Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

生体から不良細胞を除去する「細胞競合」の仕組みの一端を解明 --不良細胞は小胞体ストレス応答機構を使ってタンパク質合成量を低下させ除去される--. 京都大学プレスリリース. 2021-12-08.Cell competition is a context-dependent cell elimination via cell-cell interaction whereby unfit cells (‘losers’) are eliminated from the tissue when confronted with fitter cells (‘winners’). Despite extensive studies, the mechanism that drives loser’s death and its physiological triggers remained elusive. Here, through a genetic screen in Drosophila, we find that endoplasmic reticulum (ER) stress causes cell competition. Mechanistically, ER stress upregulates the bZIP transcription factor Xrp1, which promotes phosphorylation of the eukaryotic translation initiation factor eIF2α via the kinase PERK, leading to cell elimination. Surprisingly, our genetic data show that different cell competition triggers such as ribosomal protein mutations or RNA helicase Hel25E mutations converge on upregulation of Xrp1, which leads to phosphorylation of eIF2α and thus causes reduction in global protein synthesis and apoptosis when confronted with wild-type cells. These findings not only uncover a core pathway of cell competition but also open the way to understanding the physiological triggers of cell competition

Reproducibility and Validity of Muscle Strength in Hip Abduction with Flexion While Seated in Older Adults Who Need Nursing Care

Objective: This study aimed to determine the usefulness of the strength of the muscles in hip abduction with flexion while seated (SMHAF-S) in older adults who need nursing care. To achieve this, we examined the reproducibility and validity of a method to measure the SMHAF-S in older adults who need nursing care using a hand-held dynamometer. Methods: This cross-sectional study enrolled 40 older women who needed nursing care in September 2021 and completed the SMHAF-S and underwent quadriceps muscle strength, grip strength, 10-s chair stand test for frail older adults (FCS-10), one-legged stance test (OLST), and timed-up-and-go (TUG) test. The reproducibility of the SMHAF-S was examined by determining the intraclass correlation coefficient (ICC). The validity of the relationship between the SMHAF-S and quadriceps muscle strength and other measurement items was examined by calculating Pearson’s correlation coefficients. Results: In this cohort (age 83.6±5.2 years), the reproducibility of the SMHAF-S was excellent (ICC 0.91). Significant correlations were found between the SMHAF-S and quadriceps muscle strength, grip strength, FCS-10, OLST, and TUG test results (pConclusion: The SMHAF-S is a highly reproducible measurement method that reflects lower limb muscle strength and whole-body muscle strength, balance, and walking ability in older adults who need nursing care

Synchronous improvement in strength and ductility of biomedical Co–Cr–Mo alloys by unique low-temperature heat treatment

The microstructure and tensile properties of Co–27Cr–6Mo (mass%) alloys heat-treated at 673–1373 K were studied. Lower elongation was observed after heat treatment at 1073 K due to formation of carbonitride precipitates. In contrast, when low-temperature heat treatment (LTHT) was applied at 673–873 K, both the ultimate tensile strength and elongation synchronously improved compared with the solution-treated alloy. Electron backscatter diffraction analysis for plastic-strained alloys and in situ X-ray diffraction analysis under stress-induced conditions revealed that the strain-induced martensitic transformation (SIMT) of the γ(fcc)-phase to ε(hcp)-phase during plastic deformation was suppressed by the LTHT. Stacking faults (thin ε-phase) were observed to collide in the LTHT alloys. The following mechanisms for the synchronous improvement in the tensile strength and elongation after LHTH are proposed. First, stacking faults with multiple variants were formed during LTHT. Then, the ε-phase of a single variant formed by SIMT during plastic deformation collides with preexisting multi-variant stacking faults formed during LTHT, increasing the tensile strength. In addition, the SIMT during plastic deformation is suppressed in the high-plastic-strain region by the collision. This decreases the total amount of ε-phase formed during plastic deformation, which improves the ductility. We demonstrated that LTHT of Co–Cr–Mo alloys effectively improves the performance and mechanical safety of spinal fixation implants, which often fracture because of fatigue cracking.Ueki K., Abe M., Ueda K., et al. Synchronous improvement in strength and ductility of biomedical Co–Cr–Mo alloys by unique low-temperature heat treatment. Materials Science and Engineering A, 739, 53. https://doi.org/10.1016/j.msea.2018.10.016

Multi-drug therapy for epilepsy influenced bispectral index after a bolus propofol administration without affecting propofol's pharmacokinetics: a prospective cohort study

Some previous studies have indicated that valproate (VPA) might change the pharmacokinetics and enhance the effects of propofol. We evaluated whether clinical VPA therapy affected the propofol blood level, the protein-unbound free propofol level, and/or the anesthetic effects of propofol in the clinical setting. The subjects were divided into the control group (not medicated with antiepileptics), the mono-VPA group (medicated with VPA alone), and the poly-VPA group (medicated with VPA, other antiepileptics, and/or psychoactive drugs). General anesthesia was induced via the administration of a single bolus of propofol and a remifentanil infusion, and when the bispectral index (BIS) exceeded 60 sevoflurane was started. There were no significant differences in the total blood propofol level at 5, 10, 15, and 20 min or the protein-unbound free propofol level at 5 min after the intravenous administration of propofol between the 3 groups. However, the minimum BIS was significantly lower and the time until the BIS exceeded 60 was significantly longer in the poly-VPA group. In the multivariate regression analysis, belonging to the poly-VPA group was found to be independently associated with the minimum BIS value and the time until the BIS exceeded 60. Clinical VPA therapy did not influence the pharmacokinetics of propofol. However, multi-drug therapy involving VPA might enhance the anesthetic effects of propofol

