Comparison of type I error for multiple test corrections in large single-nucleotide polymorphism studies using principal components versus haplotype blocking algorithms

Although permutation testing has been the gold standard for assessing significance levels in studies using multiple markers, it is time-consuming. A Bonferroni correction to the nominal p-value that uses the underlying pair-wise linkage disequilibrium (LD) structure among the markers to determine the number of effectively independent tests has recently been proposed. We propose using the number of independent LD blocks plus the number of independent single-nucleotide polymorphisms for correction. Using the Collaborative Study on the Genetics of Alcoholism LD data for chromosome 21, we simulated 1,000 replicates of parent-child trio data under the null hypothesis with two levels of LD: moderate and high. Assuming haplotype blocks were independent, we calculated the number of independent statistical tests using 3 haplotype blocking algorithms. We then compared the type I error rates using a principal components-based method, the three blocking methods, a traditional Bonferroni correction, and the unadjusted p-values obtained from FBAT. Under high LD conditions, the PC method and one of the blocking methods were slightly conservative, whereas the 2 other blocking methods exceeded the target type I error rate. Under conditions of moderate LD, we show that the blocking algorithm corrections are closest to the desired type I error, although still slightly conservative, with the principal components-based method being almost as conservative as the traditional Bonferroni correction

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Background/Aims: Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy

An Empirical reionization history model inferred from the low-redshift Lyman continuum survey and the star-forming galaxies at z>8z>8

We present a new analysis of the rest-frame UV and optical spectra of a sample of three $z>8$ galaxies discovered behind the gravitational lensing cluster RX\,J2129.4+0009. We combine these observations with $z>7.5$ galaxies from the literature, for which similar measurements are available. As already pointed out in other studies, the high [\oiii]$\lambda$5007/[\oii]$\lambda$3727 ratios ($O_{32}$) and steep UV continuum slopes ($\beta$) are consistent with the values observed for low redshift Lyman continuum emitters, suggesting that such galaxies contribute to the ionizing budget of the intergalactic medium. We construct a logistic regression model to estimate the probability of a galaxy being a Lyman continuum emitter based on the measured \MUV, $\beta$, and $O_{32}$. Using this probability and the UV luminosity function, we construct an empirical model that estimates the contribution of high redshift galaxies to reionization. The preferred scenario in our analysis shows that at $z\sim8$, the average escape fraction of the galaxy population (i.e., including both LyC emitters and non-emitters) varies with \MUV, with intermediate UV luminosity ($-19<M_{UV}<-16$) galaxies having larger escape fraction. Galaxies with faint UV luminosity ($-16<M_{UV}<-13.5$) contribute most of the ionizing photons. The relative contribution of faint versus bright galaxies depends on redshift, with the intermediate UV galaxies becoming more important over time. UV bright galaxies, although more likely to be LCEs at a given log($O_{32}$) and $\beta$, contribute the least of the total ionizing photon budget.Comment: 10 pages, 7 figures, accepted by MNRA

Pyrimidine catabolism is required to prevent the accumulation of 5-methyluridine in RNA

5-Methylated cytosine is a frequent modification in eukaryotic RNA and DNA influencing mRNA stability and gene expression. Here we show that free 5-methylcytidine (5mC) and 5-methyl-2′-deoxycytidine are generated from nucleic acid turnover in Arabidopsis thaliana, and elucidate how these cytidines are degraded, which is unclear in eukaryotes. First CYTIDINE DEAMINASE produces 5-methyluridine (5mU) and thymidine which are subsequently hydrolyzed by NUCLEOSIDE HYDROLASE 1 (NSH1) to thymine and ribose or deoxyribose. Interestingly, far more thymine is generated from RNA than from DNA turnover, and most 5mU is directly released from RNA without a 5mC intermediate, since 5-methylated uridine (m5U) is an abundant RNA modification (m5U/U ∼1%) in Arabidopsis. We show that m5U is introduced mainly by tRNA-SPECIFIC METHYLTRANSFERASE 2A and 2B. Genetic disruption of 5mU degradation in the NSH1 mutant causes m5U to occur in mRNA and results in reduced seedling growth, which is aggravated by external 5mU supplementation, also leading to more m5U in all RNA species. Given the similarities between pyrimidine catabolism in plants, mammals and other eukaryotes, we hypothesize that the removal of 5mU is an important function of pyrimidine degradation in many organisms, which in plants serves to protect RNA from stochastic m5U modification

