A radioprotective agonist for p53 transactivation

Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seems to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose-reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in Trp53-KO mice. These results indicate that the pharmacological upregulation of radioprotective p53-target genes is an effective strategy for addressing the gastrointestinal syndrome

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Differences in acquisition of organic nitrogen in soils between bok choy and tomato

Seedlings of bok choy and tomato were grown in soils with different N nitrogen [no N (-N), ammonium sulfate (AS), and cattle farmyard manure (CM)]. Comparison between soils treated with -N and CM indicated that the growth and N accumulation in bok choy were significantly enhanced by CM treatment, whereas no difference was found in tomato. In the rhizosphere soils, the highest protease activity was detected in CM treatment irrespective of species. Correlation analysis between rhizospheric protease activity and total N accumulation of plant treated with -N and CM showed a significant positive correlation only for bok choy. The determination of amino acid absorption rate in excised roots indicated that glycine was taken up at a significantly higher rate in bok choy than tomato. This study suggested that at least two possible factors affected the acquisition of organic N: rhizospheric protease activity and ability to absorb amino acids in roots

Factors associated with anesthetic satisfaction after cesarean delivery under neuraxial anesthesia

Abstract Introduction Evaluating patient satisfaction with anesthesia is critical for improving their experiences. We investigated perioperative anesthetic satisfaction and associated predictive factors in patients receiving cesarean delivery under neuraxial anesthesia (spinal anesthesia only or combined spinal-epidural anesthesia). Methods This was an institutionally approved retrospective chart review of patients who received cesarean delivery under spinal anesthesia and postoperative evaluation administered by anesthesiologists from January 2009 to December 2013. Multiple pregnancies and patients reporting headache prior to cesarean delivery were excluded. Patients were divided into satisfied and not satisfied groups according to their scores from the 4-point Likert scale. Multivariate analysis was used to identify explanatory factors associated with satisfaction. Results Of 813 patients enrolled, 425 (52.2%) were classified as satisfied. Combined spinal–epidural anesthesia (CSEA) (odds ratio, 3.3; 95% confidence interval, 1.08–10.1) was positively associated with satisfaction. Paresthesia during needle insertion (odds ratio, 0.56; 95% confidence interval, 0.42–0.76), lightning pain during neuraxial anesthesia (odds ratio 0.62; 95% confidence interval, 0.39–0.98), failed block (odds ratio 0.28; 95% confidence interval, 0.09–0.87), and intraoperative use of antiemetic (odds ratio 0.71; 95% confidence interval, 0.53–0.94) were negatively associated with satisfaction. In the 792 patients receiving spinal anesthesia only, the same factors except for CSEA were associated with satisfaction. Conclusions The addition of epidural to spinal anesthesia for cesarean delivery can increase patient satisfaction, whereas paresthesia during needle insertion, lightning pain, failed block, and the use of intraoperative antiemetic were major obstacles to patient satisfaction

Difference in Acquisition of Soil Organic Nitrogen between Pak-Choi and Tomato

This study was to elucidate the factors contributing to organic nitrogen (N) acquisition in different plant species, pak-choi (Brassica rapa L. var. chinensis) and tomato (Solanum lycopersicum L.). Two hypotheses were proposed and examined: 1) higher protease activity in rhizosphere contributes to the ability to utilize organic N in soils; 2) the differences in ability to absorb amino acids are responsible for the different characteristics of organic N utilization. Seedlings were grown in soils mixed with vermiculite with different N sources (no N (-N), ammonium sulfate (AS), and cattle farmyard manure (CM)). Plant growth and N accumulation were the best in the AS treatment in both species. When comparing the growth and N accumulation between -N and CM treatments, those of pak-choi were significantly enhanced in the CM treatment, but no difference was found in tomato. In the rhizosphere soils, the highest protease activities were detected in the CM treatment irrespective of plant species. The correlation analysis between rhizospheric protease activity and plant total N accumulation in the -N and CM treatments showed that a significant positive correlation only in pak-choi. The determination of amino acid absorption rate in excised roots indicated that glycine was taken up at significantly higher rate in pak-choi than in tomato. Taken together, two possible factors for the acquisition of organic N was suggested from this study: protease activity in rhizosphere and ability to absorb amino acids

Difference in Acquisition of Soil Organic Nitrogen between Pak-Choi and Tomato

This study was to elucidate the factors contributing to organic nitrogen (N) acquisition in different plant species, pak-choi (Brassica rapa L. var. chinensis) and tomato (Solanum lycopersicum L.). Two hypotheses were proposed and examined: 1) higher protease activity in rhizosphere contributes to the ability to utilize organic N in soils; 2) the differences in ability to absorb amino acids are responsible for the different characteristics of organic N utilization. Seedlings were grown in soils mixed with vermiculite with different N sources (no N (-N), ammonium sulfate (AS), and cattle farmyard manure (CM)). Plant growth and N accumulation were the best in the AS treatment in both species. When comparing the growth and N accumulation between -N and CM treatments, those of pak-choi were significantly enhanced in the CM treatment, but no difference was found in tomato. In the rhizosphere soils, the highest protease activities were detected in the CM treatment irrespective of plant species. The correlation analysis between rhizospheric protease activity and plant total N accumulation in the -N and CM treatments showed that a significant positive correlation only in pak-choi. The determination of amino acid absorption rate in excised roots indicated that glycine was taken up at significantly higher rate in pak-choi than in tomato. Taken together, two possible factors for the acquisition of organic N was suggested from this study: protease activity in rhizosphere and ability to absorb amino acids