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https://www.readbyqxmd.com/read/29785143/pilot-study-of-the-antifibrotic-effects-of-the-multikinase-inhibitor-pacritinib-in-a-mouse-model-of-liver-fibrosis
#1
Suliman Al-Fayoumi, Taishi Hashiguchi, Yuka Shirakata, John Mascarenhas, Jack W Singer
Background: Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK-STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients...
2018: Journal of Experimental Pharmacology
https://www.readbyqxmd.com/read/29784948/simultaneous-cell-disruption-and-semi-quantitative-activity-assays-for-high-throughput-screening-of-thermostable-l-asparaginases
#2
Xu Li, Xian Zhang, Shuqin Xu, Hengwei Zhang, Meijuan Xu, Taowei Yang, Li Wang, Haifeng Qian, Huiling Zhang, Haitian Fang, Tolbert Osire, Zhiming Rao, Shangtian Yang
L-asparaginase, which catalyses the hydrolysis of L-asparagine to L-aspartate, has attracted the attention of researchers due to its expanded applications in medicine and the food industry. In this study, a novel thermostable L-asparaginase from Pyrococcus yayanosii CH1 was cloned and over-expressed in Bacillus subtilis 168. To obtain thermostable L-asparaginase mutants with higher activity, a robust high-throughput screening process was developed specifically for thermophilic enzymes. In this process, cell disruption and enzyme activity assays are simultaneously performed in 96-deep well plates...
May 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29784935/a-causal-mechanism-for-childhood-acute-lymphoblastic-leukaemia
#3
REVIEW
Mel Greaves
In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia...
May 21, 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29784885/-pseudomonas-aeruginosa-regulated-intramembrane-proteolysis-rip-protease-mucp-can-overcome-mutations-in-the-algo-periplasmic-protease-to-restore-alginate-production-in-nonmucoid-revertants
#4
Camila Delgado, Laura Florez, Ivonne Lollett, Christine Lopez, Shiva Kangeyan, Hansi Kumari, Marios Stylianou, Robert J Smiddy, Lisa Schneper, Robert T Sautter, George Szatmari, Kalai Mathee
The progression of cystic fibrosis (CF) from an acute to a chronic disease is often associated with the conversion of the opportunistic pathogen Pseudomonas aeruginosa from a nonmucoid form to a mucoid form in the lung. This conversion involves the overproduction of the exopolysaccharide alginate, whose production is under control of the AlgT/U sigma factor. This factor is regulated posttranslationally by an extremely unstable process and has been commonly attributed to mutations in the algT/U gene. By exploiting this unstable phenotype, we isolated 34 spontaneous nonmucoid variants arising from the mucoid strain PDO300, a PAO1 derivative containing the mucA22 allele commonly found in mucoid CF isolates...
May 21, 2018: Journal of Bacteriology
https://www.readbyqxmd.com/read/29784674/clinically-relevant-cytotoxic-immune-cell-signatures-and-clonal-expansion-of-t-cell-receptors-in-high-risk-mycn-not-amplified-human-neuroblastoma
#5
Jun S Wei, Igor B Kuznetsov, Shile Zhang, Young K Song, Shahab Asgharzadeh, Sivasish Sindiri, Xinyu Wen, Rajesh Patidar, Sushma Nagaraj, Ashley Walton, Jaime M Guidry Auvil, Daniela S Gerhard, Aysen Yuksel, Daniel R Catchpoole, Stephen M Hewitt, Paul M Sondel, Robert C Seeger, John M Maris, Javed Khan
PURPOSE: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). EXPERIMENTAL DESIGN: We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas...
May 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29781985/testing-the-role-of-multicopy-plasmids-in-the-evolution-of-antibiotic-resistance
#6
Jose Antonio Escudero, R Craig MacLean, Alvaro San Millan
Multicopy plasmids are extremely abundant in prokaryotes but their role in bacterial evolution remains poorly understood. We recently showed that the increase in gene copy number per cell provided by multicopy plasmids could accelerate the evolution of plasmid-encoded genes. In this work, we present an experimental system to test the ability of multicopy plasmids to promote gene evolution. Using simple molecular biology methods, we constructed a model system where an antibiotic resistance gene can be inserted into Escherichia coli MG1655, either in the chromosome or on a multicopy plasmid...
