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https://www.readbyqxmd.com/read/28646491/sickle-cells-produce-functional-immune-modulators-and-cytotoxics
#1
Chiao-Wang Sun, Li-Chen Wu, Peter L Knopick, David S Bradley, Tim Townes, David S Terman
Sickle erythrocytes' (SSRBCs) unique physical adaptation to hypoxic conditions renders them able to home to hypoxic tumor niches in vivo, shut down tumor blood flow and induce tumoricidal responses. SSRBCs are also useful vehicles for transport of encapsulated drugs and oncolytic virus into hypoxic tumors with enhanced anti-tumor effects. In search of additional modes for arming sickle cells with cytotoxics, we turned to a lentiviral β-globin vector with optimized Locus Control Region/β-globin coding region/promoter/enhancers...
June 24, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28646478/newborn-screening-for-fabry-disease-in-the-north-west-of-spain
#2
Cristobal Colon, Saida Ortolano, Cristina Melcon-Crespo, Jose V Alvarez, Olalla E Lopez-Suarez, Maria L Couce, José R Fernández-Lorenzo
Fabry disease is an X-linked lysosomal storage disorder caused by the impairment of α-galactosidase A. Enzyme replacement therapy is available to treat patients, who often experience delayed diagnosis. A newborn screening for Fabry disease was performed to study the prevalence of the pathology and to evaluate the possibility to implement the test in systematic screenings. We collected 14,600 dried blood spot samples (7575 males and 7025 females) and carried out a diagnostic study by fluorometric measurement of α-galactosidase A enzymatic activity and GLA gene sequencing...
June 23, 2017: European Journal of Pediatrics
https://www.readbyqxmd.com/read/28646206/crispr-cas9-mediated-genome-editing-via-postnatal-administration-of-aav-vector-cures-haemophilia-b-mice
#3
Tsukasa Ohmori, Yasumitsu Nagao, Hiroaki Mizukami, Asuka Sakata, Shin-Ichi Muramatsu, Keiya Ozawa, Shin-Ichi Tominaga, Yutaka Hanazono, Satoshi Nishimura, Osamu Nureki, Yoichi Sakata
Haemophilia B, a congenital haemorrhagic disease caused by mutations in coagulation factor IX gene (F9), is considered an appropriate target for genome editing technology. Here, we describe treatment strategies for haemophilia B mice using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Administration of adeno-associated virus (AAV) 8 vector harbouring Staphylococcus aureus Cas9 (SaCas9) and single guide RNA (sgRNA) to wild-type adult mice induced a double-strand break (DSB) at the target site of F9 in hepatocytes, sufficiently developing haemophilia B...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646116/tonic-b-cell-receptor-signaling-in-diffuse-large-b-cell-lymphoma
#4
Ondrej Havranek, Jingda Xu, Stefan Köhrer, Zhiqiang Wang, Lisa Becker, Justin M Comer, Jared Henderson, Wencai Ma, John Man Chun Ma, Jason R Westin, Dipanjan Ghosh, Nicholas Shinners, Luhong Sun, Allen F Yi, Anusha R Karri, Jan A Burger, Tomasz Zal, R Eric Davis
We used CRISPR/Cas9-mediated genomic modification to investigate B-cell receptor (BCR) signaling in cell lines of diffuse large B-cell lymphoma (DLBCL). Three manipulations that altered BCR genes without affecting surface BCR levels showed that BCR signaling differs between the germinal center B-cell (GCB) subtype, which is insensitive to BTK inhibition by ibrutinib, and the activated B-cell (ABC) subtype. Replacing antigen-binding BCR regions had no effect on BCR signaling in GCB-DLBCL lines, reflecting this subtype's exclusive use of tonic BCR signaling...
