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1.  Effect of pre-analytical treatments on bovine milk acute phase proteins 
BMC Veterinary Research  2016;12:151.
Samples for diagnostic procedures often require some form of pre-analytical preparation for preservation or safe handling during transportation prior to analysis in the laboratory. This is particularly important for milk samples which frequently need preservatives to retain milk composition as close to that found in freshly collected samples as possible.
Milk samples were treated by heating at 56 °C for 30 min or preserved by addition of either potassium dichromate or bronopol respectively. Haptoglobin (Hp), mammary associated serum amyloid A3 (M-SAA3) and C-reactive protein (CRP) were measured in the various treatment groups and in control samples which were not treated, using enzyme linked immunoassays. The concentrations of each APP were compared between treated and non-treated groups using the Wilcoxon signed ranks tests.
Heat treatment of samples was found to have a significant lowering effect on milk M-SAA3 and CRP but not Hp. The use of potassium dichromate and bronopol as preservatives in milk had no significant effects on milk Hp and M-SAA3 concentration but lowered milk CRP values compared to controls.
The observed effects of heating and preservative use on milk APP should be taken into consideration when assaying samples which have undergone heat treatment as a result of international transfer regulations involving biological samples or samples needing chemical preservation prior to transport to laboratory.
PMCID: PMC4960790  PMID: 27457305
C-reactive protein; Haptoglobin; Thermal stability; Mammary associated serum amyloid A3; Milk preservatives
2.  Housing need in Canada: Healthy lives start at home 
Paediatrics & Child Health  2015;20(7):403-407.
Housing affects the health of children and youth. One-third of households in Canada live in substandard conditions or in housing need. The present statement reviews the literature documenting the impacts of housing on personal health and the health care system. Types of housing need are defined, including unsuitable or crowded housing, unaffordable housing and inadequate housing, or housing in need of major repairs. The health effects of each type of housing need, as well as of unsafe neighbourhoods, infestations and other environmental exposures are outlined. Paediatricians and other physicians caring for children need to understand the housing status of patients to fully determine their health issues and ability to access and engage in health care. Recommendations and sample tools to assess and address housing need at the patient, family, community and policy levels are described. Canada is the only G8 country without a national housing strategy. Recommendations also include advocating for enhanced action at all levels of government and for housing-supportive policies, including a national housing strategy.
PMCID: PMC4614099  PMID: 26527164
Determinants of health; Health advocacy; Housing; Public health; Social paediatrics
4.  Calibrating longitudinal cognition in Alzheimer’s disease across diverse test batteries and datasets 
Neuroepidemiology  2014;43(0):194-205.
We sought to identify optimal approaches calibrating longitudinal cognitive performance across studies with different neuropsychological batteries.
We examined four approaches to calibrate cognitive performance in nine longitudinal studies of Alzheimer’s disease (AD) (N=10,875): (1) common test, (2) standardize and average available tests, (3) confirmatory factor analysis (CFA) with continuous indicators, and (4) CFA with categorical indicators. To compare precision, we determined minimum sample sizes needed to detect 25% cognitive decline with 80% power. To compare criterion validity, we correlated cognitive change from each approach with 6-year changes in average cortical thickness and hippocampal volume using available MRI data from the AD Neuroimaging Initiative.
CFA with categorical indicators required the smallest sample size to detect 25% cognitive decline with 80% power (N=232) compared to common test (N=277), standardize- and-average (N=291), and CFA with continuous indicators (N=315) approaches. Associations with changes in biomarkers changes were strongest for CFA with categorical indicators.
CFA with categorical indicators demonstrated greater power to detect change and superior criterion validity compared to other approaches. It has wide applicability to directly compare cognitive performance across studies, making it a good way to obtain operational phenotypes for genetic analyses of cognitive decline among people with AD.
PMCID: PMC4297570  PMID: 25402421
calibration; neuropsychological performance; Alzheimer’s disease
5.  The major acute phase proteins of bovine milk in a commercial dairy herd 
BMC Veterinary Research  2015;11:207.
Milk acute phase proteins (APP) have been identified and show promise as biomarkers of mastitis. However analysis of their profile in dairy cows from a production herd is necessary in order to confirm their benefits in mastitis diagnosis. The profiles of milk haptoglobin (Hp), mammary associated serum amyloid A3 (M-SAA3) and C-reactive protein (CRP) were determined in 54 composite milk (milk from all functional quarters of a cow’s udder collected in a common receptacle) samples (CMS) from a commercial dairy farm. Milk Hp was also determined in individual quarter milk (milk from a single udder quarter) samples (QMS) (n = 149) of the cows.
An ELISA was developed and validated for the determination of milk Hp while commercial kits were used for M-SAA3 and CRP assay respectively. Composite milk APP results were compared with cow factors including parity, stage of lactation, percentage protein and fat as well as somatic cell counts (SCC).
