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1.  Aspirin Use Associated With Amyotrophic Lateral Sclerosis: a Total Population-Based Case-Control Study 
Journal of Epidemiology  2015;25(2):172-177.
The association of aspirin use and nonsteroid anti-inflammatory drug (NSAID) use with amyotrophic lateral sclerosis (ALS) risk is unclear. This study determined whether use of any individual compound is associated with ALS risk by conducting a total population-based case-control study in Taiwan.
A total of 729 patients with newly diagnosed ALS who had a severely disabling disease certificate between January 1, 2002, and December 1, 2008, comprised the case group. These cases were compared with 7290 sex-, age-, residence-, and insurance premium-matched controls. Drug use by each Anatomical Therapeutic Chemical code was analyzed using conditional logistic regression models. False discovery rate (FDR)-adjusted P values were reported in order to avoid inflating false positives.
Of the 1336 compounds, only the 266 with use cases exceeding 30 in our database were included in the screening analysis. Without controlling for steroid use, the analysis failed to reveal any compound that was inversely associated with ALS risk according to FDR criteria. After controlling for steroid use, we found use of the following compounds to be associated with ALS risk: aspirin, diphenhydramine (one of the antihistamines), and mefenamic acid (one of the NSAIDs). A multivariate analysis revealed that aspirin was independently inversely associated with ALS risk after controlling for diphenhydramine, mefenamic acid, and steroid use. The inverse association between aspirin and ALS was present predominately in patients older than 55 years.
The results of this study suggested that aspirin use might reduce the risk of ALS, and the benefit might be more prominent for older people.
PMCID: PMC4310879
amyotrophic lateral sclerosis; aspirin; case-control study
2.  Federal Regulation of Unapproved Chelation Products 
Journal of Medical Toxicology  2013;9(4):313-317.
Chelation products can be helpful in the treatment of metal poisoning. However, many unapproved products with unproven effectiveness and safety are marketed to consumers, frequently via the internet. This paper describes the primary responsibility of the Health Fraud and Consumer Outreach Branch of the United States Food and Drug Administration to identify and address health fraud products. Efforts to prevent direct and indirect hazards to the population’s health through regulatory actions are described.
PMCID: PMC3846963  PMID: 24197664
Chelation products; FDA; Health fraud; FD&C Act; Federal regulatory action
3.  Differential expression of mGluR2 in the developing cerebral cortex of the mouse 
Glutamatergic synaptic transmission is an essential component of neural circuits in the central nervous system. Glutamate exerts its effects by binding to various types of glutamate receptors, which are found distributed on neurons throughout the central nervous system. These receptors are broadly classified into two main groups, ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). Unlike iGluRs, the mGluRs are G-protein coupled receptors that exert their effects on postsynaptic membrane conductance indirectly through the downstream modification of ion channels. A subtype of mGluRs, the Group II mGluRs, are particularly interesting since their activation by glutamate results in a hyperpolarizing response. Thus, glutamate can act potentially as an inhibitory neurotransmitter, by binding to postsynaptic Group II mGluRs. Given the potential importance of these receptors in synaptic processing, the development of the central nervous system, and neurological disorders, we sought to characterize the expression of mGluR2 in the developing neocortex of the mouse. Therefore, we examined the distribution of mGluR2 in the developing cerebral cortex. We found a general caudal to rostral gradient in the expression of these receptors, with ventral cortical regions labeled caudally and dorsal regions labeled rostrally. Limbic regions highly expressed mGluR2 throughout the brain, as did sensory and motor cortical areas. Finally, other non-cortical structures, such as the thalamic reticular nucleus, amygdala, and mammillary bodies were found to have significant expression of the receptor. These results suggest that mGluR2 may play important roles in mediating glutamatergic inhibition in these structures and also could have a role in shaping the development of mature neural networks in the forebrain.