June 23, 2017: Blood
https://www.readbyqxmd.com/read/28646112/crispr-cas12a-assisted-recombineering-in-bacteria
#5
Mei-Yi Yan, Hai-Qin Yan, Gai-Xian Ren, Ju-Ping Zhao, Xiao-Peng Guo, Yi-Cheng Sun
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a (Cpf1) has emerged as an effective genome editing tool in many organisms. Here, we developed and optimized a CRISPR-Cas12a assisted recombineering system to facilitate genetic manipulation in bacteria. Using this system, point mutations, deletions, insertions, and gene replacements can be easily generated on the chromosome or native plasmids in Escherichia coli, Yersinia pestis, and Mycobacterium smegmatis Because CRISPR-Cas12a-assisted recombineering does not require introduction of an antibiotic resistance gene into the chromosome to select for recombinants, it is an efficient approach for generating markerless and scarless mutations in bacteria...
June 23, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28645917/multivalent-binding-of-pwwp2a-to-h2a-z-regulates-mitosis-and-neural-crest-differentiation
#6
Sebastian Pünzeler, Stephanie Link, Gabriele Wagner, Eva C Keilhauer, Nina Kronbeck, Ramona Mm Spitzer, Susanne Leidescher, Yolanda Markaki, Edith Mentele, Catherine Regnard, Katrin Schneider, Daisuke Takahashi, Masayuki Kusakabe, Chiara Vardabasso, Lisa M Zink, Tobias Straub, Emily Bernstein, Masahiko Harata, Heinrich Leonhardt, Matthias Mann, Ralph Aw Rupp, Sandra B Hake
Replacement of canonical histones with specialized histone variants promotes altering of chromatin structure and function. The essential histone variant H2A.Z affects various DNA-based processes via poorly understood mechanisms. Here, we determine the comprehensive interactome of H2A.Z and identify PWWP2A as a novel H2A.Z-nucleosome binder. PWWP2A is a functionally uncharacterized, vertebrate-specific protein that binds very tightly to chromatin through a concerted multivalent binding mode. Two internal protein regions mediate H2A...
June 23, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28645701/effect-of-phosphate-solubilizing-bacteria-on-phosphorus-dynamics-and-the-bacterial-community-during-composting-of-sugarcane-industry-waste
#7
German A Estrada-Bonilla, Cintia M Lopes, Ademir Durrer, Paulo R L Alves, Nicolle Passaglia, Elke J B N Cardoso
Sugarcane processing generates a large quantity of residues, such as filter cake and ashes, which are sometimes composted prior to their amendment in soil. However, important issues still have to be addressed on this subject, such as the description of bacterial succession that occurs throughout the composting process and the possibilities of using phosphate-solubilizing bacteria (PSB) during the process to improve phosphorus (P) availability in the compost end product. Consequently, this study evaluated the bacterial diversity and P dynamics during the composting process when inoculated with Pseudomonas aeruginosa PSBR12 and Bacillus sp...
June 7, 2017: Systematic and Applied Microbiology
https://www.readbyqxmd.com/read/28642712/investigations-into-the-sarcomeric-protein-and-ca-2-regulation-abnormalities-underlying-hypertrophic-cardiomyopathy-in-cats-felix-catus
#8
Andrew E Messer, Jasmine Chan, Alex Daley, O'Neal Copeland, Steven B Marston, David J Connolly
Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28642118/current-state-of-the-art-for-cardiac-arrhythmia-gene-therapy
#9
REVIEW
J Kevin Donahue
Cardiac arrhythmias are a leading cause of morbidity and mortality. Currently available therapeutic options lack sufficient efficacy and safety. Gene therapy has been proposed for treatment of cardiac arrhythmias. This review will discuss the current state of development for arrhythmia gene therapy. So far, all published studies are short-term, proof-of-concept animal studies. Potential replacement of cardiac pacemakers has been shown for combination gene therapy using the HCN2 gene and either the gene for adenylate cyclase, the skeletal muscle isoform of the sodium channel, or a dominant negative mutant of the potassium channel responsible for resting membrane potential...
June 19, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28642028/discovery-of-novel-5-oxa-2-6-diazaspiro-3-4-oct-6-ene-derivatives-as-potent-selective-and-orally-available-somatostatin-receptor-subtype-5-sstr5-antagonists-for-treatment-of-type-2-diabetes-mellitus
#10
Hideki Hirose, Takeshi Yamasaki, Masaki Ogino, Ryo Mizojiri, Yumiko Tamura-Okano, Hiroaki Yashiro, Yo Muraki, Yoshihide Nakano, Jun Sugama, Akito Hata, Shinji Iwasaki, Masanori Watanabe, Tsuyoshi Maekawa, Shizuo Kasai
Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity...