Composite milk Hp ranged from <0.4–55 μg/ml with a median of 3.5 μg/ml; composite milk M-SAA3 ranged from <0.6–50 μg/ml and had a median of 1.2 μg/ml, while CRP ranged from <1.80–173 ng/ml and had a median of 24.6 ng/ml. Significant correlations were found between composite SCC and Hp (P-value <0.009) as well as parity and Hp (P < 0.009), but not between M-SAA3 and SCC, M-SAA3 and Hp, M-SAA3 and CRP or M-SAA3 and parity. Milk CRP was correlated with % fat (P = 0.002) and % protein (P = 0.001) of the milk samples. The lack of correlation of SCC with the M-SAA3 and CRP could result from these APP being more sensitive to intra-mammary infection than SCC. Quarter milk Hp had a range of <0.4–420 μg/ml with a median value of 3.6 μg/ml, with 92 % of samples below 20 μg/ml.
Baseline values of Hp, M-SAA3 and CRP were established in composite milk from cows with normal SCC on the dairy farm. Parity was recognized as a possible confounding factor when diagnosing mastitis using Hp. The value of the APP, Hp, M-SAA3 and CRP as substitutes or to complement SCC in indicating udder inflammation, was demonstrated.
PMCID: PMC4536752  PMID: 26276568
Haptoglobin; Serum amyloid A; C-reactive protein; Somatic cell counts; Bovine mastitis
6.  Regulatory analysis of the C. elegans genome with spatiotemporal resolution 
Nature  2014;512(7515):400-405.
Discovering the structure and dynamics of transcriptional regulatory events in the genome with cellular and temporal resolution is crucial to understanding the regulatory underpinnings of development and disease. We determined the genomic distribution of binding sites for 92 transcription factors (TFs) and regulatory proteins across multiple stages of C. elegans development by performing 241 ChIP-seq experiments. Integrating regulatory binding and cellular-resolution expression data yielded a spatiotemporally-resolved metazoan TF binding map. Using this map, we explore developmental regulatory circuits that encode combinatorial logic at the levels of co-binding and co-expression of TFs, characterizing (1) the genomic coverage and clustering of regulatory binding, (2) the binding preferences of and biological processes regulated by TFs, (3) the global TF co-associations and genomic subdomains that suggest shared patterns of regulation, and (4) key TFs and TF co-associations for fate specification of individual lineages and cell-types.
PMCID: PMC4530805  PMID: 25164749
Transcription Factor; Gene Regulation; ChIP-seq; Cellular Expression; Development
7.  Social Media Use in Research: Engaging Communities in Cohort Studies to Support Recruitment and Retention 
JMIR Research Protocols  2015;4(3):e90.
This paper presents the first formal evaluation of social media (SM) use in the National Children’s Study (NCS). The NCS is a prospective, longitudinal study of the effects of environment and genetics on children’s health, growth and development. The Study employed a multifaceted community outreach campaign in combination with a SM campaign to educate participants and their communities about the Study. SM essentially erases geographic differences between people due to its omnipresence, which was an important consideration in this multi-site national study. Using SM in the research setting requires an understanding of potential threats to confidentiality and privacy and the role that posted content plays as an extension of the informed consent process.
This pilot demonstrates the feasibility of creating linkages and databases to measure and compare SM with new content and engagement metrics.
Metrics presented include basic use metrics for Facebook as well as newly created metrics to assist with Facebook content and engagement analyses.
Increasing Likes per month demonstrates that online communities can be quickly generated. Content and Engagement analyses describe what content of posts NCS Study Centers were using, what content they were posting about, and what the online NCS communities found most engaging.
These metrics highlight opportunities to optimize time and effort while determining the content of future posts. Further research about content analysis, optimal metrics to describe engagement in research, the role of localized content and stakeholders, and social media use in participant recruitment is warranted.
PMCID: PMC4527013  PMID: 26201259
social media; longitudinal studies; pilot project; community outreach
8.  Specific roles for the GATA transcription factors end-1 and end-3 during C. elegans E-lineage development 
Developmental biology  2011;358(2):345-355.
end-1 and end-3 are GATA transcription factors important for specifying endoderm cell fate in Caenorhabditis elegans. Deletion of both factors together results in larval arrest, 0% survival and a fate change in the endoderm-specifying E lineage. Individual deletions of either factor, however, result in the development of viable, fertile adults, with 100% of worms developing to adults for end-1(−) and 95% for end-3(−). We sought to quantify the variable phenotypes seen in both deletions using automated cell lineaging. We quantified defects in cell lifetime, cell movement and division axis in end-3(−) embryos, while quantifying perturbations in downstream reporter gene expression in strains with homozygous deletions for either gene, showing that each deletion leads to a unique profile of downstream perturbations in gene expression and cellular phenotypes with a high correlation between early and late defects. Combining observations in both cellular and gene expression defects we found that misaligned divisions at the E2 stage resulted in ectopic expression of the Notch target ref-1 in end-3(−) embryos. Using a maximum likelihood phylogenetic approach we found end-1 and end-3 split to form two distinct clades within the Caenorhabditis lineage with distinct DNA-binding structures. These results indicate that end-1 and end-3 have each evolved into genes with unique functions during endoderm development, that end-3(−) embryos have a delay in the onset of E lineage cell fate and that end-1 has only a partially penetrant ability to activate E lineage fate.
