Genomic Instability and the Oncohistone H3K27M Drive Gliomagenesis in a Murine Model

Maintaining genome stability is crucial for human health and it is of particular importance in neural cells during early brain development. Genome maintenance occurs at two broad stages; surveillance during DNA replication and DNA damage repair in differentiating and mature cells. Neural cells are particularly sensitive to DNA strand breaks and defective DNA damage responses can result in detrimental effects on the nervous system, including cancer. Multiple DNA repair pathways play critical roles in preventing DNA damage accumulation in stem and neural progenitor cells. The mechanisms that protect progenitor genomes also suppress DNA mutations that can result in cancer. A primary objective of this dissertation is to understand the relative contributions of key DNA repair factors that prevent tumorigenesis during cortical development. We have compared the differential effects of inhibition of homologous recombination (HR), via BRCA2-inactivation and non-homologous end-joining (NHEJ), via LIG4-inactivation towards tumorigenesis by directing their deletion specifically to early cortical progenitors using an Emx1-cre recombinase driver. We find that coincident loss of either of these repair pathways with p53 inhibition result in distinct high-grade glioma (HGG) formation resulting from elevated genome instability by DNA damage accumulation during embryogenesis. Furthermore, the presence of the oncohistone H3K27M mutation, commonly found in pediatric HGGs, enhances genome instability and accelerates cortical gliomagenesis with p53 inactivation and defective HR or NHEJ. Additionally, the H3K27M resultant gliomas showed distinctive differences in increased brain tumor penetrance and diffusion. Through RNA-sequencing and whole exome sequencing we identify upregulation of genes normally controlled by bivalent gene promoter post-translational modifications, which result in transcriptional alterations in genes important for both neural development and tumorigenesis. Mechanistically, this is done by targeting specific populations of cortical cells that are more susceptible to DNA damage and transformations that may cause additional critical mutations during a limited timeframe of early cortical development which eventually result in HGGs. We provide evidence supporting that BRCA2 functions to provide DSBR and genome stability to the early-born proliferating cortical progenitor cell population, while LIG4 provides the same function but to a lesser extent to progenitor cells and more so to post-mitotic neurons. Since, epigenetic regulation is tightly connected with neural development and differentiation, we propose the specific genes that H3K27M effects may differ depending on the time period and particular cell state from which the HGG initiates. We believe this contributes to reduced heterogeneity in glioma expression signatures with H3K27M in addition to either HR- or NHEJ-deficiency. Ultimately this work highlights the power of inducible genetically engineered mouse models as an approach to better understand the complexities of providing a connection between genome instability and gliomagenesis

The genetic implications of multiple ovulation and embryo transfer in small dairy herds

<p/

Breeding decisions within the herd: practical experiences from a service activity in the swedish ai organization

<p/

Laboratory observation of a nonlinear interaction between shear Alfv\'{e}n waves

An experimental investigation of nonlinear interactions between shear Alfv\'{e}n waves in a laboratory plasma is presented. Two Alfv\'{e}n waves, generated by a resonant cavity, are observed to beat together, driving a low frequency nonlinear psuedo-mode at the beat frequency. The psuedo-mode then scatters the Alfv\'{e}n waves, generating a series of sidebands. The observed interaction is very strong, with the normalized amplitude of the driven psuedo-mode comparable to the normalized magnetic field amplitude ($\delta B/B$) of the interacting Alfv\'{e}n waves.Comment: 10 pages, 4 figures, submitted to Phys. Rev. Let

Climate, Conflict and Society: Changing Responses to Weather Extremes in Nineteenth Century Zululand

Changing climates affect human societies differently depending on societal structures, cultural perceptions and their relative vulnerability and resilience. In this study, we explore the complex relationship between climate, conflict and society in nineteenth century Zululand. The paper first reviews current debates surrounding the links between climatic change, societal transformation and the rise of the Zulu Kingdom from the late-eighteenth to early-nineteenth centuries. It then considers new empirical evidence relating to conflict and socio-economic changes at a local scale in Zululand from the early-mid-nineteenth century onwards, using a combination of unpublished archival materials written by missionaries and other observers, together with oral histories and traditions. Our analysis highlights how changing precipitation patterns, especially towards drier conditions, may have contributed to changes in societal responses, including dominant narratives about rain-control, the migration and dissolution of society, and conflicts and unrest. We suggest that temporal differences in these responses were contingent upon the role of leaders, power structures, and the willingness and ability of leaders to yield this power. The case of nineteenth century Zululand exemplifies the complexity of environment-society interactions, and strengthens the call for a thorough scrutiny of the narratives of social unrest in specific socio-cultural contexts

