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Synthetic genetics

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https://www.readbyqxmd.com/read/29222760/computational-prediction-of-synthetic-lethals-in-genome-scale-metabolic-models-using-fast-sl
#1
Karthik Raman, Aditya Pratapa, Omkar Mohite, Shankar Balachandran
In this chapter, we describe Fast-SL, an in silico approach to predict synthetic lethals in genome-scale metabolic models. Synthetic lethals are sets of genes or reactions where only the simultaneous removal of all genes or reactions in the set abolishes growth of an organism. In silico approaches to predict synthetic lethals are based on Flux Balance Analysis (FBA), a popular constraint-based analysis method based on linear programming. FBA has been shown to accurately predict the viability of various genome-scale metabolic models...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29222754/template-assisted-metabolic-reconstruction-and-assembly-of-hybrid-bacterial-models
#2
Tiziano Vignolini, Alessio Mengoni, Marco Fondi
Intraspecific genomic exchanges happen frequently between bacteria living in the same natural environment and can also be performed artificially in the laboratory for basic research or genetic/metabolic engineering purposes. In silico metabolic reconstruction and simulation of the metabolism of the hybrid strains that result from these processes can be used to predict the phenotypic outcome of such genomic rearrangements; this can be especially helpful as a designing tool in the purview of synthetic biology...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29222753/integration-of-comparative-genomics-with-genome-scale-metabolic-modeling-to-investigate-strain-specific-phenotypical-differences
#3
Jonathan Monk, Emanuele Bosi
Genome-scale metabolic reconstructions are powerful resources that allow translation biological knowledge and genomic information to phenotypical predictions using a number of constraint-based methods. This approach has been applied in recent years to gain deep insights into the cellular phenotype role of the genes at a systems-level, driving the design of targeted experiments and paving the way for knowledge-based synthetic biology.The identification of genetic determinants underlying the variability at the phenotypical level is crucial to understand the evolutionary trajectories of a bacterial species...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29221460/goldenpics-a-golden-gate-derived-modular-cloning-system-for-applied-synthetic-biology-in-the-yeast-pichia-pastoris
#4
Roland Prielhofer, Juan J Barrero, Stefanie Steuer, Thomas Gassler, Richard Zahrl, Kristin Baumann, Michael Sauer, Diethard Mattanovich, Brigitte Gasser, Hans Marx
BACKGROUND: State-of-the-art strain engineering techniques for the host Pichia pastoris (syn. Komagataella spp.) include overexpression of homologous and heterologous genes, and deletion of host genes. For metabolic and cell engineering purposes the simultaneous overexpression of more than one gene would often be required. Very recently, Golden Gate based libraries were adapted to optimize single expression cassettes for recombinant proteins in P. pastoris. However, an efficient toolbox allowing the overexpression of multiple genes at once was not available for P...
December 8, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/29212027/melanoma-therapeutic-strategies-that-select-against-resistance-by-exploiting-myc-driven-evolutionary-convergence
#5
Katherine R Singleton, Lorin Crawford, Elizabeth Tsui, Haley E Manchester, Ophelia Maertens, Xiaojing Liu, Maria V Liberti, Anniefer N Magpusao, Elizabeth M Stein, Jennifer P Tingley, Dennie T Frederick, Genevieve M Boland, Keith T Flaherty, Shannon J McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J Adams, Jason W Locasale, Karen Cichowski, Sayan Mukherjee, Kris C Wood
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29207308/road-maps-to-engineer-host-microbiomes
#6
REVIEW
Ben O Oyserman, Marnix H Medema, Jos M Raaijmakers
Microbiomes contribute directly or indirectly to host health and fitness. Thus far, investigations into these emergent traits, referred to here as microbiome-associated phenotypes (MAPs), have been primarily qualitative and taxonomy-driven rather than quantitative and trait-based. We present the MAPs-first approach, a theoretical and experimental roadmap that involves quantitative profiling of MAPs across genetically variable hosts and subsequent identification of the underlying mechanisms. We outline strategies for developing 'modular microbiomes'-synthetic microbial consortia that are engineered in concert with the host genotype to confer different but mutually compatible MAPs to a single host or host population...