PMCID: PMC4454387  PMID: 21854766
C. elegans; Endoderm; GATA factors; Gene expression; Cell fate; Cell migration; Gastrulation
9.  Remarkably Divergent Regions Punctuate the Genome Assembly of the Caenorhabditis elegans Hawaiian Strain CB4856 
Genetics  2015;200(3):975-989.
The Hawaiian strain (CB4856) of Caenorhabditis elegans is one of the most divergent from the canonical laboratory strain N2 and has been widely used in developmental, population, and evolutionary studies. To enhance the utility of the strain, we have generated a draft sequence of the CB4856 genome, exploiting a variety of resources and strategies. When compared against the N2 reference, the CB4856 genome has 327,050 single nucleotide variants (SNVs) and 79,529 insertion–deletion events that result in a total of 3.3 Mb of N2 sequence missing from CB4856 and 1.4 Mb of sequence present in CB4856 but not present in N2. As previously reported, the density of SNVs varies along the chromosomes, with the arms of chromosomes showing greater average variation than the centers. In addition, we find 61 regions totaling 2.8 Mb, distributed across all six chromosomes, which have a greatly elevated SNV density, ranging from 2 to 16% SNVs. A survey of other wild isolates show that the two alternative haplotypes for each region are widely distributed, suggesting they have been maintained by balancing selection over long evolutionary times. These divergent regions contain an abundance of genes from large rapidly evolving families encoding F-box, MATH, BATH, seven-transmembrane G-coupled receptors, and nuclear hormone receptors, suggesting that they provide selective advantages in natural environments. The draft sequence makes available a comprehensive catalog of sequence differences between the CB4856 and N2 strains that will facilitate the molecular dissection of their phenotypic differences. Our work also emphasizes the importance of going beyond simple alignment of reads to a reference genome when assessing differences between genomes.
PMCID: PMC4512556  PMID: 25995208
C. elegans; genome assembly; evolution; variation
10.  Blinded by the light: why the treatment of metastatic melanoma has created a new paradigm for the management of cancer 
Until recently, treatment for metastatic melanoma was characterised by a limited availability of treatment options that offer objective survival benefit. Cytotoxic agents fundamentally lack the ability to achieve disease control and cytokine therapy with interleukin-2 has an unacceptably high – for the use across all patient cohorts – rate of toxicities. The validation of braf as an oncogene driving melanoma tumorigenesis, as well as the discovery of the role of CTLA-4 receptor in the evasion of anticancer immune response by melanoma, has revolutionised our treatment options against a disease with dismal prognosis. Quick implementation of translational discoveries brought about BRAF/MEK inhibition in clinic, while at the same time, wider experience with CTLA-4 blockade enabled clinicians to manage previously fatal immune-related toxicities with greater confidence. The suitability for clinical use of other oncogenic drivers such as NRAS and c-kit is currently being tested whilst the PD-1/PD-L1/PD-L2 axis has emerged as a new immunotherapy target with exciting early phase results. The recent exponential progress in treatment of melanoma has set an example of translational medicine and the current review aims to explain why, as well as suggesting new goals for the future.
