CCAAT/enhancer-binding protein (C/EBP) β is required for both mitotic clonal expansion (MCE) and terminal adipocyte differentiation of 3T3-L1 preadipocytes. Although the role of C/EBPβ in terminal adipocyte differentiation is well defined, its mechanism of action during MCE is not. In this report, histone demethylase Kdm4b, as well as cell cycle genes Cdc45l (cell division cycle 45 homolog), Mcm3 (mini-chromosome maintenance complex component 3), Gins1 (GINS complex subunit 1) and Cdc25c (cell division cycle 25 homolog c), were identified as potential C/EBPβ target genes during MCE by utilizing promoter-wide chromatin immunoprecipitation (ChIP)-on-chip analysis combined with gene expression microarrays. The expression of Kdm4b is induced during MCE and its induction is dependent on C/EBPβ. ChIP, Electrophoretic Mobility Shift Assay (EMSA) and luciferase assay confirmed that the promoter of Kdm4b is bound and activated by C/EBPβ. Knockdown of Kdm4b impaired MCE. Furthermore, Kdm4b interacted with C/EBPβ and was recruited to the promoters of C/EBPβ-regulated cell cycle genes, including Cdc45l, Mcm3, Gins1, and Cdc25c, demethylated H3K9me3 and activated their transcription. These findings suggest a novel feed forward mechanism involving a DNA binding transcription factor (C/EBPβ) and a chromatin regulator (Kdm4b) in the regulation of MCE by controlling cell cycle gene expression.
3T3-L1 preadipocytes; adipocyte differentiation; mitotic clonal expansion; C/EBPβ; Kdm4b; ChIP-on-chip
This study was conducted to evaluate chemical composition, nitrogen-corrected true metabolizable energy (TMEn) and true amino acids digestibility of corn distillers dried grains with solubles (DDGS) produced in China. Twenty five sources of corn DDGS was collected from 8 provinces of China. A precision-fed rooster assay was used to determine TMEn and amino acids digestibility with 35 adult cecectomized roosters, in which each DDGS sample was tube fed (30 g). The average content of ash, crude protein, total amino acid, ether extract, crude fiber and neutral detergent fiber were 4.81, 27.91, 22.51, 15.22, 6.35 and 37.58%, respectively. TMEn of DDGS ranged from 1,779 to 3,071 kcal/kg and averaged 2,517 kcal/kg. Coefficient of variation for non-amino acid crude protein, ether extract, crude fiber and TMEn were 55.0, 15.7, 15.9 and 17.1%, respectively. The average true amino acid digestibility was 77.32%. Stepwise regression analysis obtained the following equation: TMEn, kcal/kg = −2,995.6+0.88×gross energy+49.63×a* (BIC = 248.8; RMSE = 190.8; p<0.01). Removing gross energy from the model obtained the following equation: TMEn, kcal/kg = 57.88×ether extracts+87.62×a* (BIC = 254.3, RMSE = 223.5; p<0.01). No correlation was found between color scores and lysine true digestibility (p>0.05). These results suggest that corn DDGS produced in China has a large variation in chemical composition, and gross energy and a* value can be used to generate TMEn predict equation.
Amino Acid; Corn Distillers Dried Grains with Solubles; Nitrogen-corrected True Metabolizable Energy; Rooster
Bone size is an important determinant of bone strength and is under strong genetic control.
To identify quantitative trait loci (QTL) for areal bone size variation, a large‐scale genomewide linkage scan was carried out in 451 Caucasian families.
Participants and methods
Of 4124 people with phenotypes, 3899 were genotyped with 410 microsatellite markers. Multipoint linkage analyses were carried out in the entire sample, as well as in men and women separately. Potential epistatic interactions between identified genomic regions were also assessed.
Several potentially important genomic regions were identified, such as 8q24 for hip bone size (logarithm of the ratio of the odds that two loci are linked (LOD) 3.27) and 2p24 (LOD 2.04) for spine bone size. 8q24 may also interact with 19p13 to affect hip bone size. Several sex‐specific QTL were also detected, such as 14q21 (LOD 2.94) for wrist bone size in women and 16q12 (LOD 2.19) for hip bone size in men.
