Publications by authors named "Adam C Smith"

42 Publications

Bridging research and practice in conservation.

Conserv Biol 2021 Mar 18. Epub 2021 Mar 18.

Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada.

Salafsky et al. (2019) added their voices to a growing call for biodiversity conservation practice to be more evidence-based. We agree that guidance for the use of evidence in conservation practice needs to be improved; however, we suggest that evidence-based conservation will not be realized without improved access to evidence. In medicine, unlike in conservation, a well-established and well-funded layer of intermediary individuals and organizations engage with medical practitioners, synthesize primary research that is relevant to decision-making, and make it easily accessible. These intermediaries prepare targeted evidence summaries and distribute them in a suitable form to practitioners faced with time-sensitive and value-laden decisions. To be effective, these intermediaries, which we term "evidence bridges" should identify research topics based on the priorities of practitioners; synthesize evidence; prepare and distribute easy-to-find and easy-to-use evidence summaries; and develop and maintain networks of connections with researchers and practitioners. Based on a review of the literature regarding evidence intermediaries in conservation and environmental management, as well as an anonymous questionnaire searching for such organizations, we found few intermediaries that meet all these criteria. Moreover, we found that the few evidence bridges that do exist are unable to reach most conservation practitioners, which include resource managers in government and industry, conservation organizations, and farmers and other private landowners. We argue that the lack of evidence bridges from research to practitioners contributes to "evidence complacency" and limits the use of evidence in conservation action. Nevertheless, several existing organizations do help to reduce the gap between evidence and practice and could serve as a foundation for building additional components of evidence bridges in conservation. While evidence bridges need expertise in research and evidence synthesis, they also require expertise in identifying and communicating with the community of practitioners most in need of clear and concise syntheses of evidence. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/cobi.13732DOI Listing
March 2021

Wintering bird communities are tracking climate change faster than breeding communities.

J Anim Ecol 2021 May 15;90(5):1085-1095. Epub 2021 Feb 15.

Sovon Dutch Centre for Field Ornithology, GA Nijmegen, The Netherlands.

Global climate change is driving species' distributions towards the poles and mountain tops during both non-breeding and breeding seasons, leading to changes in the composition of natural communities. However, the degree of season differences in climate-driven community shifts has not been thoroughly investigated at large spatial scales. We compared the rates of change in the community composition during both winter (non-breeding season) and summer (breeding) and their relation to temperature changes. Based on continental-scale data from Europe and North America, we examined changes in bird community composition using the community temperature index (CTI) approach and compared the changes with observed regional temperature changes during 1980-2016. CTI increased faster in winter than in summer. This seasonal discrepancy is probably because individuals are less site-faithful in winter, and can more readily shift their wintering sites in response to weather in comparison to the breeding season. Regional long-term changes in community composition were positively associated with regional temperature changes during both seasons, but the pattern was only significant during summer due to high annual variability in winter communities. Annual changes in community composition were positively associated with the annual temperature changes during both seasons. Our results were broadly consistent across continents, suggesting some climate-driven restructuring in both European and North American avian communities. Because community composition has changed much faster during the winter than during the breeding season, it is important to increase our knowledge about climate-driven impacts during the less-studied non-breeding season.
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http://dx.doi.org/10.1111/1365-2656.13433DOI Listing
May 2021

Fibromatosis colli leading to positional plagiocephaly with gross anatomical and sonographic correlation.

BMJ Case Rep 2021 Jan 11;14(1). Epub 2021 Jan 11.

Diagnostic Radiology, Tripler Army Medical Center, Honolulu, Hawaii, USA.

Fibromatosis colli, also known as 'sternocleidomastoid tumour of infancy' or 'pseudotumour of infancy', is a rare condition involving fibrosis and swelling, or 'tumour' of the sternocleidomastoid muscle in newborns that typically occurs after a traumatic delivery. Although usually self-limited, fibromatosis colli can lead to congenital muscular torticollis and positional plagiocephaly due to uneven forces on the neonatal skull. Ultrasound is the diagnostic imaging modality of choice and can prevent additional imaging and unnecessary intervention.
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http://dx.doi.org/10.1136/bcr-2020-239236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802680PMC
January 2021

A cost efficient spatially balanced hierarchical sampling design for monitoring boreal birds incorporating access costs and habitat stratification.

PLoS One 2020 16;15(6):e0234494. Epub 2020 Jun 16.

Environment and Climate Change Canada, Quebec City, QC, Canada.

Predicting and mitigating impacts of climate change and development within the boreal biome requires a sound understanding of factors influencing the abundance, distribution, and population dynamics of species inhabiting this vast biome. Unfortunately, the limited accessibility of the boreal biome has resulted in sparse and spatially biased sampling, and thus our understanding of boreal bird population dynamics is limited. To implement effective conservation of boreal birds, a cost-effective approach to sampling the boreal biome will be needed. Our objective was to devise a sampling scheme for monitoring boreal birds that would improve our ability to model species-habitat relationships and monitor changes in population size and distribution. A statistically rigorous design to achieve these objectives would have to be spatially balanced and hierarchically structured with respect to ecozones, ecoregions and political jurisdictions. Therefore, we developed a multi-stage hierarchically structured sampling design known as the Boreal Optimal Sampling Strategy (BOSS) that included cost constraints, habitat stratification, and optimization to provide a cost-effective alternative to other common monitoring designs. Our design provided similar habitat and spatial representation to habitat stratification and equal-probability spatially balanced designs, respectively. Not only was our design able to achieve the desired habitat representation and spatial balance necessary to meet our objectives, it was also significantly less expensive (1.3-2.6 times less) than the alternative designs we considered. To further balance trade-offs between cost and representativeness prior to field implementation, we ran multiple iterations of the BOSS design and selected the one which minimized predicted costs while maximizing a multi-criteria evaluation of representativeness. Field implementation of the design in three vastly different regions over three field seasons showed that the approach can be implemented in a wide variety of logistical scenarios and ecological conditions. We provide worked examples and scripts to allow our approach to be implemented or adapted elsewhere. We also provide recommendations for possible future refinements to our approach, but recommend that our design now be implemented to provide unbiased information to assess the status of boreal birds and inform conservation and management actions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297386PMC
August 2020

Fusion of Large Polypeptides to Human Adenovirus Type 5 Capsid Protein IX Can Compromise Virion Stability and DNA Packaging Capacity.