PMCID: PMC4235154  PMID: 25414764
metabotropic glutamate receptor; mouse; cortex; mGluR2; Group II mGluR
4.  Functional convergence of thalamic and intrinsic projections to cortical layers 4 and 6 
Neurophysiology  2013;45(5-6):396-406.
Ascending sensory information is conveyed from the thalamus to layers 4 and 6 of sensory cortical areas. Interestingly, receptive field properties of cortical layer 6 neurons are different from those in layer 4. Do such differences reflect distinct inheritance patterns from the thalamus or are they derived instead from local cortical circuits? To distinguish between these possibilities, we utilized in vitro slice preparations containing the thalamocortical pathways in the auditory and somatosensory systems. Responses from neurons in layers 4 and 6 that resided in the same column were recorded using whole-cell patch clamp. Laser-scanning photostimulation via uncaging of glutamate in the thalamus and cortex was used to map the functional topography of thalamocortical and intracortical inputs to each layer. In addition, we assessed the functional divergence of thalamocortical inputs by optical imaging of flavoprotein autofluorescence. We found that the thalamocortical inputs to layers 4 and 6 originated from the same thalamic domain, but the intracortical projections to the same neurons differed dramatically. Our results suggest that the intracortical projections, rather than the thalamic inputs, to each layer contribute more to the differences in their receptive field properties.
PMCID: PMC3928022  PMID: 24563558
5.  The ecological dichotomy of ammonia-oxidizing archaea and bacteria in the hyper-arid soils of the Antarctic Dry Valleys 
The McMurdo Dry Valleys of Antarctica are considered to be one of the most physically and chemically extreme terrestrial environments on the Earth. However, little is known about the organisms involved in nitrogen transformations in these environments. In this study, we investigated the diversity and abundance of ammonia-oxidizing archaea (AOA) and bacteria (AOB) in four McMurdo Dry Valleys with highly variable soil geochemical properties and climatic conditions: Miers Valley, Upper Wright Valley, Beacon Valley and Battleship Promontory. The bacterial communities of these four Dry Valleys have been examined previously, and the results suggested that the extremely localized bacterial diversities are likely driven by the disparate physicochemical conditions associated with these locations. Here we showed that AOB and AOA amoA gene diversity was generally low; only four AOA and three AOB operational taxonomic units (OTUs) were identified from a total of 420 AOA and AOB amoA clones. Quantitative PCR analysis of amoA genes revealed clear differences in the relative abundances of AOA and AOB amoA genes among samples from the four dry valleys. Although AOB amoA gene dominated the ammonia-oxidizing community in soils from Miers Valley and Battleship Promontory, AOA amoA gene were more abundant in samples from Upper Wright and Beacon Valleys, where the environmental conditions are considerably harsher (e.g., extremely low soil C/N ratios and much higher soil electrical conductivity). Correlations between environmental variables and amoA genes copy numbers, as examined by redundancy analysis (RDA), revealed that higher AOA/AOB ratios were closely related to soils with high salts and Cu contents and low pH. Our findings hint at a dichotomized distribution of AOA and AOB within the Dry Valleys, potentially driven by environmental constraints.
PMCID: PMC4179728  PMID: 25324835
archaea; AOA; bacteria; AOB; ammonia oxidizers; Antarctica; Dry Valleys
6.  ROS1 Immunohistochemistry for Detection of ROS1-Rearranged Lung Adenocarcinomas 
The American journal of surgical pathology  2013;37(9):10.1097/PAS.0b013e3182960fa7.
