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Suicide genomics

Chizuru Iwasawa, Ryota Tamura, Yuki Sugiura, Sadafumi Suzuki, Naoko Kuzumaki, Minoru Narita, Makoto Suematsu, Masaya Nakamura, Kazunari Yoshida, Masahiro Toda, Hideyuki Okano, Hiroyuki Miyoshi
Human induced pluripotent stem cells (iPSCs) hold enormous promise for regenerative medicine. The major safety concern is the tumorigenicity of transplanted cells derived from iPSCs. A potential solution would be to introduce a suicide gene into iPSCs as a safety switch. The herpes simplex virus type 1 thymidine kinase ( HSV-TK ) gene, in combination with ganciclovir, is the most widely used enzyme/prodrug suicide system from basic research to clinical applications. In the present study, we attempted to establish human iPSCs that stably expressed HSV-TK with either lentiviral vectors or CRISPR/Cas9-mediated genome editing...
February 14, 2019: International Journal of Molecular Sciences
Leslie A Brick, Marisa E Marraccini, Lauren Micalizzi, Chelsie E Benca-Bachman, Valerie S Knopik, Rohan H C Palmer
BACKGROUND: Suicide is the second leading cause of death among adolescents and young adults. Several studies have indicated significant genetic influences on suicide-related phenotypes and mounting evidence from neurobiological research has linked deficits in neurocognitive abilities to suicide phenotypes. The goal of the present study was to estimate the heritability of suicidal ideation (SI) in a large sample of adolescents and determine if SI is genetically correlated with neurocognitive functioning...
February 6, 2019: Journal of Affective Disorders
Rona J Strawbridge, Joey Ward, Amy Ferguson, Nicholas Graham, Richard J Shaw, Breda Cullen, Robert Pearsall, Laura M Lyall, Keira J A Johnston, Claire L Niedzwiedz, Jill P Pell, Daniel Mackay, Julie Langan Martin, Donald M Lyall, Mark E S Bailey, Daniel J Smith
BACKGROUND: Suicide is a major issue for global public health. Suicidality describes a broad spectrum of thoughts and behaviours, some of which are common in the general population. Although suicide results from a complex interaction of multiple social and psychological factors, predisposition to suicidality is at least partly genetic. METHODS: Ordinal genome-wide association study of suicidality in the UK Biobank cohort comparing: 'no suicidality' controls (N = 83,557); 'thoughts that life was not worth living' (N = 21,063); 'ever contemplated self-harm' (N = 13,038); 'act of deliberate self-harm in the past' (N = 2498); and 'previous suicide attempt' (N = 2666)...
February 7, 2019: EBioMedicine
Dóra Tombácz, Zoltán Maróti, Tibor Kalmár, Miklós Palkovits, Michael Snyder, Zsolt Boldogkői
Suicide is one of the leading causes of mortality worldwide; it causes the death of more than one million patients each year. Suicide is a complex, multifactorial phenotype with environmental and genetic factors contributing to the risk of the forthcoming suicide. These factors first generally lead to mental disorders, such as depression, schizophrenia and bipolar disorder, which then become the direct cause of suicide. Here we present a high quality dataset (including processed BAM and VCF files) gained from the high-throughput whole-exome Illumina sequencing of 23 suicide victims - all of whom had suffered from major depressive disorder - and 21 control patients to a depth of at least 40-fold coverage in both cohorts...
February 5, 2019: Scientific Data
Nathalie Bailo, Hussein Kanaan, Elisabeth Kay, Xavier Charpentier, Patricia Doublet, Christophe Gilbert
Studying bacterial physiology and pathogenesis often requires isolation of targeted mutants. From the early days of bacterial genetics, many genetic tools have been developed to achieve this goal in a lot of bacteria species, and a major key is to be able to manipulate the targeted genome region with a minimum impact on the rest of the genome. Here, we described a two-step protocol relevant in Legionella pneumophila. This efficient two-step protocol uses the natural transformability of L. pneumophila and linear DNA fragments as substrates for recombination without the necessity of intermediate hosts to amplify targeted DNA...
2019: Methods in Molecular Biology
Qing-Ting Bu, Pin Yu, Jue Wang, Zi-Yue Li, Xin-Ai Chen, Xu-Ming Mao, Yong-Quan Li
BACKGROUND: Streptomyces chattanoogensis L10 is the industrial producer of natamycin and has been proved a highly efficient host for diverse natural products. It has an enormous potential to be developed as a versatile cell factory for production of heterologous secondary metabolites. Here we developed a genome-reduced industrial Streptomyces chassis by rational 'design-build-test' pipeline. RESULTS: To identify candidate large non-essential genomic regions accurately and design large deletion rationally, we performed genome analyses of S...
