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Membrane localization of the NlpC/P60 family protein EGL-26 correlates with regulation of vulval cell morphogenesis in Caenorhabditis elegans.

Vulval morphogenesis in Caenorhabditis elegans generates a stack of toroidal cells enclosing a tubular lumen. Mutation of egl-26 is associat … nol acyltransferase) subfamily of the NlpC/P60 superfamily of catalytic proteins. Via site-directed mutagenesis, we demonstrate a requirement of the putative catalytic residues for EGL-26 function in vivo. We also show that mutation of conserved serine 275 perturbs the apical membrane localization and the function of the EGL-26 protein. Additional mutagenesis …

An ENU-induced mutation in the Ankrd11 gene results in an osteopenia-like phenotype in the mouse mutant Yoda.

The mechanisms that regulate bone mass are important in a variety of complex diseases such as osteopenia and osteoporosis. Regulation of bone mass is a polygenic trait and is also influenced by various environmental and lifestyle factors, making analysis of the genetic basis difficult. As an effort toward identifying novel genes involved in regulation of bone mass, N-ethyl-N-nitrosourea (ENU) mutagenesis in mice has been utilized. Here we describe a mouse mutant termed Yoda that was identified in an ENU mutagenesis screen for dominantly acting mutations. Mice heterozygous for the Yoda mutation…

Molecular modelling of specific and non-specific anaesthetic interactions.

There has been rapid progress in molecular modelling in recent years. The convergence of improved software for molecular mechanics and dynamics, techniques for chimeric substitution and site-directed mutations, and the first x-ray structures of transmembrane ion channels have made it possible to build and test models of anaesthetic binding sites. These models have served as guides for site-directed mutagenesis and as starting points for understanding the molecular dynamics of anaesthetic-site interactions. Ligand-gated ion channels are targets for inhaled anaesthetics and alcohols in the centr…

Spontaneous mutation of cell oncogenes plays a minor role in neoplastic transformation of virus-induced murine T-cell lymphomas.

Mink cell focus-forming viruses (MCF) are slow-transforming retroviruses that are able to accelerate the appearance of T-cell lymphomas when … evement of the fully neoplastic phenotype in MCF-infected mice. To evaluate the role of spontaneous mutagenesis phenomena in murine virus-induced lymphomagenesis, we analyzed a series of 18 MCF247-induced thymic lymphomas and derived cell lines for the presence of p53 and c-ras gene mutations. Only 1 mutation at the p53 gene and 1 mutation at the ki-ras gene …

Всеобъемлющий анализ two Китайские геномы огурцов и мутантов как ресурсы для точного размножения.

Cumuis sativus L., известный как огурец, является важным овощным растениеводством во всем мире, крупнейшим производителем которого является Китай, в особенности северный и южно-китайский типы. В то время как обширные геномные исследования были сосредоточены на Северном Китае, особенно на китайском Лонге. 9930, исследования по Южно-Китайскому типу остаются ограниченными. В этом исследовании мы собрали высококачественные геномы two широко культивируемые и репрезентативные родные разновидности: S36 (тип Северной Китая) и H19 (тип Южной Китая) и провели анализ мутагенезов. Сравнительный анализ ген

Совпадение в аннотации оригинала
Cucumis sativus L., commonly known as cucumber, is an important vegetable crop worldwide, with China as the largest producer, particularly o … d representative parent varieties: S36 (North China type) and H19 (South China type), and conducted mutagenesis analyses. Comparative genome analysis revealed a large number of structural variants between two North China types and two South China types, with many of the affected genes showing strong homology to known functional loci, potentially contributing …

When DNA Mutations Interplay with Cellular Proliferation: A Narrative History of Theories of Carcinogenesis.

