Functional and population genetic features of copy number variations in two dairy cattle populations

Background: Copy Number Variations (CNVs) are gain or loss of DNA segments that are known to play a role in shaping a wide range of phenotypes. In this study, we used two dairy cattle populations, Holstein Friesian and Jersey, to discover CNVs using the Illumina BovineHD Genotyping BeadChip aligned to the ARS-UCD1.2 assembly. The discovered CNVs were investigated for their functional impact and their population genetics features. Results: We discovered 14,272 autosomal CNVs, which were aggregated into 1755 CNV regions (CNVR) from 451 animals. These CNVRs together cover 2.8% of the bovine autosomes. The assessment of the functional impact of CNVRs showed that rare CNVRs (MAF 2 = ~ 0.1 at 10 kb distance) than the rest. Nevertheless, this LD is still lower than SNP-SNP LD (r 2 = ~ 0.5 at 10 kb distance). Conclusions: Our analyses showed that CNVRs detected using BovineHD BeadChip arrays are likely to be functional. This finding indicates that CNVs can potentially disrupt the function of genes and thus might alter phenotypes. Also, the population differentiation index revealed two candidate genes, MGAM and ADAMTS17, which hint at adaptive evolution between the two populations. Lastly, low CNVR-SNP LD implies that genetic variation from CNVs might not be fully captured in routine animal genetic evaluation, which relies solely on SNP markers.</p

Genetic Control of the Trigger for the G2/M Checkpoint

The work undertaken in this project addressed two seminal areas of low dose radiation biology that are poorly understood and controversial. These areas are the challenge to the linear-no-threshold (LNT) paradigm at low doses of radiation and, the fundamental elements of radiation bystander effect biology Genetic contributions to low dose checkpoint engagement: The LNT paradigm is an extrapolation of known, measured cancer induction endpoints. Importantly, data for lower doses is often not available. Debatably, radiation protection standards have been introduced which are prudently contingent on the adherence of cancer risk to the established trend seen at higher doses. Intriguing findings from other labs have hinted at separate DNA damage response programs that engage at low or high levels of radiation. Individual radiation sensitivity commensurate with hemizygosity for a radiation sensitivity gene has been estimated at 1-2% in the U.S.. Careful interrogation of the DNA damage response at low doses of radiation became important and served as the basis for this grant. Several genes were tested in combinations to determine if combined haploinsufficiency for multiple radiosensitizing genes could render a cell more sensitive to lower levels of acute radiation exposure. We measured a classical radiation response endpoint, cell cycle arrest prior to mitosis. Mouse embryo fibroblasts were used and provided a uniform, rapidly dividing and genetically manipulable population of study. Our system did not report checkpoint engagement at acute doses of gamma rays below 100 mGy. The system did report checkpoint engagement reproducibly at 500 mGy establishing a threshold for activation between 100 and 500 mGy. Engagement of the checkpoint was ablated in cells nullizygous for ATM but was otherwise unperturbed in cells combinatorially haploinsufficient for ATM and Rad9, ATM and PTEN or PTEN and Rad9. Taken together, these experiments tell us that, in a sensitive fibroblast culture system, the engagement of the G2/M checkpoint only occurs at doses where most of the cells are bound for mitotic catastrophe. Further, compound haploinsufficiency of various radiosensitizing genes does not impact the threshold of activation. The experiments confirm a threshold of activation for the G2/M checkpoint, hinting at two separate radiation response programs acting below and above this threshold. Small RNA transfer in bystander effect biology: Small regulatory RNA molecules have now risen in prominence and utility. Specific examples are small interfering RNAs (siRNA) which are employed in cell level expression ablation projects and micro-RNAs (miRNA) which are a pool of short transcription products which serve to modulate the expression of other transcripts emerging from the genome in a meta-regulatory fine tuning of gene expression. The existing tenets of bystander effect radiation biology involve the communication of inflammatory mediators or direct intercellular communication of reactive oxygen/nitrogen species in cell-to-cell communicative organelles called gap junctions. By ablating gap junctions, reducing the ROS/inflammatory cytokine expression one can attenuate bystander effect signaling in cell culture systems. We hypothesized that miRNAs are a competent intercellular communication molecule and therefore a possible component of the bystander response. This view is supported by the observation that miRNA are secreted from cells in exosomes found in the circulation. This circulating pool reports disease type and severity in humans. We proposed use of microbeam irradiation technology at our facilities and enhancement of this capability with a new sorting technology which would allow us to sort irradiated and non-irradiated cells with absolute fidelity. Pursuing direct quantitative transfer assessment, we succeeded in designing and constructing a new add-on sorting appliance which harmonized with our existing instruments. The sorter allowed us to gently sort single fluorescently labeled cells. The plans for this appliance were published and are now available for use in other laboratories for single-cell analyses. Our microfluidic cell sorting modality is being integrated into subsequent microbeam irradiation experiments that are planned and ongoing. We generated and irradiated pools of specially engineered Donor-Recipient cell lines in co-culture that would report a small RNA transfer event by modulation of fluorescent protein expression. Both induction and reciprocal silencing designs were tested. We observed elevation of miRNA/siRNA transfer in response to radiation at doses of 5Gy in experiments to date. The reproducibility of these findings has not been good. Future studies will involve refinement of the reporting systems and a decrease in acute dose of radiation used to determine the lowest dose at which miRNA transfer between cells contributes to radiation bystander effect biology

The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells.