January 28, 2019: Microbial Cell Factories
Daniel F Levey, Renato Polimanti, Zhongshan Cheng, Hang Zhou, Yaira Z Nuñez, Sonia Jain, Feng He, Xiaoying Sun, Robert J Ursano, Ronald C Kessler, Jordan W Smoller, Murray B Stein, Henry R Kranzler, Joel Gelernter
In 2015, ~800,000 people died by suicide worldwide. For every death by suicide there are as many as 25 suicide attempts, which can result in serious injury even when not fatal. Despite this large impact on morbidity and mortality, the genetic influences on suicide attempt are poorly understood. We performed a genome-wide association study (GWAS) of severity of suicide attempts to investigate genetic influences. A discovery GWAS was performed in Yale-Penn sample cohorts of European Americans (EAs, n = 2,439) and African Americans (AAs, n = 3,881)...
January 17, 2019: Translational Psychiatry
Da-Yong Lu, Peng-Peng Zhu, Hong-Ying Wu, Nagendra Sastry Yarla, Bin Xu, Jian Ding, Ting-Ren Lu
Suicide is still a major event of human mortality (2 %) worldwide. However, no magic bullet (high efficacy drug targeting suicide categories >80%) has been developed due to limitation of biological knowledge of suicide events and pharmacological progress. Influenced by complex environmental factors, social-economic conditions, diverse suicidal-associated genes/molecules, drug development grows slowly and narrow-spectra. In search of pharmaceutical options against human suicide, an accelerating pace of transition from psychoanalysis (cognitive, behavior and emotional) into psycho-morphology disciplines (genetics/image) through neurobiology study (neural-transmitter, receptors and different neural-locations) is more potential now...
January 15, 2019: Central Nervous System Agents in Medicinal Chemistry
Anna D Corts, Lynn C Thomason, Ryan T Gill, Jeffrey A Gralnick
Shewanella oneidensis MR-1 is an invaluable host for the discovery and engineering of pathways important for bioremediation of toxic and radioactive metals and understanding extracellular electron transfer. However, genetic manipulation is challenging due to the lack of genetic tools. Previously, the only reliable method used for introducing DNA into Shewanella spp. at high efficiency was bacterial conjugation, enabling transposon mutagenesis and targeted knockouts using suicide vectors for gene disruptions...
January 10, 2019: Scientific Reports
Yi Zhou, Pierre-Eric Lutz, El Chérif Ibrahim, Philippe Courtet, Eleni Tzavara, Gustavo Turecki, Raoul Belzeaux
Aberrant gene expression can contribute to brain and nervous system dysfunction that causes many psychiatric illnesses. Here, we review how transcriptomic approaches have deepened our understanding of the neurobiological underpinnings of psychiatric disorders and how they have to the identification of biomarkers for these disorders, with a focus on their relevance to suicide and suicide behaviors. We begin by providing an overview of the genetic, transcriptomic, and epigenetic factors (including non-coding RNAs) implicated in suicide and their roles in the regulation of gene expression...
December 18, 2018: Journal of Neuroscience Research
Kareem N Mohni, Sarah R Wessel, Runxiang Zhao, Andrea C Wojciechowski, Jessica W Luzwick, Hillary Layden, Brandt F Eichman, Petria S Thompson, Kavi P M Mehta, David Cortez
Abasic sites are one of the most common DNA lesions. All known abasic site repair mechanisms operate only when the damage is in double-stranded DNA. Here, we report the discovery of 5-hydroxymethylcytosine (5hmC) binding, ESC-specific (HMCES) as a sensor of abasic sites in single-stranded DNA. HMCES acts at replication forks, binds PCNA and single-stranded DNA, and generates a DNA-protein crosslink to shield abasic sites from error-prone processing. This unusual HMCES DNA-protein crosslink intermediate is resolved by proteasome-mediated degradation...
December 1, 2018: Cell
Chiara Fabbri, Siegfried Kasper, Alexander Kautzky, Lucie Bartova, Markus Dold, Joseph Zohar, Daniel Souery, Stuart Montgomery, Diego Albani, Ilaria Raimondi, Dimitris Dikeos, Dan Rujescu, Rudolf Uher, Cathryn M Lewis, Julien Mendlewicz, Alessandro Serretti
BACKGROUND: Treatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine. METHOD: A sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray...
January 2019: British Journal of Psychiatry: the Journal of Mental Science
Qin Liang, Claudio Monetti, Maria V Shutova, Eric J Neely, Sabiha Hacibekiroglu, Huijuan Yang, Christopher Kim, Puzheng Zhang, Chengjin Li, Kristina Nagy, Maria Mileikovsky, Istvan Gyongy, Hoon-Ki Sung, Andras Nagy
Human pluripotent cell lines hold enormous promise for the development of cell-based therapies. Safety, however, is a crucial prerequisite condition for clinical applications. Numerous groups have attempted to eliminate potentially harmful cells through the use of suicide genes1 , but none has quantitatively defined the safety level of transplant therapies. Here, using genome-engineering strategies, we demonstrate the protection of a suicide system from inactivation in dividing cells. We created a transcriptional link between the suicide gene herpes simplex virus thymidine kinase (HSV-TK) and a cell-division gene (CDK1); this combination is designated the safe-cell system...