PMCID: PMC4346213  PMID: 25755683
BRAF/MEK inhibition; ipilimumab; metastatic melanoma; molecularly targeted treatment; PD-1/PD-L1/PD-L2 axis
11.  Comparative Analysis of the Transcriptome across Distant Species 
Gerstein, Mark B. | Rozowsky, Joel | Yan, Koon-Kiu | Wang, Daifeng | Cheng, Chao | Brown, James B. | Davis, Carrie A | Hillier, LaDeana | Sisu, Cristina | Li, Jingyi Jessica | Pei, Baikang | Harmanci, Arif O. | Duff, Michael O. | Djebali, Sarah | Alexander, Roger P. | Alver, Burak H. | Auerbach, Raymond | Bell, Kimberly | Bickel, Peter J. | Boeck, Max E. | Boley, Nathan P. | Booth, Benjamin W. | Cherbas, Lucy | Cherbas, Peter | Di, Chao | Dobin, Alex | Drenkow, Jorg | Ewing, Brent | Fang, Gang | Fastuca, Megan | Feingold, Elise A. | Frankish, Adam | Gao, Guanjun | Good, Peter J. | Guigó, Roderic | Hammonds, Ann | Harrow, Jen | Hoskins, Roger A. | Howald, Cédric | Hu, Long | Huang, Haiyan | Hubbard, Tim J. P. | Huynh, Chau | Jha, Sonali | Kasper, Dionna | Kato, Masaomi | Kaufman, Thomas C. | Kitchen, Robert R. | Ladewig, Erik | Lagarde, Julien | Lai, Eric | Leng, Jing | Lu, Zhi | MacCoss, Michael | May, Gemma | McWhirter, Rebecca | Merrihew, Gennifer | Miller, David M. | Mortazavi, Ali | Murad, Rabi | Oliver, Brian | Olson, Sara | Park, Peter J. | Pazin, Michael J. | Perrimon, Norbert | Pervouchine, Dmitri | Reinke, Valerie | Reymond, Alexandre | Robinson, Garrett | Samsonova, Anastasia | Saunders, Gary I. | Schlesinger, Felix | Sethi, Anurag | Slack, Frank J. | Spencer, William C. | Stoiber, Marcus H. | Strasbourger, Pnina | Tanzer, Andrea | Thompson, Owen A. | Wan, Kenneth H. | Wang, Guilin | Wang, Huaien | Watkins, Kathie L. | Wen, Jiayu | Wen, Kejia | Xue, Chenghai | Yang, Li | Yip, Kevin | Zaleski, Chris | Zhang, Yan | Zheng, Henry | Brenner, Steven E. | Graveley, Brenton R. | Celniker, Susan E. | Gingeras, Thomas R | Waterston, Robert
Nature  2014;512(7515):445-448.
PMCID: PMC4155737  PMID: 25164755
12.  Comparative analysis of regulatory information and circuits across distant species 
Nature  2014;512(7515):453-456.
Despite the large evolutionary distances, metazoan species show remarkable commonalities, which has helped establish fly and worm as model organisms for human biology1,2. Although studies of individual elements and factors have explored similarities in gene regulation, a large-scale comparative analysis of basic principles of transcriptional regulatory features is lacking. We mapped the genome-wide binding locations of 165 human, 93 worm, and 52 fly transcription-regulatory factors (RFs) generating a total of 1,019 data sets from diverse cell-types, developmental stages, or conditions in the three species, of which 498 (48.9%) are presented here for the first time. We find that structural properties of regulatory networks are remarkably conserved and that orthologous RF families recognize similar binding motifs in vivo and show some similar co-associations. Our results suggest that gene-regulatory properties previously observed for individual factors are general principles of metazoan regulation that are remarkably well-preserved despite extensive functional divergence of individual network connections. The comparative maps of regulatory circuitry provided here will drive an improved understanding in the regulatory underpinnings of model organism biology and how these relate to human biology, development, and disease.
PMCID: PMC4336544  PMID: 25164757
Transcription Factor; Regulatory Information; Gene Regulation; Single Nucleotide Polymorphisms; ChIP-seq
13.  Isolation of Specific Neurons from C. elegans Larvae for Gene Expression Profiling 
PLoS ONE  2014;9(11):e112102.
The simple and well-described structure of the C. elegans nervous system offers an unprecedented opportunity to identify the genetic programs that define the connectivity and function of individual neurons and their circuits. A correspondingly precise gene expression map of C. elegans neurons would facilitate the application of genetic methods toward this goal. Here we describe a powerful new approach, SeqCeL (RNA-Seq of C. elegans cells) for producing gene expression profiles of specific larval C. elegans neurons.
Methods and Results
We have exploited available GFP reporter lines for FACS isolation of specific larval C. elegans neurons for RNA-Seq analysis. Our analysis showed that diverse classes of neurons are accessible to this approach. To demonstrate the applicability of this strategy to rare neuron types, we generated RNA-Seq profiles of the NSM serotonergic neurons that occur as a single bilateral pair of cells in the C. elegans pharynx. These data detected >1,000 NSM enriched transcripts, including the majority of previously known NSM-expressed genes.
This work offers a simple and robust protocol for expression profiling studies of post-embryonic C. elegans neurons and thus provides an important new method for identifying candidate genes for key roles in neuron-specific development and function.
PMCID: PMC4221280  PMID: 25372608
14.  A genome scale resource for in vivo tag-based protein function exploration in C. elegans 
Cell  2012;150(4):855-866.