December 2, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/29207182/antitumor-activity-of-the-synthetic-retinoid-st1926-on-primary-effusion-lymphoma-in-vitro-and-in-vivo-models
#7
Louna Karam, Bilal Houshaymi, Rana Abdel-Samad, Mariam Jaafar, Iman Halloum, Claudio Pisano, Frank Neipel, Nadine Darwiche, Raghida Abou Merhi
Primary effusion lymphoma (PEL) is a rare B-cell neoplasm, associated with Kaposi sarcoma-associated herpes virus/human herpes virus-8 (KSHV/HHV-8), arising as malignant effusions in body cavities. PEL cells do not harbor conventional genetic cancer mutations; however, their oncogenesis is mainly attributed to HHV-8 latent genes. Treatment strategies are inefficient resulting in poor prognosis of PEL patients, stressing the need for new effective therapy. ST1926 is a synthetic retinoid with favorable antitumor properties and no cross-resistance with the natural retinoid, all-trans retinoic acid...
December 5, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29205771/homoeologous-exchange-is-a-major-cause-of-gene-presence-absence-variation-in-the-amphidiploid-brassica-napus
#8
Bhavna Hurgobin, Agnieszka A Golicz, Philipp E Bayer, Chon-Kit Kenneth Chan, Soodeh Tirnaz, Aria Dolatabadian, Sarah V Schiessl, Birgit Samans, Juan D Montenegro, Isobel A P Parkin, J Chris Pires, Boulos Chalhoub, Graham J King, Rod Snowdon, Jacqueline Batley, David Edwards
Homoeologous exchanges (HEs) have been shown to generate novel gene combinations and phenotypes in a range of polyploid species. Gene presence/absence variation (PAV) is also a major contributor to genetic diversity. In the present study we show that there is an association between these two events, particularly in recent Brassica napus synthetic accessions, and that these represent a novel source of genetic diversity, which can be captured for the improvement of this important crop species. By assembling the pangenome of B...
December 4, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/29204879/reconstitution-of-membrane-tethering-mediated-by-rab-family-small-gtpases
#9
REVIEW
Joji Mima
Membrane tethering is one of the most critical steps to determine the spatiotemporal specificity of membrane trafficking, which is the process to selectively transport proteins, lipids, and other biological molecules to the appropriate locations in eukaryotic cells, such as subcellular organelles, the plasma membrane, and the extracellular space. Based on genetic, cell biological, biochemical, and structural studies, Rab-family small GTPases and a number of Rab-interacting proteins (termed Rab effectors), including coiled-coil tethering proteins and multisubunit tethering complexes, have been proposed to be key protein components for membrane tethering...
December 4, 2017: Biophysical Reviews
https://www.readbyqxmd.com/read/29203440/car-t-cells-and-combination-therapies-what-s-next-in-the-immunotherapy-revolution
#10
Maria C Ramello, Eric B Haura, Daniel Abate-Daga
Cancer immunotherapies are dramatically reshaping the clinical management of oncologic patients. For many of these therapies, the guidelines for administration, monitoring, and management of associated toxicities are still being established. This is especially relevant for adoptively transferred, genetically-modified T cells, which have unique pharmacokinetic properties, due to their ability to replicate and persist long-term, following a single administration. Furthermore, in the case of CAR-T cells, the use of synthetic immune receptors may impact signaling pathways involved in T cell function and survival in unexpected ways...