Evolution of the Mass-Metallicity Relation from Redshift z≈8z\approx8 to the Local Universe

A tight positive correlation between the stellar mass and the gas-phase metallicity of galaxies has been observed at low redshifts. The redshift evolution of this correlation can strongly constrain theories of galaxy evolution. The advent of JWST allows probing the mass-metallicity relation at redshifts far beyond what was previously accessible. Here we report the discovery of two emission-line galaxies at redshifts 8.15 and 8.16 in JWST NIRCam imaging and NIRSpec spectroscopy of targets gravitationally lensed by the cluster RXJ2129.4$+$0005. We measure their metallicities and stellar masses along with nine additional galaxies at $7.2 < z_{\rm spec} < 9.5$ to report the first quantitative statistical inference of the mass-metallicity relation at $z\approx8$. We measure $\sim 0.9$ dex evolution in the normalization of the mass-metallicity relation from $z \approx 8$ to the local Universe; at fixed stellar mass, galaxies are 8 times less metal enriched at $z \approx 8$ compared to the present day. Our inferred normalization is in agreement with the predictions of the FIRE simulations. Our inferred slope of the mass-metallicity relation is similar to or slightly shallower than that predicted by FIRE or observed at lower redshifts. We compare the $z \approx 8$ galaxies to extremely low metallicity analog candidates in the local Universe, finding that they are generally distinct from extreme emission-line galaxies or "green peas" but are similar in strong emission-line ratios and metallicities to "blueberry galaxies". Despite this similarity, at fixed stellar mass, the $z \approx 8$ galaxies have systematically lower metallicities compared to blueberry galaxies.Comment: Published in Ap

Spectroscopy from Lyman alpha to [O III] 5007 of a Triply Imaged Magnified Galaxy at Redshift z = 9.5

Given their extremely faint apparent brightness, the nature of the first galaxies and how they reionized the Universe's gas are not yet understood. Here we report the discovery, in James Webb Space Telescope (JWST) imaging, of a highly magnified, low-mass (log(M_*/M_sol)=7.70^{+0.11}_{-0.09}) galaxy visible when the Universe was only 510 Myr old, and follow-up prism spectroscopy of the galaxy extending from Lyman alpha to [O III] 5007 in its rest frame. Our JWST spectrum provides [O III] 5007 and H beta detections with a respective signal-to-noise ratio (S/N) of 40 and 13, as well as six additional lines with S/N > 3. These emission lines yield a redshift of z=9.51 and star-formation rate of 2.12 +- 0.53 solar masses per year. The galaxy's large inferred value of [O III]/[O II] = 16 +- 6 suggests that this galaxy has an escape fraction of ionizing radiation larger than 10%, indicating that a population of similar objects could contribute substantially to the reionization budget. Using multiple techniques, we infer a gas oxygen abundance of 12 + log(O/H) = 7.48 +- 0.05 dex, consistent within 2 sigma of the mass-metallicity relation observed for dwarf galaxies in the local Universe

Postoperative serum squamous cell carcinoma antigen and carcinoembryonic antigen predict overall survival in surgical patients with esophageal squamous cell carcinoma

BackgroundTumor markers are routinely used in clinical practice. However, for resectable patients with esophageal squamous cell carcinoma (ESCC), they are applied infrequently as their prognostic significance is incompletely understood.MethodsThis historical cohort study included 2769 patients with resected ESCC from 2011 to 2018 in a high-risk area in northern China. Their clinical data were extracted from the Electronic Medical Record. Survival analysis of eight common tumor markers was performed with multivariable Cox proportional hazards regressions.ResultsWith a median follow-up of 39.5 months, 901 deaths occurred. Among the eight target markers, elevated postoperative serum SCC (Squamous cell carcinoma antigen) and CEA (Carcinoembryonic antigen) predicted poor overall survival (SCC HRadjusted: 2.67, 95% CI: 1.70-4.17; CEA HRadjusted: 2.36, 95% CI: 1.14-4.86). In contrast, preoperative levels were not significantly associated with survival. Stratified analysis also demonstrated poorer survival in seropositive groups of postoperative SCC and CEA within each TNM stage. The above associations were generally robust using different quantiles of concentrations above the upper limit of the clinical normal range as alternative cutoffs. Regarding temporal trends of serum levels, SCC and CEA were similar. Their concentrations fell rapidly after surgery and thereafter remained relatively stable.ConclusionPostoperative serum SCC and CEA levels predict the overall survival of ESCC surgical patients. More importance should be attached to the use of these markers in clinical applications