Together with previous findings, this study has further delineated the genetic basis of bone size and laid a foundation for future studies to eventually elucidate the mechanisms of bone size regulation and associated fracture risks.
Investigations using Drosophila melanogaster have shown that the circadian clock gene period can influence behavioral responses to cocaine, and the mouse homologues, mPer1 and mPer2, modulate cocaine sensitization and reward. In the present study, we applied DNAzyme targeting mPer1 to interfere the expression of mPer1 in CNS in mice and studied the role of mPer1 on morphine dependence. We found that the DNAzyme could attenuate the expression of mPer1 in CNS in mice. Mice treated with DNAzyme and morphine synchronously did not show preference to the morphine-trained side, whereas the control group did. In contrast, mice treated with DNAzyme after morphine showed preference to the morphine-trained side as well as the control group did. These results indicate that drug dependence seems to be influenced at least partially by mPer1, but mPer1 cannot affect morphine dependence that has been formed.
drug dependence; DNAzyme; learning and memory; circadian; i.c.v.
Objective: To test the hypothesis that activation of peroxisome proliferator activated receptor γ (PPAR-γ) reduces experimental autoimmune myocarditis (EAM) associated with inhibitor κB (IκB) α induction, blockade of nuclear factor κB (NF-κB), and inhibition of inflammatory cytokine expression.
Methods: EAM was induced in Lewis rats by immunisation with porcine cardiac myosin. PPAR-γ activators 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and pioglitazone (PIO) were administered to rats with EAM.
Results: Enhanced PPAR-γ expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of 15d-PGJ2 and PIO greatly reduced the severity of myocarditis and suppressed myocardial mRNA and protein expression of inflammatory cytokines in rats with EAM. In addition, treatment with PPAR-γ activators enhanced IκB concentrations in the cytoplasmic fractions and nuclear fractions from inflammatory myocardium. Concurrently, NF-κB was greatly activated in myocarditis; this activation was blocked in the 15d-PGJ2 treated and PIO treated groups.
Conclusions: PPAR-γ may have a role in the pathophysiology of EAM. Because an increase in IκB expression and inhibition of translocation of the NF-κB subunit p65 to the nucleus in inflammatory cells correlated with the protective effects of PPAR-γ activators, these results suggest that PPAR-γ activators act sequentially through PPAR-γ activation, IκB induction, blockade of NF-κB activation, and inhibition of inflammatory cytokine expression. These results suggest that PPAR-γ activators such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.
myocarditis; immunity; PPAR-γ; NF-κB; cytokine; inflammation
To evaluate the efficacy and safety of phacoemulsification using torsional modality with different parameter settings for hard nucleus cataract extraction.
A prospective, randomised clinical study.
A clinical practice study conducted at the Cataract Service, Zhongshan Ophthalmic Center, Sun-Yat-Sen University, and Guangzhou. One eye each from 198 consecutive patients with cataract density grade IV according to the Emery–Little system classification system, requiring phacoemulsification and intraocular lens implantation, was included. Eyes were randomly assigned to the Linear Torsional combined with Ultrasound power group (Linear Tor+US group, n = 66), 100% Fixed Torsional group (Fixed Tor group, n = 65) and conventional Ultrasound burst group (US group, n = 67). All surgeries were performed by a single experienced surgeon and outcomes evaluated by another surgeon masked to treatment. Intraoperative parameters were Ultrasound Time (UST), Cumulative Dissipated Energy (CDE) and surgical complications. Patients were examined on post-op days 1, 7 and 30. Postoperative outcomes were final best corrected visual acuity (BCVA), average central and incisional corneal thickness and central endothelial cell counts.
The mean UST was lower in the Fixed Tor group than in the US group and in the Lin US+Tor group (p⩽0.0001). The mean CDE was lower in the Lin Tor+US group and in the Fixed Tor group than in the US group (p⩽0.0001). Comparing with the two Tor group, the US group had a lower average BCVA on post-op 1, 7 (p⩽0.0001) and 30 (p>0.01), greater average central corneal and incisional thickness on days 1, 7 (p⩽0.0001) and 30 (p>0.01), and higher average corneal endothelial cell losses on day 7 and 30 days (p⩽0.0001).
Torsional combined with ultrasound power or high fixed torsional amplitude can yield more effective hard nucleus phacoemulsification than conventional ultrasound modality.