Understanding the in vivo dynamics of protein localization and their physical interactions is important for many problems in Biology. To enable systematic protein function interrogation in a multicelluar context, we built a genome-scale transgenic platform for in vivo expression of fluorescent and affinity tagged proteins in Caenorhabditis elegans under endogenous cis regulatory control. The platform combines computer-assisted transgene design, massively parallel DNA engineering and next generation sequencing to generate a resource of 14637 genomic DNA transgenes, which covers 73% of the proteome. The multipurpose tag used allows any protein of interest to be localized in vivo or affinity purified using standard tag-based assays. We illustrate the utility of the resource by systematic chromatin immunopurification and automated 4D imaging, which produced detailed DNA binding and cell/tissue distribution maps for key transcription factor proteins
PMCID: PMC3979301  PMID: 22901814
15.  A High-Fidelity Cell Lineage Tracing Method for Obtaining Systematic Spatiotemporal Gene Expression Patterns in Caenorhabditis elegans 
G3: Genes|Genomes|Genetics  2013;3(5):851-863.
Advances in microscopy and fluorescent reporters have allowed us to detect the onset of gene expression on a cell-by-cell basis in a systematic fashion. This information, however, is often encoded in large repositories of images, and developing ways to extract this spatiotemporal expression data is a difficult problem that often uses complex domain-specific methods for each individual data set. We present a more unified approach that incorporates general previous information into a hierarchical probabilistic model to extract spatiotemporal gene expression from 4D confocal microscopy images of developing Caenorhabditis elegans embryos. This approach reduces the overall error rate of our automated lineage tracing pipeline by 3.8-fold, allowing us to routinely follow the C. elegans lineage to later stages of development, where individual neuronal subspecification becomes apparent. Unlike previous methods that often use custom approaches that are organism specific, our method uses generalized linear models and extensions of standard reversible jump Markov chain Monte Carlo methods that can be readily extended to other organisms for a variety of biological inference problems relating to cell fate specification. This modeling approach is flexible and provides tractable avenues for incorporating additional previous information into the model for similar difficult high-fidelity/low error tolerance image analysis problems for systematically applied genomic experiments.
PMCID: PMC3656732  PMID: 23550142
C. elegans; cell fate; gene expression; image analysis; lineage
16.  The effect of robenacoxib on the concentration of C-reactive protein in synovial fluid from dogs with osteoarthritis 
Robenacoxib is a novel and highly selective inhibitor of COX-2 in dogs and cats and because of its acidic nature is regarded as being tissue-selective. Thirty four dogs with stifle osteoarthritis secondary to failure of the cranial cruciate ligament were recruited into this study. Lameness, radiographic features, synovial cytology and C-reactive protein concentrations in serum and synovial fluid were assessed before and 28 days after commencing a course of Robenacoxib at a dose of 1 mg/kg SID.
There was a significant reduction in the lameness score (P < 0.01) and an increase in the radiographic score (P < 0.05) between pre- and post-treatment assessments. There was no difference between pre- (median 1.49 mg/l; Q1-Q3 0.56-4.24 mg/L) and post – (1.10 mg/L; 0.31-1.78 mg/L) treatment serum C-reactive protein levels although synovial fluid levels were significantly reduced (pre- : 0.44 mg/L; 0.23-1.62 mg/L; post- : 0.17 mg/L; 0.05-0.49 mg/L) (P < 0.05). There was no correlation between C-reactive protein concentrations in serum and matched synovial fluid samples.
Robenacoxib proved effective in reducing lameness in dogs with failure of the cranial cruciate ligament and osteoarthritis of the stifle joint. The drug also reduced levels of C-reactive protein in the synovial fluid taken from the affected stifle joint. Robenacoxib appears to reduce articular inflammation as assessed by C-reactive protein which supports the concept that Robenacoxib is a tissue-selective non-steroidal anti-inflammatory drug.
PMCID: PMC3610148  PMID: 23452411
Stifle; Osteoarthritis; Cruciate disease; C-reactive protein; Synovial fluid; Robenacoxib
17.  Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster 
Nature genetics  2011;43(12):1179-1185.
Many animal species use a chromosome-based mechanism of sex determination, which has led to the coordinate evolution of dosage-compensation systems. Dosage compensation not only corrects the imbalance in the number of X chromosomes between the sexes but also is hypothesized to correct dosage imbalance within cells that is due to monoallelic X-linked expression and biallelic autosomal expression, by upregulating X-linked genes twofold (termed ‘Ohno’s hypothesis’). Although this hypothesis is well supported by expression analyses of individual X-linked genes and by microarray-based transcriptome analyses, it was challenged by a recent study using RNA sequencing and proteomics. We obtained new, independent RNA-seq data, measured RNA polymerase distribution and reanalyzed published expression data in mammals, C. elegans and Drosophila. Our analyses, which take into account the skewed gene content of the X chromosome, support the hypothesis of upregulation of expressed X-linked genes to balance expression of the genome.
