Ubiquitin and Parkinson's disease through the looking glass of Genetics

Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Machine Descriptors of Retargetable Parallelization

90 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2006.The concepts and structure of the EMD framework are described in this dissertation. The implementation and use of the EMD within a parallelizing compiler framework are also described. Finally, the effectiveness of this system description framework for retargeting compiler parallelization is demonstrated.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Effective Cross-Platform, Multilevel Parallelism via Dynamic Adaptive Execution

This paper presents preliminary efforts to develop compilation and execution environments that achieve performance portability of multilevel parallelization on hierarchical architectures. Using the NAS parallel benchmarks, we first illustrate the lack of portable performance on stateof-the-art scalable parallel systems despite the use of two portable programming models, MPI and OpenMP. Then we present a dynamic compilation and execution framework that provides the desired portability through the use of program slices. These slices are used to select the optimal program decomposition on each architecture. Currently, our framework uses a simple incremental algorithm, which effectively identifies single or multi-level program decompositions that maximize performance. This algorithm can be used as a rule of thumb for automatic multilevel parallelization. The effectiveness of the approach is demonstrated on the NAS benchmarks running on two architectural platforms. 1

Sex- and tissue-specific profiles of chemosensory gene expression in a herbivorous gall-inducing fly (Diptera: Cecidomyiidae)

Background: The chemical senses of insects mediate behaviors that are closely linked to survival and reproduction. The order Diptera contains two model organisms, the vinegar fly Drosophila melanogaster and the mosquito Anopheles gambiae, whose chemosensory genes have been extensively studied. Representing a third dipteran lineage with an interesting phylogenetic position, and being ecologically distinct by feeding on plants, the Hessian fly (Mayetiola destructor Say, Diptera: Cecidomyiidae) genome sequence has recently become available. Among plant-feeding insects, the Hessian fly is unusual in ‘reprogramming’ the plant to create a superior food and in being the target of plant resistance genes, a feature shared by plant pathogens. Chemoreception is essential for reproductive success, including detection of sex pheromone and plant-produced chemicals by males and females, respectively. Results: We identified genes encoding 122 odorant receptors (OR), 28 gustatory receptors (GR), 39 ionotropic receptors (IR), 32 odorant binding proteins, and 7 sensory neuron membrane proteins in the Hessian fly genome. We then mapped Illumina-sequenced transcriptome reads to the genome to explore gene expression in male and female antennae and terminal abdominal segments. Our results reveal that a large number of chemosensory genes have up-regulated expression in the antennae, and the expression is in many cases sex-specific. Sex-specific expression is particularly evident among the Or genes, consistent with the sex-divergent olfactory-mediated behaviors of the adults. In addition, the large number of Ors in the genome but the reduced set of Grs and divergent Irs suggest that the short-lived adults rely more on long-range olfaction than on short-range gustation. We also report up-regulated expression of some genes from all chemosensory gene families in the terminal segments of the abdomen, which play important roles in reproduction. Conclusions: We show that a large number of the chemosensory genes in the Hessian fly genome have sex- and tissue-specific expression profiles. Our findings provide the first insights into the molecular basis of chemoreception in plant-feeding flies, representing an important advance toward a more complete understanding of olfaction in Diptera and its links to ecological specialization

Sputtered-deposited thin brass films in a modified glow discharge Grimm-type source

Modification of the non-assisted gas flow-line across the target surface in a Grimm-type glow discharge source is described. The new flow–line permits the gas to flow through a cylindrical annular space ending with a disc-space annular gap, facing the target surface. This configuration would cause directed jet assisted gas flow rays to impinge on infinite points across the cathode surface. Improvement has been achieved in the V-I characteristics where $\Delta V$/$\Delta I$ increases from 1.8 to 3.5 V/mA. The sputtering as well as simultaneous deposition rates, have been increased by a factor of 16 and 17 respectively. These roll over with increasing sputtering time, their maximum values at a characteristic time, toc of 21 min. The toc value was constant for different operating parameters provided that the source geometry assembly is kept fixed. The presence of a glass substrate in the anode cavity has, apparently, no effect on the obtained data. Improvements have also been achieved in the crater profile, characterized by an approximately flat crater bottom with nearly vertical walls, and less re-deposited particles on the crater depth and edge. Fixing the distance Z of the substrate from target surface, along the cell axis, and varying the deposition time from 1 to 30 min, a sequence of changes in the deposited film were observed by X-ray diffraction and energy dispersion X-ray (EDX). These changes start with an amorphous structure, followed by the appearance of Cu and Zn crystallites and a probable deposition of Cu5Zn8 clusters. The profile of the number of sputtered particles at different Z values is characterized by a number of peaks and troughs. This behavior has been explained by the occurrence of local cluster-dissociation and formation, by different collision processes. The improvements achieved by the application of the present jet assisted gas flow can be of value in the analytical application of this type of glow discharge