May 2, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29781609/enhancement-and-analysis-of-human-anti-aflatoxin-b1-afb1-scfv-antibody-ligand-interaction-using-chain-shuffling
#7
Kuntalee Rangnoi, Kiattawee Choowongkomon, Richard O'Kennedy, Florian Rüker, Montarop Yamabhai
A human anti-aflatoxin B1 (AFB1) scFv antibody (yAFB1-c3), selected from a naïve human phage-displayed scFv library, was used as a template for improving and analysis of antibody-ligand interactions using the chain-shuffling technique. The variable heavy and variable light (VH/VL) shuffled library was constructed from the VH of 25 pre-selected clones recombined with the VL of yAFB1-c3 and vice versa. Affinity selection from these library demonstrated that the VH domain played an important role in the binding of scFv to free AFB1...
May 21, 2018: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29781574/melanocyte-development-in-the-mouse-tail-epidermis-requires-the-adamts9-metalloproteinase
#8
Grace Tharmarajah, Ulrich Eckhard, Fagun Jain, Giada Marino, Anna Prudova, Oscar Urtatiz, Helmut Fuchs, Martin Hrabe de Angelis, Christopher M Overall, Catherine D Van Raamsdonk
The mouse tail has an important role in the study of melanogenesis, because mouse tail skin can be used to model human skin pigmentation. To better understand the development of melanocytes in the mouse tail, we cloned two dominant ENU-generated mutations of the Adamts9 gene, Und3 and Und4, which cause an unpigmented ring of epidermis in the middle of the tail, but do not alter pigmentation in the rest of the mouse. Adamts9 encodes a widely expressed zinc metalloprotease with thrombospondin type 1 repeats with few known substrates...
May 21, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29781496/a-universal-platform-for-selection-and-high-resolution-phenotypic-screening-of-bacterial-mutants-using-the-nanowell-slide
#9
H Antypas, M Veses-Garcia, E Weibull, H Andersson-Svahn, A Richter-Dahlfors
The Petri dish and microtiter plate are the golden standard for selection and screening of bacteria in microbiological research. To improve on the limited resolution and throughput of these methods, we developed a universal, user-friendly platform for selection and high-resolution phenotypic screening based on the nanowell slide. This miniaturized platform has an optimal ratio between throughput and assay complexity, holding 672 nanowells of 500 nl each. As monoclonality is essential in bacterial genetics, we used FACS to inoculate each nanowell with a single bacterium in 15 min...
May 21, 2018: Lab on a Chip
https://www.readbyqxmd.com/read/29780592/preleukemic-and-second-hit-mutational-events-in-an-acute-myeloid-leukemia-patient-with-a-novel-germline-runx1-mutation
#10
Isaac Ks Ng, Joanne Lee, Christopher Ng, Bustamin Kosmo, Lily Chiu, Elaine Seah, Michelle Meng Huang Mok, Karen Tan, Motomi Osato, Wee-Joo Chng, Benedict Yan, Lip Kun Tan
Background: Germline mutations in the RUNX1 transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear...