J Virol 2020 08 17;94(17). Epub 2020 Aug 17.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

The human adenovirus (HAdV) protein IX (pIX) is a minor component of the capsid that acts in part to stabilize the hexon-hexon interactions within the mature capsid. Virions lacking pIX have a reduced DNA packaging capacity and exhibit thermal instability. More recently, pIX has been developed as a platform for presentation of large polypeptides, such as fluorescent proteins or large targeting ligands, on the viral capsid. It is not known whether such modifications affect the natural ability of pIX to stabilize the HAdV virion. In this study, we show that addition of large polypeptides to pIX does not alter the natural stability of virions containing sub-wild-type-sized genomes. However, similar virions containing wild-type-sized genomes tend to genetically rearrange, likely due to selective pressure caused by virion instability as a result of compromised pIX function. Human adenovirus capsid protein IX (pIX) is involved in stabilizing the virion but has also been developed as a platform for presentation of various polypeptides on the surface of the virion. Whether such modifications affect the ability of pIX to stabilize the virion is unknown. We show that addition of large polypeptides to pIX can reduce both the DNA packaging capacity and the heat stability of the virion, which provides important guidance for the design of pIX-modified vectors.
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http://dx.doi.org/10.1128/JVI.01112-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431804PMC
August 2020

Centromeric cohesion failure invokes a conserved choreography of chromosomal mis-segregations in pancreatic neuroendocrine tumor.

Genome Med 2020 04 28;12(1):38. Epub 2020 Apr 28.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Background: Pancreatic neuroendocrine tumors (PANETs) are rare, slow growing cancers that often present with local and distant metastasis upon detection. PANETS contain distinct karyotypes, epigenetic dysregulation, and recurrent mutations in MEN1, ATRX, and DAXX (MAD+); however, the molecular basis of disease progression remains uncharacterized.

Methods: We evaluated associations between aneuploidy and the MAD+ mutational state of 532 PANETs from 11 published genomic studies and 19 new cases using a combination of exome, targeted panel, shallow WGS, or RNA-seq. We mapped the molecular timing of MAD+ PANET progression using cellular fractions corrected for inferred tumor content.

Results: In 287 PANETs with mutational data, MAD+ tumors always exhibited a highly recurrent signature of loss of heterozygosity (LOH) and copy-number alterations affecting 11 chromosomes, typically followed by genome doubling upon metastasis. These LOH chromosomes substantially overlap with those that undergo non-random mis-segregation due to ectopic CENP-A localization to flanking centromeric regions in DAXX-depleted cell lines. Using expression data from 122 PANETs, we found decreased gene expression in the regions immediately adjacent to the centromere in MAD+ PANETs. Using 43 PANETs from AACR GENIE, we inferred this signature to be preceded by mutations in MEN1, ATRX, and DAXX. We conducted a meta-analysis on 226 PANETs from 8 CGH studies to show an association of this signature with metastatic incidence. Our study shows that MAD+ tumors are a genetically diverse and aggressive subtype of PANETs that display extensive chromosomal loss after MAD+ mutation, which is followed by genome doubling.

Conclusions: We propose an evolutionary model for a subset of aggressive PANETs that is initiated by mutation of MEN1, ATRX, and DAXX, resulting in defects in centromere cohesion from ectopic CENP-A deposition that leads to selective loss of chromosomes and the LOH phenotype seen in late-stage metastatic PANETs. These insights aid in disease risk stratification and nominate potential therapeutic vulnerabilities to treat this disease.
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http://dx.doi.org/10.1186/s13073-020-00730-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189550PMC
April 2020

Status and trends of tundra birds across the circumpolar Arctic.

Ambio 2020 Mar 18;49(3):732-748. Epub 2020 Jan 18.

Canadian Wildlife Service, Environment and Climate Change Canada, 1125 Colonel By Dr, Ottawa, ON, K1S 5B6, Canada.

Tundra-breeding birds face diverse conservation challenges, from accelerated rates of Arctic climate change to threats associated with highly migratory life histories. Here we summarise the status and trends of Arctic terrestrial birds (88 species, 228 subspecies or distinct flyway populations) across guilds/regions, derived from published sources, raw data or, in rare cases, expert opinion. We report long-term trends in vital rates (survival, reproduction) for the handful of species and regions for which these are available. Over half of all circumpolar Arctic wader taxa are declining (51% of 91 taxa with known trends) and almost half of all waterfowl are increasing (49% of 61 taxa); these opposing trends have fostered a shift in community composition in some locations. Declines were least prevalent in the African-Eurasian Flyway (29%), but similarly prevalent in the remaining three global flyways (44-54%). Widespread, and in some cases accelerating, declines underscore the urgent conservation needs faced by many Arctic terrestrial bird species.
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http://dx.doi.org/10.1007/s13280-019-01308-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989588PMC
March 2020

Decline of the North American avifauna.