ROS1 gene rearrangements are reported in 1–2% of lung adenocarcinomas (ACA) and are associated with response to the multitargeted tyrosine kinase inhibitor, crizotinib. ROS1 rearrangements can be detected using fluorescence in situ hybridization (FISH) however immunohistochemistry (IHC) for ROS1 protein is a promising alternate screening modality. In this study we examine the correlation between ROS1 IHC and FISH and describe the clinicopathologic characteristics of ROS1-rearranged lung tumors. ROS1 IHC was performed using clone D4D6 (Cell Signaling Technology, Danvers, MA) on whole tissue sections. In a validation cohort, IHC was compared to ROS1 break-apart FISH in 53 cases of lung ACA enriched for an absence of known genetic alterations and never-smoking status. In a screening cohort, we performed ROS1 IHC on 167 consecutive cases of lung ACA from a routine molecular diagnostics practice and confirmed positive results by FISH. In the validation cohort, 6 cases (11%) were both FISH and IHC positive. One FISH-negative case was strongly ROS1 IHC positive. All IHC negative cases were FISH negative. In the screening cohort, 2 of 167 (1.2%) had strong, diffuse ROS1 protein expression; a rearrangement was confirmed by FISH in both. ROS1-translocated tumors were wild type for EGFR, KRAS, and ALK and commonly had solid growth with mucinous/cribriform features and psammomatous calcification. ROS1 protein expression in tumor cells is 100% sensitive and 92% specific for ROS1 rearrangements by FISH. ROS1 IHC is an effective screening tool for this rare but clinically important subset of lung ACA.
PMCID: PMC3831351  PMID: 23887156
ROS1; lung adenocarcinoma; immunohistochemistry
7.  The Distribution and Identity of Edaphic Fungi in the McMurdo Dry Valleys 
Biology  2014;3(3):466-483.
Contrary to earlier assumptions, molecular evidence has demonstrated the presence of diverse and localized soil bacterial communities in the McMurdo Dry Valleys of Antarctica. Meanwhile, it remains unclear whether fungal signals so far detected in Dry Valley soils using both culture-based and molecular techniques represent adapted and ecologically active biomass or spores transported by wind. Through a systematic and quantitative molecular survey, we identified significant heterogeneities in soil fungal communities across the Dry Valleys that robustly correlate with heterogeneities in soil physicochemical properties. Community fingerprinting analysis and 454 pyrosequencing of the fungal ribosomal intergenic spacer region revealed different levels of heterogeneity in fungal diversity within individual Dry Valleys and a surprising abundance of Chytridiomycota species, whereas previous studies suggested that Dry Valley soils were dominated by Ascomycota and Basidiomycota. Critically, we identified significant differences in fungal community composition and structure of adjacent sites with no obvious barrier to aeolian transport between them. These findings suggest that edaphic fungi of the Antarctic Dry Valleys are adapted to local environments and represent an ecologically relevant (and possibly important) heterotrophic component of the ecosystem.
PMCID: PMC4192622  PMID: 25079129
Antarctica; fungi; Dry Valleys; soil; biogeography; microbial ecology
8.  Thalamic and cortical pathways supporting auditory processing 
Brain and language  2012;126(1):22-28.
The neural processing of auditory information engages pathways that begin initially at the cochlea and that eventually reach forebrain structures. At these higher levels, the computations necessary for extracting auditory source and identity information rely on the neuroanatomical connections between the thalamus and cortex. Here, the general organization of these connections in the medial geniculate body (thalamus) and the auditory cortex is reviewed. In addition, we consider two models organizing the thalamocortical pathways of the non-tonotopic and multimodal auditory nuclei. Overall, the transfer of information to the cortex via the thalamocortical pathways is complemented by the numerous intracortical and corticocortical pathways. Although interrelated, the convergent interactions among thalamocortical, corticocortical, and commissural pathways enable the computations necessary for the emergence of higher auditory perception.
PMCID: PMC3483386  PMID: 22728130
thalamus; cortex; medial geniculate body; auditory; thalamocortical; corticocortical; commissural
10.  Diverse mechanisms of somatic structural variations in human cancer genomes 
Cell  2013;153(4):919-929.
Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten tumor types. We characterize the relative contributions of different types of rearrangements and their mutational mechanisms, find that ~20% of the somatic deletions are complex deletions formed by replication errors, and describe the differences between the mutational mechanisms in somatic and germline alterations. Importantly, we provide detailed reconstructions of the events responsible for loss of CDKN2A/B and gain of EGFR in glioblastoma, revealing that these alterations can result from multiple mechanisms even in a single genome and that both DNA double-strand breaks and replication errors drive somatic rearrangements.