November 14, 2018: Nature
Ying-Jie Yang, Raghvendra Pratap Singh, Xin Lan, Cheng-Sheng Zhang, Yue-Zhong Li, Yi-Qiang Li, Duo-Hong Sheng
Myxococcus xanthus DK1622 is a rich source of novel secondary metabolites, and it is often used as an expression host of exogenous biosynthetic gene clusters. However, the frequency of obtaining large genome-deletion variants by using traditional strategies is low, and progenies generated by homologous recombination contain irregular deletions. The present study aims to develop an efficient genome-engineering system for this bacterium based on the Cre/loxP system. We first verified the functionality of the native cre system that was integrated into the chromosome with an inducible promoter P cuoA ...
November 6, 2018: Biomolecules
Marcus Sokolowski, Jerzy Wasserman, Danuta Wasserman
Suicidal behavior (SB) has a complex etiology involving different polygenic and environmental components. Here we used an excess of significant markers (ESM) test to study gene-level associations in previous genome-wide association studies (GWAS) SNP data from a family-based sample, having medically severe suicide attempt (SA) as main outcome in the offspring. In SA without major psychiatric disorders (N = 498), a screening of 5,316 genes across the genome suggested association 17 genes (at fdr < 0...
December 2018: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Santa S Naorem, Jin Han, Stephanie Y Zhang, Junyi Zhang, Lindsey B Graham, Angelou Song, Cameron V Smith, Fariha Rashid, Huatao Guo
BACKGROUND: Transposon mutagenesis is highly valuable for bacterial genetic and genomic studies. The transposons are usually delivered into host cells through conjugation or electroporation of a suicide plasmid. However, many bacterial species cannot be efficiently conjugated or transformed for transposon saturation mutagenesis. For this reason, temperature-sensitive (ts) plasmids have also been developed for transposon mutagenesis, but prolonged incubation at high temperatures to induce ts plasmid loss can be harmful to the hosts and lead to enrichment of mutants with adaptive genetic changes...
October 24, 2018: BMC Microbiology
Hilary Coon, Todd M Darlington, Emily DiBlasi, W Brandon Callor, Elliott Ferris, Alison Fraser, Zhe Yu, Nancy William, Sujan C Das, Sheila E Crowell, Danli Chen, John S Anderson, Michael Klein, Leslie Jerominski, Dale Cannon, Andrey Shabalin, Anna Docherty, Megan Williams, Ken R Smith, Brooks Keeshin, Amanda V Bakian, Erik Christensen, Qingqin S Li, Nicola J Camp, Douglas Gray
Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of ~ 4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide...
October 23, 2018: Molecular Psychiatry
Jianli Wang, Wenjian Ma, Yuzhou Wang, Lin Lin, Tianyi Wang, Yuqian Wang, Ye Li, Xiaoyuan Wang
Pseudomonas putida KT2442, a natural producer of polyhydroxyalkanoate, spends a lot of energy and carbon sources to form flagella and pili; therefore, deleting the genes involved in the biosynthesis and assembly of flagella and pili might improve PHA productivity. In this study, two novel deletion systems were constructed in order to efficiently remove the 76 genes involved in the biosynthesis and assembly of flagella and pili in P. putida KT2442. Both systems combine suicide-plasmid-based homologous recombination and mutant lox site-specific recombination and involve three plasmids...
December 2018: Applied Microbiology and Biotechnology
Ching-Ning Huang, Wolfgang Liebl, Armin Ehrenreich
Background: Clostridium saccharobutylicum NCP 262 is a solventogenic bacterium that has been used for the industrial production of acetone, butanol, and ethanol. The lack of a genetic manipulation system for C. saccharobutylicum currently limits (i) the use of metabolic pathway engineering to improve the yield, titer, and productivity of n -butanol production by this microorganism, and (ii) functional genomics studies to better understand its physiology. Results: In this study, a marker-less deletion system was developed for C...
2018: Biotechnology for Biofuels
Domenico De Berardis, Michele Fornaro, Alessandro Valchera, Marilde Cavuto, Giampaolo Perna, Marco Di Nicola, Gianluca Serafini, Alessandro Carano, Maurizio Pompili, Federica Vellante, Laura Orsolini, Annastasia Fiengo, Antonio Ventriglio, Kim Yong-Ku, Giovanni Martinotti, Massimo Di Giannantonio, Carmine Tomasetti
Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate of a suicide every 40 s. The weightiest concern about suicidal behavior is how difficult it is for healthcare professionals to predict. However, recent evidence in genomic studies has pointed out the essential role that genetics could play in influencing person's suicide risk...
September 23, 2018: International Journal of Molecular Sciences
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