Science 2019 10 19;366(6461):120-124. Epub 2019 Sep 19.

Migratory Bird Center, Smithsonian Conservation Biology Institute, National Zoological Park, P.O. Box 37012 MRC 5503, Washington, DC 20013-7012, USA.

Species extinctions have defined the global biodiversity crisis, but extinction begins with loss in abundance of individuals that can result in compositional and functional changes of ecosystems. Using multiple and independent monitoring networks, we report population losses across much of the North American avifauna over 48 years, including once-common species and from most biomes. Integration of range-wide population trajectories and size estimates indicates a net loss approaching 3 billion birds, or 29% of 1970 abundance. A continent-wide weather radar network also reveals a similarly steep decline in biomass passage of migrating birds over a recent 10-year period. This loss of bird abundance signals an urgent need to address threats to avert future avifaunal collapse and associated loss of ecosystem integrity, function, and services.
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http://dx.doi.org/10.1126/science.aaw1313DOI Listing
October 2019

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors.

Beilstein J Org Chem 2019 16;15:2170-2183. Epub 2019 Sep 16.

Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany.

The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the original stilbenoid structure exerted unfavourable photochemical characteristics it was remodelled to its heteroarylic diazeno analogue. By this intramolecular azologization, the shape of the molecule was left unaltered, whereas the photoswitching ability was improved. As anticipated, the highly analogous compound showed similar activity in its thermodynamically stable stretched-out ()-form. Irradiation of this isomer triggers isomerisation to the long-lived ()-configuration with a bent geometry causing a considerably shorter end-to-end distance. The resulting affinity shifts are intended to enable real-time photomodulation of sirtuins in vitro.
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http://dx.doi.org/10.3762/bjoc.15.214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774072PMC
September 2019

Anaplastic lymphoma kinase 5A4 immunohistochemistry as a diagnostic assay in lung cancer: A Canadian reference testing center's results in population-based reflex testing.

Cancer 2019 Nov 7;125(22):4043-4051. Epub 2019 Aug 7.

Laboratory Medicine Program, Department of Pathology, Princess Margaret Cancer Centre and University Health Network, Toronto, Ontario, Canada.

Background: The presence of anaplastic lymphoma kinase (ALK) rearrangement predicts response to ALK tyrosine kinase inhibitor (TKI) therapy. Fluorescence in situ hybridization (FISH) was the initial reference standard to detect ALK rearrangement, but immunohistochemistry (IHC) using D5F3 has gained acceptance as an alternative diagnostic method. ALK IHC assays using other ALK antibodies have also been used as screening methods, but data supporting their utility as diagnostic tests have not been widely reported.

Methods: Data from reflexive clinical ALK IHC test using the 5A4 clone concurrent with epidermal growth factor receptor (EGFR) mutation testing were analyzed. ALK IHC results were reported as negative (-), equivocal, or positive (+), with equivocal or positive staining validated by FISH break-apart probe testing. Treatment outcomes were reviewed for ALK IHC+ patients.

Results: Between 2012 and 2015, 146 (2.5%) cases were reported as ALK IHC+, 188 (3.2%) were reported as equivocal, and 5624 (94.4%) were reported as ALK IHC-. Of the ALK IHC+ cases, 131/143(91.6%) were ALK FISH+. Excluding 6 cases in which FISH was inconclusive or not performed, the positive predictive value was 95.6%, and the negative predictive value was 100%. Most specimens (n = 5352 [89.6%]) were also successfully tested for EGFR. Clinical responses to ALK TKIs were noted in 49 ALK IHC+ patients, with a median progression-free survival of 9.9 months.

Conclusions: ALK 5A4 IHC can serve as a robust diagnostic test for ALK-rearranged lung cancer and is associated with treatment response and survival. Optimized tissue allocation resulted in high success rates of combined reflex EGFR and ALK testing.
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http://dx.doi.org/10.1002/cncr.32422DOI Listing
November 2019

Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.

Mod Pathol 2019 12 15;32(12):1823-1833. Epub 2019 Jul 15.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Gastric-type endocervical adenocarcinoma is an uncommon aggressive type of endocervical adenocarcinoma that is not associated with human papillomavirus (HPV). At present, this tumor is classified under the spectrum of mucinous carcinoma of the uterine cervix. The clinical stage of gastric-type endocervical adenocarcinoma at the time of diagnosis is usually more advanced compared to the HPV-associated endocervical adenocarcinoma. Widespread dissemination to unusual sites, such as omentum, peritoneum, and distant organs, can be present. Owing to its rare incidence, diagnostic dilemmas, and aggressive behavior, clinical management can be challenging. In this study, we aimed to elucidate the molecular characteristics of these tumors by using next-generation sequencing (NGS) to assess 161 unique cancer-driver genes for single-nucleotide and copy-number variations, gene fusions, and insertions/deletions within gastric-type endocervical adenocarcinoma tumors. In total, 92 variants were detected across the 14 samples tested (7 variants on average per tumor). TP53 was the most recurrently mutated gene followed by MSH6, CDKN2A/B, POLE, SLX4, ARID1A, STK11, BRCA2, and MSH2. Abnormal p53 expression was observed in nine cases by immunohistochemistry, of which TP53 variants were present in four cases. MDM2 gene amplification in 12q15 (69202190-69233452) locus was seen in two cases that express normal p53 levels by immunohistochemistry. Four cases had STK11 null (frameshift/nonsense) variants, three of which were previously reported in Peutz-Jeghers syndrome. Overall, genes that are implicated in DNA damage, repair, cell cycle, Fanconi anemia pathway, and the PI3K-AKT signaling pathways were found to be mutated. Of note, genes known to have acquired and/or inherited variants in endometrial tumors were enriched within our cohort. In conclusion, our study shows the genetic heterogeneity of gastric-type endocervical adenocarcinoma with some potentially actionable molecular alterations, which highlights the importance of further molecular characterization for better identification of this rare entity, and hence better clinical management.
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http://dx.doi.org/10.1038/s41379-019-0305-xDOI Listing
December 2019

Cross-scale effects of spruce budworm outbreaks on boreal warblers in eastern Canada.