PMCID: PMC3576853  PMID: 22019781
18.  Genetic Control of Vulval Development in Caenorhabditis briggsae 
G3: Genes|Genomes|Genetics  2012;2(12):1625-1641.
The nematode Caenorhabditis briggsae is an excellent model organism for the comparative analysis of gene function and developmental mechanisms. To study the evolutionary conservation and divergence of genetic pathways mediating vulva formation, we screened for mutations in C. briggsae that cause the egg-laying defective (Egl) phenotype. Here, we report the characterization of 13 genes, including three that are orthologs of Caenorhabditis elegans unc-84 (SUN domain), lin-39 (Dfd/Scr-related homeobox), and lin-11 (LIM homeobox). Based on the morphology and cell fate changes, the mutants were placed into four different categories. Class 1 animals have normal-looking vulva and vulva-uterine connections, indicating defects in other components of the egg-laying system. Class 2 animals frequently lack some or all of the vulval precursor cells (VPCs) due to defects in the migration of P-cell nuclei into the ventral hypodermal region. Class 3 animals show inappropriate fusion of VPCs to the hypodermal syncytium, leading to a reduced number of vulval progeny. Finally, class 4 animals exhibit abnormal vulval invagination and morphology. Interestingly, we did not find mutations that affect VPC induction and fates. Our work is the first study involving the characterization of genes in C. briggsae vulva formation, and it offers a basis for future investigations of these genes in C. elegans.
PMCID: PMC3516484  PMID: 23275885
C. briggsae; C. elegans; vulva; development; cell proliferation; differentiation; morphogenesis; egg-laying defective
19.  Sensory neuropathy as part of the cerebellar ataxia neuropathy vestibular areflexia syndrome 
Neurology  2011;76(22):1903-1910.
The syndrome of cerebellar ataxia with bilateral vestibulopathy was delineated in 2004. Sensory neuropathy was mentioned in 3 of the 4 patients described. We aimed to characterize and estimate the frequency of neuropathy in this condition, and determine its typical MRI features.
Retrospective review of 18 subjects (including 4 from the original description) who met the criteria for bilateral vestibulopathy with cerebellar ataxia.
The reported age at onset range was 39–71 years, and symptom duration was 3–38 years. The syndrome was identified in one sibling pair, suggesting that this may be a late-onset recessive disorder, although the other 16 cases were apparently sporadic. All 18 had sensory neuropathy with absent sensory nerve action potentials, although this was not apparent clinically in 2, and the presence of neuropathy was not a selection criterion. In 5, the loss of pinprick sensation was virtually global, mimicking a neuronopathy. However, findings in the other 11 with clinically manifest neuropathy suggested a length-dependent neuropathy. MRI scans showed cerebellar atrophy in 16, involving anterior and dorsal vermis, and hemispheric crus I, while 2 were normal. The inferior vermis and brainstem were spared.
Sensory neuropathy is an integral component of this syndrome. It may result in severe sensory loss, which contributes significantly to the disability. The MRI changes are nonspecific, but, coupled with loss of sensory nerve action potentials, may aid diagnosis. We propose a new name for the condition: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Neurology® 2011;76:1903–1910
PMCID: PMC3115806  PMID: 21624989
20.  Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project 
Gerstein, Mark B. | Lu, Zhi John | Van Nostrand, Eric L. | Cheng, Chao | Arshinoff, Bradley I. | Liu, Tao | Yip, Kevin Y. | Robilotto, Rebecca | Rechtsteiner, Andreas | Ikegami, Kohta | Alves, Pedro | Chateigner, Aurelien | Perry, Marc | Morris, Mitzi | Auerbach, Raymond K. | Feng, Xin | Leng, Jing | Vielle, Anne | Niu, Wei | Rhrissorrakrai, Kahn | Agarwal, Ashish | Alexander, Roger P. | Barber, Galt | Brdlik, Cathleen M. | Brennan, Jennifer | Brouillet, Jeremy Jean | Carr, Adrian | Cheung, Ming-Sin | Clawson, Hiram | Contrino, Sergio | Dannenberg, Luke O. | Dernburg, Abby F. | Desai, Arshad | Dick, Lindsay | Dosé, Andréa C. | Du, Jiang | Egelhofer, Thea | Ercan, Sevinc | Euskirchen, Ghia | Ewing, Brent | Feingold, Elise A. | Gassmann, Reto | Good, Peter J. | Green, Phil | Gullier, Francois | Gutwein, Michelle | Guyer, Mark S. | Habegger, Lukas | Han, Ting | Henikoff, Jorja G. | Henz, Stefan R. | Hinrichs, Angie | Holster, Heather | Hyman, Tony | Iniguez, A. Leo | Janette, Judith | Jensen, Morten | Kato, Masaomi | Kent, W. James | Kephart, Ellen | Khivansara, Vishal | Khurana, Ekta | Kim, John K. | Kolasinska-Zwierz, Paulina | Lai, Eric C. | Latorre, Isabel | Leahey, Amber | Lewis, Suzanna | Lloyd, Paul | Lochovsky, Lucas | Lowdon, Rebecca F. | Lubling, Yaniv | Lyne, Rachel | MacCoss, Michael | Mackowiak, Sebastian D. | Mangone, Marco | McKay, Sheldon | Mecenas, Desirea | Merrihew, Gennifer | Miller, David M. | Muroyama, Andrew | Murray, John I. | Ooi, Siew-Loon | Pham, Hoang | Phippen, Taryn | Preston, Elicia A. | Rajewsky, Nikolaus | Rätsch, Gunnar | Rosenbaum, Heidi | Rozowsky, Joel | Rutherford, Kim | Ruzanov, Peter | Sarov, Mihail | Sasidharan, Rajkumar | Sboner, Andrea | Scheid, Paul | Segal, Eran | Shin, Hyunjin | Shou, Chong | Slack, Frank J. | Slightam, Cindie | Smith, Richard | Spencer, William C. | Stinson, E. O. | Taing, Scott | Takasaki, Teruaki | Vafeados, Dionne | Voronina, Ksenia | Wang, Guilin | Washington, Nicole L. | Whittle, Christina M. | Wu, Beijing | Yan, Koon-Kiu | Zeller, Georg | Zha, Zheng | Zhong, Mei | Zhou, Xingliang | Ahringer, Julie | Strome, Susan | Gunsalus, Kristin C. | Micklem, Gos | Liu, X. Shirley | Reinke, Valerie | Kim, Stuart K. | Hillier, LaDeana W. | Henikoff, Steven | Piano, Fabio | Snyder, Michael | Stein, Lincoln | Lieb, Jason D. | Waterston, Robert H.
Science (New York, N.Y.)  2010;330(6012):1775-1787.
We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor–binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor–binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
PMCID: PMC3142569  PMID: 21177976
21.  A Comprehensive Analysis of Gene Expression Changes Provoked by Bacterial and Fungal Infection in C. elegans 
PLoS ONE  2011;6(5):e19055.
While Caenorhabditis elegans specifically responds to infection by the up-regulation of certain genes, distinct pathogens trigger the expression of a common set of genes. We applied new methods to conduct a comprehensive and comparative study of the transcriptional response of C. elegans to bacterial and fungal infection. Using tiling arrays and/or RNA-sequencing, we have characterized the genome-wide transcriptional changes that underlie the host's response to infection by three bacterial (Serratia marcescens, Enterococcus faecalis and otorhabdus luminescens) and two fungal pathogens (Drechmeria coniospora and Harposporium sp.). We developed a flexible tool, the WormBase Converter (available at, to allow cross-study comparisons. The new data sets provided more extensive lists of differentially regulated genes than previous studies. Annotation analysis confirmed that genes commonly up-regulated by bacterial infections are related to stress responses. We found substantial overlaps between the genes regulated upon intestinal infection by the bacterial pathogens and Harposporium, and between those regulated by Harposporium and D. coniospora, which infects the epidermis. Among the fungus-regulated genes, there was a significant bias towards genes that are evolving rapidly and potentially encode small proteins. The results obtained using new methods reveal that the response to infection in C. elegans is determined by the nature of the pathogen, the site of infection and the physiological imbalance provoked by infection. They form the basis for future functional dissection of innate immune signaling. Finally, we also propose alternative methods to identify differentially regulated genes that take into account the greater variability in lowly expressed genes.
PMCID: PMC3094335  PMID: 21602919
22.  Oxaliplatin-induced coronary artery spasm: first report of an important side-effect 
BMJ Case Reports  2009;2009:bcr06.2008.0334.
A 67-year-old woman with metastatic colorectal cancer was given her first oxaliplatin infusion as part of the XELOX protocol. She developed chest pain with ECG changes leading subsequently to a diagnosis of coronary artery spasm. To our knowledge, this is the first report of oxaliplatin-induced coronary artery spasm.
PMCID: PMC3028146  PMID: 21686854
23.  A Negative Regulatory Loop between MicroRNA and Hox Gene Controls Posterior Identities in Caenorhabditis elegans 
PLoS Genetics  2010;6(9):e1001089.