While cancer is one of the most documented diseases, how normal cells become cancerous is still debated. To address this question, in the fi … rogressively refined by the notions of initiation, promotion, and progression thanks to advances in mutagenesis and cellular proliferation. In the second part of this review, recent discoveries and paradigms in carcinogenesis, notably the role of the protein ATM, a major actor of the stress response involved in both mutagenesis and cellular proliferation, wer …

Adenine base editing of the DUX4 polyadenylation signal for targeted genetic therapy in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by chromatin relaxation of the D4Z4 repeat resulting in misexpression of the D4Z4-encoded DUX4 gene in skeletal muscle. One of the key genetic requirements for the stable production of full-length DUX4 mRNA in skeletal muscle is a functional polyadenylation signal (ATTAAA) in exon three of DUX4 that is used in somatic cells. Base editors hold great promise to treat DNA lesions underlying genetic diseases through their ability to carry out specific and rapid nucleotide mutagenesis even in postmitotic cells such as skeletal muscle. In this …

Antibiotic-induced DNA damage results in a controlled loss of pH homeostasis and genome instability.

Extracellular pH has been assumed to play little if any role in how bacteria respond to antibiotics and antibiotic resistance development. H … of a protein central to control of the bacterial DNA damage response system. Finally, two different mutagenesis assays indicate that environmental pH affects antibiotic resistance development. Specifically, at environmental pH's greater than six we find that mutagenesis plays a significant role in producing antibiotic resistant mutants. At pH's less than or e …

Leishmania is not prone to develop resistance to tamoxifen.

Tamoxifen, an antineoplastic agent, is active in vitro and in vivo against the parasitic protozoa Leishmania. As part of our efforts to unravel this drug's mechanisms of action against the parasite and understand how resistance could arise, we tried to select tamoxifen-resistant Leishmania amazonensis. Three different strategies to generate tamoxifen resistant mutants were used: stepwise increase in drug concentration applied to promastigote cultures, chemical mutagenesis followed by drug selection and treatment of infected mice followed by selection of amastigotes. For amastigote selection, w…

A protein functional leap: how a single mutation reverses the function of the transcription regulator TetR.

Today's proteome is the result of innumerous gene duplication, mutagenesis, drift and selection processes. Whereas random mutagenesis introduces predominantly only gradual changes in protein function, a case can be made that an abrupt switch in function caused by single amino acid substitutions will not only considerably further evolution but might constitute a prerequisite for the appearance of novel functionalities for which no promiscuous protein intermediates can be envisaged. Recently, tetracycline repressor (TetR) variants were identified in which binding of tetracycline triggers the rep…

Triplex targeted genomic crosslinks enter separable deletion and base substitution pathways.

We have synthesized triple helix forming oligonucleotides (TFOs) that target a psoralen (pso) interstrand crosslink to a specific chromosomal site in mammalian cells. Mutagenesis of the targeted crosslinks results in base substitutions and deletions. Identification of the gene products involved in mutation formation is important for developing practical applications of pso-TFOs, and may be informative about the metabolism of other interstrand crosslinks. We have studied mutagenesis of a pso-TFO genomic crosslink in repair proficient and deficient cells. Deficiencies in non homologous end joini…

Active-site engineering of a GH2 bifidobacterial β-galactosidase for improved formation of N-acetyl-lactosamine - a core structure of human milk oligosaccharides.

N-Acetyl-lactosamine (LacNAc), forming the core structure of certain human milk oligosaccharides, can be synthesized via transgalactosylation catalyzed by β-galactosidases, using lactose as the galactosyl donor and N-acetyl-glucosamine (GlcNAc) as the galactosyl acceptor. To improve LacNAc yield, a GH2 β-galactosidase (Bbreβgal-II) from Bifidobacterium breve DSM 20213, was subjected to alanine-scanning mutagenesis targeting the galactose-binding amino acid residues at its active site. Disruption of the hydrogen bonds at non-conserved residues severely reduced enzymatic activity. Loosening the …

Azanucleoside treatment leads to B-cell precursor acute lymphoblastic leukemia.