2018: Biomarker Research
https://www.readbyqxmd.com/read/29780320/cloning-and-transcriptional-activity-analysis-of-the-porcine-abcb1-gene-promoter-transcription-factor-sp1-regulates-the-expression-of-porcine-abcb1
#11
Tingting Guo, Jinhu Huang, Changchao Huan, Fang He, Yujuan Zhang, Zohaib A Bhutto, Liping Wang
P-Glycoprotein (P-gp, Abcb1) plays a crucial role in drug disposition and functions by hydrolyzing ATP. However, little is known about the regulatory elements governing the transcription of the porcine Abcb1 gene. In this study, the transcription start site of the pig Abcb1 gene was identified by 5'-RACE. A 1.9-kb fragment of the 5'-flanking region of the Abcb1 gene was cloned from pig genomic DNA and sequenced. The region critical for its promoter activity was investigated via progressive deletions. Further, using mutation assays, two proximal Sp1 binding sites within the 5'-flanking region of Abcb1 were proven to be important cis- regulatory elements involved in regulating the constitutive expression of porcine Abcb1 ...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29780013/use-of-internal-transcribed-spacer-sequence-polymorphisms-as-a-method-for-trichomonas-vaginalis-genotyping
#12
Hatice Ertabaklar, Sema Ertuğ, Serçin Özlem Çalışkan, Erdoğan Malatyalı, Bülent Bozdoğan
OBJECTIVE: Trichomonas vaginalis is the most common non-viral, sexually transmitted pathogen with a worldwide distribution. The aim of the present study was to design a new genotyping tool for T. vaginalis isolates using internal transcribed spacer (ITS) sequences. METHODS: First, a total of 20 cryopreserved T. vaginalis isolates were thawed and genomic DNA was isolated from fresh cultures. A polymerase chain reaction (PCR) was performed to amplify the ITS regions and the amplicons were sequenced...
March 2018: Türkiye Parazitolojii Dergisi
https://www.readbyqxmd.com/read/29779891/fixation-and-spread-of-somatic-mutations-in-adult-human-colonic-epithelium
#13
Anna M Nicholson, Cora Olpe, Alice Hoyle, Ann-Sofie Thorsen, Teja Rus, Mathilde Colombé, Roxanne Brunton-Sim, Richard Kemp, Kate Marks, Phil Quirke, Shalini Malhotra, Rogier Ten Hoopen, Ashraf Ibrahim, Cecilia Lindskog, Meagan B Myers, Barbara Parsons, Simon Tavaré, Mark Wilkinson, Edward Morrissey, Douglas J Winton
We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0...
May 11, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29777707/functional-analysis-of-juxta-and-intra-membrane-domains-of-murine-app-by-genome-editing-in-neuro2a-cells
#14
Nanaka Kaneshiro, Ryosuke Imaoka, Masato Komai, Taku Kashiyama, Takashi Sakurai, Takashi Uehara, Nobumasa Takasugi
Amyloid-β precursor protein (APP) correlates with the pathogenesis of certain brain diseases, such as Alzheimer disease (AD). APP is cleaved by several enzymes to produce APP metabolites, including the amyloid beta peptide (Aβ), which accumulates in the brain of AD patients. However, the exact functions of APP metabolites remain elusive. In this study, using genome editing technology, we mutated juxta- and intra-membrane domains of murine APP in the mouse neuroblastoma cell line, Neuro2a. We identified several clones that expressed characteristic patterns of APP metabolites...
May 16, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29777592/early-identification-of-unusually-clustered-mutations-and-a-root-cause-in-therapeutic-antibody-development
#15
Yueming Qian, Zhiqiang Chen, Xin Huang, Xuning Wang, Xuankuo Xu, Stefan Kirov, Richard Ludwig, Nan-Xin Qian, Kandasamy Ravi, Li Tao, Michael C Borys, Zheng Jian Li
This study reports findings of an unusual cluster of mutations spanning 22 base pairs in a monoclonal antibody (mAb) expression vector. It was identified by two orthogonal methods: mass spectrometry on expressed protein and next-generation sequencing (NGS) on the plasmid DNA. While the initial NGS analysis confirmed the designed sequence modification, intact mass analysis detected an additional mass of the antibody molecule expressed in CHO cells. The extra mass was eventually found to be associated with unmatched nucleotides in a distal region by checking full-length sequence alignment plots...
May 19, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29776931/shuffling-the-neutral-drift-of-unspecific-peroxygenase-in-saccharomyces-cerevisiae
#16
Javier Martin-Diaz, Carmen Paret, Eva García-Ruiz, Patricia Molina-Espeja, Miguel Alcalde
Unspecific peroxygenase (UPO) is a highly promiscuous biocatalyst and its selective mono(per)oxygenase activity makes it useful for many synthetic chemistry applications. Among the broad repertory of library creation methods for directed enzyme evolution, genetic drift allows neutral mutations to be accumulated gradually within a polymorphic network of variants. In this study, we conducted a campaign of genetic drift with UPO in Saccharomyces cerevisiae so that neutral mutations were simply added and recombined in vivo With low mutational loading and an activity threshold of 45% of the parent's native function, mutant libraries enriched in folded and active UPO variants were generated...