June 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28641667/-research-progress-on-genetic-factors-and-hemophilia-a-clotting-factor-inhibitor-review
#11
Zheng-Bin Hu, Xin Sun, Li-Ya He
Hemophilia A (Hemophilia A, HA) is an X-linked recessive hereditary coagulation function disorder, the deficiency and dysfunction of blood coagulation were caused by the mutations of gene encoding clotting factor VIII. The treatment of hemophilia A still depends on the replacement therapy with blood coagulation factor. However, the repeated infusion of clotting factor will produce the neutralizing antibody against FVIII, then resulting in one of the serious complications. The reports on the incidence of inhibitor are different at home and abroad...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28641396/geneticization-in-mim-omim%C3%A2-exploring-historic-and-epistemic-drivers-of-contemporary-understandings-of-genetic-disease
#12
Rachel A Ankeny
Prior to the genomic sequencing era, the bible for those working in clinical genetics was McKusick's Mendelian Inheritance in Man (MIM), which appeared in multiple editions between the 1960s and the late 1990s. This catalogue was organized according to general patterns of inheritance and focused on phenotypes. Beginning in the mid-1980s, it was replaced by Online Mendelian Inheritance in Man (OMIM®), a continuously updated catalogue documenting molecular relationships between genetic variation and phenotypic expression...
June 21, 2017: Journal of Medicine and Philosophy
https://www.readbyqxmd.com/read/28639376/mfat-1-transgene-protects-cultured-adult-neural-stem-cells-against-cobalt-chloride-mediated-hypoxic-injury-by-activating-nrf2-are-pathways
#13
Junfeng Yu, Haiyuan Yang, Bin Fang, Zhengwei Zhang, Ying Wang, Yifan Dai
Ischemic stroke is a devastating neurological disorder and one of the leading causes of death and serious disability in adults. Adult neural stem cell (NSC) replacement therapy is a promising treatment for both structural and functional neurological recovery. However, for the treatment to work, adult NSCs must be protected against hypoxic-ischemic damage in the ischemic penumbra. In the present study, we aimed to investigate the neuroprotective effects of the mfat-1 transgene on cobalt chloride (CoCl2 )-induced hypoxic-ischemic injury in cultured adult NSCs as well as its underlying mechanisms...
June 22, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28638070/thioesterase-ybgc-affects-motility-by-modulating-c-di-gmp-levels-in-shewanella-oneidensis
#14
Tong Gao, Qiu Meng, Haichun Gao
Because of ubiquity of thioesters, thioesterases play a critical role in metabolism, membrane biosynthesis, signal transduction, and gene regulation. In many bacteria, YbgC is such an enzyme, whose coding gene mostly resides in the tol-pal cluster. Although all other proteins encoded in the tol-pal cluster are clearly involved in maintaining cell envelope integrity and cell division, little is known about the physiological role of YbgC. In this study, we identify in Shewanella oneidensis, a γ-proteobacterium used as a research model for environmental microbes, YbgC as a motility regulator...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28637490/lipoid-congenital-adrenal-hyperplasia-by-steroidogenic-acute-regulatory-protein-star-gene-mutation-in-an-italian-infant-an-uncommon-cause-of-adrenal-insufficiency
#15
Carla Bizzarri, Elisa Pisaneschi, Mafalda Mucciolo, Stefania Pedicelli, Daniela Galeazzi, Antonio Novelli, Marco Cappa
BACKGROUND: Lipoid congenital adrenal hyperplasia (CAH) (OMIM n. 201710) is the most severe form of congenital adrenal hyperplasia. It is characterized by severe adrenal and gonadal steroidogenesis impairment due to a defect in the conversion of cholesterol to pregnenolone. Affected infants experience salt loss, but glucocorticoid and mineralocorticoid replacement therapy enables long-term survival. Classic lipoid congenital adrenal hyperplasia is relatively common in Japan and Korea but extremely rare in Caucasian populations...
