Although many common diseases occur mostly in old age, the impact of ageing itself on disease risk and expression often goes unevaluated. To consider the impact of ageing requires some useful means ...of measuring variability in health in animals of the same age. In humans, this variability has been quantified by counting age-related health deficits in a frailty index. Here we show the results of extending that approach to mice. Across the life course, many important features of deficit accumulation are present in both species. These include gradual rates of deficit accumulation (slope = 0.029 in humans; 0.036 in mice), a submaximal limit (0.54 in humans; 0.44 in mice), and a strong relationship to mortality (1.05 1.04-1.05 in humans; 1.15 1.12-1.18 in mice). Quantifying deficit accumulation in individual mice provides a powerful new tool that can facilitate translation of research on ageing, including in relation to disease.
We present an X-ray point-source catalogue from the XMM-Large Scale Structure (XMMLSS) survey region, one of the XMM-Spitzer Extragalactic Representative Volume Survey (XMM-SERVS) fields. We target ...the XMM-LSS region with 1.3 Ms of new XMM-Newton AO-15 observations, transforming the archival X-ray coverage in this region into a 5.3 deg2 contiguous field with uniform X-ray coverage totaling 2.7 Ms of flare-filtered exposure, with a 46 ks median PN exposure time. We provide an X-ray catalogue of 5242 sources detected in the soft (0.5-2 keV), hard (2-10 keV), and/or full (0.5-10 keV) bands with a 1 per cent expected spurious fraction determined from simulations. A total of 2381 new X-ray sources are detected compared to previous source catalogues in the same area. Our survey has flux limits of 1.7 × 10-15, 1.3 × 10-14, and 6.5 × 10-15 erg cm-2 s-1 over 90 per cent of its area in the soft, hard, and full bands, respectively, which is comparable to those of the XMM-COSMOS survey. We identify multiwavelength counterpart candidates for 99.9 per cent of the X-ray sources, of which 93 per cent are considered as reliable based on their matching likelihood ratios. The reliabilities of these high-likelihood-ratio counterparts are further confirmed to be ≈97 per cent reliable based on deep Chandra coverage over ≈5 per cent of the XMM-LSS region. Results of multiwavelength identifications are also included in the source catalogue, along with basic optical-to-infrared photometry and spectroscopic redshifts from publicly available surveys. We compute photometric redshifts for X-ray sources in 4.5 deg2 of our field where forced-aperture multiband photometry is available; > 70 per cent of the X-ray sources in this subfield have either spectroscopic or high-quality photometric redshifts.
We investigate the dependence of black hole accretion rate (BHAR) on host-galaxy star formation rate (SFR) and stellar mass (M*) in the CANDELS/GOODS-South field in the redshift range of . Our sample ...consists of galaxies, allowing us to probe galaxies with and/or . We use sample-mean BHAR to approximate long-term average BHAR. Our sample-mean BHARs are derived from the Chandra Deep Field-South 7 Ms observations, while the SFRs and M* have been estimated by the CANDELS team through spectral energy distribution fitting. The average BHAR is correlated positively with both SFR and M*, and the BHAR-SFR and BHAR-M* relations can both be described acceptably by linear models with a slope of unity. However, BHAR appears to be correlated more strongly with M* than SFR. This result indicates that M* is the primary host-galaxy property related to supermassive black hole (SMBH) growth, and the apparent BHAR-SFR relation is largely a secondary effect due to the star-forming main sequence. Among our sources, massive galaxies ( ) have significantly higher BHAR/SFR ratios than less massive galaxies, indicating that the former have higher SMBH fueling efficiency and/or higher SMBH occupation fraction than the latter. Our results can naturally explain the observed proportionality between and M* for local giant ellipticals and suggest that their is higher than that of local star-forming galaxies. Among local star-forming galaxies, massive systems might have higher compared to dwarfs.