May 18, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29775500/endosperm-sugar-accumulation-caused-by-mutation-of-phs8-isa1-leads-to-pre-harvest-sprouting-in-rice
#17
Lin Du, Fan Xu, Jun Fang, Shaopei Gao, Jiuyou Tang, Shuang Fang, Hongru Wang, Hongning Tong, Fengxia Zhang, Jinfang Chu, Guodong Wang, Chengcai Chu
Pre-harvest sprouting (PHS) is an unfavorable trait in cereal crops which could seriously decrease grain yield and quality. Although some PHS-associated quantitative trait loci (QTL) or genes in cereals have been reported, the molecular mechanism underlying PHS remains largely elusive. Here, we characterized a rice mutant, phs8, which exhibits PHS phenotype accompanied by sugary endosperm. Map-based cloning revealed that PHS8 encodes a starch debranching enzyme named isoamylase1. Mutation in PHS8 resulted in the phytoglycogen breakdown and sugar accumulation in the endosperm...
May 18, 2018: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/29774030/changes-in-the-tcr%C3%AE-repertoire-and-tumor-immune-signature-from-a-cutaneous-melanoma-patient-immunized-with-the-csf-470-vaccine-a-case-report
#18
Mariana Aris, Alicia Inés Bravo, María Betina Pampena, Paula Alejandra Blanco, Ibel Carri, Daniel Koile, Patricio Yankilevich, Estrella Mariel Levy, María Marcela Barrio, José Mordoh
The allogeneic therapeutic vaccine CSF-470 has demonstrated a significant benefit over medium-dose IFNα2b in the distant metastasis-free survival for stages IIB-IIC-III cutaneous melanoma patients in a randomized phase II/III clinical trial (CASVAC-0401, NCT01729663). At the end of the 2-year CSF-470 immunization protocol, patient #006 developed several lung and one subcutaneous melanoma metastases; this later was excised. In this report, we analyzed the changes throughout vaccination of immune populations in blood and in the tumor tissue, with special focus on the T-cell repertoire...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29773895/crispr-cas9-system-targeting-regulatory-genes-of-hiv-1-inhibits-viral-replication-in-infected-t-cell-cultures
#19
Youdiil Ophinni, Mari Inoue, Tomohiro Kotaki, Masanori Kameoka
The CRISPR/Cas9 system provides a novel and promising tool for editing the HIV-1 proviral genome. We designed RNA-guided CRISPR/Cas9 targeting the HIV-1 regulatory genes tat and rev with guide RNAs (gRNA) selected from each gene based on CRISPR specificity and sequence conservation across six major HIV-1 subtypes. Each gRNA was cloned into lentiCRISPRv2 before co-transfection to create a lentiviral vector and transduction into target cells. CRISPR/Cas9 transduction into 293 T and HeLa cells stably expressing Tat and Rev proteins successfully abolished the expression of each protein relative to that in non-transduced and gRNA-absent vector-transduced cells...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29773106/-expression-and-purification-of-flt3-and-flt3-itd-mutated-proteins-in-hek293t-cells
#20
Fan Yang, Jiahui Du, Jie Wu, Puyu Yuan, Qian Su, Rong Han, Qiaocheng Qiu, Shengli Xue, Songbai Liu, Zhongwen Sun
Objective To construct the eukaryotic expression vectors of human fms related tyrosine kinase 3 (FLT3) gene and FLT3-internal tandem duplication (FLT3-ITD) mutants and purify the native proteins through immunoprecipitation from HEK293T cell lysates. Methods The cDNA fragments of FLT3wt and FLT3-ITD were amplified from bone marrow cells of healthy individuals and FLT3-ITD-mutated acute myeloid leukemia (AML) patients with specific primers, and the PCR products were cloned in CD530A-T2A-GFP expression vectors...
March 2018: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
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