Conception and design: ZY, XW, and QZ. Administrative support: XW, HL, and QZ. Experiment operation: HL, ZY, LS, YK, RL, XZ, YG, and CL. Data analysis and interpretation: HL, QZ, ZY, and LS. Manuscript writing: all authors. Final approval of manuscript: all authors. All authors contributed to the article and approved the submitted version. Funding Wiese, C., Grieskamp, T., Airik, R., Mommersteeg, M. T. M., Gardiwal, A., de Gier-de Vries, C., Schuster-Gossler, K., Moorman, A. F. M., Kispert, A., Christoffels, V. M. Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4 ( 607343), a gene encoding a zinc finger transcription factor, cause similar upper limb and heart defects. Mutations in SALL4 are responsible for the Duane-radial ray syndrome ( 607323); mutations in TBX5 are responsible for the Holt-Oram syndrome ( 142900). Koshiba-Takeuchi et al. (2006) showed that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 showed limb and heart defects that modeled human disease. Tbx5 and Sall4 interacted both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes.

They receive free parking between the hours of 7.30pm and 8.00am while visiting the child. This would apply to a maximum of 2 vehicles. 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 debtTo 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.

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). Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth.

References

By microdissection of the mouse ventricular conduction system, followed by serial analysis of gene expression (SAGE) of the left bundle branch, Moskowitz et al. (2007) identified Id2 (600386) as a conduction system-specific transcript. Analysis of the Id2 promoter showed that conduction system-specific expression of Id2 was dependent on Nkx2.5 and Tbx5. Moskowitz et al. (2007) concluded that a molecular pathway including Id2, Nkx2.5, and Tbx5 coordinates specification of ventricular myocytes into the ventricular conduction system lineage. 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

A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. 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 Material Kantaputra et al. (2002) described a Thai family in which the mother and 3 offspring were affected with a dominantly inherited malformation syndrome with short stature, upper limb anomaly, and minor craniofacial anomalies suggestive of HOS; however, molecular studies did not reveal any mutations in the TBX5 gene. One of the offspring, a 23-year-old man, was cardiologically asymptomatic, although echocardiography revealed he had a quadricuspid aortic valve associated with mild aortic regurgitation. If the individual receiving a benefit makes any contribution towards that benefit, the contribution will normally be taken into account in determining the amount or value of the benefit.

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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 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. 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).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. 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.