Background: Osteoporosis is a major public health problem, mainly quantified by low bone mineral density (BMD). The majority of BMD variation is determined by genetic effects. A pilot whole genome linkage scan (WGS) was previously reported in 53 white pedigrees with 630 subjects. Several genomic regions were suggested to be linked to BMD variation.
Objective: To substantiate these previous findings and detect new genomic regions.
Methods: A WGS was conducted on an extended sample where the size was almost tripled (1816 subjects from 79 pedigrees). All the subjects were genotyped with 451 microsatellite markers spaced ∼8.1 cM apart across the human genome. Two point and multipoint linkage analyses were carried out using the variance component method.
Results: The strongest linkage signal was obtained on Xq27 with two point LOD scores of 4.30 for wrist BMD, and 2.57 for hip BMD, respectively. Another important region was 11q23, which achieved a maximum LOD score of 3.13 for spine BMD in multipoint analyses, confirming the results on this region in two earlier independent studies. Suggestive linkage evidence was also found on 7p14 and 20p12.
Conclusions: Together with the findings from other studies, the current study has further delineated the genetic basis of bone mass and highlights the importance of increasing sample size to confirm linkage findings and to identify new regions of linkage.
Osteoarthritis (OA) risk is widely recognized to be heritable but few loci have been identified. Observational studies have identified higher systemic bone mineral density (BMD) to be associated with an increased risk of radiographic knee osteoarthritis. With this in mind, we sought to evaluate whether well-established genetic loci for variance in BMD are associated with risk for radiographic OA in the Osteoarthritis Initiative (OAI) and the Johnston County Osteoarthritis (JoCo) Project. Cases had at least one knee with definite radiographic OA defined as the presence of definite osteophytes with or without joint space narrowing (KL grade ≥ 2) and controls were absent for definite radiographic OA in both knees (KL grade ≤ 1bilaterally). There were 2014 and 658 Caucasian cases, respectively, in the OAI and JoCo Studies, and 953 and 823 controls. Single nucleotide polymorphisms (SNPs) were identified for association analysis from the literature. Genotyping was carried out on the Illumina 2.5M and 1M arrays in GeCKO and JoCo, respectively and imputation was done. Association analyses were carried out separately in each cohort with adjustments for age, BMI, and sex and then parameter estimates were combined across the two cohorts by meta-analysis. We identified 4 SNPs significantly associated with prevalent radiographic knee OA. The strongest signal (p=0.0009, OR=1.22, 95% CI[1.08–1.37]) maps to 12q3 which contains a gene coding for SP7. Additional loci map to 7p14.1 (TXNDC3), 11q13.2 (LRP5) and 11p14.1 (LIN7C). For all four loci the allele associated with higher BMD was associated with higher odds of OA. A BMD risk allele score was not significantly associated with OA risk. This meta-analysis demonstrates that several GWAS-identified BMD SNPs are nominally associated with prevalent radiographic knee OA and further supports the hypothesis that BMD, or its determinants, may be a risk factor contributing to OA development.
Genetic Research/Human Association studies; Osteoarthritis
Arginine metabolism by oral bacteria via the arginine deiminase system (ADS) increases the local pH, which can neutralize the effects of acidification from sugar metabolism and reduce the cariogenicity of oral biofilms. To explore the relationship between oral arginine metabolism and dental caries experience in children, we measured ADS activity in oral samples from 100 children and correlated it with their caries status and type of dentition. Supragingival dental plaque was collected from tooth surfaces that were caries-lesion-free (PF) and from dentinal (PD) and enamel (PE) caries lesions. Regardless of children’s caries status or type of dentition, PF (378.6) had significantly higher ADS activity compared with PD (208.4; p < .001) and PE (194.8; p = .005). There was no significant difference in the salivary arginolytic activity among children with different caries status. Mixed-model analysis showed that plaque caries status is significantly associated with ADS activity despite children’s age, caries status, and dentition (p < .001), with healthy plaque predicting higher ADS activity compared with diseased plaque. Plaque arginine metabolism varies greatly among children and tooth sites, which may affect their susceptibility to caries.
oral biolfim; dental plaque; dental caries; bacteria; arginine; risk factor
Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as ‘probably damaging’ missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N =315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N =923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.