Ecol Evol 2018 Aug 27;8(15):7334-7345. Epub 2018 Jun 27.

Faculty of Forestry and Environmental Management University of New Brunswick Fredericton New Brunswick Canada.

Insect outbreaks are major natural disturbance events that affect communities of forest birds, either directly by affecting the food supply or indirectly by changing the vegetation composition of forest canopies. An examination of correlations between measures of bird and insect abundance across different spatial scales and over varying time lag effects may provide insight into underlying mechanisms. We developed a hierarchical Bayesian model to assess correlations between counts of eight warbler species from the Breeding Bird Survey in eastern Canada, 1966 to 2009, with the presence of spruce budworm ( Clem.) at immediate local scales and time-lagged regional scales, as measured by extent of defoliation on host tree species. Budworm-associated species Cape May warbler (), bay-breasted warbler (), and Tennessee warbler () responded strongly and positively to both local and regional effects. In contrast, non-budworm-associated species, Blackburnian warbler (), magnolia warbler (), Canada warbler (), black-throated blue warbler (), and black-throated green warbler (), only responded to regional effects in a manner that varied across eastern Canada. The complex responses by forest birds to insect outbreaks involve both increased numerical responses to food supply and to longer term responses to changes in forest structure and composition. These effects can vary across spatial scales and be captured in hierarchical population models, which can serve to disentangle common trends from data when examining drivers of population dynamics like forest management or climate change.
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http://dx.doi.org/10.1002/ece3.4244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106201PMC
August 2018

Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia.

Leukemia 2019 01 8;33(1):37-51. Epub 2018 Jun 8.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.
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http://dx.doi.org/10.1038/s41375-018-0167-0DOI Listing
January 2019

Our use, misuse, and abandonment of a concept: Whither habitat?

Ecol Evol 2018 Apr 2;8(8):4197-4208. Epub 2018 Apr 2.

Natural Resource Conservation, Parks Canada Gatineau QC Canada.

The foundational concept of habitat lies at the very root of the entire science of ecology, but inaccurate use of the term compromises scientific rigor and communication among scientists and nonscientists. In 1997, Hall, Krausman & Morrison showed that 'habitat' was used correctly in only 55% of articles. We ask whether use of the term has been more accurate since their plea for standardization and whether use varies across the broader range of journals and taxa in the contemporary literature (1998-2012). We searched contemporary literature for 'habitat' and habitat-related terms, ranking usage as either correct or incorrect, following a simplified version of Hall et al.'s definitions. We used generalized linear models to compare use of the term in contemporary literature with the papers reviewed by Hall et al. and to test the effects of taxa, journal impact in the contemporary articles and effects due to authors that cited Hall et al. Use of the term 'habitat' has not improved; it was still only used correctly about 55% of the time in the contemporary data. Proportionately more correct uses occurred in articles that focused on animals compared to ones that included plants, and papers that cited Hall et al. did use the term correctly more often. However, journal impact had no effect. Some habitat terms are more likely to be misused than others, notably 'habitat type', usually used to refer to vegetation type, and 'suitable habitat' or 'unsuitable habitat', which are either redundant or nonsensical by definition. Inaccurate and inconsistent use of the term can lead to (1) misinterpretation of scientific findings; (2) inefficient use of conservation resources; (3) ineffective identification and prioritization of protected areas; (4) limited comparability among studies; and (5) miscommunication of science-based findings. Correct usage would improve communication with scientists and nonscientists, thereby benefiting conservation efforts, and ecology as a science.
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http://dx.doi.org/10.1002/ece3.3812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916312PMC
April 2018

Nitrogen-Containing, Light-Absorbing Oligomers Produced in Aerosol Particles Exposed to Methylglyoxal, Photolysis, and Cloud Cycling.

Environ Sci Technol 2018 04 13;52(7):4061-4071. Epub 2018 Mar 13.

Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA), UMR7583, CNRS , Université Paris-Est-Créteil (UPEC) et Université Paris Diderot (UPD), Institut Pierre Simon Laplace (IPSL) , 94010 Créteil , France.

Aqueous methylglyoxal chemistry has often been implicated as an important source of oligomers in atmospheric aerosol. Here we report on chemical analysis of brown carbon aerosol particles collected from cloud cycling/photolysis chamber experiments, where gaseous methylglyoxal and methylamine interacted with glycine, ammonium, or methylammonium sulfate seed particles. Eighteen N-containing oligomers were identified in the particulate phase by liquid chromatography/diode array detection/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry. Chemical formulas were determined and, for 6 major oligomer products, MS fragmentation spectra were used to propose tentative structures and mechanisms. Electronic absorption spectra were calculated for six tentative product structures by an ab initio second order algebraic-diagrammatic-construction/density functional theory approach. For five structures, matching calculated and measured absorption spectra suggest that they are dominant light-absorbing species at their chromatographic retention times. Detected oligomers incorporated methylglyoxal and amines, as expected, but also pyruvic acid, hydroxyacetone, and significant quantities of acetaldehyde. The finding that ∼80% (by mass) of detected oligomers contained acetaldehyde, a methylglyoxal photolysis product, suggests that daytime methylglyoxal oligomer formation is dominated by radical addition mechanisms involving CHCO*. These mechanisms are evidently responsible for enhanced browning observed during photolytic cloud events.
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http://dx.doi.org/10.1021/acs.est.7b06105DOI Listing
April 2018

Clonal evolution as detected by interphase fluorescence in situ hybridization is associated with worse overall survival in a population-based analysis of patients with chronic lymphocytic leukemia in British Columbia, Canada.

