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Using lineage tracing in mice, Wang et al. (2015) found that Axin2 (604025) identifies a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3 and are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Wang et al. (2015) concluded that they identified a cell population in the liver that subserves homeostatic hepatocyte renewal, characterizes its anatomic niche, and identifies molecular signals that regulate its activity. Garg et al. (2003) demonstrated that GATA4 (600576) interacts with TBX5 and showed that a missense mutation in GATA4, G296S (600576.0001), abrogated this interaction. Conversely, interaction of GATA4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. Garg et al. (2003) concluded that their results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5. The main aim of this study was to assess the global metabonomics and metastasis changes in A549 cell line after carbon ion radiation. Ionizingradiationis defined as aradiationwhich has sufficient energy to ionize biological molecules. Carbon ion therapy is more advantageous than conventional radiotherapy because of the protection of normal tissues adjacent to the tumor during dose-escalation therapy ( 20). In this study, we first investigated the direct effects of carbon ions on A549 cells, and carbon ion radiation caused changes in the colony formation and proliferation of A549 cells. We observed that the colony formation rate of A549 cells irradiated with carbon ion rays was significantly lower, and the colony formation rate and survival fraction of A549 cells were significantly lower after irradiation at each dose (1, 2, and 4 Gy) compared with 0 Gy, especially this change was most pronounced at 4 Gy. Carbon ions could inhibit the proliferation of A549 cells, and the activity of A549 cells was the lowest at 24h after irradiation, as we previously observed in esophageal cancer ( 21). Secondly, we studied the effect of carbon ion irradiation on the metastasis of A549 cells, and analyzed the migration and invasion of A549 cells after carbon ion irradiation. We observed that carbon ion 2 and 4 Gy significantly inhibited the migration and invasion of A549 cells 24h after irradiation compared with 0 Gy. Different LET rays can inhibit the migration and invasion of tumor cells ( 22), with a dependent relationship between the inhibitory ability and irradiation dose ( 23). At the same time, the indirect effect of carbon ion irradiation on A549 cells was studied. The culture medium collected 24h after 2 Gy carbon ion irradiation on human normal cells (WI-38) was transferred to A549 cells by the method reported by ( 13, 24), and the metastasis changes of A549 cells were observed again. The co-culture method was used to study the bystander effect induced by iron ion irradiation in AG01522 cells and its relationship with time ( 25). It was found that the medium of A549 cells after carbon ion radiation was used as a medium, thus changing the biology of non-irradiated cells. Carbon ions induce upsurge in bystander cell death in lung carcinoma cells, but manifest Type II bystander effects in hepatoma cells ( 26). It is possible that the primary bystander cells themselves are capable of producing secondary bystander signals to their neighboring cells and creating the radiation-induced Type II bystander effect. Murakami et al. (2005) found that TAZ (WWTR1; 300394) was a potent TBX5 transactivator. TAZ associated with TBX5 and stimulated TBX5-dependent promoters by interacting with the histone acetyltransferases p300 (EP300; 602700) and PCAF ( 602303). YAP ( 606608), a TAZ-related protein, also stimulated TBX5-dependent transcription. TBX5 with HOS-associated truncation mutations could not be stimulated by TAZ, but TBX5 with HOS-associated point mutations was unimpaired in its ability to respond to TAZ. Koshiba-Takeuchi, K., Takeuchi, J. K., Matsumoto, K., Momose, T., Uno, K., Hoepker, V., Ogura, K., Takahashi, N., Nakamura, H., Yasuda, K., Ogura, T.
