Slope in preload recruitable stroke work relationship predicts survival after left ventriculoplasty and mitral repair in patients with idiopathic cardiomyopathy

AbstractBackgroundLeft ventriculoplasty (LVP) and mitral valve plasty (MVP) are sometimes effective for patients with idiopathic dilated cardiomyopathy (DCM) who are not eligible for heart transplantation. Strict patient selection is warranted for these controversial procedures.Methods and resultsThe subjects were 18 patients with idiopathic DCM and mitral regurgitation who had not been indicated for heart transplantation due to either older age or patient refusal, and who underwent LVP and MVP. Their mean age was 57±14 years and 50% were dependent on catecholamine infusion. The preload recruitable stroke work (PRSW) relationship and its slope (Mw) were estimated by a single-beat technique using transthoracic echocardiography. There were one 30-day mortality and six (33%) hospital deaths due to heart failure. The one-year survival rate was 50%. Left ventricular end-diastolic dimension (LVDd) decreased from 77±11 to 68±11mm (p=0.001) whereas the ejection fraction did not change. Preoperative Mw was significantly higher in one-year survivors than that in non-survivors (54±17ergcm−3103 vs. 31±10ergcm−3103, p=0.005). Preoperative LVDd was not different between the groups. The cut-off value of 42ergcm−3103 for Mw predicted one-year survival with high sensitivity (100%) and specificity (77%).ConclusionsMw, the slope in the PRSW relationship, may predict survival after LVP and MVP in patients with idiopathic DCM

APOBEC3B is preferentially expressed at the G2/M phase of cell cycle

APOBEC3B (A3B) is a cytosine deaminase that converts cytosine to uracil in single-stranded DNA. Cytosine-to-thymine and cytosine-to-guanine base substitution mutations in trinucleotide motifs (APOBEC mutational signatures) were found in various cancers including lymphoid hematological malignancies such as multiple myeloma and A3B has been shown to be an enzymatic source of mutations in those cancers. Although the importance of A3B is being increasingly recognized, it is unclear how A3B expression is regulated in cancer cells as well as normal cells. To answer these fundamental questions, we analyzed 1276 primary myeloma cells using single-cell RNA-sequencing (scRNA-seq) and found that A3B was preferentially expressed at the G2/M phase, in sharp contrast to the expression patterns of other APOBEC3 genes. Consistently, we demonstrated that A3B protein was preferentially expressed at the G2/M phase in myeloma cells by cell sorting. We also demonstrated that normal blood cells expressing A3B were also enriched in G2/M-phase cells by analyzing scRNA-seq data from 86, 493 normal bone marrow mononuclear cells. Furthermore, we revealed that A3B was expressed mainly in plasma cells, CD10+ B cells and erythroid cells, but not in granulocyte-macrophage progenitors. A3B expression profiling in normal blood cells may contribute to understanding the defense mechanism of A3B against viruses, and partially explain the bias of APOBEC mutational signatures in lymphoid but not myeloid malignancies. This study identified the cells and cellular phase in which A3B is highly expressed, which may help reveal the mechanisms behind carcinogenesis and cancer heterogeneity, as well as the biological functions of A3B in normal blood cells

Measurement of Decay Time Constant of Shielding Current in ITER-TF Joint Samples

Joint sample tests have been carried out as a qualification test for ITER Toroidal Field (TF) coils. The joint sample comprises two short TF conductors that have "twin-box" joint terminals at both ends. The lower joint is a testing part that is a full size joint of the TF coils. Hall probes are attached on the lower joint box at around the center of the external field coil of the test facility. The magnetic field induced by shielding currents in the joint can be estimated from the difference between the measured magnetic field strength and the magnetic field generated by the external field coil. The magnetic field by the shielding currents during shut-off of the external field coil from -1.0 T is evaluated for six samples. The decay time constants of the shielding currents are gradually elongated with decrease of the shielding currents in all the samples. In comparison with simulation results, it is considered that the main shielding current flows in superconducting cables in the two conductors with crossing the jointed plane and that the joint resistance is decreased at low total current

Evaluation of ITER TF Coil Joint Performance

To evaluate the ITER TF joint performance, the joint test sample, which consists of two short TF conductors and has full size joint, shall be tested using NIFS test facility under the condition of current of 68 kA and external field of 2 T. For high accuracy, the issue of voltage difference between cable and jacket had been anticipated in the evaluation of joint resistance. If a voltage difference exist between them, it is difficult to measure real joint resistance using voltage taps on the jacket. Therefore, the author first calculated the position where voltage of cable and jacket become equipotential and then decided the voltage tap position where the influence of voltage drop could be avoided. Thus, a high accuracy measurement of joint resistance could be achieved and the joint resistance was accurately evaluated as around 1 n Ω , which is well below the ITER requirement of 3 n Ω

Test of ITER-TF Joint Samples With NIFS Test Facilities

Qualification tests of the ITER toroidal field (TF) conductor joints have been carried out by testing joint samples with test facilities in the National Institute for Fusion Science, NINS, Toki, Japan. The joint sample consists of two short TF conductors with the length of 1535 mm, which is restricted by the test facility with 9-T split coils and 100-kA current leads. The sample current is supplied from a dc 75-kA power supply. Each conductor has two joint boxes at both terminals. The lower joint is a testing part that is a full-size joint of the TF coil. The joint resistance of the lower joint is estimated from the increase of the average voltage drop among the six taps on the conductor against the currents. Five joint samples were tested until 2016, and all the samples satisfied the requirement of the joint resistance at less than 3 nΩ. The method of the measurement and the results are summarized, and the voltage distribution among the voltage taps is discussed

Results of All ITER TF Full-Size Joint Sample Tests in Japan

Nine toroidal field (TF) coils have been developed in Japan for the international thermonuclear experimental reactor (ITER). The joint resistance of TF coil should satisfy the requirement of smaller than 3 nano-ohm at 2 T of external magnetic field and 68 kA of transport current. Full-size joint sample (FSJS) tests were performed for joint development and for TF coil manufacture, as part of the process control. 11 FSJS tests are conducted in total. FSJS tests were conducted with assistance from a test faculty in the National Institute for Fusion Science as reported in a previous paper. All FSJS tests successfully satisfied the requirement of resistance less than 3 nΩ at 2 T. Additionally, the TF coil joints are subjected to cyclic electromagnetic force and warm-up/cool-down during the ITER operation. The authors investigated the joint performance for the abovementioned influence. The results showed no degradation in the joint resistance. Thus, the TF joint developed in Japan was qualified successfully

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