Cancer Genet 2017 01 3;210:1-8. Epub 2016 Nov 3.

Division of Hematology, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada; Leukemia/BMT Program of BC, Vancouver General Hospital and British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. Electronic address:

This study evaluates prognostic markers as predictors of clonal evolution (CE) and assesses the impact of CE on overall survival (OS) in a population-based cohort of 159 consecutive eligible patients with chronic lymphocytic leukemia (CLL) obtained from the British Columbia Provincial CLL Database. CE was detected by interphase fluorescence in situ hybridization (FISH) in 34/159 patients (21%) with 65% of CE patients acquiring deletion 17p or 11q. CD38 positive status (≥30%) on flow cytometry predicted 2.7 times increased risk of high-risk CE (acquisition of deletion 17p or 11q) on multivariate analysis. Prior CLL therapy was not a significant predictor of CE. CE was associated with 4.1 times greater risk of death when analyzed as a time-dependent variable for OS after adjusting for age, lymphocyte count, and FISH timing. High-risk CE was associated with worse OS while acquisition of low/intermediate-risk abnormalities (trisomy 12, deletion 13q, and IGH translocation) had no difference in OS. Our study demonstrates the negative impact of CE detected by FISH on OS in this population-based cohort. These data provide support for repeating FISH testing during CLL follow-up as patients with high-risk CE have reduced survival and may require closer observation.
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http://dx.doi.org/10.1016/j.cancergen.2016.10.006DOI Listing
January 2017

New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes.

Dis Model Mech 2017 04 9;10(4):463-474. Epub 2017 Feb 9.

Université Côte d'Azur, Nice, France

Cytoplasmic FMRP interacting protein 1 () is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is highly conserved during evolution, sharing high homology with its homolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE regulatory complex (WRC), thus representing a link between translational regulation and the actin cytoskeleton. Here, we present data showing a correlation between mRNA levels of and other members of the WRC. This suggests a tight regulation of the levels of the WRC members, not only by post-translational mechanisms, as previously hypothesized. Moreover, we studied the impact of loss of function of both CYFIP1 and FMRP on neuronal growth and differentiation in two animal models - fly and mouse. We show that these two proteins antagonize each other's function not only during neuromuscular junction growth in the fly but also during new neuronal differentiation in the olfactory bulb of adult mice. Mechanistically, FMRP and CYFIP1 modulate mTor signaling in an antagonistic manner, likely via independent pathways, supporting the results obtained in mouse as well as in fly at the morphological level. Collectively, our results illustrate a new model to explain the cellular roles of FMRP and CYFIP1 and the molecular significance of their interaction.
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http://dx.doi.org/10.1242/dmm.025809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399562PMC
April 2017

Characterization of treatment and outcomes in a population-based cohort of patients with chronic lymphocytic leukemia referred for cytogenetic testing in British Columbia, Canada.

Leuk Res 2017 04 15;55:79-90. Epub 2017 Jan 15.

Division of Hematology, Leukemia/BMT Program of BC, Vancouver General Hospital, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada. Electronic address:

This study evaluates outcomes in chronic lymphocytic leukemia (CLL) based on first-line therapy in a large consecutive population-based cohort of 669 patients with fluorescence in-situ hybridization (FISH) data in British Columbia, Canada during the period when chemoimmunotherapy was standard first-line treatment. When analyzed as a time-dependent variable, patients who required treatment (n=336) had a 4.7 times higher hazard of death than patients who did not (95% confidence interval 2.8-7.9, P<0.001). The majority of patients received fludarabine-rituximab (FR) in front-line. On multivariate Cox regression analysis, fludarabine-based first-line therapy predicted longer time-to-next-treatment (TTNT) (HR 0.53, 95% confidence interval 0.33-0.87, P=0.012) but no difference in overall survival (OS) compared to alkylator-based therapy. Deletion 17p was an independent predictor of worse TTNT and OS. The most common second-line treatments were cyclophosphamide-vincristine-prednisone-rituximab and FR. There was no difference in OS between patients retreated in second-line with the same first-line regimen (n=33) versus different regimen (n=113). In conclusion, front-line treatment with fludarabine leads to a longer time until need for next treatment than alkylator-based therapy; however, fludarabine or alkylator therapy produces no difference in OS. This study provides a historical baseline for the comparison of novel agents with standard treatments in CLL on a population-level.
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http://dx.doi.org/10.1016/j.leukres.2017.01.023DOI Listing
April 2017

The role of tachysterol in vitamin D photosynthesis - a non-adiabatic molecular dynamics study.

Phys Chem Chem Phys 2017 Feb;19(8):5763-5777

Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellower Boulevard, Long Beach, CA 90840, USA.

