scholarly journals XAF1 as a modifier of p53 function and cancer susceptibility

2020 ◽  
Vol 6 (26) ◽  
pp. eaba3231
Author(s):  
Emilia M. Pinto ◽  
Bonald C. Figueiredo ◽  
Wenan Chen ◽  
Henrique C.R. Galvao ◽  
Maria Nirvana Formiga ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Whole Genome ◽  
Wild Type ◽  
Patients With Cancer ◽  
Aggressive Cancer ◽  
Cancer Phenotype ◽  
The Common ◽  
Functional Analyses ◽  
Mutant Haplotype ◽  
Founder Allele

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

Whole-genome analysis-based phylogeographic investigation of Streptococcus pneumoniae serotype 19A sequence type 320 isolates in Japan.

2021 ◽  
Author(s):  
Satoshi Nakano ◽  
Takao Fujisawa ◽  
Bin Chang ◽  
Yutaka Ito ◽  
Hideki Akeda ◽  
...  
Keyword(s):  
Common Ancestor ◽  
Sampling Bias ◽  
Health Concern ◽  
Recent Common Ancestor ◽  
Whole Genome ◽  
Whole Genome Analysis ◽  
Identification Rate ◽  
Most Recent Common Ancestor ◽  
The Common ◽  
The U.S

After the introduction of the seven-valent pneumococcal conjugate vaccine, the global spread of multidrug resistant serotype 19A-ST320 strains became a public health concern. In Japan, the main genotype of serotype 19A was ST3111, and the identification rate of ST320 was low. Although the isolates were sporadically detected in both adults and children, their origin remains unknown. Thus, by combining pneumococcal isolates collected in three nationwide pneumococcal surveillance studies conducted in Japan between 2008 and 2020, we analyzed 56 serotype 19A-ST320 isolates along with 931 global isolates, using whole-genome sequencing to uncover the transmission route of the globally distributed clone in Japan. The clone was frequently detected in Okinawa Prefecture, where the U.S. returned to Japan in 1972. Phylogenetic analysis demonstrated that the isolates from Japan were genetically related to those from the U.S.; therefore, the common ancestor may have originated in the U.S. In addition, Bayesian analysis suggested that the time to the most recent common ancestor of the isolates form Japan and the U.S. was approximately the 1990s to 2000, suggesting the possibility that the common ancestor could have already spread in the U.S. before the Taiwan 19F-14 isolate was first identified in a Taiwanese hospital in 1997. The phylogeographical analysis supported the transmission of the clone from the U.S. to Japan, but the analysis could be influenced by sampling bias. These results suggested the possibility that the serotype 19A-ST320 clone had already spread in the U.S. before being imported into Japan.

scholarly journals Metabolic reprogramming by folate restriction leads to a less aggressive cancer phenotype

2016 ◽  
Author(s):  
Z. Ashkavand ◽  
C. O'Flanagan ◽  
M. Hennig ◽  
X. Du ◽  
S. D. Hursting ◽  
...  
Keyword(s):  
Metabolic Reprogramming ◽  
Aggressive Cancer ◽  
Cancer Phenotype

Genetic characterization of Rhizobium sp. strain TAL1145 that nodulates tree legumes

1994 ◽  
Vol 40 (3) ◽  
pp. 208-215 ◽  
Author(s):  
M. L. C. George ◽  
J. P. W. Young ◽  
D. Borthakur
Keyword(s):  
Rhizobium Leguminosarum ◽  
Genetic Characterization ◽  
Rhizobium Meliloti ◽  
Wild Type ◽  
Tree Legumes ◽  
Wide Range ◽  
The Common ◽  
Rrna Sequences ◽  
Rhizobium Sp

Rhizobium sp. strain TALI 145 nodulates Leucaena ieucocephaia and Phaseolus vulgaris, in addition to a wide range of tropical tree legumes. Six overlapping clones that complemented nodulation defects in leucaena and bean rhizobia were isolated and a 40-kb map of the symbiosis region was constructed. The common nod and nifA genes were situated approximately 17 kb apart, with the nodlJ genes in between. These clones enabled a derivative of TAL1145 carrying a partially deleted pSym to form ineffective nodules on both leucaena and bean, and a similar derivative of Rhizobium etli TAL182 to form ineffective nodules on bean. When two representative clones, pUHR9 and pUHR114, were each transferred to wild-type rhizobial strains, they allowed ineffective nodulation by Rhizobium meliloti on both leucaena and bean and by Rhizobium leguminosarum bv. viciae on bean. Transconjugants of R. leguminosarum bv. trifolii formed effective nodules on leucaena and ineffective nodules on bean. Tn5 mutagenesis of the symbiosis region resulted in a variety of nodulation and fixation phenotypes on leucaena and bean. On the basis of 16S rRNA sequences, TAL1145 was found to be distinct from both R. tropici and NGR234, the two groups of leucaena symbionts that were previously described.Key words: Rhizobium, Leucaena leucocephala, nodulation, nitrogen fixation.