December 1, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29202468/polycomb-subunit-bmi1-determines-uterine-progesterone-responsiveness-essential-for-normal-embryo-implantation
#11
Qiliang Xin, Shuangbo Kong, Junhao Yan, Jingtao Qiu, Bo He, Chan Zhou, Zhangli Ni, Haili Bao, Lin Huang, Jinhua Lu, Guoliang Xia, Xicheng Liu, Zi-Jiang Chen, Chao Wang, Haibin Wang
Natural and synthetic progestogens have been commonly used to prevent recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity. However, the clinical efficacy of progesterone and its analogs for maintaining pregnancy is variable. Additionally, the underlying cause of impaired endometrial progesterone responsiveness during early pregnancy remains unknown. Here, we demonstrated that uterine-selective depletion of BMI1, a key component of the polycomb repressive complex-1 (PRC1), hampers uterine progesterone responsiveness and derails normal uterine receptivity, resulting in implantation failure in mice...
November 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29201859/predictable-tunable-protein-production-in-salmonella-for-studying-host-pathogen-interactions
#12
Kendal G Cooper, Audrey Chong, Tregei Starr, Ciaran E Finn, Olivia Steele-Mortimer
Here we describe the use of synthetic genetic elements to improve the predictability and tunability of episomal protein production in Salmonella. We used a multi-pronged approach, in which a series of variable-strength synthetic promoters were combined with a synthetic transcriptional terminator, and plasmid copy number variation. This yielded a series of plasmids that drive uniform production of fluorescent and endogenous proteins, over a wide dynamic range. We describe several examples where this system is used to fine-tune constitutive expression in Salmonella, providing an efficient means to titrate out toxic effects of protein production...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29201559/genomic-characterization-of-a-new-endophytic-streptomyces-kebangsaanensis-identifies-biosynthetic-pathway-gene-clusters-for-novel-phenazine-antibiotic-production
#13
Juwairiah Remali, Nurul 'Izzah Mohd Sarmin, Chyan Leong Ng, John J L Tiong, Wan M Aizat, Loke Kok Keong, Noraziah Mohamad Zin
Background: Streptomyces are well known for their capability to produce many bioactive secondary metabolites with medical and industrial importance. Here we report a novel bioactive phenazine compound, 6-((2-hydroxy-4-methoxyphenoxy) carbonyl) phenazine-1-carboxylic acid (HCPCA) extracted from Streptomyces kebangsaanensis, an endophyte isolated from the ethnomedicinal Portulaca oleracea. Methods: The HCPCA chemical structure was determined using nuclear magnetic resonance spectroscopy...
2017: PeerJ
https://www.readbyqxmd.com/read/29200199/programmable-full-adder-computations-in-communicating-three-dimensional-cell-cultures
#14
David Ausländer, Simon Ausländer, Xavier Pierrat, Leon Hellmann, Leila Rachid, Martin Fussenegger
Synthetic biologists have advanced the design of trigger-inducible gene switches and their assembly into input-programmable circuits that enable engineered human cells to perform arithmetic calculations reminiscent of electronic circuits. By designing a versatile plug-and-play molecular-computation platform, we have engineered nine different cell populations with genetic programs, each of which encodes a defined computational instruction. When assembled into 3D cultures, these engineered cell consortia execute programmable multicellular full-adder logics in response to three trigger compounds...
December 4, 2017: Nature Methods
https://www.readbyqxmd.com/read/29198740/early-transmissible-ampicillin-resistance-in-zoonotic-salmonella-enterica-serotype-typhimurium-in-the-late-1950s-a-retrospective-whole-genome-sequencing-study
#15
Alicia Tran-Dien, Simon Le Hello, Christiane Bouchier, François-Xavier Weill
BACKGROUND: Ampicillin, the first semi-synthetic penicillin active against Enterobacteriaceae, was released onto the market in 1961. The first outbreaks of disease caused by ampicillin-resistant strains of Salmonella enterica serotype Typhimurium were identified in the UK in 1962 and 1964. We aimed to date the emergence of this resistance in historical isolates of S enterica serotype Typhimurium. METHODS: In this retrospective, whole-genome sequencing study, we analysed 288 S enterica serotype Typhimurium isolates collected between 1911 and 1969 from 31 countries on four continents and from various sources including human beings, animals, feed, and food...
