality could be selected for following endosymbiont infection

Evidence for Centromere Drive in the Holocentric Chromosomes of Caenorhabditis

In monocentric organisms with asymmetric meiosis, the kinetochore proteins, such as CENH3 and CENP-C, evolve adaptively to counterbalance the deleterious effects of centromere drive, which is caused by the expansion of centromeric satellite repeats. The selection regimes that act on CENH3 and CENP-C genes have not been analyzed in organisms with holocentric chromosomes, although holocentrism is speculated to have evolved to suppress centromere drive. We tested both CENH3 and CENP-C for positive selection in several species of the holocentric genus Caenorhabditis using the maximum likelihood approach and sliding-window analysis. Although CENP-C did not show any signs of positive selection, positive selection has been detected in the case of CENH3. These results support the hypothesis that centromere drive occurs in Nematoda, at least in the telokinetic meiosis of Caenorhabditis

Spectral morphometric characterization of breast carcinoma cells

The spectral morphometric characteristics of standard haematoxylin and eosin breast carcinoma specimens were evaluated by light microscopy combined with a spectral imaging system. Light intensity at each wavelength in the range of 450–800 nm was recorded for 104 pixels from each field and represented as transmitted light spectra. A library of six characteristic spectra served to scan the cells and reconstruct new images depicting the nuclear area occupied by each spectrum. Fifteen cases of infiltrating ductal carcinoma and six cases of lobular carcinoma were examined; nine of the infiltrating ductal carcinoma and three of the lobular carcinoma showed an in situ component. The spectral morphometric analysis revealed a correlation between specific patterns of spectra and different groups of breast carcinoma cells. The most consistent result was that lobular carcinoma cells of in situ and infiltrating components from all patients showed a similar spectral pattern, whereas ductal carcinoma cells displayed spectral variety. Comparison of the in situ and the infiltrating ductal solid, cribriform and comedo carcinoma cells from the same patient revealed a strong similarity of the spectral elements and their relative distribution in the nucleus. The spectrum designated as number 5 in the library incorporated more than 40% of the nuclear area in 74.08% of the infiltrating lobular cells and in 13.64% of the infiltrating ductal carcinoma cells (P < 0.001). Spectrum number 2 appeared in all infiltrating ductal cells examined and in none of the lobular cells. These results indicate that spectrum number 5 is related to infiltrating lobular carcinoma, whereas spectrum number 2 is characteristic for infiltrating ductal carcinoma cells. Spectral similarity mapping of central necrotic regions of comedo type in situ carcinoma revealed nuclear fragmentation into defined segments composed of highly condensed chromatin. We conclude that the spectral morphometric features found for lobular and ductal cell populations may serve future automated histological diagnostics. © 1999 Cancer Research Campaig

A bovine lymphosarcoma cell line infected with theileria annulata exhibits an irreversible reconfiguration of host cell gene expression

Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner

The availability of novelty sweets within the high school fringe

Background Reducing sugar consumption is a primary focus of current global public health policy. Achieving 5% of total energy from free sugars will be difficult acknowledging the concentration of free sugars in sugar sweetened beverages, confectionery and as hidden sugars in many savoury items. The expansion of the novelty sweet market in the UK has significant implications for children and young adults as they contribute to dental caries, dental erosion and obesity. Objective To identify the most available types of novelty sweets within the high school fringe in Cardiff, UK and to assess their price range and where and how they were displayed in shops. Subjects and methods Shops within a ten minute walking distance around five purposively selected high schools in the Cardiff aea representing different levels of deprivation were visited. Shops in Cardiff city centre and three supermarkets were also visited to identify the most commonly available novelty sweets. Results The ten most popular novelty sweets identified in these scoping visits were (in descending order): Brain Licker, Push Pop, Juicy Drop, Lickedy Lips, Big Baby Pop, Vimto candy spray, Toxic Waste, Tango candy spray, Brain Blasterz Bitz and Mega Mouth candy spray. Novelty sweets were located on low shelves which were accessible to all age-groups in 73% (14 out of 19) of the shops. Novelty sweets were displayed in the checkout area in 37% (seven out of 19) shops. The price of the top ten novelty sweets ranged from 39p to £1. Conclusion A wide range of acidic and sugary novelty sweets were easily accessible and priced within pocket money range. Those personnel involved in delivering dental and wider health education or health promotion need to be aware of recent developments in children's confectionery. The potential effects of these novelty sweets on both general and dental health require further investigation

Overexpression of LCMR1 is significantly associated with clinical stage in human NSCLC

<p>Abstract</p> <p>Background</p> <p>Lung cancer is one of the most common human cancers and the leading cause of cancer death worldwide. The identification of lung cancer associated genes is essential for lung cancer diagnosis and treatment.</p> <p>Methods</p> <p>Differential Display-PCR technique was used to achieve the novel cDNA, which were then verified by real-time PCR. Northern blot was utilized to observe the expression of LCMR1 in different human tissues. 84 cases human NSCLC tissues and normal counterparts were analyzed for the expression of LCMR1 by immunohistochemistry.</p> <p>Results</p> <p>A novel 778-bp cDNA fragment from human large cell lung carcinoma cell lines 95C and 95D was obtained, and named <it>LCMR1 </it>(Lung Cancer Metastasis Related protein 1). LCMR1 was differentially expressed in different human tissues. LCMR1 was strongly overexpressed in NSCLC and its expression was significantly associated with clinical stage.</p> <p>Conclusion</p> <p>Our data indicated that <it>LCMR1</it>, strongly overexpressed in NSCLC, might have applications in the clinical diagnosis and treatment of lung cancer.</p

Transcriptomic, proteomic and metabolomic analysis of UV-B signaling in maize

<p>Abstract</p> <p>Background</p> <p>Under normal solar fluence, UV-B damages macromolecules, but it also elicits physiological acclimation and developmental changes in plants. Excess UV-B decreases crop yield. Using a treatment twice solar fluence, we focus on discovering signals produced in UV-B-irradiated maize leaves that translate to systemic changes in shielded leaves and immature ears.</p> <p>Results</p> <p>Using transcriptome and proteomic profiling, we tracked the kinetics of transcript and protein alterations in exposed and shielded organs over 6 h. In parallel, metabolic profiling identified candidate signaling molecules based on rapid increase in irradiated leaves and increased levels in shielded organs; pathways associated with the synthesis, sequestration, or degradation of some of these potential signal molecules were UV-B-responsive. Exposure of just the top leaf substantially alters the transcriptomes of both irradiated and shielded organs, with greater changes as additional leaves are irradiated. Some phenylpropanoid pathway genes are expressed only in irradiated leaves, reflected in accumulation of pathway sunscreen molecules. Most protein changes detected occur quickly: approximately 92% of the proteins in leaves and 73% in immature ears changed after 4 h UV-B were altered by a 1 h UV-B treatment.</p> <p>Conclusions</p> <p>There were significant transcriptome, proteomic, and metabolomic changes under all conditions studied in both shielded and irradiated organs. A dramatic decrease in transcript diversity in irradiated and shielded leaves occurs between 0 h and 1 h, demonstrating the susceptibility of plants to short term UV-B spikes as during ozone depletion. Immature maize ears are highly responsive to canopy leaf exposure to UV-B.</p