MicroRNAs (miRNAs) have been found to regulate gene expression across eukaryotic species, but the function of most miRNA genes remains unknown. Here we describe how the analysis of the expression patterns of a well-conserved miRNA gene, mir-57, at cellular resolution for every minute during early development of Caenorhabditis elegans provided key insights in understanding its function. Remarkably, mir-57 expression shows strong positional bias but little tissue specificity, a pattern reminiscent of Hox gene function. Despite the minor defects produced by a loss of function mutation, overexpression of mir-57 causes dramatic posterior defects, which also mimic the phenotypes of mutant alleles of a posterior Hox gene, nob-1, an Abd homolog. More importantly, nob-1 expression is found in the same two posterior AB sublineages as those expressing mir-57 but with an earlier onset. Intriguingly, nob-1 functions as an activator for mir-57 expression; it is also a direct target of mir-57. In agreement with this, loss of mir-57 function partially rescues the nob-1 allele defects, indicating a negative feedback regulatory loop between the miRNA and Hox gene to provide positional cues. Given the conservation of the miRNA and Hox gene, the regulatory mechanism might be broadly used across species. The strategy used here to explore mir-57 function provides a path to dissect the regulatory relationship between genes.
Author Summary
miRNAs are small RNAs found in many multi-cellular species that inhibit gene expression. Many of them play important roles in cancer and cell fate determination, but the function of most miRNAs is uncertain. Using live cell imaging and automated expression analysis, we found a miRNA gene, mir-57, is expressed in a position rather than tissue dependent way. Hox genes also regulate cell fate patterning along anterior-posterior (a-p) axis across different tissues. By investigating interactions between genes of these classes expressed in mir-57 expressing cells, we demonstrated by both genetic analysis and gene expression assays that a negative feedback loop between a posterior Hox gene, nob-1, and mir-57 regulates posterior cell fate determination in C. elegans. On the one hand, the Hox gene is required for normal activation of mir-57 expression, and on the other, the Hox gene functions as a direct target of and is repressed by the miRNA. Given the conservation of the two genes, a negative feedback loop between Hox and miRNA genes might be broadly used across species to regulate cell fate along the a-p axis. Detailed expression analysis may provide a general way to dissect the regulatory role of miRNAs.
PMCID: PMC2932687  PMID: 20824072
24.  Comparison and calibration of transcriptome data from RNA-Seq and tiling arrays 
BMC Genomics  2010;11:383.
Tiling arrays have been the tool of choice for probing an organism's transcriptome without prior assumptions about the transcribed regions, but RNA-Seq is becoming a viable alternative as the costs of sequencing continue to decrease. Understanding the relative merits of these technologies will help researchers select the appropriate technology for their needs.
Here, we compare these two platforms using a matched sample of poly(A)-enriched RNA isolated from the second larval stage of C. elegans. We find that the raw signals from these two technologies are reasonably well correlated but that RNA-Seq outperforms tiling arrays in several respects, notably in exon boundary detection and dynamic range of expression. By exploring the accuracy of sequencing as a function of depth of coverage, we found that about 4 million reads are required to match the sensitivity of two tiling array replicates. The effects of cross-hybridization were analyzed using a "nearest neighbor" classifier applied to array probes; we describe a method for determining potential "black list" regions whose signals are unreliable. Finally, we propose a strategy for using RNA-Seq data as a gold standard set to calibrate tiling array data. All tiling array and RNA-Seq data sets have been submitted to the modENCODE Data Coordinating Center.
Tiling arrays effectively detect transcript expression levels at a low cost for many species while RNA-Seq provides greater accuracy in several regards. Researchers will need to carefully select the technology appropriate to the biological investigations they are undertaking. It will also be important to reconsider a comparison such as ours as sequencing technologies continue to evolve.
PMCID: PMC3091629  PMID: 20565764
25.  Improved Discrimination of Visual Stimuli Following Repetitive Transcranial Magnetic Stimulation 
PLoS ONE  2010;5(4):e10354.
Repetitive transcranial magnetic stimulation (rTMS) at certain frequencies increases thresholds for motor-evoked potentials and phosphenes following stimulation of cortex. Consequently rTMS is often assumed to introduce a “virtual lesion” in stimulated brain regions, with correspondingly diminished behavioral performance.
Methodology/Principal Findings
Here we investigated the effects of rTMS to visual cortex on subjects' ability to perform visual psychophysical tasks. Contrary to expectations of a visual deficit, we find that rTMS often improves the discrimination of visual features. For coarse orientation tasks, discrimination of a static stimulus improved consistently following theta-burst stimulation of the occipital lobe. Using a reaction-time task, we found that these improvements occurred throughout the visual field and lasted beyond one hour post-rTMS. Low-frequency (1 Hz) stimulation yielded similar improvements. In contrast, we did not find consistent effects of rTMS on performance in a fine orientation discrimination task.
Overall our results suggest that rTMS generally improves or has no effect on visual acuity, with the nature of the effect depending on the type of stimulation and the task. We interpret our results in the context of an ideal-observer model of visual perception.
PMCID: PMC2860988  PMID: 20442776

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