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https://www.readbyqxmd.com/read/28346402/large-scale-design-of-robust-genetic-circuits-with-multiple-inputs-and-outputs-for-mammalian-cells
#1
Benjamin H Weinberg, N T Hang Pham, Leidy D Caraballo, Thomas Lozanoski, Adrien Engel, Swapnil Bhatia, Wilson W Wong
Engineered genetic circuits for mammalian cells often require extensive fine-tuning to perform as intended. We present a robust, general, scalable system, called 'Boolean logic and arithmetic through DNA excision' (BLADE), to engineer genetic circuits with multiple inputs and outputs in mammalian cells with minimal optimization. The reliability of BLADE arises from its reliance on recombinases under the control of a single promoter, which integrates circuit signals on a single transcriptional layer. We used BLADE to build 113 circuits in human embryonic kidney and Jurkat T cells and devised a quantitative, vector-proximity metric to evaluate their performance...
March 27, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28344069/selective-post-training-time-window-for-memory-consolidation-interference-of-cannabidiol-into-the-prefrontal-cortex-reduced-dopaminergic-modulation-and-immediate-gene-expression-in-limbic-circuits
#2
Matheus Teixeira Rossignoli, Cleiton Lopes-Aguiar, Rafael Naime Ruggiero, Raquel Araujo Do Val da Silva, Lezio Soares Bueno-Junior, Ludmyla Kandratavicius, José Eduardo Peixoto-Santos, José Alexandre Crippa, Jaime Eduardo Cecilio Hallak, Antonio Waldo Zuardi, Raphael Escorsim Szawka, Janete Anselmo-Franci, João Pereira Leite, Rodrigo Neves Romcy-Pereira
The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents...
March 23, 2017: Neuroscience
https://www.readbyqxmd.com/read/28337978/microrna-filters-hox-temporal-transcription-noise-to-confer-boundary-formation-in-the-spinal-cord
#3
Chung-Jung Li, Tian Hong, Ying-Tsen Tung, Ya-Ping Yen, Ho-Chiang Hsu, Ya-Lin Lu, Mien Chang, Qing Nie, Jun-An Chen
The initial rostrocaudal patterning of the neural tube leads to differential expression of Hox genes that contribute to the specification of motor neuron (MN) subtype identity. Although several 3' Hox mRNAs are expressed in progenitors in a noisy manner, these Hox proteins are not expressed in the progenitors and only become detectable in postmitotic MNs. MicroRNA biogenesis impairment leads to precocious expression and propagates the noise of Hoxa5 at the protein level, resulting in an imprecise Hoxa5-Hoxc8 boundary...
March 24, 2017: Nature Communications
https://www.readbyqxmd.com/read/28334849/icf-specific-dnmt3b-dysfunction-interferes-with-intragenic-regulation-of-mrna-transcription-and-alternative-splicing
#4
Sole Gatto, Miriam Gagliardi, Monica Franzese, Sylwia Leppert, Mariarosaria Papa, Marco Cammisa, Giacomo Grillo, Guillame Velasco, Claire Francastel, Shir Toubiana, Maurizio D'Esposito, Claudia Angelini, Maria R Matarazzo
Hypomorphic mutations in DNA-methyltransferase DNMT3B cause majority of the rare disorder Immunodeficiency, Centromere instability and Facial anomalies syndrome cases (ICF1). By unspecified mechanisms, mutant-DNMT3B interferes with lymphoid-specific pathways resulting in immune response defects. Interestingly, recent findings report that DNMT3B shapes intragenic CpG-methylation of highly-transcribed genes. However, how the DNMT3B-dependent epigenetic network modulates transcription and whether ICF1-specific mutations impair this process remains unknown...
March 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28329684/cis-regulatory-circuits-regulating-nek6-kinase-overexpression-in-transformed-b-cells-are-super-enhancer-independent
#5
Yue Huang, Olivia I Koues, Jiang-Yang Zhao, Regina Liu, Sarah C Pyfrom, Jacqueline E Payton, Eugene M Oltz
Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28325831/landscape-genomic-insights-into-the-historic-migration-of-mountain-hemlock-in-response-to-holocene-climate-change
#6
Jeremy S Johnson, Keith D Gaddis, David M Cairns, Kranti Konganti, Konstantin V Krutovsky
PREMISE OF THE STUDY: Untangling alternative historic dispersal pathways in long-lived tree species is critical to better understand how temperate tree species may respond to climatic change. However, disentangling these alternative pathways is often difficult. Emerging genomic technologies and landscape genetics techniques improve our ability to assess these pathways in natural systems. We address the question to what degree have microrefugial patches and long-distance dispersal been responsible for the colonization of mountain hemlock (Tsuga mertensiana) on the Alaskan Kenai Peninsula...