Lenz (1968) noted that the involvement of the arms in the Holt-Oram syndrome can be sufficiently severe to simulate thalidomide embryopathy. In a Czech mother and 2 daughters who were diagnosed with Holt-Oram syndrome, Borozdin et al. (2006) identified a 2.19 to 2.27-Mb contiguous deletion encompassing the TBX5 and TBX3 genes. Clinical reexamination confirmed the presence of features of ulnar-mammary syndrome that were previously unrecognized. Borozdin et al. (2006) noted that the contiguous deletion also included the RBM19 gene (616444), but commented that it was unlikely to contribute to or modify the phenotype since all the anomalies present in the affected individuals could be explained by either TBX5 or TBX3 haploinsufficiency. Bruneau et al. (2001) generated heterozygous Tbx5 -/+ mice to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5 -/-) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (Anf, or Nppa) and connexin-40 (Cx40; 121013) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50% reduction of T-box transcription factors causes disease. Direct and cooperative transactivation of the Anf and Cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provided a potential explanation for Holt-Oram syndrome conduction system defects, suggested mechanisms for intrafamilial phenotypic variability, and accounted for related cardiac malformations caused by other transcription factor mutations. Results: Compared with 0 Gy, the colony formation, migration, and invasion of A549 cells were significantly inhibited by carbon ion 2 and 4 Gy irradiation, while the inhibitory effect was not significant after 1 Gy irradiation. Compared with 0 Gy, the culture medium 24h after carbon ion 2 Gy irradiation significantly inhibited the metastasis of tumor cells ( p = 0.03). LC-MS analysis showed that 23 differential metabolites were obtained in the cell culture medium 24h after carbon ion 0 and 2 Gy irradiation (9 up-regulated and 14 down-regulated). Among them, two were up-regulated and two down-regulated ( p = 2.9 × 10 −3). 41 target proteins were corresponding to these four differential molecules. Through the analysis of the KEGG signal pathway, it was found that these target molecules were mainly enriched in purine metabolism, tyrosine metabolism, cysteine and methionine metabolism, peroxisome, and carbon metabolism. Neuroactive ligand-receptor interaction, calcium signaling pathway, arachidonic acid metabolism, and Fc epsilon RI signaling pathway.Where the benefit received is in the form of an asset, other than cash, and the ownership of that asset actually passes to the individual as opposed to an asset being made available for use which remains in the ownership of the provider. The amount or value of the benefit is likely to be determined by reference to the value of the asset at the point in time when it is received by the individual. In most cases this is likely to be similar to the approach that may be adopted for capital gains purposes where it may be appropriate to determine the open market acquisition value of the asset to the individual. Satisfying a debt Zhu et al. (2008) generated mice with haploinsufficiency of Tbx5 in ventricular myocytes only and observed diastolic dysfunction due to a cell-autonomous defect in myocyte relaxation but no atrial or ventricular septal defects or conduction defects. Tbx5-haploinsufficient mice had significantly decreased left ventricular protein levels of SERCA2a (ATP2A2; 108740) and decreased mRNA levels of Tbx5 and Atp2a2. Similarly, there was a decrease in rate and amplitude of Ca(2+) uptake and Ca(2+) transient prolongation in left ventricular tissue. The authors demonstrated that Tbx5 activated an Atp2a2 promoter-reporter construct. Doppler analysis of 8 patients with clinically diagnosed Holt-Oram syndrome, 1 of whom was known to carry a mutation in the TBX5 gene, showed diastolic filling abnormalities of variable severity and type. Zhu et al. (2008) concluded that there is a direct genetic pathway regulating cardiac diastolic function, and that patients with structural congenital heart defects may also have underlying anomalies in heart function. A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Newbury-Ecob et al. (1996) reported a detailed study of a large cohort of patients that included 44 familial and 11 sporadic cases. Association of cardiac and radial abnormalities was a criterion for inclusion of familial cases. Limb defects were found in all affected persons. The thumb was the most commonly affected structure, although in 7 of 44 cases, the thumbs were normal. In most cases, the thumb defects (absence in 19/44, hypoplasia in 17/44, triphalangeal thumbs in 8/44) were associated with hypoplastic thenar or limited supination of the forearm. Radial hypoplasia (18/44) was more frequent than absence of radius (10/44). Ulnar hypoplasia occurred only in patients with radial defects. Most patients had narrow, sloping shoulders. Limb defects were always bilateral and often asymmetrical, the left side being more severely affected. Cardiac involvement was found in 95% of familial cases; secundum atrial septal defect (15) and ventricular septal defect (11) were the most common defects. In 17 of the familial cases, only ECG abnormalities were found. Both cardiac and limb abnormalities were more severe in the sporadic group. Newbury-Ecob et al. (1996) found a significant positive correlation (r = 0.49) between severity of the limb and cardiac defects. The patients with atrial septal defects had more severe limb abnormalities. Correlation between sibs was greater than that between parent and offspring. Garg et al. (2003) demonstrated that GATA4 ( 600576) interacts with TBX5 and showed that a missense mutation in GATA4, G296S ( 600576.0001), abrogated this interaction. Conversely, interaction of GATA4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. Garg et al. (2003) concluded that their results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.