To investigate the role of tachysterol in the photophysical/photochemical regulation of vitamin D photosynthesis, we studied its electronic absorption properties and excited state dynamics using time-dependent density functional theory (TDDFT), second-order approximate coupled cluster theory (CC2), and non-adiabatic surface hopping molecular dynamics in the gas phase. In excellent agreement with experiments, the simulated electronic spectrum shows a broad absorption band with a remarkably higher extinction coefficient than the other vitamin D photoisomers provitamin D, lumisterol, and previtamin D. The broad band arises from the spectral overlap of four different ground state rotamers. After photoexcitation, the first excited singlet state (S) decays with a lifetime of 882 fs. The S dynamics is characterized by a strong twisting of the central double bond. In 96% of all trajectories this is followed by unreactive relaxation to the ground state near a conical intersection. The double-bond twisting in the chemically unreactive trajectories induces a strong interconversion between the different rotamers. In 2.3% of the trajectories we observed [1,5]-sigmatropic hydrogen shift forming the partly deconjugated toxisterol D1. 1.4% previtamin D formation is observed via hula-twist double bond isomerization. In both reaction channels, we find a strong dependence between photoreactivity and dihedral angle conformation: hydrogen shift only occurs in cEc and cEt rotamers and double bond isomerization occurs mainly in cEc rotamers. Hence, our study confirms the previously formed hypothesis that cEc rotamers are more prone to previtamin D formation than other isomers. In addition, we also observe the formation of a cyclobutene-toxisterol in the hot ground state in 3 trajectories (0.7%). Due to its large extinction coefficient and mostly unreactive behavior, tachysterol acts mainly as a Sun shield suppressing previtamin D formation. Tachysterol shows stronger toxisterol formation than previtamin D and can thus be seen as the major degradation route of vitamin D. Absorption of low energy ultraviolet light by the cEc rotamer can lead to previtamin D formation. In addition, the cyclobutene-toxisterol, which possibly reacts thermally to previtamin D, is also preferably formed at long wavelengths. These two mechanisms are consistent with the wavelength dependent photochemistry found in experiments. Our study reinforces a recent hypothesis that tachysterol constitutes a source of previtamin D when only low energy ultraviolet light is available, as it is the case in winter or in the morning and evening hours of the day.
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http://dx.doi.org/10.1039/c6cp08064bDOI Listing
February 2017

Influence of clone and deletion size on outcome in chronic lymphocytic leukemia patients with an isolated deletion 13q in a population-based analysis in British Columbia, Canada.

Genes Chromosomes Cancer 2016 Jan 22;55(1):16-24. Epub 2015 Sep 22.

Pathology and Laboratory Medicine, Vancouver General Hospital University of British Columbia, Vancouver, BC, Canada.

Deletion of the long arm of chromosome 13 (del(13q)) as the sole abnormality in chronic lymphocytic leukemia (CLL) portends a good prognosis; however, there is great outcome heterogeneity within this subgroup. The percentage of cells with a del(13q) (clone size) and the extent of the deletion are two factors that may affect outcome in CLL patients with isolated del(13q). We analyzed 248 CLL patients from the BC Provincial CLL database identified as having isolated del(13q) detected pretreatment by interphase fluorescence in situ hybridization to determine what impact clone and deletion size had on overall survival (OS) and treatment free survival (TFS). Patients with 60% or more of nuclei with a del(13q) had shorter TFS and shorter OS. A large deletion, encompassing the RB1 gene locus, was detected in half of the 90 cases with available specimens for testing, and there was no significant difference in OS and TFS between RB1-deleted and RB1-not-deleted cases. Further study in a larger sample size is required to determine the clinical interest of RB1 locus testing; however, clone size of del(13q) does predict TFS and OS and may better refine prognosis in this clinically heterogeneous population.
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http://dx.doi.org/10.1002/gcc.22294DOI Listing
January 2016

Change Points in the Population Trends of Aerial-Insectivorous Birds in North America: Synchronized in Time across Species and Regions.

PLoS One 2015 6;10(7):e0130768. Epub 2015 Jul 6.

Canadian Wildlife Service, Environment Canada, Ottawa, Ontario, Canada.

North American populations of aerial insectivorous birds are in steep decline. Aerial insectivores (AI) are a group of bird species that feed almost exclusively on insects in flight, and include swallows, swifts, nightjars, and flycatchers. The causes of the declines are not well understood. Indeed, it is not clear when the declines began, or whether the declines are shared across all species in the group (e.g., caused by changes in flying insect populations) or specific to each species (e.g., caused by changes in species' breeding habitat). A recent study suggested that population trends of aerial insectivores changed for the worse in the 1980s. If there was such a change point in trends of the group, understanding its timing and geographic pattern could help identify potential causes of the decline. We used a hierarchical Bayesian, penalized regression spline, change point model to estimate group-level change points in the trends of 22 species of AI, across 153 geographic strata of North America. We found evidence for group-level change points in 85% of the strata. Change points for flycatchers (FC) were distinct from those for swallows, swifts and nightjars (SSN) across North America, except in the Northeast, where all AI shared the same group-level change points. During the 1980s, there was a negative change point across most of North America, in the trends of SSN. For FC, the group-level change points were more geographically variable, and in many regions there were two: a positive change point followed by a negative change point. This group-level synchrony in AI population trends is likely evidence of a response to a common environmental factor(s) with similar effects on many species across broad spatial extents. The timing and geographic patterns of the change points that we identify here should provide a spring-board for research into the causes behind aerial insectivore declines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130768PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493114PMC
April 2016

Population-based characterization of the genetic landscape of chronic lymphocytic leukemia patients referred for cytogenetic testing in British Columbia, Canada: the role of provincial laboratory standardization.

Cancer Genet 2014 Jul-Aug;207(7-8):316-25. Epub 2014 Aug 29.

Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, Canada. Electronic address:

Detection of recurrent chromosome abnormalities by fluorescence in situ hybridization (FISH) is an essential component of care in chronic lymphocytic leukemia (CLL) patients. In the province of British Columbia (BC), Canada, population 4.6 million, CLL patients receive uniform evaluation and therapy with FISH testing performed in three jurisdictions. The aims of this study were to (i) validate CLL-FISH testing among the BC cytogenetic laboratories to ensure standardization of results and (ii) characterize population-level CLL-FISH abnormalities by pooling provincial data. From 2004 to 2011, 585 consecutive patients underwent pretreatment CLL-FISH testing at laboratory A (50.1%), laboratory B (32.3%), or laboratory C (17.6%). For validation purposes, 26 CLL-FISH abnormalities were tested by each laboratory's protocol, with 91% result concordance. Discordant results involved percent abnormalities at or near cutoff values; therefore, a 10% universal cutoff was established when pooling results. Applying the universal cutoff to the provincial cohort, CLL-FISH abnormalities were detected in 74.9%: 54.9% 13q-, 18.8% +12, 8.5% 11q-, and 7.7% 17p-. In this large population-based cohort of patients referred for CLL-FISH testing, frequencies of abnormalities detected by FISH analysis were highly consistent with those reported in single-institution and clinical trial populations. Provinces or districts that work together to care for CLL patients can effectively pool data with appropriate laboratory validation to ensure standardization of results.
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http://dx.doi.org/10.1016/j.cancergen.2014.08.006DOI Listing
January 2015

Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression.

Genomics 2012 Jan 3;99(1):25-35. Epub 2011 Nov 3.

Dept of Pathology and Laboratory Medicine, BC Cancer Agency - Vancouver Centre, 600 W 10th Ave., Vancouver, BC, Canada V5Z 4E6.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with genetic or epigenetic alterations in one of two imprinted domains on chromosome 11p15.5. Rarely, chromosomal translocations or inversions of chromosome 11p15.5 are associated with BWS but the molecular pathophysiology in such cases is not understood. In our series of 3 translocation and 2 inversion patients with BWS, the chromosome 11p15.5 breakpoints map within the centromeric imprinted domain, 2. We hypothesized that either microdeletions/microduplications adjacent to the breakpoints could disrupt genomic sequences important for imprinted gene regulation. An alternate hypothesis was that epigenetic alterations of as yet unknown regulatory DNA sequences, result in the BWS phenotype. A high resolution Nimblegen custom microarray was designed representing all non-repetitive sequences in the telomeric 33 Mb of the short arm of human chromosome 11. For the BWS-associated chromosome 11p15.5 translocations and inversions, we found no evidence of microdeletions/microduplications. DNA methylation was also tested on this microarray using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. This high-resolution DNA methylation microarray analysis revealed a gain of DNA methylation in the translocation/inversion patients affecting the p-ter segment of chromosome 11p15, including both imprinted domains. BWS patients that inherited a maternal translocation or inversion also demonstrated reduced expression of the growth suppressing imprinted gene, CDKN1C in Domain 2. In summary, our data demonstrate that translocations and inversions involving imprinted domain 2 on chromosome 11p15.5, alter regional DNA methylation patterns and imprinted gene expression in cis, suggesting that these epigenetic alterations are generated by an alteration in "chromatin context".
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http://dx.doi.org/10.1016/j.ygeno.2011.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679140PMC
January 2012

A poorly known high-latitude parasitoid wasp community: unexpected diversity and dramatic changes through time.

PLoS One 2011 29;6(8):e23719. Epub 2011 Aug 29.

Department of Integrative Biology and Biodiversity, Institute of Ontario, Guelph, Ontario, Canada.

Climate change will have profound and unanticipated effects on species distributions. The pace and nature of this change is largely unstudied, especially for the most diverse elements of terrestrial communities--the arthropods--here we have only limited knowledge concerning the taxonomy and the ecology of these groups. Because Arctic ecosystems have already experienced significant increases in temperature over the past half century, shifts in community structure may already be in progress. Here we utilise collections of a particularly hyperdiverse insect group--parasitoid wasps (Hymenoptera; Braconidae; Microgastrinae)--at Churchill, Manitoba, Canada in the early and mid-twentieth century to compare the composition of the contemporary community to that present 50-70 years ago. Morphological and DNA barcoding results revealed the presence of 79 species of microgastrine wasps in collections from Churchill, but we estimate that 20% of the local fauna awaits detection. Species composition and diversity between the two time periods differ significantly; species that were most common in historic collections were not found in contemporary collections and vice versa. Using barcodes we compared these collections to others from across North America; contemporary Churchill species are most affiliated with more south-western collections, while historic collections were more affiliated with eastern collections. The past five decades has clearly seen a dramatic change of species composition within the area studied coincident with rising temperature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023719PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163582PMC
December 2011

Low-grade fibromyxoid sarcoma of the perineum with heterotopic ossification: case report and review of the literature.

Hum Pathol 2011 Nov 11;42(11):1804-9. Epub 2011 Jun 11.

Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia V5Z1M9, Canada.