March 21, 2017: American Journal of Botany
https://www.readbyqxmd.com/read/28324764/enhancing-mitofusin-marf-ameliorates-neuromuscular-dysfunction-in-drosophila-models-of-tdp-43-proteinopathies
#7
Bilal Khalil, Marie-Jeanne Cabirol-Pol, Laetitia Miguel, Alexander J Whitworth, Magalie Lecourtois, Jean-Charles Liévens
Transactive response DNA-binding protein 43 kDa (TDP-43) is considered a major pathological protein in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The precise mechanisms by which TDP-43 dysregulation leads to toxicity in neurons are not fully understood. Using TDP-43-expressing Drosophila, we examined whether mitochondrial dysfunction is a central determinant in TDP-43 pathogenesis. Expression of human wild-type TDP-43 in Drosophila neurons results in abnormally small mitochondria...
February 27, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28324652/positive-feedback-genetic-circuit-incorporating-a-constitutively-active-mutant-gal3-into-yeast-gal-induction-system
#8
Shintaro Ryo, Jun Ishii, Toshihide Matsuno, Yasuyuki Nakamura, Daiki Matsubara, Masahiro Tominaga, Akihiko Kondo
The GAL expression system is the most frequently used induction technique in the yeast Saccharomyces cerevisiae. Here we report a simple but powerful genetic circuit for use with the GAL induction system. Briefly, an artificial positive feedback circuit was incorporated into the GAL regulatory network. We selected green fluorescent protein (GFP) as a reporter of GAL1 induction, and designed a strain that expressed a constitutively active Gal3 mutant protein (Gal3(c)) under control of the GAL10 promoter. In the resulting strain, GAL1 and GAL10 promoters regulate the expression of GFP and GAL3(c), respectively...
March 27, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28323272/constipation-predominant-irritable-bowel-syndrome-females-have-normal-colonic-barrier-and-secretory-function
#9
Stephanie A Peters, Shoko Edogawa, Wendy J Sundt, Roy B Dyer, Daniel A Dalenberg, Amelia Mazzone, Ravinder J Singh, Natalie Moses, Thomas C Smyrk, Christopher Weber, David R Linden, Wallace K MacNaughton, Jerrold R Turner, Michael Camilleri, David A Katzka, Gianrico Farrugia, Madhusudan Grover
OBJECTIVES: The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function. METHODS: A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g (13)C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression...
March 21, 2017: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/28319101/a-vibrio-cholerae-autoinducer-receptor-pair-that-controls-biofilm-formation
#10
Kai Papenfort, Justin E Silpe, Kelsey R Schramma, Jian-Ping Cong, Mohammad R Seyedsayamdost, Bonnie L Bassler
Quorum sensing (QS) is a cell-cell communication process that enables bacteria to track cell population density and orchestrate collective behaviors. QS relies on the production and detection of, and the response to, extracellular signal molecules called autoinducers. In Vibrio cholerae, multiple QS circuits control pathogenesis and biofilm formation. Here, we identify and characterize a new QS autoinducer-receptor pair. The autoinducer is 3,5-dimethylpyrazin-2-ol (DPO). DPO is made from threonine and alanine, and its synthesis depends on threonine dehydrogenase (Tdh)...
March 20, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28316565/six-years-of-research-on-the-national-institute-of-mental-health-s-research-domain-criteria-rdoc-initiative-a-systematic-review
#11
REVIEW
Dean Carcone, Anthony C Ruocco
Six years have passed since the National Institute of Mental Health (NIMH) in the United States launched the Research Domain Criteria (RDoC) initiative. The RDoC introduces a framework for research on the biology of mental illness that integrates research findings across multiple levels of information. The framework outlines constructs that represent specific quantifiable dimensions of behavior (e.g., responses to acute threat, cognitive control) and corresponding units of analysis that can be used to study the constructs, beginning at the levels of genes, molecules, cells, circuits and physiology, and moving up to behaviors and self-reports...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28315412/engineering-bacterial-translation-initiation-do-we-have-all-the-tools-we-need
#12
REVIEW
Justin Vigar, Hans-Joachim Wieden
BACKGROUND: Reliable tools that allow precise and predictable control over gene expression are critical for the success of nearly all bioengineering applications. Translation initiation is the most regulated phase during protein biosynthesis, and is therefore a promising target for exerting control over gene expression. At the translational level, the copy number of a protein can be fine-tuned by altering the interaction between the translation initiation region of an mRNA and the ribosome...
March 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28300664/gene-expression-changes-in-immune-response-pathways-following-oral-administration-of-tetrabromobisphenol-a-tbbpa-in-female-wistar-han-rats
#13
Samantha M Hall, Sherry J Coulter, Gabriel A Knudsen, J Michael Sanders, Linda S Birnbaum
Tetrabromobisphenol A (TBBPA) is a brominated flame retardant used globally at high volumes, primarily in the epoxy resin of circuit boards. It has been detected in the environment and in humans. The National Toxicology Program found that chronic oral TBBPA treatment of 250mg/kg and higher caused an increased incidence of uterine lesions in female Wistar Han rats. The present laboratory has previously reported changes in gene expression associated with estrogen homeostasis in liver and uterine tissue of adult female Wistar Han rats after five days of gavage with 250mg/kg of TBBPA...