An assessment of the causes of the errors in the 2015 UK General Election opinion polls

The opinion polls undertaken prior to the 2015 UK General Election under-estimated the Conservative lead over Labour by an average of 7 percentage points. This collective failure led politicians and commentators to question the validity and utility of political polling and raised concerns regarding a broader public loss of confidence in survey research. In this paper, we assess the likely causes of the 2015 polling errors. We begin by setting out a formal account of the statistical methodology and assumptions required for valid estimation of party vote shares using quota sampling. We then describe the current approach of polling organisations for estimating sampling variability and suggest a new method based on bootstrap re-sampling. Next, we use poll micro-data to assess the plausibility of different explanations of the polling errors. Our conclusion is that the primary cause of the polling errors in 2015 was unrepresentative sampling

Two lensed star candidates at z≃4.8z\simeq4.8 behind the galaxy cluster MACS J0647.7+7015

We report the discovery of two extremely magnified lensed star candidates behind the galaxy cluster MACS J0647.7+7015, in recent multi-band James Webb Space Telescope (JWST) NIRCam observations. The candidates are seen in a previously known, $z_{phot}\simeq4.8$ dropout giant arc that straddles the critical curve. The candidates lie near the expected critical curve position but lack clear counter images on the other side of it, suggesting these are possibly stars undergoing caustic crossings. We present revised lensing models for the cluster, including multiply imaged galaxies newly identified in the JWST data, and use them to estimate a background macro-magnification of at least $\gtrsim90$ and $\gtrsim50$ at the positions of the two candidates, respectively. With these values, we expect effective, caustic-crossing magnifications of $10^4-10^5$ for the two star candidates. The Spectral Energy Distributions (SEDs) of the two candidates match well spectra of B-type stars with best-fit surface temperatures of $\sim10,000$ K, and $\sim12,000$ K, respectively, and we show that such stars with masses $\gtrsim20$ M$_{\odot}$ and $\gtrsim50$ M$_{\odot}$, respectively, can become sufficiently magnified to be observed. We briefly discuss other alternative explanations and conclude these are likely lensed stars, but also acknowledge that the less magnified candidate may instead be or reside in a star cluster. These star candidates constitute the second highest-redshift examples to date after Earendel at $z_{phot}\simeq6.2$, establishing further the potential of studying extremely magnified stars to high redshifts with the JWST. Planned visits including NIRSpec observations will enable a more detailed view of the candidates already in the near future.Comment: 12 pages, 5 figures, 2 tables. Fixed Fig 3. comments are welcom

Polymorphisms of TP53 codon 72 with breast carcinoma risk: evidence from 12226 cases and 10782 controls

<p>Abstract</p> <p>Background</p> <p>Previously, TP53 codon 72 polymorphisms have been implicated as risk factors for various cancers. A number of studies have conducted on the association of TP53 codon 72 polymorphisms with susceptibility to breast carcinoma and have yielded inconclusive results. The aim of the present study was to derive a more precise estimation of the relationship.</p> <p>Methods</p> <p>We conducted a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Jan 2009. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications.</p> <p>Results</p> <p>A total of seventeen case-control studies, including 12226 cases and 10782 controls, met the included criteria and thus were selected. Ultimately, the relevant data were extracted and further analyzed using systematic meta-analyses. Overall, no associations of TP53 codon 72 polymorphisms with breast carcinoma were observed (for Arg/Arg vs Pro/Pro: OR = 1.20; 95%CI = 0.96–1.50; for dominant model: OR = 1.12; 95%CI = 0.96–1.32; for recessive model: OR = 1.13; 95%CI = 0.98–1.31). In the subgroup analysis by ethnicity, statistically similar results were obtained when the data were stratified as Asians, Caucasians and Africans.</p> <p>Conclusion</p> <p>Collectively, the results of the present study suggest that <it>TP53 codon 72 </it>polymorphisms might not be a low-penetrant risk factor for developing breast carcinoma.</p