Relation of own growth of sires of bulls to sons in progeny test stations

Abstract: Live weights and daily gains of 8 243 performance tested young sires of Czech Fleckvieh (dual purpose) till the age 400 days were analysed using Random Regression (RR) and Single Trait Animal Models. Evaluations were for entire period and for daily gains in various consecutive monthly intervals. Systematic environmental effects explained a higher proportion of variability in the RR for gains in short consecutive intervals (GSCI) than for other definitions of growth. The expected average reliability of estimated Breeding Values (BV) of young animals was similar for all methods from 0.42 to 0.46, but the rankings of animals differed. Determination (r 2 ) of BV between methods ranged from 0.64 to 0.94. Within-method correlations of BV of parents with progeny according the data from performance-test stations were highest for the GSCI. Correlations of BV of sires for own growth at performance-test stations with the BV of net gain of groups of progeny at progeny-test stations with the final live weight around 600 kg and age 500 days were according the method of sires evaluation from 0.26 to 0.38. Preferred method was according GSCI. This method also allows include more data in the evaluations, and separate the growth curve into genetic and non-genetic parts

Relationship between starch and lipid accumulation induced by nutrient depletion and replenishment in the microalga Parachlorella kessleri

Photosynthetic carbon partitioning into starch and neutral lipids, as well as the influence of nutrient depletion and replenishment on growth, pigments and storage compounds, were studied in the microalga, Parachlorella kessleri. Starch was utilized as a primary carbon and energy storage compound, but nutrient depletion drove the microalgae to channel fixed carbon into lipids as secondary storage compounds. Nutrient depletion inhibited both cellular division and growth and caused degradation of chlorophyll. Starch content decreased from an initial value of 25, to around 10% of dry weight (DW), while storage lipids increased from almost 0 to about 29% of DW. After transfer of cells into replenished mineral medium, growth, reproductive processes and chlorophyll content recovered within 2 days, while the content of both starch and lipids decreased markedly to 3 or less % of DW; this suggested that they were being used as a source of energy and carbon.This study was supported by grant CREST of Japan Science and Technology Agency, by Grant No. LH12145 of Ministry of Education, Youth and Sports of the Czech Republic, by Grant for International Collaboration Academy of Sciences of the Czech Republic No. M200201205 and by the Technology Agency of the Czech Republic, project No. TE01020080

Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

Climate, conflict and society: changing responses to weather extremes in nineteenth century Zululand

Changing climates affect human societies differently depending on societal structures, cultural perceptions and their relative vulnerability and resilience. In this study, we explore the complex relationship between climate, conflict and society in nineteenth century Zululand. The paper first reviews current debates surrounding the links between climatic change, societal transformation and the rise of the Zulu Kingdom from the late-eighteenth to early-nineteenth centuries. It then considers new empirical evidence relating to conflict and socio-economic changes at a local scale in Zululand from the early-mid-nineteenth century onwards, using a combination of unpublished archival materials written by missionaries and other observers, together with oral histories and traditions. Our analysis highlights how changing precipitation patterns, especially towards drier conditions, may have contributed to changes in societal responses, including dominant narratives about rain-control, the migration and dissolution of society, and conflicts and unrest. We suggest that temporal differences in these responses were contingent upon the role of leaders, power structures, and the willingness and ability of leaders to yield this power. The case of nineteenth century Zululand exemplifies the complexity of environment-society interactions, and strengthens the call for a thorough scrutiny of the narratives of social unrest in specific socio-cultural contexts

Impact of the earthworm Lumbricus terrestris (L.) on As, Cu, Pb and Zn mobility and speciation in contaminated soils

To assess the risks that contaminated soils pose to the environment properly a greater understanding of how soil biota influence the mobility of metal(loid)s in soils is required. Lumbricus terrestris L. were incubated in three soils contaminated with As, Cu, Pb and Zn. The concentration and speciation of metal(loid)s in pore waters and the mobility and partitioning in casts were compared with earthworm-free soil. Generally the concentrations of water extractable metal(loid)s in earthworm casts were greater than in earthworm-free soil. The impact of the earthworms on concentration and speciation in pore waters was soil and metal specific and could be explained either by earthworm induced changes in soil pH or soluble organic carbon. The mobilisation of metal(loid)s in the environment by earthworm activity may allow for leaching or uptake into biota