PMCID: PMC3704973  PMID: 23663786
11.  Methanol oxidation by temperate soils and environmental determinants of associated methylotrophs 
The ISME Journal  2012;7(5):1051-1064.
The role of soil methylotrophs in methanol exchange with the atmosphere has been widely overlooked. Methanol can be derived from plant polymers and be consumed by soil microbial communities. In the current study, methanol-utilizing methylotrophs of 14 aerated soils were examined to resolve their comparative diversities and capacities to utilize ambient concentrations of methanol. Abundances of cultivable methylotrophs ranged from 106–108 gsoilDW−1. Methanol dissimilation was measured based on conversion of supplemented 14C-methanol, and occurred at concentrations down to 0.002 μmol methanol gsoilDW−1. Tested soils exhibited specific affinities to methanol (a0s=0.01 d−1) that were similar to those of other environments suggesting that methylotrophs with similar affinities were present. Two deep-branching alphaproteobacterial genotypes of mch responded to the addition of ambient concentrations of methanol (⩽0.6 μmol methanol gsoilDW−1) in one of these soils. Methylotroph community structures were assessed by amplicon pyrosequencing of genes of mono carbon metabolism (mxaF, mch and fae). Alphaproteobacteria-affiliated genotypes were predominant in all investigated soils, and the occurrence of novel genotypes indicated a hitherto unveiled diversity of methylotrophs. Correlations between vegetation type, soil pH and methylotroph community structure suggested that plant–methylotroph interactions were determinative for soil methylotrophs.
PMCID: PMC3635236  PMID: 23254514
aerated soil; amplicon pyrosequencing; mxaF; mch; fae; Michaelis–Menten kinetics
12.  The zebrafish reference genome sequence and its relationship to the human genome 
Howe, Kerstin | Clark, Matthew D. | Torroja, Carlos F. | Torrance, James | Berthelot, Camille | Muffato, Matthieu | Collins, John E. | Humphray, Sean | McLaren, Karen | Matthews, Lucy | McLaren, Stuart | Sealy, Ian | Caccamo, Mario | Churcher, Carol | Scott, Carol | Barrett, Jeffrey C. | Koch, Romke | Rauch, Gerd-Jörg | White, Simon | Chow, William | Kilian, Britt | Quintais, Leonor T. | Guerra-Assunção, José A. | Zhou, Yi | Gu, Yong | Yen, Jennifer | Vogel, Jan-Hinnerk | Eyre, Tina | Redmond, Seth | Banerjee, Ruby | Chi, Jianxiang | Fu, Beiyuan | Langley, Elizabeth | Maguire, Sean F. | Laird, Gavin K. | Lloyd, David | Kenyon, Emma | Donaldson, Sarah | Sehra, Harminder | Almeida-King, Jeff | Loveland, Jane | Trevanion, Stephen | Jones, Matt | Quail, Mike | Willey, Dave | Hunt, Adrienne | Burton, John | Sims, Sarah | McLay, Kirsten | Plumb, Bob | Davis, Joy | Clee, Chris | Oliver, Karen | Clark, Richard | Riddle, Clare | Eliott, David | Threadgold, Glen | Harden, Glenn | Ware, Darren | Mortimer, Beverly | Kerry, Giselle | Heath, Paul | Phillimore, Benjamin | Tracey, Alan | Corby, Nicole | Dunn, Matthew | Johnson, Christopher | Wood, Jonathan | Clark, Susan | Pelan, Sarah | Griffiths, Guy | Smith, Michelle | Glithero, Rebecca | Howden, Philip | Barker, Nicholas | Stevens, Christopher | Harley, Joanna | Holt, Karen | Panagiotidis, Georgios | Lovell, Jamieson | Beasley, Helen | Henderson, Carl | Gordon, Daria | Auger, Katherine | Wright, Deborah | Collins, Joanna | Raisen, Claire | Dyer, Lauren | Leung, Kenric | Robertson, Lauren | Ambridge, Kirsty | Leongamornlert, Daniel | McGuire, Sarah | Gilderthorp, Ruth | Griffiths, Coline | Manthravadi, Deepa | Nichol, Sarah | Barker, Gary | Whitehead, Siobhan | Kay, Michael | Brown, Jacqueline | Murnane, Clare | Gray, Emma | Humphries, Matthew | Sycamore, Neil | Barker, Darren | Saunders, David | Wallis, Justene | Babbage, Anne | Hammond, Sian | Mashreghi-Mohammadi, Maryam | Barr, Lucy | Martin, Sancha | Wray, Paul | Ellington, Andrew | Matthews, Nicholas | Ellwood, Matthew | Woodmansey, Rebecca | Clark, Graham | Cooper, James | Tromans, Anthony | Grafham, Darren | Skuce, Carl | Pandian, Richard | Andrews, Robert | Harrison, Elliot | Kimberley, Andrew | Garnett, Jane | Fosker, Nigel | Hall, Rebekah | Garner, Patrick | Kelly, Daniel | Bird, Christine | Palmer, Sophie | Gehring, Ines | Berger, Andrea | Dooley, Christopher M. | Ersan-Ürün, Zübeyde | Eser, Cigdem | Geiger, Horst | Geisler, Maria | Karotki, Lena | Kirn, Anette | Konantz, Judith | Konantz, Martina | Oberländer, Martina | Rudolph-Geiger, Silke | Teucke, Mathias | Osoegawa, Kazutoyo | Zhu, Baoli | Rapp, Amanda | Widaa, Sara | Langford, Cordelia | Yang, Fengtang | Carter, Nigel P. | Harrow, Jennifer | Ning, Zemin | Herrero, Javier | Searle, Steve M. J. | Enright, Anton | Geisler, Robert | Plasterk, Ronald H. A. | Lee, Charles | Westerfield, Monte | de Jong, Pieter J. | Zon, Leonard I. | Postlethwait, John H. | Nüsslein-Volhard, Christiane | Hubbard, Tim J. P. | Crollius, Hugues Roest | Rogers, Jane | Stemple, Derek L.
Nature  2013;496(7446):498-503.
Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3–5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
PMCID: PMC3703927  PMID: 23594743
13.  Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility 
Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focused almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs).
To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma-susceptibility variants at these loci.
We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20,092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT-CNV.
Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In 6 instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried 6 asthma-candidate CNVs (range 1–29). However, the vast majority of identified CNVs were of rare frequency (< 5%), and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma.
Although a substantial proportion of asthma-susceptibility genes harbor polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma-associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.
PMCID: PMC3609036  PMID: 23517041
14.  Laser-scanning photostimulation of optogenetically targeted forebrain circuits 
The sensory forebrain is composed of intricately connected cell types, of which functional properties have yet to be fully elucidated. Understanding the interactions of these forebrain circuits has been aided recently by the development of optogenetic methods for light-mediated modulation of neuronal activity. Here, we describe a protocol for examining the functional organization of forebrain circuits in vitro using laser-scanning photostimulation of channelrhodopsin, expressed optogenetically via viral-mediated transfection. This approach also exploits the utility of cre-lox recombination in transgenic mice to target expression in specific neuronal cell types. Following transfection, neurons are physiologically recorded in slice preparations using whole-cell patch clamp to measure their evoked responses to laser-scanning photostimulation of channelrhodopsin expressing fibers. This approach enables an assessment of functional topography and synaptic properties. Morphological correlates can be obtained by imaging the neuroanatomical expression of channelrhodopsin expressing fibers using confocal microscopy of the live slice or post-fixed tissue. These methods enable functional investigations of forebrain circuits that expand upon more conventional approaches.
PMCID: PMC3966657  PMID: 24430760
optogenetics; cortex; thalamus; channelrhodopsin; photostimulation; auditory; visual; somatosensory
15.  Frequency transformation in the auditory lemniscal thalamocortical system 
The auditory lemniscal thalamocortical (TC) pathway conveys information from the ventral division of the medial geniculate body to the primary auditory cortex (A1). Although their general topographic organization has been well characterized, functional transformations at the lemniscal TC synapse still remain incompletely codified, largely due to the need for integration of functional anatomical results with the variability observed with various animal models and experimental techniques. In this review, we discuss these issues with classical approaches, such as in vivo extracellular recordings and tracer injections to physiologically identified areas in A1, and then compare these studies with modern approaches, such as in vivo two-photon calcium imaging, in vivo whole-cell recordings, optogenetic methods, and in vitro methods using slice preparations. A surprising finding from a comparison of classical and modern approaches is the similar degree of convergence from thalamic neurons to single A1 neurons and clusters of A1 neurons, although, thalamic convergence to single A1 neurons is more restricted from areas within putative thalamic frequency lamina. These comparisons suggest that frequency convergence from thalamic input to A1 is functionally limited. Finally, we consider synaptic organization of TC projections and future directions for research.
PMCID: PMC4086294  PMID: 25071456
tonotopy; receptive field; tracer injections; laser-scanning photostimulation; calcium imaging; optogenetics; whole-cell recording; brain slice
16.  Expression and Characterization of Coprothermobacter proteolyticus Alkaline Serine Protease 
The Scientific World Journal  2013;2013:396156.
A putative protease gene (aprE) from the thermophilic bacterium Coprothermobacter proteolyticus was cloned and expressed in Bacillus subtilis. The enzyme was determined to be a serine protease based on inhibition by PMSF. Biochemical characterization demonstrated that the enzyme had optimal activity under alkaline conditions (pH 8–10). In addition, the enzyme had an elevated optimum temperature (60°C). The protease was also stable in the presence of many surfactants and oxidant. Thus, the C. proteolyticus protease has potential applications in industries such as the detergent market.
PMCID: PMC3886229  PMID: 24453843
17.  Underlying Cause and Place of Death Among Patients With Amyotrophic Lateral Sclerosis in Taiwan: A Population-Based Study, 2003–2008 
Journal of Epidemiology  2013;23(6):424-428.
Few studies have assessed cause of death among patients with amyotrophic lateral sclerosis (ALS). We investigated underlying cause and place of death among patients with ALS in Taiwan during 2003–2008.
The data source was the Taiwan National Health Insurance database for the period 2003–2008. In total, 751 patients older than 15 years with a primary diagnosis of ALS were included and followed until 2008 in the national mortality database. Crude mortality rates (per 100 person-years) and standardized mortality ratios (SMRs) were calculated in relation to cause of death, sex, and age group (15–44, 45–64, 65+ years).
In total, 297 (39.6%) patients died during the follow-up period, an age- and sex-standardized mortality rate 13 times (95% CI, 10.6–15.6) that of the Taiwanese general population. The leading cause of death among the patients was respiratory diseases, and the second most frequent cause was cardiovascular diseases. During the first year after an ALS diagnosis, suicide was much more frequent (SMR, 6.9; 95% CI, 1.9–17.6) than among the general population.
During 2003–2008, respiratory diseases and cardiovascular diseases were the most frequent causes of death among Taiwanese patients with ALS. In addition, our findings indicate that suicide prevention is an urgent priority during the period soon after an ALS diagnosis.
PMCID: PMC3834279  PMID: 23933623
amyotrophic lateral sclerosis; cause of death; respiratory disease; suicide
18.  Congenital Diaphragmatic Hernia Interval on Chromosome 8p23.1 Characterized by Genetics and Protein Interaction Networks 
Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n =18) or a gain (n =1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein–protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5–12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks.
PMCID: PMC3761361  PMID: 23165946
congenital diaphragmatic hernia; congenital heart defect; DNA copy number variants; deletion 8p23 1; duplication 8p23 1; CNVConnect; GATA4; SOX7; NEIL2
19.  Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma 
PLoS Genetics  2013;9(8):e1003727.
Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS – identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer.
Author Summary
Cancer is a complex genetic disease that is often associated with regional gains and losses of genomic DNA segments. These changes result in aberrant gene expression and drive continued tumor growth. Because amplified and deleted DNA segments tend to span large regions of chromosomes, it has been challenging to identify the genes that are required for continued tumor growth and progression. Array comparative genomic hybridization (array CGH) is an effective technology in identifying abnormal copy number variations in cancer genomes. In this study, array CGH was used in a zebrafish model of embryonal rhabdomyosarcoma - a pediatric muscle tumor. Our work shows that the zebrafish cancer genome contains a small number of recurrent DNA copy number changes, which are also commonly amplified in the human disease. Moreover, these chromosomal regions are small, facilitating rapid identification of candidate oncogenes. A subset of genes identified in zebrafish array CGH was prioritized for functional characterization in human ERMS, identifying evolutionarily conserved pathways that regulate proliferation, migration, differentiation, and neovascularization. Our results demonstrate the broad utility of cross-species array CGH comparisons of human and zebrafish cancer and provide a much needed discovery platform for identifying critical cancer-causing genes in a wide range of malignancies.
PMCID: PMC3757044  PMID: 24009521
20.  Intracortical convergence of layer 6 neurons 
Neuroreport  2012;23(12):736-740.
Axonal branches from a subset of neurons in cerebral cortical layer 6 innervate both cortical layer 4 and the thalamus. As such, these neurons are poised to modulate thalamocortical transmission at multiple forebrain sites. Here, we examined the functional organization of the layer 6 intracortical projections in auditory, somatosensory and visual cortical areas using an optogenetic approach to specifically target these neurons. We characterized the anatomical and physiological organization of these projections using laser-scanning photostimulation to functionally map the elicited postsynaptic responses in layer 4. We found that these responses originated from regions over 1 mm in width, eliciting short-term facilitating responses. These results indicate that intracortical modulation of layer 4 occurs via widespread layer 6 projections in each sensory cortical area.
PMCID: PMC3462588  PMID: 22776905
cortex; thalamus; layer 6; layer 4; optogenetics; cre-lox recombination; auditory; somatosensory; visual
21.  Diffuse flow environments within basalt- and sediment-based hydrothermal vent ecosystems harbor specialized microbial communities 
Hydrothermal vents differ both in surface input and subsurface geochemistry. The effects of these differences on their microbial communities are not clear. Here, we investigated both alpha and beta diversity of diffuse flow-associated microbial communities emanating from vents at a basalt-based hydrothermal system along the East Pacific Rise (EPR) and a sediment-based hydrothermal system, Guaymas Basin. Both Bacteria and Archaea were targeted using high throughput 16S rRNA gene pyrosequencing analyses. A unique aspect of this study was the use of a universal set of 16S rRNA gene primers to characterize total and diffuse flow-specific microbial communities from varied deep-sea hydrothermal environments. Both surrounding seawater and diffuse flow water samples contained large numbers of Marine Group I (MGI) Thaumarchaea and Gammaproteobacteria taxa previously observed in deep-sea systems. However, these taxa were geographically distinct and segregated according to type of spreading center. Diffuse flow microbial community profiles were highly differentiated. In particular, EPR dominant diffuse flow taxa were most closely associated with chemolithoautotrophs, and off axis water was dominated by heterotrophic-related taxa, whereas the opposite was true for Guaymas Basin. The diversity and richness of diffuse flow-specific microbial communities were strongly correlated to the relative abundance of Epsilonproteobacteria, proximity to macrofauna, and hydrothermal system type. Archaeal diversity was higher than or equivalent to bacterial diversity in about one third of the samples. Most diffuse flow-specific communities were dominated by OTUs associated with Epsilonproteobacteria, but many of the Guaymas Basin diffuse flow samples were dominated by either OTUs within the Planctomycetes or hyperthermophilic Archaea. This study emphasizes the unique microbial communities associated with geochemically and geographically distinct hydrothermal diffuse flow environments.
PMCID: PMC3721025  PMID: 23898323
diffuse flow; microbial diversity; 16S rRNA; pyrosequencing; hydrothermal vents
22.  Multiple Sclerosis Incidence Associated with the Soil Lead and Arsenic Concentrations in Taiwan 
PLoS ONE  2013;8(6):e65911.
Few studies in the world have assessed the incidence of multiple sclerosis (MS) with soil heavy metal concentrations. We explored the association of soil heavy metal factors and the MS incidence in Taiwan.
There were 1240 new MS cases from the National Health Insurance Research Database and were verified with serious disabling disease certificates, 1997–2008. Soil heavy metal factors records included arsenic, mercury, cadmium, chromium, copper, nickel, lead and zinc in Taiwan from 1986 to 2002. Spatial regression was used to reveal the association of soil heavy metals and age- and gender-standardized incidence ratios for townships by controlling sunlight exposure hours, smoking prevalence and spatial autocorrelation.
The lead (Pb) concentration in the soil positively correlated with the township incidence; on the other hand, the arsenic (As) concentration in soil negatively correlated with the township incidence and when found together controlled each other. The positive correlation of lead (Pb) predominated in males, whereas the negative correlation of arsenic (As) in soil predominated in females.
We conclude that exposure to lead (Pb) in soil positive associated with incidence of MS in Taiwan, especially in males. Exposure to arsenic (As) in soil negative associated with MS in Taiwan, especially in females.
PMCID: PMC3684615  PMID: 23799061
23.  Exploring the role of copy number variants in human adaptation 
Trends in genetics : TIG  2012;28(6):245-257.
Over the past decade, the ubiquity of copy number variants (CNVs, the gain or loss of genomic material) in the genomes of healthy humans has become apparent. Although some of these variants are associated with disorders, a handful of studies documented an adaptive advantage conferred by CNVs. In this review, we propose that CNVs are substrates for human evolution and adaptation. We discuss the possible mechanisms and evolutionary processes in which CNVs are selected, outline the current challenges in identifying these loci, and highlight that copy number variable regions allow for the creation of novel genes that may diversify the repertoire of such genes in response to rapidly changing environments. We expect that many more adaptive CNVs will be discovered in the coming years, and we believe that these new findings will contribute to our understanding of human-specific phenotypes.
PMCID: PMC3533238  PMID: 22483647
copy number variation; adaptation; human evolution
24.  Landscape of Somatic Retrotransposition in Human Cancers 
Science (New York, N.Y.)  2012;337(6097):967-971.
Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.
PMCID: PMC3656569  PMID: 22745252
25.  Copy number variation genotyping using family information 
BMC Bioinformatics  2013;14:157.
In recent years there has been a growing interest in the role of copy number variations (CNV) in genetic diseases. Though there has been rapid development of technologies and statistical methods devoted to detection in CNVs from array data, the inherent challenges in data quality associated with most hybridization techniques remains a challenging problem in CNV association studies.
To help address these data quality issues in the context of family-based association studies, we introduce a statistical framework for the intensity-based array data that takes into account the family information for copy-number assignment. The method is an adaptation of traditional methods for modeling SNP genotype data that assume Gaussian mixture model, whereby CNV calling is performed for all family members simultaneously and leveraging within family-data to reduce CNV calls that are incompatible with Mendelian inheritance while still allowing de-novo CNVs. Applying this method to simulation studies and a genome-wide association study in asthma, we find that our approach significantly improves CNV calls accuracy, and reduces the Mendelian inconsistency rates and false positive genotype calls. The results were validated using qPCR experiments.
In conclusion, we have demonstrated that the use of family information can improve the quality of CNV calling and hopefully give more powerful association test of CNVs.
PMCID: PMC3668900  PMID: 23656838

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