scholarly journals Mapping blood pressure loci in (A/J × B6)F2 mice

2003 ◽  
Vol 15 (3) ◽  
pp. 236-242 ◽  
Author(s):  
David D. L. Woo ◽  
Ira Kurtz
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Environmental Variables ◽  
Chromosome 17 ◽  
Whole Genome ◽  
Lod Score ◽  
Human Hypertension ◽  
Complex Genetics ◽  
The Common ◽  
Human Chromosome 17

Although the genetics of rare, monogenic, forms of human hypertension are fairly well defined, the genetics of the common polygenic form of human essential hypertension is only emerging. With the ability to control environmental variables, animal models have provided valuable tools with which to study blood pressure (BP) homeostasis. We have now studied BP genetics in a model consisting of 1,521 F2 mice from a series of (A/J × B6) intercrosses kept under standardized conditions. Using whole genome quantitative trait loci (QTL) mapping, we have identified four novel significant BP loci. These included Abbp1 on mouse chromosome MMU1 [maximum LOD score (MLS) at ∼35 cM = 6.8], Abbp2 on MMU4 (MLS at ∼25 cM = 9.8), Abbp3 on MMU7 (MLS at ∼25 cM = 5.4), and Abbp4 on MMU11 (MLS at ∼58 cM = 6.3). Compared with A/J homozygotes, homozygosity for the B6 alleles of Abbp1, Abbp2, or Abbp4 is independently associated with a 7–12 mmHg increase in BP. In contrast Abbp3 interacts epistatically with a locus on MMU17 (near D17Mit180) to modulate BPs in female (A/J × B6)F2 mice. Interestingly, Abbp4 on MMU11 is homologous to a major confirmed BP locus, BP1, on rat chromosome 10 and to a major confirmed BP locus, HYT1, on human chromosome 17. Defining the molecular differences between the A/J and the B6 alleles at these novel loci with major influences on the BP phenotype will contribute to our understanding of the complex genetics of BP control.

scholarly journals Mechanism of PQQ and CoQ10 overproduction in Methylobacterium as revealed by comparative genomic analysis between mutant and wild-type strains

2020 ◽  
Author(s):  
Changle Zhao ◽  
Yinping Wan ◽  
Xiaojie Cao ◽  
Huili Zhang ◽  
Xin Bao
Keyword(s):  
Mutant Strain ◽  
Type Strain ◽  
Wild Type Strain ◽  
Genomic Analysis ◽  
Comparative Genomic Analysis ◽  
Comparative Genomic ◽  
Regulation Mechanism ◽  
Whole Genome ◽  
Wild Type ◽  
Coq10 Production

Abstract Background The microbial synthesis of pyrroloquinoline quinone (PQQ) and Coenzyme Q10 (CoQ10) remains the most promising industrial production route. Methylobacterium has been used to generate PQQ and other value-added chemicals from cheap carbon feedstocks.However, the low PQQ and CoQ10 production capacity of the Methylobacterium strains is a major limitation The regulation mechanism for PQQ and CoQ10 biosynthesis in this strain has also not been fully elucidated. Results Methylobacterium sp. CLZ strain was isolated from soil contaminated with chemical wastewater, which can simultaneously produce PQQ, CoQ10, and carotenoids by using cheap methanol as carbon source. We investigated a mutant strain NI91, which increased the PQQ and CoQ10 yield by 72.44% and 59.80%, respectively. Whole-genome sequencing of NI91 and wild-type strain CLZ revealed that both contain a 5.28 Mb chromosome. The comparative genomic analysis and validation study revealed that a significant increase in biomass and PQQ production was associated with the base mutations in the methanol dehydrogenase (MDH) synthesis genes, mxaD and mxaJ. The significant increase in CoQ10 production may be associated with the base mutations in dxs gene, a key gene in the MEP/DOXP pathway. Conclusions A PQQ producing strain that simultaneously produces CoQ10 and carotenoids was selected and after ANI analysis, named as Methylobacterium sp. CLZ. After random mutagenesis of this strain, we obtained NI91 strain, which showed increased production of PQQ and CoQ10. Based on comparative genomic analysis of the whole genome of mutant strain NI91 and wild-type strain CLZ, a total of 270 SNPs and InDels events were detected, which provided a reference for subsequent research. The mutations in mxaD, mxaJ and dxs genes may be related to the high yield of PQQ and CoQ10. These findings will enhance our understanding of the PQQ and CoQ10 over-production mechanism in Methylobacterium sp. NI91 at the genomic level. It will also provide useful clues for strain engineering in order to improve the PQQ and CoQ10 production.

scholarly journals Whole genome analysis of the common pathogens associated with microbial keratitis

2019 ◽  
Vol 1 (1A) ◽  
Author(s):  
Michael Glenn ◽  
Stephen Kaye ◽  
Timothy Neal ◽  
Paul Roberts ◽  
Craig Winstanley ◽  
...  
Keyword(s):  
Genome Analysis ◽  
Whole Genome ◽  
Microbial Keratitis ◽  
Whole Genome Analysis ◽  
The Common

scholarly journals Identification of TAZ as a Binding Partner of the Polyomavirus T Antigens