June 20, 2017: Italian Journal of Pediatrics
https://www.readbyqxmd.com/read/28636657/novel-sirna-formulation-to-effectively-knockdown-mutant-p53-in-osteosarcoma
#16
Anup K Kundu, Swathi V Iyer, Sruti Chandra, Amit S Adhikari, Tomoo Iwakuma, Tarun K Mandal
OBJECTIVES: The tumor suppressor p53 plays a crucial role in the development of osteosarcoma. The primary objective of this study is to develop and optimize lipid based nanoparticle formulations that can carry siRNA and effectively silence mutant p53 in 318-1, a murine osteosarcoma cell line. METHODS: The nanoparticles were composed of a mixture of two lipids (cholesterol and DOTAP) and either PLGA or PLGA-PEG and prepared by using an EmulsiFlex-B3 high pressure homogenizer...
2017: PloS One
https://www.readbyqxmd.com/read/28636310/sensing-mechanisms-in-the-redox-regulated-2fe-2s-cluster-containing-bacterial-transcriptional-factor-soxr
#17
Kazuo Kobayashi
Bacteria possess molecular biosensors that enable responses to a variety of stressful conditions, including oxidative stress, toxic compounds, and interactions with other organisms, through elaborately coordinated regulation of gene expression. In Escherichia coli and related bacteria, the transcription factor SoxR functions as a sensor of oxidative stress and nitric oxide (NO). SoxR protein contains a [2Fe-2S] cluster essential for its transcription-enhancing activity, which is regulated by redox changes in the [2Fe-2S] cluster...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28634560/atypical-lipomatous-tumor-well-differentiated-liposarcoma-developed-in-a-patient-with-progressive-muscular-dystrophy-a-case-report-and-review-of-the-literature
#18
Ryo Miyagi, Toshihiko Nishisho, Shinjiro Takata, Yoshimitsu Shimatani, Shunichi Toki, Koichi Sairyo
BACKGROUND: Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLS) is an intermediate or locally aggressive form of adipocytic soft tissue sarcoma. Muscular dystrophy (MD) is characterized by progressive muscle atrophy and its replacement by adipose and fibrous tissue. Recently, some authors have reported that MD genes are related to neoplastic formation, but there have been no detailed clinical reports of ALT associated with MD. CASE PRESENTATION: A 73-year-old woman with a diagnosis of limb-girdle MD visited our department for recurrence of a huge tumor in her left thigh...
2017: Case Reports in Orthopedics
https://www.readbyqxmd.com/read/28634401/ohrr-of-mycobacterium-smegmatis-senses-and-responds-to-intracellular-organic-hydroperoxide-stress
#19
Omar A Garnica, Kishore Das, Subramanian Dhandayuthapani
Organic hydroperoxide reductase regulator (OhrR) in bacteria is a sensor for organic hydroperoxide stress and a transcriptional regulator for the enzyme organic hydroperoxide reductase (Ohr). In this study we investigated, using a GFP reporter system, whether Mycobacterium smegmatis OhrR has the ability to sense and respond to intracellular organic hydroperoxide stress. It was observed that M. smegmatis strains bearing the pohr-gfpuv fusion construct were able to express GFP only in the absence of an intact ohrR gene, but not in its presence...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28634034/absence-of-%C3%AE-chain-in-keratinocytes-alters-chemokine-secretion-resulting-in-reduced-immune-cell-recruitment
#20
Karolin Nowak, Daniela Linzner, Adrian J Thrasher, Paul F Lambert, Wei Li Di, Siobhan O Burns
Loss of function mutations in the common gamma (γc) chain cytokine receptor subunit give rise to severe combined immunodeficiency (SCID) characterised by lack of T and natural killer cells and infant death from infection. Haematopoietic stem cell transplantation or gene therapy offer cure but despite successful replacement of lymphoid immune lineages a long-term risk of severe cutaneous human papilloma virus (HPV) infections persists, possibly related to persistent γc-deficiency in other cell types. Here we demonstrate that keratinocytes, the only cell type directly infected by HPV, express functional γc and its co-receptors...
June 17, 2017: Journal of Investigative Dermatology
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