The blue straggler binary WOCS 5379 is a member of the old (6-7 Gyr) open cluster NGC 188. WOCS 5379 comprises a blue straggler star with a white dwarf companion in a 120 day eccentric orbit. ...Combined with the orbital period, this helium white dwarf is evidence of previous mass transfer by a red giant. Detailed models of the system evolution from a progenitor main-sequence binary, including mass transfer, are made using the Modules for Experiments in Stellar Astrophysics. Both of the progenitor stars are evolved in the simulation. WOCS 5379 is well reproduced with a primary star of initial mass 1.19 M , whose core becomes the white dwarf. The secondary star initially is 1.01 M . The secondary finished receiving mass from the donor 300 Myr ago, having moved beyond the NGC 188 turnoff as a 1.20 M blue straggler. The successful model has a mass-transfer efficiency of 22%. This nonconservative mass transfer is key to expanding the orbit fast enough to permit stable mass transfer. Even so, the mass transfer begins with a short unstable phase, during which half of the accreted mass is transferred. With increasing mass, the secondary evolves from a radiative core to a convective core. The final blue straggler interior is remarkably similar to a 2.1 Gyr old 1.21 M main-sequence star at the same location in the H-R diagram. The white dwarf effective temperature is also reproduced, but the modeled white dwarf mass of 0.33 M is smaller than the measured mass of 0.42 M .
AIM: The goal of this study was to investigate the synergic effects between magnolol and azoles, and the potential antifungal mechanisms. METHODS AND RESULTS: Microdilution checkerboard, time‐kill ...and agar diffusion assay were employed to evaluate the synergic effects between magnolol and fluconazole (FLC). Magnolol significantly decreased the efflux of rhodamine 123 (Rh123), leading to greater intracellular accumulation of Rh123 in Candida albicans cells. Compared to the Candida drug resistance (cdr) 2 or multidrug resistance (mdr) 1 deletion mutant, the growth of cdr1 strain was most sensitive to magnolol exposure. In the presence of magnolol, MDR1 overexpressing cells were sensitive to FLC, whereas CDR1 and CDR2 overexpressing cells displayed tolerance to FLC. Magnolol treatment correlated with up‐regulation of transporter and ergosterol biosynthesis pathway genes, analyzed by real‐time reverse transcription‐polymerase chain reaction. The ergosterol content of C. albicansSC5314 was significantly decreased after magnolol exposure. CONCLUSIONS: Magnolol synergizes with azoles for targeting of C. albicans by inducing a higher intracellular content of antifungals, by tapping into the competitive effect of ABC transporter Cdr1p substrates, and enhancing the effect by targeting of the ergosterol biosynthesis pathway. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results provide the first evidence that magnolol may function as a Cdr1p substrate and as an inhibitor of ergosterol biosynthesis. This function can thus be exploited in combination with azoles to reverse multidrug resistance of C. albicans strains.
Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. ...Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.
Vitamin C (VC) intakes, serum VC, fasting plasma glucose, and A1c levels of 25,206 adult men and 26,944 adult women with 6807 type 2 and 428 type 1 diabetes from the NHANES database between 1999 and ...2018 were analyzed. Our hypothesis is that low VC intake and serum VC level may be a health risk for US adults with diabetes. Analyses revealed total VC intake below the estimated average requirement (EAR) increased from 38.1% to 46.5% between 1999–2018. VC intake and serum VC levels were inversely associated with markers of pre-diabetes and type 2 diabetes, namely, fasting plasma glucose and A1c levels. Risks of type 2 diabetes increased in adults with VC intake below the EAR and with no VC supplement (odds ratio 1.20, 95% CI 1.1–1.3 and 1.28, 95% CI 1.18–1.40, respectively). Median survivor years of diabetic adults with lower and deficient serum VC were shorter than that of diabetic adults with normal serum VC. Mortality risks of type 2 diabetes with low VC intake and/or deficient serum VC levels were elevated compared to those with adequate VC intake and normal serum VC (HR 1.25, 95% CI 1.05–1.49 and 1.84, 95% CI 1.10–3.08, respectively). Observation of declining VC intake and deleterious consequences of low serum VC in US adults with diabetes suggests encouragement of VC intake, including VC supplementation of 500–1000 mg/day, may be beneficial for pre-diabetic and diabetic US adults.
Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an ...antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.
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