Antimicrobial prescription practices for outpatients with uncomplicated cystitis in Japan

To promote antimicrobial stewardship, we studied antimicrobial prescription rates for uncomplicated cystitis, a common outpatient disease requiring antibiotic treatment. This multicenter retrospective study was performed from January 1, 2018, to December 31, 2020, in Japan, targeting outpatients aged >= 20 years whose medical records revealed International Classification of Diseases (ICD-10) codes suggesting uncomplicated cystitis (N300). The data of 1445 patients were collected and that of 902 patients were analyzed. The overall median patient age was 71 years and a proportion of those aged less than 50 years was 18.8% with a female dominance (82.6%). Antimicrobials were prescribed for 884 patients (98.0%) and a total of 623 patients (69.1%) were treated with broad-spectrum drugs, including fluoroquinolones (36.0%), third-generation cephalosporins (29.9%) and faropenem (3.1%). A logistic regression model revealed that the broad-spectrum agents were significantly prescribed for the older patients, male patients, and those who visited internists. Recurrence was observed in 37 (4.1%) cases, and the multivariate analysis suggested any of age, sex, or antimicrobial types were not associated with the recurrence. Collectively, approximately two-thirds of antimicrobials prescribed for uncomplicated cystitis were broad-spectrum agents. The present data would be an indicator for antimicrobial prescriptions in uncomplicated cystitis in Japan

Impact of the day of the week on the discontinuation of broad-spectrum antibiotic prescriptions; a multi-centered observational study

To encourage and guide antimicrobial stewardship team (AST) activity and promote appropriate antibiotic use, we studied the impact of day of the week on the initiation and discontinuation of antibiotic administration. This was a multicenter observational study conducted at 8 Japanese hospitals from April 1 to September 30, 2019, targeting patients who underwent treatment with broad-spectrum antibiotics, such as anti-methicillin-resistant Staphylococcus aureus agents and anti-pseudomonal agents. We compared the weekly numbers of initiations and discontinuations of antibiotic prescription on each day of the week or on the days after a holiday. There was no statistical difference in the number of antibiotic initiations on both weekdays and the day after a holiday. However, antibiotic discontinuation was significantly higher from Tuesday onward than Monday and from the second day than the first day after a holiday. Similar trends were observed regardless of the categories of antibiotics, hospital and admission ward, and AST activity. This study suggests that broad-spectrum antibiotics tend to be continued during weekends and holidays and are most likely to be discontinued on Tuesday or the second day after a holiday. This was probably due to behavioral factors beyond medical indications, requiring further antimicrobial stewardship efforts in the future

神経心理学的検査を用いて評価した実行機能の発達的側面

Children with executive dysfunction may have a decreased quality of life. Neuropsychological tests include the Stroop test, Trail-making Test, Wisconsin Card Sorting Test, Continuous Performance Test, and the Rey-Osterrieth Complex Figure Test are administered to evaluate the above functions. To broaden the opportunities for clinical application,we have modified these tests to make them applicable to younger children and to obtain their standard values. The purpose of this research is to study the developmental aspects of these tests, focusing on the difference between the original method and the modified method. Index scores that reflected executive function were rapidly reduced until 9 to 11 years of age, and developments showed a deceleration during the adolescent period. This result was comparable with that of the index scores of the original tests. We also discussed the involvement of background neuronal maturation associated with developmental changes in these tests.実行機能の障害は、子どもの生活の質の低下につながる可能性があるため、Stroop Test,Trail Making Test, Wisconsin Card Sorting Test, Continuous Performance Test,Rey-Osterrieth Complex Figure Testなどの神経心理学的検査を用いて同機能を適切に評価することが求められている。すでに我々は、これら検査の臨床応用の機会を広げるために、低年齢の子どもに運用が可能な短縮版を開発し成果の報告を行ってきた。本研究は、従来の方法と短縮化された方法との成績の違いに焦点を当て、これらのテストの発達的側面を研究することを目的とした。実行機能を反映した指標のスコアは、9歳から11歳まで急速に減少し、発達は青年期に減速傾向を示した。この結果は、従来の検査の指数スコアと同等であった。我々はまた、これらの検査指標における発達的変化と背景に存在するニューロン成熟課程との関連についても考察した

Nutritional status, feeding practice and incidence of infectious diseases among children aged 6 to 18 months in northern mountainous Vietnam

To assess the prevalence of undernutrition, incidence of infectious diseases and the situation of feeding practices to determine the risk factors for undernutrition among children aged 6 to 18 months in rural Vietnam. Design : A cross-sectional study was conducted among one hundred eighty-eight mother-child pairs in Bac Giang, Vietnam. Weight and height of the children were measured and referred to data from the WHO/CDC/NCHS. Incidence of infectious diseases was diagnosed based on the WHO Recommended Surveillance Standards. Data on socio-demographic variables and feeding practices were obtained through a structured questionnaire. Result : The prevalence of underweight, stunting and wasting was 19.7%, 23.4% and 5.3%, respectively. The incidence of diarrhea and acute respiratory infections (ARIs) during the last 14 days of the interview was 12.2% and 20.2%, respectively. Although 99% of the children were breastfed, the prevalence of exclusive breastfeeding in the first 4 mo was 21.3%. Non-exclusive breastfeeding in the first 4 month (OR 3.95, p=0.025) and low birth weight (OR 4.38, p=0.009) were associated with underweight in the children, while incidence of infectious disease was not (OR 1.16, p=0.734). Conclusion : Undernutrition is highly prevalent in the study site and non-exclusive breast feeding is one of the risk factors

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