November 29, 2017: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/29198111/expansion-of-the-genetic-alphabet-a-chemist-s-approach-to-synthetic-biology
#16
Aaron W Feldman, Floyd E Romesberg
The information available to any organism is encoded in a four nucleotide, two base pair genetic code. Since its earliest days, the field of synthetic biology has endeavored to impart organisms with novel attributes and functions, and perhaps the most fundamental approach to this goal is the creation of a fifth and sixth nucleotide that pair to form a third, unnatural base pair (UBP) and thus allow for the storage and retrieval of increased information. Achieving this goal, by definition, requires synthetic chemistry to create unnatural nucleotides and a medicinal chemistry-like approach to guide their optimization...
December 2, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29196917/development-of-a-linear-dual-column-hplc-ms-ms-method-and-clinical-genetic-evaluation-for-tramadol-and-its-phase-i-and-ii-metabolites-in-oral-fluid
#17
Hyerim Yu, Seongkuk Hong, Chul-Ho Jeong, Jung-Woo Bae, Sooyeun Lee
Tramadol is a centrally acting synthetic opioid analgesic and has received special attention due to its abuse potential and unexpected responses induced by CYP2D6 polymorphism. Oral fluid is an advantageous biofluid for drug analysis due to non-invasive sampling and high correlation of drug concentrations with plasma. However, few studies have been performed on distribution of tramadol and its metabolites in oral fluid. In the present study, a linear dual column HPLC-MS/MS method was developed and fully validated for the simultaneous determination of tramadol and its phase I [O-desmethyltramadol (ODMT), N-desmethyltramadol (NDMT) and N,O-didesmethyltramadol (NODMT)] and II metabolites in oral fluid...
December 1, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29196861/crispr-based-strategies-for-studying-regulatory-elements-and-chromatin-structure-in-mammalian-gene-control
#18
REVIEW
Cia-Hin Lau, Yousin Suh
The development of high-throughput methods has enabled the genome-wide identification of putative regulatory elements in a wide variety of mammalian cells at an unprecedented resolution. Extensive genomic studies have revealed the important role of regulatory elements and genetic variation therein in disease formation and risk. In most cases, there is only correlative evidence for the roles of these elements and non-coding changes within these elements in pathogenesis. With the advent of genome- and epigenome-editing tools based on the CRISPR technology, it is now possible to test the functional relevance of the regulatory elements and alterations on a genomic scale...
December 1, 2017: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/29196671/concurrent-structural-and-biophysical-traits-link-with-immunoglobulin-light-chains-amyloid-propensity
#19
Luca Oberti, Paola Rognoni, Alberto Barbiroli, Francesca Lavatelli, Rosaria Russo, Martina Maritan, Giovanni Palladini, Martino Bolognesi, Giampaolo Merlini, Stefano Ricagno
Light chain amyloidosis (AL), the most common systemic amyloidosis, is caused by the overproduction and the aggregation of monoclonal immunoglobulin light chains (LC) in target organs. Due to genetic rearrangement and somatic hypermutation, virtually, each AL patient presents a different amyloidogenic LC. Because of such complexity, the fine molecular determinants of LC aggregation propensity and proteotoxicity are, to date, unclear; significantly, their decoding requires investigating large sets of cases. Aiming to achieve generalizable observations, we systematically characterised a pool of thirteen sequence-diverse full length LCs...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29194629/ubigate-a-synthetic-biology-toolbox-to-analyse-ubiquitination
#20
Kathrin Kowarschik, Wolfgang Hoehenwarter, Sylvestre Marillonnet, Marco Trujillo
Ubiquitination is mediated by an enzymatic cascade that results in the modification of substrate proteins, redefining their fate. This post-translational modification is involved in most cellular processes, yet its analysis faces manifold obstacles due to its complex and ubiquitous nature. Reconstitution of the ubiquitination cascade in bacterial systems circumvents several of these problems and was shown to faithfully recapitulate the process. Here, we present UbiGate - a synthetic biology toolbox, together with an inducible bacterial expression system - to enable the straightforward reconstitution of the ubiquitination cascades of different organisms in Escherichia coli by 'Golden Gate' cloning...
November 30, 2017: New Phytologist
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