Low-grade fibromyxoid sarcoma was first described more than 20 years ago. Subsequently, it was discovered to carry the recurrent chromosomal translocation t(7;16)(q33;p11) encoding a FUS-CREB3L2 fusion oncoprotein. Molecular tests for this pathognomonic gene fusion can confirm the identity of histologic variants (such as hyalinizing spindle cell tumor with giant rosettes) and suggest that some cases of sclerosing epithelioid fibrosarcoma may represent a high-grade version of this entity. We present a case of an ossifying tumor of the perineum that required an open biopsy and fluorescent in situ hybridization testing for FUS and CREB3L2 for diagnosis as a variant of low-grade fibromyxoid sarcoma. Subsequent excision revealed characteristic areas with collagen rosettes as well as foci of heterotopic ossification. Significant ossification, which is well documented in entities such as synovial sarcoma, ossifying fibromyxoid tumor, and extraskeletal osteosarcoma, has not been reported previously in low-grade fibromyxoid sarcoma. This case demonstrates the value of having a distinctive confirmatory molecular pathology test for diagnosis and expands our knowledge of the histologic variants possible in low-grade fibromyxoid sarcoma.
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http://dx.doi.org/10.1016/j.humpath.2011.01.023DOI Listing
November 2011

Antibacterial autophagy occurs at PI(3)P-enriched domains of the endoplasmic reticulum and requires Rab1 GTPase.

Autophagy 2011 Jan 1;7(1):17-26. Epub 2011 Jan 1.

Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.

Autophagy mediates the degradation of cytoplasmic components in eukaryotic cells and plays a key role in immunity. The mechanism of autophagosome formation is not clear. Here we examined two potential membrane sources for antibacterial autophagy: the ER and mitochondria. DFCP1, a marker of specialized ER domains known as 'omegasomes,' associated with Salmonella-containing autophagosomes via its PtdIns(3)P and ER-binding domains, while a mitochondrial marker (cytochrome b5-GFP) did not. Rab1 also localized to autophagosomes, and its activity was required for autophagosome formation, clearance of protein aggregates and peroxisomes, and autophagy of Salmonella. Overexpression of Rab1 enhanced antibacterial autophagy. The role of Rab1 in antibacterial autophagy was independent of its role in ER-to-Golgi transport. Our data suggest that antibacterial autophagy occurs at omegasomes and reveal that the Rab1 GTPase plays a crucial role in mammalian autophagy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039730PMC
http://dx.doi.org/10.4161/auto.7.1.13840DOI Listing
January 2011

Retargeting of adenovirus vectors through genetic fusion of a single-chain or single-domain antibody to capsid protein IX.

J Virol 2010 Oct 14;84(19):10074-86. Epub 2010 Jul 14.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Adenovirus (Ad) vectors are the most commonly used system for gene therapy applications, due in part to their ability to infect a wide array of cell types and tissues. However, many therapies would benefit from the ability to target the Ad vector only to specific cells, such as tumor cells for cancer gene therapy. In this study, we investigated the utility of capsid protein IX (pIX) as a platform for the presentation of single-chain variable-fragment antibodies (scFv) and single-domain antibodies (sdAb) for virus retargeting. We show that scFv can be displayed on the capsid through genetic fusion to native pIX but that these molecules fail to retarget the virus, due to improper folding of the scFv. Redirecting expression of the fusion protein to the endoplasmic reticulum (ER) results in correct folding of the scFv and allows it to recognize its epitope; however, ER-targeted pIX-scFv was incorporated into the Ad capsid at a very low level which was not sufficient to retarget virus infection. In contrast, a pIX-sdAb construct was efficiently incorporated into the Ad capsid and enhanced virus infection of cells expressing the targeted receptor. Taken together, our data indicate that pIX is an effective platform for presentation of large targeting polypeptides on the surface of the virus capsid, but the nature of the ligand can significantly affect its association with virions.
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http://dx.doi.org/10.1128/JVI.02665-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937758PMC
October 2010

Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell-Silver syndrome.

Am J Med Genet A 2009 Nov;149A(11):2415-23

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Over a 10-year period blood samples were collected from 57 individuals with growth restriction and RSS-like features. Our goal was to identify epigenetic abnormalities in this cohort, including uniparental disomy of chromosome 7 (UPD7), methylation changes at chromosome 11p15, as well as new epigenomic alterations. We evaluated the methylation status of 7 imprinting control regions on chromosomes 7, 11, 14, and 15. UPD7 and chromosome 7 structural abnormalities had been previously identified in five patients. Epigenetic alterations on chromosome 11p15 were identified in 11 patients. Of interest, in 3 of these 11 patients, the epigenetic alterations were limited to the H19 promoter and the distal region of its associated imprinting center, ICR1. In addition, in one patient, we detected methylation changes consistent with maternal UPD at all tested imprinted regions. This patient series suggests that epimutations on chromosome 11p15 can be most efficiently detected in RSS patients by screening for DNA methylation defects at the H19 promoter or the distal region of ICR.
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http://dx.doi.org/10.1002/ajmg.a.33065DOI Listing
November 2009

DNA genome size affects the stability of the adenovirus virion.

J Virol 2009 Feb 26;83(4):2025-8. Epub 2008 Nov 26.

Ottawa Health Research Institute, Ontario, Canada.

Replication-defective adenovirus (Ad) vectors can vary considerably in genome length, but whether this affects virion stability has not been investigated. Helper-dependent Ad vectors with a genome size of approximately 30 kb were 100-fold more sensitive to heat inactivation than their parental helper virus (>36 kb), and increasing the genome size of the vector significantly improved heat stability. A similar relationship between genome size and stability existed for Ad with early region 1 deleted. Loss of infectivity was due to release of vertex proteins, followed by disintegration of the capsid. Thus, not only does the viral DNA encode all of the heritable information essential for virus replication, it also plays a critical role in maintaining capsid strength and integrity.
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http://dx.doi.org/10.1128/JVI.01644-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2643769PMC
February 2009