ADNI; CARD10; imaging genetics; mild cognitive impairment; PARP1; whole-exome sequencing
The neurovascular unit is now well accepted as a conceptual framework for investigating the mechanisms of ischemic stroke. From a molecular and cellular perspective, three broad mechanisms may underlie stroke pathophysiology – excitotoxicity, oxidative stress and inflammation. To date, however, most investigations of these basic mechanisms have focused on neuronal responses. In this mini-review, we ask whether these mechanisms of excitotoxicity, oxidative stress and inflammation can also be examined in terms of non-neuronal interactions in the neurovascular unit, including the release of extracellular vesicles for cell-cell signaling.
Neurovascular unit; stroke; neuronal cell death; neuroprotection; extracellular vesicles; cell-cell interaction
Secondhand smoke is one of the most common toxic environmental exposures to children, and maternal health problems also have substantial negative effects on children. We are unaware of any studies examining the association of living with smokers and maternal health.
To investigate whether non-smoking mothers who live with smokers have worse physical and mental health than non-smoking mothers who live in homes without smokers.
Nationally representative data from the 2000–2004 Medical Expenditure Panel Survey were used. The health of non-smoking mothers with children <18 years (n=18,810) was assessed, comparing those living with one or more smokers (n=3,344) to those living in households with no adult smokers (n=14,836). Associations between maternal health, household smoking, and maternal age, race/ethnicity, and marital, educational, poverty and employment status were examined in bivariable and multivariable analyses using SUDAAN software to adjust for the complex sampling design. Scores on the Medical Outcomes Short Form-12 (SF-12) Physical Component Scale (PCS) and Mental Component Scale (MCS) were used to assess maternal health.
79.2% of mothers in the USA are non-smokers and 17.4% of them live with ≥1 adult smokers: 14.2% with 1 and 3.2% with ≥ 2 smokers. Among non-smoking mothers, the mean MCS score is 50.5 and mean PCS is 52.9. The presence of an adult smoker and increasing number of smokers in the home are both negatively associated with MCS and PCS scores in bivariable analyses (p<0.001 for each). Non-smoking mothers with at least one smoker in the household had an 11 % (95% CI=0.80–0.99) lower odds of scoring at or above the mean MCS score and a 19 % (95%CI=0.73–0.90) lower odds of scoring at or above the mean PCS score_compared to non-smoking mothers with no smokers in the household. There is an evidence of a dose response relationship with increasing number of smokers in the household for PCS (p<0.001).
These findings demonstrate a previously unrecognized child health risk: living with smokers is independently associated with worse physical and mental health among non-smoking mothers.
maternal health; secondhand smoke
The kidney urea transport protein UT-B is an attractive target for the development of small-molecule inhibitors with a novel diuretic (‘urearetic’) action. Previously, two compounds in the triazolothienopyrimidine scaffold (1a and 1c) were reported as UT-B inhibitors. Compound 1c incorporates a 1,1-difluoroethyl group, which affords improved microsomal stability when compared to the corresponding ethyl-substituted compound 1a. Here, a small focused library (4a–4f) was developed around lead inhibitor 1c to investigate the requirement of an amidine-linked thiophene in the inhibitor scaffold. Two compounds (4a and 4b) with nanomolar inhibitory potency (IC50 ≈ 40 nM) were synthesized. Computational docking of lead structure 1c and 4a–4f into a homology model of the UT-B cytoplasmic surface suggested binding with the core heterocycle buried deep into the hydrophobic pore region of the protein.
Urea transport protein; Triazolothienopyrimidine; Microsomal stability; Molecular docking
Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4–SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4–SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.
IRF4; SRF; ischaemic stroke; neuronal survival
Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma.
To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls.
The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10−24, minor allele frequency ∼0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown.
Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3′-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.
inherited susceptibility; glioma; risk
Bcl-2-like members have been found to be inherently overexpressed in many types of haematologic malignancies. The small-molecule S1 is a BH3 mimetic and a triple inhibitor of Bcl-2, Mcl-1 and Bcl-XL.