5-Aza-4'-thio-2'-deoxycytidine (ATC) is an azanucleoside cytidine analog under investigation in preclinical studies for solid tumors as a pr … t with a noncovalent DNMT1 inhibitor indicated that methylated cytosines were preferred targets for mutagenesis. This study reveals that ATC exposure leads to both DNMT1-dependent and -independent mutagenesis and provides a direct link between ATC exposure, a complex mutational signature, and malignant transformation.

Genome-wide screen reveals glycerol-induced aminoglycoside potentiation against Staphylococcus aureus via boosting GlpK-initiated energy metabolism.

Potentiation of existing antibiotics represents a promising strategy for combating the global health crisis of antibiotic resistance. Here w … e-dependent aminoglycoside uptake. Atmospheric and room temperature plasma (ARTP)-based genome-wide mutagenesis screens further reveal the genetic basis of this potentiation, highlighting a central role for glycerol kinase (GlpK). Mechanistically, GlpK initiates glycerol catabolism and boosts cellular energy metabolism, thereby increasing proton motive force- …

Gene fitness landscapes of Vibrio cholerae at important stages of its life cycle.

Vibrio cholerae has evolved to adeptly transition between the human small intestine and aquatic environments, leading to water-borne spread and transmission of the lethal diarrheal disease cholera. Using a host model that mimics the pathology of human cholera, we applied high density transposon mutagenesis combined with massively parallel sequencing (Tn-seq) to determine the fitness contribution of >90% of all non-essential genes of V. cholerae both during host infection and dissemination. Targeted mutagenesis and validation of 35 genes confirmed our results for the selective conditions with a…

Identification of cardiac malformations in mice lacking Ptdsr using a novel high-throughput magnetic resonance imaging technique.

BACKGROUND: Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo. RESULTS: We developed and optimized a novel method for high-throughput multi-embryo magnetic resonance imaging (MRI). Using this approach we identified cardiac m…

Mouse mutants from chemically mutagenized embryonic stem cells.

The drive to characterize functions of human genes on a global scale has stimulated interest in large-scale generation of mouse mutants. Conventional germ-cell mutagenesis with N-ethyl-N-nitrosourea (ENU) is compromised by an inability to monitor mutation efficiency, strain and interlocus variation in mutation induction, and extensive husbandry requirements. To overcome these obstacles and develop new methods for generating mouse mutants, we devised protocols to generate germline chimaeric mice from embryonic stem (ES) cells heavily mutagenized with ethylmethanesulphonate (EMS). Germline chima…

Isolation and characterization of Pseudomonas aeruginosa mutants requiring salicylic acid for pyochelin biosynthesis.

Pseudomonas aeruginosa mutants requiring salicylic acid for pyochelin biosynthesis were isolated after chemical mutagenesis by plating on a siderophore detection medium. Like the wild type, these mutants incorporated 7-[14C]salicylic acid into pyochelin, demonstrating that salicylic acid is an intermediate in the biosynthesis pathway of pyochelin.

Ion channels: Manipulating the munchies in mice.

Crystal structure and drug pharmacophore structure-activity data guided a combined mutagenesis and chemical screen to develop ligand-gated ion channels activated by unique chemical agonists. Through genetic engineering, these channels can be used to manipulate neuronal excitability and dissect the neuronal circuitry responsible for complex behaviors.

A new conceptual framework for PKD1 in ADPKD; integrating DNA structures and inflammation.

In ADPKD renal function is corrupted by the accumulation and growth of fluid-filled cysts. Disruption of the PKD1 gene product, polycystin-1 … cond-hit event. Why human PKD1 is prone to inactivation and why the rodent orthologs escape similar mutagenesis is a mystery that, once solved, promises to provide important insights into the molecular mechanisms governing cyst initiation. A step toward that goal came from the characterization of the guanine-rich sequence architecture of human PKD1 that disti …