In 2018, there were 18.1 million new cases of cancer worldwide, of which the incidence of lung cancer was 11.6% and the mortality rate was 18.4% ( 1). However, the metastasis of lung cancer is a major cause of treatment failure ( 2). Carbon ions with high LET rays ( 12C 6+) can inhibit the metastasis of tumor cells by their advantages in physics and biology ( 3, 4). Radiation induces bystander effect (RIBE) refers to the plethora of biological phenomena occurring in non-irradiated cells as a result of signal transmission from an irradiated cell ( 5). The study of proton targeting cancer cells and unirradiated normal fibroblasts also found an induced bi-directional bystander effect, and RIBE was detected in vitro, 3D tissues and mouse models ( 6).Growing evidence show that bystander responses can be regulated by four mechanisms-(i) gap junction intercellular communication (ii) communication of soluble factors released by irradiated cells or organs (iii) clastogenic factors and exosomes ( 7, 8).Through this study, we prove the potential value of metabonomics after carbon ion radiation. The bystander effects induced by carbon ion radiation may change the non-irradiated tumor microenvironment, thus increasing or decreasing the corresponding metabolites. These metabolites can act on targeted molecules and finally show the ability of collective complex signal regulatory network to act on the metastasis and invasion of malignant tumor cells. The further study of radiation bystander effect and malignant tumor metastasis and its mechanism is expected to provide a scientific basis for the optimization of clinical tumor radiotherapy and radiation protection. A better understanding of the cellular and molecular mechanisms of the bystander phenomenon, together with evidence of their occurrence in vivo, will allow us to formulate a more accurate model in assessing the health effects of low doses of high LET radiation. Data Availability Statement Sowden et al. (2001) examined the role of Drosophila 'optomotor blind' (omb)-related T-box genes in the development of human and mouse retina. Murine Tbx2 ( 600747), Tbx3, and Tbx5 and human TBX2 cDNAs were isolated from retina cDNA libraries by hybridization to the Drosophila omb gene. Human and mouse TBX2, TBX3, and TBX5 were expressed asymmetrically across the embryonic neural retina, with highest levels of mRNA within dorsal and peripheral retina. The dorsoventral gradient of TBX2 expression disappeared before the ganglion cell layer (GCL) formed. Its expression became restricted to the inner neuroblastic retina and later to the GCL and inner nuclear layer (INL). The dorsal expression domains of TBX5 and TBX3 were maintained during formation of the GCL. As the retina matured, TBX3 expression was restricted to the INL, and TBX5 was expressed within the GCL. The authors concluded that the expression patterns of TBX2, TBX3, and TBX5 within the developing retina support the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping in differentiation of distinct cell types across the laminar axis of the retina.
Parking will be provided free to all outpatients who attend hospital for an appointment at least 3 times within a month and for an overall period of at least 3 months. A ‘month’ is defined as a period of 30 days. Basson et al. (1999) identified heterozygous mutations in the TBX5 gene in affected members of several families segregating HOS (see, e.g., 601620.0002-601620.0005). Brassington, A.-M. E., Sung, S. S., Toydemir, R. M., Le, T., Roeder, A. D., Rutherford, A. E., Whitby, F. G., Jorde, L. B., Bamshad, M. J. Heavy ions were obtained from the carbon ion ( 12C 6+) beam of the Deep Therapy Terminal, Institute of Modern Physics, Chinese Academy of Sciences (HIRFL-CSR) (Ray parameters: energy of 100 MeV, the dose rate of 1 Gy/min, broadened Bragg peak of 5mm, radiation field of 5cm × 5cm), for cell irradiation. Irradiation doses were 0, 1, 2, and 4 Gy. The experiment was repeated four times. Medium Transfer ProtocolNadadur, R. D., Broman, M. T., Boukens, B., Mazurek, S. R., Yang, X., van den Boogaard, M., Bekeny, J., Gadek, M., Ward, T., Zhang, M., Qiao, Y., Martin, J. F., Seidman, C. E., Seidman, J., Christoffels, V., Efimov, I. R., McNally, E. M., Weber, C. R., Moskowitz, I. P. In affected members of a large 3-generation Turkish family segregating autosomal dominant ulnar-mammary syndrome, Wollnik et al. (2002) identified heterozygosity for a frameshift mutation in TBX3 ( 601621.0004). BlueTooth Heading Sensor detects changes in the boats Heading due to wind and current and communicated to the-iPilot system, to minimise boat swing for a more accurate stronger hold (requires separate power supply)
To understand better the role of TBX5 in forelimb and heart development, Basson et al. (1999) studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities in both limb and heart. In contrast, missense mutations produced distinct phenotypes: gly80-to-arg (601620.0004) caused significant cardiac malformations but only minor skeletal abnormalities, whereas arg237-to-gln (601620.0003) and arg237-to-trp (601620.0005) caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the 3-dimensional structure of a related T-box transcription factor, Xbra (of X. laevis), bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggested that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences. The article were supported by the Lanzhou Innovation and Entrepreneurship Talent Project (award number: 2017-RC-23/2020-RC-113) and the Science and Technology Plan Project of Chengguan District, Lanzhou (award number: no. 2020-2-2-5). Conflict of Interest The parent of a child in hospital overnight is a parent or guardian of a child or young person, under 18 years of age, who is admitted as an inpatient at hospital overnight. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Supplementary MaterialWhere the benefit received is the provision of accommodation without charge to the individual, the amount or value of the benefit is likely to be determined from a consideration of the market rental that the property may have fetched at the time the benefit is received.
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