The lethal dose 50 (LD50) values of S1 in five leukaemic cell lines and 41 newly diagnosed leukaemia samples were tested. The levels of Bcl-2 family members and phosphorylated Bcl-2 were semiquantitatively measured by western blotting. The interactions between Bcl-2 family members were tested by co-immunoprecipitation. The correlation between the LD50 and expression levels of Bcl-2 family members, alone or in combination, was analysed.
S1 exhibited variable sensitivity with LD50 values ranging >2 logs in both established and primary leukaemic cells. The ratio of pBcl-2/(Bcl-2+Mcl-1) could predict the S1 response. Furthermore, we demonstrated that pBcl-2 antagonised S1 by sequestering the Bak and Bim proteins that were released from Mcl-1, andpBcl-2/Bak, pBcl-2/Bax and pBcl-2/Bim complexes cannot be disrupted by S1.
A predictive index was obtained for the novel BH3 mimetic S1. The shift of proapoptotic proteins from being complexed with Mcl-1 to being complexed with pBcl-2 was revealed for the first time, which is the mechanism underlying the index value described herein.
Bcl-2 phosphorylation; S1; BH3 mimetics; antileukaemic
The ovarian surface epithelium (OSE) plays an important role in normal ovarian physiology. During each reproductive cycle, the OSE takes part in the cyclical ovulatory ruptures and repair. The aim of this study was to investigate the immunolocalization of nerve growth factor (NGF) and its receptors, tyrosine kinase A (TrkA) and p75, in the OSE cells of the wild ground squirrels during the breeding and nonbreeding seasons. There were marked variations in ovarian weight and size between the breeding and the nonbreeding seasons. Histologically, cuboidal cells and squamous cells were identified in the OSE of both seasons. Yet, stronger immunostaining of NGF, TrkA and p75 were observed in cuboidal cells and squamous cells in the breeding season as compared to the nonbreeding season. In addition, plasma gonadotropin concentrations were higher in the breeding season than in the nonbreeding season, suggesting that the expression patterns of NGF, TrkA and p75 in the OSE were correlated with changes in plasma gonadotropins. These findings suggested that NGF and its receptor TrkA and p75 may be involved in the regulation of seasonal changes in the OSE of wild ground squirrel.
ground squirrel; NGF; OSE; p75; TrkA
This study used MCNPX code to investigate the brachytherapy 192Ir dose distributions in water, bone, and lung tissue and performed radiophotoluminescent glass dosimeter measurements to verify the obtained MCNPX results. The results showed that the dose-rate constant, radial dose function, and anisotropy function in water were highly consistent with data in the literature. However, the lung dose near the source would be overestimated by up to 12%, if the lung tissue is assumed to be water, and, hence, if a tumor is located in the lung, the tumor dose will be overestimated, if the material density is not taken into consideration. In contrast, the lung dose far from the source would be underestimated by up to 30%. Radial dose functions were found to depend not only on the phantom size but also on the material density. The phantom size affects the radial dose function in bone more than those in the other tissues. On the other hand, the anisotropy function in lung tissue was not dependent on the radial distance. Our simulation results could represent valid clinical reference data and be used to improve the accuracy of the doses delivered during brachytherapy applied to patients with lung cancer.
Melanoma has traditionally been viewed as a radioresistant cancer. However, recent studies suggest that under certain clinical circumstances, radiotherapy may play a significant role in the treatment of melanoma. Previous studies have demonstrated that telomere length is a hallmark of radiosensitivity. The newly discovered mammalian CTC1-STN1-TEN1 (CST) complex has been demonstrated to be an important telomere maintenance factor. In this study, by establishing a radiosensitive/radioresistant human melanoma cell model, MDA-MB-435/MDA-MB-435R, we aimed to investigate the association of CTC1 expression with radiosensitivity in human melanoma cell lines, and to elucidate the possible underlying mechanisms. We found that CTC1 mRNA and protein levels were markedly increased in the MDA-MB-435R cells compared with the MDA-MB-435 cells. Moreover, the downregulation of CTC1 enhanced radiosensitivity, induced DNA damage and promoted telomere shortening and apoptosis in both cell lines. Taken together, our findings suggest that CTC1 increases the radioresistance of human melanoma cells by inhibiting telomere shortening and apoptosis. Thus, CTC1 may be an attractive target gene for the treatment of human melanoma.
telomere-binding protein; conserved telomere maintenance component 1; radioresistance