March 11, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28299699/synthetic-cell-based-sensors-with-programmed-selectivity-and-sensitivity
#14
Elvis Bernard, Baojun Wang
Bacteria live in an ever changing environment and, to adapt their physiology, they have to sense the changes. Our current understanding of the mechanisms and elements involved in the detection and processing of these environmental signals grant us access to an array of genetic components able to process such information. As engineers can use different electronic components to build a circuit, we can rewire the cellular components to create digital logic and analogue gene circuits that will program cell behaviour in a designed manner in response to a specific stimulus...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28299654/roles-of-runx-genes-in-nervous-system-development
#15
Jae Woong Wang, Stefano Stifani
Runt-related (Runx) transcription factors play essential roles during development and adult tissue homeostasis and are responsible for several human diseases. They regulate a variety of biological mechanisms in numerous cell lineages. Recent years have seen significant progress in our understanding of the functions performed by Runx proteins in the developing and postnatal mammalian nervous system. In both central and peripheral nervous systems, Runx1 and Runx3 display remarkably specific expression in mostly non-overlapping groups of postmitotic neurons...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28289210/phosphorylation-induced-conformational-dynamics-in-an-intrinsically-disordered-protein-and-potential-role-in-phenotypic-heterogeneity
#16
Prakash Kulkarni, Mohit Kumar Jolly, Dongya Jia, Steven M Mooney, Ajay Bhargava, Luciane T Kagohara, Yihong Chen, Pengyu Hao, Yanan He, Robert W Veltri, Alexander Grishaev, Keith Weninger, Herbert Levine, John Orban
Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. Prostate-Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51...
March 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28286216/a-resource-dependent-protein-synthesis-model-for-evaluating-synthetic-circuits
#17
Wolfgang Halter, Jan Maximilian Montenbruck, Zoltan A Tuza, Frank Allgöwer
Reliable in silico design of synthetic gene networks necessitates novel approaches to model the process of protein synthesis under the influence of limited resources. We present such a novel protein synthesis model which originates from the Ribosome Flow Model and among other things describes the movement of RNA-polymerase and ribosomes on mRNA and DNA templates, respectively. By analyzing the convergence properties of this model based upon geometric considerations, we present additional insights into the dynamic mechanisms of the process of protein synthesis...
March 9, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28286179/formation-of-hippocampal-mhtt-aggregates-leads-to-impaired-spatial-memory-hippocampal-activation-and-adult-neurogenesis
#18
L C Schwab, K Richetin, R A Barker, N Déglon
Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of fronto-striatal circuits. However, emerging evidence suggests that some of the cognitive deficits in HD may have their origin in other structures including the hippocampus. Hippocampal abnormalities have been reported in HD mouse models particularly in terms of performance on the Morris Water Maze. However, in these animals, it is difficult to be certain whether the spatial memory deficits are due to local pathology within this structure or their poor mobility and motivation...
March 9, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28285855/insights-in-the-regulation-of-the-degradation-of-pahs-in-novosphingobium-sp-hr1a-and-utilization-of-this-regulatory-system-as-a-tool-for-the-detection-of-pahs
#19
Ana Segura, Verónica Hernández-Sánchez, Silvia Marqués, Lázaro Molina
Novosphingobium sp. HR1a is able to grow using diverse polycyclic aromatic hydrocarbons (PAHs) as the sole carbon sources. We have identified two transposons that contain genes encoding several ring-hydroxylating dioxygenases and we have demonstrated the crucial role of one of these dioxygenases in the PAH metabolism in this strain; a mutant in the large subunit of this dioxygenase was unable to growth with 2-, 3-, or 4-rings aromatic hydrocarbons. Using a construction of lacZ gene fused with the pathway promoter, we determined that the expression of the dioxygenase gene was specifically induced in the presence of some PAHs and intermediates of their metabolic pathway...
March 9, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/28285822/astrocytes-control-circadian-timekeeping-in-the-suprachiasmatic-nucleus-via-glutamatergic-signaling
#20
Marco Brancaccio, Andrew P Patton, Johanna E Chesham, Elizabeth S Maywood, Michael H Hastings
The suprachiasmatic nucleus (SCN) of the hypothalamus orchestrates daily rhythms of physiology and behavior in mammals. Its circadian (∼24 hr) oscillations of gene expression and electrical activity are generated intrinsically and can persist indefinitely in temporal isolation. This robust and resilient timekeeping is generally regarded as a product of the intrinsic connectivity of its neurons. Here we show that neurons constitute only one "half" of the SCN clock, the one metabolically active during circadian daytime...
March 22, 2017: Neuron
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