2004 ◽  
Vol 78 (22) ◽  
pp. 12657-12664 ◽  
Author(s):  
Yu Tian ◽  
Dawei Li ◽  
Jean Dahl ◽  
John You ◽  
Thomas Benjamin
Keyword(s):  
Dna Replication ◽  
Host Range ◽  
T Antigen ◽  
Binding Motif ◽  
Wild Type ◽  
T Antigens ◽  
Ww Domain ◽  
Binding Partner ◽  
N Terminus ◽  
The Common

ABSTRACT A polyomavirus mutant isolated by the tumor host range selection procedure (19) has a three-amino-acid deletion (Δ2-4) in the common N terminus of the T antigens. To search for a cellular protein bound by wild-type but not the mutant T antigen(s), a yeast two-hybrid screen of a mouse embryo cDNA library was carried out with a bait of wild-type small T antigen (sT) fused N terminally to the DNA-binding domain of Gal4. TAZ, a transcriptional coactivator with a WW domain and PDZ-binding motif (17), was identified as a binding partner. TAZ bound in vivo to all three T antigens with different apparent affinities estimated as 1:7:100 (large T antigen [lT]:middle T antigen [mT]:sT). The Δ2-4 mutant T antigens showed no detectable binding. The sT and mT of the host range transformation-defective (hr-t) mutant NG59 with an alteration in the common sT/mT region (179 D→NI) and a normal N terminus also failed to bind TAZ, while the unaltered lT bound but with reduced affinity compared to that seen in a wild-type virus infection. The WW domain but not the PDZ-binding motif of TAZ was essential for T antigen binding. The Δ2-4 mutant was defective in viral DNA replication. Forced overexpression of TAZ blocked wild-type DNA replication in a manner dependent on the binding site for the polyomavirus enhancer-binding protein 2α. Wild-type polyomavirus T antigens effectively block transactivation by TAZ. The functional significance of TAZ interactions with polyomavirus T antigens is discussed.

scholarly journals Thrombospondins 1 and 2 are Necessary for Synaptic Plasticity and Functional Recovery after Stroke

2008 ◽  
Vol 28 (10) ◽  
pp. 1722-1732 ◽  
Author(s):  
Jason Liauw ◽  
Stanley Hoang ◽  
Michael Choi ◽  
Cagla Eroglu ◽  
Matthew Choi ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Synapse Formation ◽  
Axonal Sprouting ◽  
Wild Type ◽  
Synaptic Density ◽  
Significant Deficit ◽  
The Common ◽  
Distal Middle Cerebral Artery

Thrombospondins 1 and 2 (TSP-1/2) belong to a family of extracellular glycoproteins with angiostatic and synaptogenic properties. Although TSP-1/2 have been postulated to drive the resolution of postischemic angiogenesis, their role in synaptic and functional recovery is unknown. We investigated whether TSP-1/2 are necessary for synaptic and motor recovery after stroke. Focal ischemia was induced in 8- to 12-week-old wild-type (WT) and TSP-1/2 knockout (KO) mice by unilateral occlusion of the distal middle cerebral artery and the common carotid artery (CCA). Thrombospondins 1 and 2 increased after stroke, with both TSP-1 and TSP-2 colocalizing mostly to astrocytes. Wild-type and TSP-1/2 KO mice were compared in angiogenesis, synaptic density, axonal sprouting, infarct size, and functional recovery at different time points after stroke. Using the tongue protrusion test of motor function, we observed that TSP-1/2 KO mice exhibited significant deficit in their ability to recover function ( P < 0.05) compared with WT mice. No differences were found in infarct size and blood vessel density between the two groups after stroke. However, TSP-1/2 KO mice exhibited significant synaptic density and axonal sprouting deficits. Deficiency of TSP-1/2 leads to impaired recovery after stroke mainly due to the role of these proteins in synapse formation and axonal outgrowth.

scholarly journals Whole genome re-sequencing of two ‘wild-type’ strains of the model cyanobacteriumSynechocystissp. PCC 6803

2014 ◽  
Vol 52 (1) ◽  
pp. 36-47 ◽  
Author(s):  
JN Morris ◽  
TS Crawford ◽  
A Jeffs ◽  
PA Stockwell ◽  
JJ Eaton-Rye ◽  
...  
Keyword(s):  
Whole Genome ◽  
Wild Type ◽  
Type Strains ◽  
Pcc 6803

scholarly journals Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4283-4287 ◽  
Author(s):  
Yue Si ◽  
Samantha Ciccone ◽  
Feng-Chun Yang ◽  
Jin Yuan ◽  
Daisy Zeng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Interferon Gamma ◽  
Cancer Susceptibility ◽  
Genetic Disorder ◽  
Wild Type ◽  
Regulatory Cytokine ◽  
Complementation Groups ◽  
Ifn Γ

Abstract Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc–/– cells to interferon-gamma (IFN-γ), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc–/– mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca–/– and Fancg–/– mice are hypersensitive to IFN-γ and that in vivo infusion of IFN-γ at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-γ conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.

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