Background: Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM). Results: The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR). Conclusions: Our results reinforce the potential therapeutic efficacy of volasertib in combination with radiation for the treatment of GBM. Methods: We used high-throughput screening (HTS) to identify drugs, out of 357 compounds in the published Protein Kinase Inhibitor Set, with the greatest efficacy against a panel of glioma stem cells (GSCs), which are representative of the classic cancer genome atlas (TCGA) molecular subtypes. Oncotarget 2018; 9(8):10497-10509

Paid work is associated with improved health-related quality of life in patients with rheumatoid arthritis

Numerous patients with rheumatoid arthritis (RA) end their working career due to consequences of the disease. No publication has reported whether there is an independent association between patients' health-related quality of life (HRQOL) and employment status. The objective of the study was to investigate the association of paid work and HRQOL in patients with RA whilst controlling for demographics and disease severity. This was a cross-sectional study. Three hundred and ten patients were consecutively recruited from two Norwegians hospitals when commencing disease modifying anti-rheumatic drug treatment. Data on demographics, employment status, disease activity (DAS28-3), physical functioning, pain, tiredness, and HRQOL (SF-36) were collected. HRQOL were compared between 123 patients working full- or part-time and 187 patients not working due to disability pension, retirement, being students or “home workers”. The regression analyses showed an independent positive association between paid work and the physical (p = 001) and the mental component (p = 012) of the SF-36 when controlling for demographics and disease severity. Paid work was statistically significantly associated with better HRQOL in patients with RA. The positive association of performing paid work and HRQOL imply that health care providers should thoroughly evaluate the possibilities for the patients to continue with paid work

The superconductor-insulator transition in 2D dirty boson systems

Universal properties of the zero temperature superconductor-insulator transition in two-dimensional amorphous films are studied by extensive Monte Carlo simulations of bosons in a disordered medium. We report results for both short-range and long-range Coulomb interactions for several different points in parameter space. In all cases we observe a transition from a superconducting phase to an insulating Bose glass phase. {}From finite-size scaling of our Monte Carlo data we determine the universal conductivity $\sigma^*$ and the critical exponents at the transition. The result $\sigma^* = (0.55 \pm 0.06) (2e)^2/h$ for bosons with long-range Coulomb interaction is roughly consistent with experiments reported so far. We also find $\sigma^* = (0.14 \pm 0.03) (2e)^2/h$ for bosons with short-range interactions.Comment: Revtex 3.0, 54 pages, 17 figures included, UBCTP-93-01

Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype

<p>Abstract</p> <p>Background</p> <p>Pseudomyxoma peritonei (PMP) is a rare malignant disease, most commonly originating from appendiceal lesions and characterized by accumulation of mucinous tumor tissue in the peritoneal cavity. Since the disease is infrequent, the task of carrying out studies of treatment efficacy and disease biology in the clinical setting is challenging, warranting the development of relevant <it>in vitro </it>and <it>in vivo </it>PMP models.</p> <p>Methods</p> <p>Human tumor tissue was implanted in the peritoneal cavity of nude mice to establish two orthotopic models exhibiting noninvasive intraperitoneal growth without metastasis development.</p> <p>Results</p> <p>Xenograft tissues have retained essential properties of the original human tumors, such as macro- and microscopic growth patterns, mucin production as well as expression of carcinoembryonal antigen, cytokeratins 20 and 7 and the proliferation marker pKi67. Upon microscopic examination, the human tumors were categorized as the PMCA-I (peritoneal mucinous carcinomatosis of intermediate features) subtype, which was conserved through 14 examined passages in mice, for the first time modeling this particular histopathologic category.</p> <p>Conclusion</p> <p>In conclusion, two novel orthotopic models of human PMP have been established that consistently portray a distinct histopathologic subtype and reflect essential human tumor properties. Xenografts can easily and reproducibly be transferred to new generations of mice with acceptable passage periods, rendering the models as attractive tools for further studies of PMP biology and treatment.</p

3D global multi‐species Hall‐MHD simulation of the Cassini T9 flyby

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94961/1/grl23831.pd

Comparisons between MHD model calculations and observations of Cassini flybys of Titan

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94689/1/jgra18227.pd

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis