Publications by authors named "Zhuozhi Wang"

36 Publications

Identification of hub genes and their novel diagnostic and prognostic significance in pancreatic adenocarcinoma.

Cancer Biol Med 2021 Aug 17. Epub 2021 Aug 17.

Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.

Objective: The main reasons for the poor prognoses of pancreatic adenocarcinoma (PA) patients are rapid early-stage progression, advanced stage metastasis, and chemotherapy resistance. Identification of novel diagnostic and prognostic biomarkers of PA is therefore urgently needed.

Methods: Three mRNA microarray datasets were obtained from the Gene Expression Omnibus database to select differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for hub genes were performed using DAVID. Correlations between expression levels of hub genes and cancer-infiltrating immune cells were investigated by TIMER. Cox proportional hazard regression analyses were also performed. Serum hub genes were screened using the HPA platform and verified for diagnostic value using ELISAs.

Results: We identified 59 hub genes among 752 DEGs. GO analysis indicated that these 59 hub genes were mainly involved in the defense response to viruses and the type I interferon signaling pathway. We also discovered that and were associated with immune cell infiltration in the PA microenvironment. Additionally, mRNA might be used as an independent risk factor for the prognoses of PA patients. Furthermore, the protein encoded by , which exists in peripheral blood, was validated as a potential diagnostic biomarker that distinguished PA patients from healthy controls (area under the curve: 0.902, 95% confidence interval: 0.819-0.961).

Conclusions: Our study suggested that and were associated with immune cell infiltration in the PA microenvironment, while mRNA expression might be an independent risk factor for the survival prognoses of PA patients. Moreover, ELISAs indicated that serum ISG15 could be a potential novel diagnostic biomarker for PA.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0516DOI Listing
August 2021

Vanillin-bioglass cross-linked 3D porous chitosan scaffolds with strong osteopromotive and antibacterial abilities for bone tissue engineering.

Carbohydr Polym 2021 Nov 16;271:118440. Epub 2021 Jul 16.

Department of Oral and Maxillofacial Surgery, University of Iowa College of Dentistry, Iowa City, IA 52242, USA; Iowa Institute for Oral Health Research, University of Iowa College of Dentistry, Iowa City, IA 52242, USA. Electronic address:

Chitosan scaffolds crosslinked by current methods insufficiently meet the demands of bone tissue engineering applications. We developed a novel effective crosslinking technique by using the natural and safe vanillin together with bioglass microparticles to generate an antibacterial, osteoconductive, and mechanically robust 3D porous chitosan-vanillin-bioglass (CVB) scaffold. In addition to the significantly improved mechanical properties, the CVB scaffolds had high porosity (>90%) and interconnected macroporous structures. Our data suggested that the crosslinking mainly resulted from the Schiff base reactions between the aldehydes of vanillin and amines of chitosan, together with the hydrogen and ionic bonds formed within them. Importantly, the CVB scaffolds not only showed good biocompatibility, bioactivity, and strong antibacterial ability but also significantly promoted osteoblastic differentiation, mineralization in vitro, and ectopic bone formation in vivo. Thus, the CVB scaffolds hold great promise for bone tissue engineering applications based on their robust mechanical properties, osteoconductivity, and antibacterial abilities.
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http://dx.doi.org/10.1016/j.carbpol.2021.118440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353169PMC
November 2021

Enhanced oxidative removal of NO by UV/in situ Fenton: Factors, kinetics and simulation.

Sci Total Environ 2021 Jul 3;778:146202. Epub 2021 Mar 3.

School of Chemical Engineering & Technology, Hebei University of Technology, Tianjin 300130, PR China. Electronic address:

A series of experiments on the oxidative removal of NO from flue gas using a novel in situ Fenton (IF) system was performed in the presence of ultraviolet light (UV). The comparison tests revealed that the in situ Fenton system facilitated by UV (UV/IF) has a better oxidation ability of NO than that of the IF system due to the photochemical effect on the generation of oxidative species like (OH). Both of the aforementioned oxidation efficiencies were higher than that of the conventional Fenton system (CF) depending on the premix of Fe and HO solutions, which attribute to the improvement of (OH) yield and valid utilization with continuous addition of fresh reagents and UV radiation. In follow-up experiments, the effects of UV power, gas flow rate, reagent temperature, Fe/HO molar ratio, initial pH, initial concentration of NO and SO and volume fraction O and CO on the oxidative removal of NO by UV/IF method were investigated respectively. Moreover, the results of kinetic analysis indicated that NO oxidation was confirmed to have a pseudo-first-order kinetics pattern. The rate constants decreased slightly with increasing liquid temperature, and then the apparent activation energy of NO oxidation reactions in the UV/IF system was calculated as -5.62 kJ/mol by the Arrhenius equation. Furthermore, the reaction mechanism and application prospects concerning NO oxidative removal by using the UV/IF system was speculated in brief. Finally, the computational fluid dynamics (CFD) simulations revealed that the improvement of axial and radial gas hold-up would enhance the gas-liquid contact and accelerate the oxidation reactions on the interface. In addition to reasonable control of process parameters, the optimization of reactor interior structure needs to be carried out via CFD simulation and experimental validation in future research, both are favourable to promote the NO oxidation efficiency and large-scale development of this technology.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146202DOI Listing
July 2021

Influence of thermal assistance on the biodegradation of organics during food waste bio-drying: Microbial stimulation and energy assessment.

Chemosphere 2021 Jun 6;272:129875. Epub 2021 Feb 6.

School of Environmental Science & Technology, Dalian University of Technology, Dalian, 116024, Liaoning, China. Electronic address:

Recently, bio-drying was highlighted in the drying pretreatment of high-moisture organic wastes for their energy recovery. In this study, to investigate the influences of thermal assistance on microbial stimulation and energy utilization in organic degradation, thermally assisted bio-drying (TB) was conducted on food waste (FW) and was compared with conventional bio-drying (CB) and thermal drying (TD). As expected, more water was removed in TB, which exhibited no lag phenomenon and intensified microbial activity. Corresponding with the stimulated enzyme activity, more readily degradable carbohydrates, lipids and lignocellulose were decomposed in TB than those in CB, and lipid degradation generated a significant proportion of the total bio-heat generated (43.13%-45.83%). Furthermore, according to the microbial analysis (qPCR and 16S rRNA gene sequencing), Bacillus was found to be the dominant genus involved in the degradation of organics during TB and CB. In the initial phase, rather than Weissella, as in CB, Ureibacillus was notable in TB for the degradation of readily degradable substrates. In the late phase, Pseudoxanthomonas and Saccharomonospora were enriched for degrading lignocellulose. In addition, heat balance and life-cycle energy assessment demonstrated that a small amount of thermal heat (11.96%) upgraded bio-drying with high energy efficiency. Compared with the CB and TD processes, the TB trial consumed less thermal energy (0.58 MJ/kg HO) and achieved a higher energy output/input ratio (3.64). This research suggests that thermal assistance is a promising approach to enhancing FW bio-drying, which exhibits efficient drying performance and great potential for energy recovery.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129875DOI Listing
June 2021

Chlorella vulgaris cultivation in simulated wastewater for the biomass production, nutrients removal and CO fixation simultaneously.

J Environ Manage 2021 Apr 6;284:112070. Epub 2021 Feb 6.

Tianjin Key Laboratory of Clean Energy and Pollution Control, School of Energy and Environmental Engineering, Hebei University of Technology, Tianjin, 300401, PR China; School of Civil and Transportation Engineering, Hebei University of Technology, Tianjin, 300401, PR China. Electronic address:

Chlorella vulgaris (C. vulgaris) was promising microalgae to simultaneously achieve biomass production, carbon dioxide (CO) fixation, nutrients removal and proteins production especially under different conditions of CO gas and wastewaters. Results presented that maximal specific growth rate of C. vulgaris was 0.21-0.35 d and 0.33-0.43 d at 0.038% and 10% CO respectively, and corresponding maximal CO fixation rate was attended with 4.51-14.26 and 56.26-85.72 mg CO·L·d. C. vulgaris showed good wastewater removal efficiency of nitrogen and phosphorus at 10% CO with 96.12%-99.61% removal rates. Nitrogen fixation amount achieved 41.86 mg L when the initial NHCl concentration was set at 60 mg L at 10% CO. Improved total protein (25.01-365.49 mg) and amino acids (24.56-196.44 mg) contents of C. vulgaris biomass was observed with the increasing of added CO and ammonium concentrations. Moreover, the developed kinetic function of C. vulgaris growth depends on both phosphorus quota and nitrogen quota with correlation coefficient (R) ranged from 0.68 to 0.97. Computed maximal consumed nutrients concentrations (ΔC) based on Logistic function are positively related to initial NH-N concentrations, which indicated that adding ammonium could stimulate the utilization of both phosphorus and nitrogen.
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http://dx.doi.org/10.1016/j.jenvman.2021.112070DOI Listing
April 2021

Effect of downregulation of serum MMP-3 levels by traditional Chinese medicine ingredients combined with methotrexate on the progression of bone injury in patients with rheumatoid arthritis: A protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2020 Oct;99(43):e22841

College of Basic Medicine.

Background: A large number of clinical studies have confirmed that after treatment with traditional Chinese medicine components such as sinomenine (SIN), the matrix -metalloproteinase3 (MMP-3) level of patients with rheumatoid arthritis (RA) shows a significant decrease, whereas MMP-3 can be involved in degrading bone matrix in humans, so in the progression of bone and joint injury in patients with RA, serum MMP-3 can be used as an important biochemical marker. The traditional Chinese medicine components commonly used in clinical practice include total glucosides of paeony (TGP), SIN, and tripterygium glycosides, which have the characteristics of disease-modifyinganti-rheumatic drugs and non-steroidal anti-inflammatory drugs, while they can reduce the toxic side effects of methotrexate (MTX), and their combination with other drugs such as MTX and leflunomide (HWA486) has become an important regimen for the treatment of RA in clinical practice. Therefore, we designed this study protocol to evaluate the adjuvant effect of commonly used traditional Chinese medicine components combined with MTX in the treatment of osteoarticular injury in RA.

Methods: The search time was set from January 2000 to September 2020 in this study. EMBASE database, Cochrane Library, PubMed, Web of Science, Science Direct, Chinese National Knowledge Infrastructure, China Biology Medicine disc (CBM), Chinese Scientifific Journals Database (VIP), and Wanfang Database were used as search sources to select the traditional Chinese medicine components that reduce MMP-3 and use MTX in the treatment of RA. Clinical randomized controlled trials were used, and inclusion criteria and exclusion criteria were set for screening. In this study, MMP-3, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), cyclic peptide containing citrulline (CCP) and rheumatoid factor (RF) were used as the main outcomes, and the improvement of Disease Activity Score 28 (DAS28), joint bone mineral density, Clinical Disease Activity Index (CDAI), and other clinically relevant symptoms was selected as the secondary outcomes. Revman software version 5.3 was used for statistical analysis of data and risk assessment of deviation in this meta-analysis. In this study, one researcher performed study direction selection, literature inquiry, and literature download, and 2 independent reviewers performed literature data extraction and literature quality assessment. Dichotomized data are expressed as relative risk, continuous data are expressed as mean difference or standard mean difference, and finally fixed-effect model or random-effect model is used for synthesis according to the heterogeneity of data.

Results: To evaluate the effect of downregulation of MMP-3 level by traditional Chinese medicine components combined with MTX on the progression of bone injury in patients with RA by serum MMP-3, ESR, CRP, CCP, and RF.

Conclusion: This study protocol can be used to evaluate the efficacy and safety of traditional Chinese medicine components combined with MTX in the treatment of bone injury in patients with RA.

Ethics And Dissemination: This study is a secondary study based on the published clinical research; therefore, approval from an ethics committee is not required for this study. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P), the results of this study will be published in peer-reviewed scientific journals and conference papers. REGISTRATION NUMBER:: is INPLASY202090064.
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http://dx.doi.org/10.1097/MD.0000000000022841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581142PMC
October 2020

Biology drives the discovery of bispecific antibodies as innovative therapeutics.

Antib Ther 2020 Jan 17;3(1):18-62. Epub 2020 Feb 17.

WuXi Biologics, 299 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China and.

A bispecific antibody (bsAb) is able to bind two different targets or two distinct epitopes on the same target. Broadly speaking, bsAbs can include any single molecule entity containing dual specificities with at least one being antigen-binding antibody domain. Besides additive effect or synergistic effect, the most fascinating applications of bsAbs are to enable novel and often therapeutically important concepts otherwise impossible by using monoclonal antibodies alone or their combination. This so-called obligate bsAbs could open up completely new avenue for developing novel therapeutics. With evolving understanding of structural architecture of various natural or engineered antigen-binding immunoglobulin domains and the connection of different domains of an immunoglobulin molecule, and with greatly improved understanding of molecular mechanisms of many biological processes, the landscape of therapeutic bsAbs has significantly changed in recent years. As of September 2019, over 110 bsAbs are under active clinical development, and near 180 in preclinical development. In this review article, we introduce a system that classifies bsAb formats into 30 categories based on their antigen-binding domains and the presence or absence of Fc domain. We further review the biology applications of approximately 290 bsAbs currently in preclinical and clinical development, with the attempt to illustrate the principle of selecting a bispecific format to meet biology needs and selecting a bispecific molecule as a clinical development candidate by 6 critical criteria. Given the novel mechanisms of many bsAbs, the potential unknown safety risk and risk/benefit should be evaluated carefully during preclinical and clinical development stages. Nevertheless we are optimistic that next decade will witness clinical success of bsAbs or multispecific antibodies employing some novel mechanisms of action and deliver the promise as next wave of antibody-based therapeutics.
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http://dx.doi.org/10.1093/abt/tbaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990219PMC
January 2020

A functional antibody cross-reactive to both human and murine cytotoxic T-lymphocyte-associated protein 4 via binding to an N-glycosylation epitope.

MAbs 2020 Jan-Dec;12(1):1725365

Biologics Discovery, WuXi Biologics, Waigaoqiao Free Trade Zone, Shanghai, China.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, CD152) is a receptor on T cells that inhibits the cell's functions. Blocking CTLA-4 with an antibody has proven effective for the treatment of cancer patients. Anti-CTLA-4 antibodies currently approved for clinical use can bind to human CTLA-4, but do not cross-react to murine CTLA-4. Here, we report the generation and characterization of a functional humanized antibody, mAb146, against both human and murine CTLA-4. Alanine scanning of CTLA-4 using mammalian cell expression cassette identified the unique epitopes of this novel antibody. In addition to the amino acid residues interacting with ligands CD80 and CD86, an N-glycosylation site on N110, conserved in CTLA-4 of human, monkey, and mouse, was identified as the specific epitope that might contribute to the cross-species binding and function of this antibody. This finding may also contribute to the understanding of the glycosylation of CTLA-4 and its related biologic function. In addition to facilitating preclinical development of anti-CTLA-4 antibodies, mAb146 may be useful as a therapeutic agent.
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http://dx.doi.org/10.1080/19420862.2020.1725365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039627PMC
February 2021

SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons.

Nat Neurosci 2019 04 25;22(4):556-564. Epub 2019 Mar 25.

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.

Heterozygous loss-of-function mutations in SHANK2 are associated with autism spectrum disorder (ASD). We generated cortical neurons from induced pluripotent stem cells derived from neurotypic and ASD-affected donors. We developed sparse coculture for connectivity assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed increases in dendrite length, dendrite complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 mutation. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in isogenic SHANK2 neurons was perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from ASD subjects.
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http://dx.doi.org/10.1038/s41593-019-0365-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475597PMC
April 2019

Complete Disruption of Autism-Susceptibility Genes by Gene Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons.

Stem Cell Reports 2018 11 1;11(5):1211-1225. Epub 2018 Nov 1.

Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3H7, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5S 3H7, Canada. Electronic address:

Autism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNA sequencing revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory postsynaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2-, and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.
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http://dx.doi.org/10.1016/j.stemcr.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235011PMC
November 2018

Paternally inherited cis-regulatory structural variants are associated with autism.

Science 2018 04;360(6386):327-331

Department of Psychiatry, Hospital Sant Joan de Déu, Barcelona, Spain.

The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.
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http://dx.doi.org/10.1126/science.aan2261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449150PMC
April 2018

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.

CMAJ 2018 02;190(5):E126-E136

The Centre for Applied Genomics (Reuter, Walker, Thiruvahindrapuram, Whitney, Yuen, Trost, Paton, Pereira, Herbrick, Wintle, Merico, Howe, MacDonald, Lu, Nalpathamkalam, Sung, Wang, Patel, Pellecchia, J. Wei, Strug, Bell, Kellam, Mahtani, Hosseini, Fiume, Marshall, Buchanan, Scherer); Divisions of Clinical Pharmacology and Toxicology (I. Cohn), or Clinical, and Metabolic Genetics (Sondheimer, Weksberg, Shuman, Bowdin, Meyn, Monfared), The Hospital for Sick Children; Departments of Paediatrics (Sondheimer, R. Cohn) and Molecular Genetics (Yuen, Weksberg, Shuman, R. Cohn, Ellis, Meyn), University of Toronto; Deep Genomics Inc. (Merico); Department of Psychiatry (Bassett), University Health Network and Centre for Addiction and Mental Health, University of Toronto; Li Ka Shing Knowledge Institute (Bombard), St. Michael's Hospital; Institute of Health Policy, Management and Evaluation (Bombard), University of Toronto; Centre for Genetic Medicine (Stavropoulos, Bowdin, Ray, Monfared); Molecular Genetics Laboratory (Stavropoulos, Ray, Marshall), Division of Genome Diagnostics, Paediatric Laboratory Medicine; Developmental and Stem Cell Biology (Hildebrandt, W. Wei, Romm, Pasceri, Ellis); Ted Rogers Cardiac Genome Clinic (Hosseini); Cytogenetics Laboratory (Joseph-George), Division of Genome Diagnostics, Paediatric Laboratory Medicine, The Hospital for Sick Children; Departments of Biochemistry and Laboratory Medicine, and Pathobiology (Keeley), University of Toronto; DNAstack (Cook, Fiume); McLaughlin Centre (Lee, Scherer), University of Toronto; Medcan Health Management Inc. (Davies, Hazell); Dalla Lana School of Public Health (Szego), Department of Family and Community Medicine, and The Joint Centre for Bioethics, University of Toronto; Centre for Clinical Ethics (Szego), St. Joseph's Health Centre, Toronto, Ont.

Background: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers.

Methods: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant.

Results: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set ( = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual.

Interpretation: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care.
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http://dx.doi.org/10.1503/cmaj.171151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798982PMC
February 2018

A Comprehensive Workflow for Read Depth-Based Identification of Copy-Number Variation from Whole-Genome Sequence Data.

Am J Hum Genet 2018 01;102(1):142-155

The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada. Electronic address:

A remaining hurdle to whole-genome sequencing (WGS) becoming a first-tier genetic test has been accurate detection of copy-number variations (CNVs). Here, we used several datasets to empirically develop a detailed workflow for identifying germline CNVs >1 kb from short-read WGS data using read depth-based algorithms. Our workflow is comprehensive in that it addresses all stages of the CNV-detection process, including DNA library preparation, sequencing, quality control, reference mapping, and computational CNV identification. We used our workflow to detect rare, genic CNVs in individuals with autism spectrum disorder (ASD), and 120/120 such CNVs tested using orthogonal methods were successfully confirmed. We also identified 71 putative genic de novo CNVs in this cohort, which had a confirmation rate of 70%; the remainder were incorrectly identified as de novo due to false positives in the proband (7%) or parental false negatives (23%). In individuals with an ASD diagnosis in which both microarray and WGS experiments were performed, our workflow detected all clinically relevant CNVs identified by microarrays, as well as additional potentially pathogenic CNVs < 20 kb. Thus, CNVs of clinical relevance can be discovered from WGS with a detection rate exceeding microarrays, positioning WGS as a single assay for genetic variation detection.
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http://dx.doi.org/10.1016/j.ajhg.2017.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777982PMC
January 2018

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

Genet Med 2018 04 3;20(4):435-443. Epub 2017 Aug 3.

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.
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http://dx.doi.org/10.1038/gim.2017.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895460PMC
April 2018

Epitope mapping reveals the binding mechanism of a functional antibody cross-reactive to both human and murine programmed death 1.

MAbs 2017 May/Jun;9(4):628-637. Epub 2017 Feb 23.

a Biologics Discovery, WuXi Biologics , Waigaoqiao Free Trade Zone, Shanghai , China.

Of the inhibitory checkpoints in the immune system, programmed death 1 (PD-1) is one of the most promising targets for cancer immunotherapy. The anti-PD-1 antibodies currently approved for clinical use or under development bind to human PD-1 (hPD-1), but not murine PD-1. To facilitate studies in murine models, we developed a functional antibody against both human and murine PD-1, and compared the epitopes of such antibody to a counterpart that only bound to hPD-1. To quickly identify the epitopes of the 2 antibodies, we used alanine scanning and mammalian cell expression cassette. The epitope identification was based on PD-1-binding ELISA and supported by affinity ranking of surface plasmon resonance results. The hPD-1 epitopes of the 2 functional antibodies were also compared with the binding region on hPD-1 that is responsible for PD-L1 interaction. In silico modeling were conducted to explain the different binding modes of the 2 antibodies, suggesting a potential mechanism of the antibody cross-species binding.
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http://dx.doi.org/10.1080/19420862.2017.1296612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419084PMC
February 2018

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.

Nat Neurosci 2017 Apr 6;20(4):602-611. Epub 2017 Mar 6.

The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.
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http://dx.doi.org/10.1038/nn.4524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501701PMC
April 2017

Genome and Transcriptome Assembly of the Canadian Beaver ().

G3 (Bethesda) 2017 02 9;7(2):755-773. Epub 2017 Feb 9.

Department of Natural History, Royal Ontario Museum, Toronto, Ontario M5S 2C6, Canada.

The Canadian beaver () is the largest indigenous rodent in North America. We report a draft annotated assembly of the beaver genome, the first for a large rodent and the first mammalian genome assembled directly from uncorrected and moderate coverage (< 30 ×) long reads generated by single-molecule sequencing. The genome size is 2.7 Gb estimated by k-mer analysis. We assembled the beaver genome using the new Canu assembler optimized for noisy reads. The resulting assembly was refined using Pilon supported by short reads (80 ×) and checked for accuracy by congruency against an independent short read assembly. We scaffolded the assembly using the exon-gene models derived from 9805 full-length open reading frames (FL-ORFs) constructed from the beaver leukocyte and muscle transcriptomes. The final assembly comprised 22,515 contigs with an N50 of 278,680 bp and an N50-scaffold of 317,558 bp. Maximum contig and scaffold lengths were 3.3 and 4.2 Mb, respectively, with a combined scaffold length representing 92% of the estimated genome size. The completeness and accuracy of the scaffold assembly was demonstrated by the precise exon placement for 91.1% of the 9805 assembled FL-ORFs and 83.1% of the BUSCO (Benchmarking Universal Single-Copy Orthologs) gene set used to assess the quality of genome assemblies. Well-represented were genes involved in dentition and enamel deposition, defining characteristics of rodents with which the beaver is well-endowed. The study provides insights for genome assembly and an important genomics resource for Castoridae and rodent evolutionary biology.
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http://dx.doi.org/10.1534/g3.116.038208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295618PMC
February 2017

Genome-wide characteristics of mutations in autism.

NPJ Genom Med 2016 Aug;1:160271-1602710

BGI-Shenzhen, Yantian, Shenzhen, China.

mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10), but they could also be found adjacent to copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10; OR=1.84), of which 15.6% (p=4.3×10) and 22.5% (p=7.0×10) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes and Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.
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http://dx.doi.org/10.1038/npjgenmed.2016.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980121PMC
August 2016

Reversible dissolution/formation of polymer nanoparticles controlled by visible light.

Nanoscale 2016 Aug 8;8(29):14070-3. Epub 2016 Jul 8.

Department of Chemistry, Florida Institute of Technology, Melbourne, FL 32901, USA.

Noncovalent crosslinking between polyvinyl pyridine and a copolymer of acrylic acid led to the formation of a polymer nanoparticle. In the presence of a metastable-state photoacid, reversible dissolution and formation of the nanoparticle can be controlled by visible light. Photo-induced proton transfer from the photoacid to the polymers broke the hydrogen bonding and ionic bonding and led to the dissolution of the nanoparticle. Cycles of dissolution and formation were controlled by turning on and off irradiation, and were demonstrated by the transmittance change.
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http://dx.doi.org/10.1039/c6nr02163hDOI Listing
August 2016

Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing.

Nat Commun 2015 Nov 2;6:8718. Epub 2015 Nov 2.

The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.

Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.
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http://dx.doi.org/10.1038/ncomms9718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667643PMC
November 2015

Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.

JAMA 2015 Sep;314(9):895-903

Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada.

Importance: The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study.

Objective: To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic.

Design, Setting, And Participants: The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and ≥6).

Exposures: All probands underwent CMA, with WES performed for 95 proband-parent trios.

Main Outcomes And Measures: The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups.

Results: Of 258 probands, 24 (9.3%, 95%CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95%CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95%CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002). [table: see text].

Conclusions And Relevance: Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.
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http://dx.doi.org/10.1001/jama.2015.10078DOI Listing
September 2015

Clinically relevant copy number variations detected in cerebral palsy.

Nat Commun 2015 Aug 3;6:7949. Epub 2015 Aug 3.

The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4.

Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (∼1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families.
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http://dx.doi.org/10.1038/ncomms8949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532872PMC
August 2015

A high-resolution copy-number variation resource for clinical and population genetics.

Genet Med 2015 Sep 11;17(9):747-52. Epub 2014 Dec 11.

The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: Chromosomal microarray analysis to assess copy-number variation has become a first-tier genetic diagnostic test for individuals with unexplained neurodevelopmental disorders or multiple congenital anomalies. More than 100 cytogenetic laboratories worldwide use the new ultra-high resolution Affymetrix CytoScan-HD array to genotype hundreds of thousands of samples per year. Our aim was to develop a copy-number variation resource from a new population sample that would enable more accurate interpretation of clinical genetics data on this microarray platform and others.

Methods: Genotyping of 1,000 adult volunteers who are broadly representative of the Ontario population (as obtained from the Ontario Population Genomics Platform) was performed with the CytoScan-HD microarray system, which has 2.7 million probes. Four independent algorithms were applied to detect copy-number variations. Reproducibility and validation metrics were quantified using sample replicates and quantitative-polymerase chain reaction, respectively.

Results: DNA from 873 individuals passed quality control and we identified 71,178 copy-number variations (81 copy-number variations/individual); 9.8% (6,984) of these copy-number variations were previously unreported. After applying three layers of filtering criteria, from our highest confidence copy-number variation data set we obtained >95% reproducibility and >90% validation rates (73% of these copy-number variations overlapped at least one gene).

Conclusion: The genotype data and annotated copy-number variations for this largely Caucasian population will represent a valuable public resource enabling clinical genetics research and diagnostics.
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http://dx.doi.org/10.1038/gim.2014.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752593PMC
September 2015

Controlled release of fragrant molecules with visible light.

Chemistry 2014 Nov 3;20(45):14637-40. Epub 2014 Oct 3.

Department of Chemistry, Florida Institute of Technology, Melbourne, FL 32901 (USA).

Controlled release of odorous molecules is the key to digital scent technology which will add another dimension to electronics. Photorelease is a cold mechanism that promises better temporal and spatial control than thermal release. Herein we report a novel material composed of an acid-sensitive polymer carrying a fragrant aldehyde and a reversible metastable-state photoacid. It releases the fragrant molecule under visible light, and stops releasing it after the light is turned off. A metastable-state photoacid with a fast reverse-reaction rate was developed to quickly stop the release after irradiation. Both the carrier polymer and the photoacid can be reused after all the fragrant molecules have been released. The material combines the advantages of visible-light activity, fast on/off rate, easy preparation, and recyclability, and thus is promising for digital scent technology.
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http://dx.doi.org/10.1002/chem.201404203DOI Listing
November 2014

Copy number variation in Han Chinese individuals with autism spectrum disorder.

J Neurodev Disord 2014 23;6(1):34. Epub 2014 Aug 23.

The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Peter Gilgan Centre for Research and Learning, Room 139800, Toronto, Ontario M5G 0A4, Canada.

Background: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions with a demonstrated genetic etiology. Rare (<1% frequency) copy number variations (CNVs) account for a proportion of the genetic events involved, but the contribution of these events in non-European ASD populations has not been well studied. Here, we report on rare CNVs detected in a cohort of individuals with ASD of Han Chinese background.

Methods: DNA samples were obtained from 104 ASD probands and their parents who were recruited from Harbin, China. Samples were genotyped on the Affymetrix CytoScan HD platform. Rare CNVs were identified by comparing data with 873 technology-matched controls from Ontario and 1,235 additional population controls of Han Chinese ethnicity.

Results: Of the probands, 8.6% had at least 1 de novo CNV (overlapping the GIGYF2, SPRY1, 16p13.3, 16p11.2, 17p13.3-17p13.2, DMD, and NAP1L6 genes/loci). Rare inherited CNVs affected other plausible neurodevelopmental candidate genes including GRID2, LINGO2, and SLC39A12. A 24-kb duplication was also identified at YWHAE, a gene previously implicated in ASD and other developmental disorders. This duplication is observed at a similar frequency in cases and in population controls and is likely a benign Asian-specific copy number polymorphism.

Conclusions: Our findings help define genomic features relevant to ASD in the Han Chinese and emphasize the importance of using ancestry-matched controls in medical genetic interpretations.
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http://dx.doi.org/10.1186/1866-1955-6-34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147384PMC
August 2014

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.

Nat Genet 2014 Jul 25;46(7):742-7. Epub 2014 May 25.

1] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10(-38); odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10(-11); OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10(-157); OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.
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http://dx.doi.org/10.1038/ng.2980DOI Listing
July 2014

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Am J Hum Genet 2014 May 24;94(5):677-94. Epub 2014 Apr 24.

Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland; Children's University Hospital Temple Street, Dublin 1, Ireland.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067558PMC
May 2014

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

Hum Mol Genet 2014 May 30;23(10):2752-68. Epub 2013 Dec 30.

The Centre for Applied Genomics.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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http://dx.doi.org/10.1093/hmg/ddt669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990173PMC
May 2014

Visible-light-responsive reversible photoacid based on a metastable carbanion.

Chemistry 2014 Jan 6;20(3):689-92. Epub 2013 Dec 6.

Department of Chemistry, Eastern Kentucky University, Richmond, KY 40475 (USA).

A new photoacid that reversibly changes from a weak to a strong acid under visible light was designed and synthesized. Irradiation generated a metastable state with high CH acidity due to high stability of a trifluoromethyl-phenyl-tricyano-furan (CF3 PhTCF) carbanion. This long-lived metastable state allows a large proton concentration to be reversibly produced with moderate light intensity. Reversible pH change of about one unit was demonstrated by using a 0.1 mM solution of the photoacid in 95 % ethanol. The quantum yield was calculated to be as high as 0.24. Kinetics of the reverse process can be fitted well to a second-order-rate equation with k=9.78×10(2)  M(-1)  s(-1) . Response to visible light, high quantum yield, good reversibility, large photoinduced proton concentration under moderate light intensity, and good compatibility with organic media make this photoacid a promising material for macroscopic control of proton-transfer processes in organic systems.
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http://dx.doi.org/10.1002/chem.201304226DOI Listing
January 2014
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