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For long QT syndrome (LQTS), recent progress in genome-sequencing technologies enabled the identification of rare genomic variants with diagnostic, prognostic, and therapeutic implications. However, pathogenic stratification of the identified variants remains challenging, especially in variants of uncertain significance. This study aimed to propose a phenotypic cell-based diagnostic assay for identifying LQTS to recognize pathogenic variants in a high-throughput manner suitable for screening. We investigated the response of LQT2-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) following IKr blockade using a multi-electrode array, finding that the response to IKr blockade was significantly smaller than in Control-iPSC-CMs. Furthermore, we found that LQT1-iPSC-CMs and LQT3-iPSC-CMs could be distinguished from Control-iPSC-CMs by IKs blockade and INa blockade, respectively. This strategy might be helpful in compensating for the shortcomings of genetic testing of LQTS patients.

The cell cycle is driven by cyclin‐dependent kinases (Cdks). The decision whether the cell cycle proceeds is made during G1 phase, when Cdk4/6 functions. Cyclin‐dependent kinase inhibitor 2 (Cdkn2) is a specific inhibitor of Cdk4/6, and their interaction depends on D84 in Cdkn2 and R24/31 in Cdk4/6. This knowledge is based mainly on studies in mammalian cells. Here, we comprehensively analyzed Cdk4/6 and Cdkn2 in invertebrates and found that Cdk4/6 was present in most of the investigated phyla, but the distribution of Cdkn2 was rather uneven among and within the phyla. The positive charge of R24/R31 in Cdk4/6 was conserved in all analyzed species in phyla with Cdkn2. The presence of Cdkn2 and the conservation of the positive charge were statistically correlated. We also found that Cdkn2 has been tightly linked to Fas associated factor 1 (Faf1) during evolution. We discuss potential interactions between Cdkn2 and Cdk4/6 in evolution and the possible cause of the strong conservation of the microsynteny. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) respond to tyrosine kinase inhibitors (TKIs); however, CML leukemic stem cells (LSCs) exhibit BCR::ABL kinase-independent growth and are insensitive to TKIs, leading to disease relapse. To prevent this, new therapies targeting CML-LSCs are needed. Rates of mitochondria-mediated oxidative phosphorylation (OXPHOS) in CD34+CML cells within the primitive CML cell population are higher than those in normal undifferentiated hematopoietic cells; therefore, the inhibition of OXPHOS in CML-LSCs may be a potential cure for CML. NK-128 (C33H61NO5S) is a structurally simplified analog of JCI-20679, the design of which was based on annonaceous acetogenins. NK-128 exhibits antitumor activity against glioblastoma and human colon cancer cells by inhibiting OXPHOS and activating AMP-activated protein kinase (AMPK). Here, we demonstrate that NK-128 effectively suppresses the growth of CML cell lines and that the combination of imatinib and NK-128 is more potent than either alone in a CML xenograft mouse model. We also found that NK-128 inhibits colony formation by CD34+ CML cells isolated from the bone marrow of untreated CML patients. Taken together, these findings suggest that targeting OXPHOS is a beneficial approach to eliminating CML-LSCs, and may improve the treatment of CML. [ABSTRACT FROM AUTHOR]

There is an urgent need for the development of a precious metal-conserving catalyst having high activity, selectivity, and durability for methylcyclohexane (MCH) dehydrogenation, a significant aspect of hydrogen storage and transportation. A Pt-single atom alloyed Fe catalyst with sub-1 nm size is a good candidate for this purpose because of meeting site requirements for enhancement of activity, durability, selectivity, and utilization efficiency of Pt. However, this design is challenging due to the high surface energy of Fe. In this study, to break the limitation of catalyst design, we used a combination of two phenomena spontaneously taking place at the solid surface, i.e., (1) Fe dispersion on Cu, and (2) substitution of metallic Fe atoms with Pt cations. Here, we report a Pt single-atom alloyed sub-1 nm thick Fe overlayer on Cu nanoparticles. The Fe overlayer serves as the host metal to restrict Pt single atoms at the surface and provides an optimal coordination environment for MCH dehydrogenation. Furthermore, the sub-1 nm thick Fe overlayer features low crystallinity and superior decoking properties, which imparts product/coke poisoning resistance to the Pt single atom site, resulting in enhancements of both durability and activity. The H2-evolution rate per Pt mass was at least 133 times higher than that of state-of-the-art catalysts: Pt-based intermetallic compounds. This research demonstrates the significance of a single-atom-alloying approach with unique nanostructures specifically formed at the solid surface for the development of more efficient sustainable catalytic transformation processes. [ABSTRACT FROM AUTHOR]

Electroluminescent devices such as circularly polarised organic light-emitting diodes (CP-OLEDs) fabricated by conventional methods do not exhibit adequate circularly polarised electroluminescence (CPEL) with high circular polarisation. Therefore, new approaches for CPEL and CP-OLED systems are needed. We developed an external-magnetic-field-driven CP-OLED device that emits red CPEL by integrating an achiral optically inactive phosphorescent platinum(II) porphyrin luminophore (PtOEP) in the emission layer (EML). This magnetic CP-OLED system can simultaneously emit circularly polarised light with opposite rotations from the EML in the N-up and S-up directions of the applied magnetic field. By utilising this mechanism that allows simultaneous emission upon the application of a magnetic field and the reflection-reversal property of circularly polarized light, we may suppress the decrease in both the luminosity and circular polarisation of CPEL. The direction of rotation of CPEL was successfully reversed by switching the Faraday geometry of the applied magnetic field. This approach can promote the development of novel CP-OLED devices. [ABSTRACT FROM AUTHOR]

Introduction: Ovarian metastasis of colorectal cancer is known to have a poor prognosis. This study aimed to elucidate the characteristics of patients who underwent oophorectomy for ovarian metastasis from colorectal cancer. Methods: This retrospective study included 16 patients who underwent oophorectomy for colorectal cancer metastasis to the ovary from January 2004 to December 2017. Improvement in patient's symptoms and pre- and postoperative changes in various nutritional and inflammatory indicators were assessed. Survival analysis and identification of prognostic factors were conducted with a median follow-up of 40.7 (5–109) months. Results: Of 16 patients, 12 had (75%) synchronous and 4 (25%) had metachronous metastasis. Fourteen patients were symptomatic but symptoms resolved postoperatively. Thirteen patients (81.3%) had ascites and 5 (31.3%) had pleural effusion on preoperative computed tomography that disappeared after surgery in all cases. The median value of prognostic nutritional factor was significantly increased postoperatively (36.0 [preoperatively] vs. 47.5, p < 0.0001). The median (interquartile range) values for lymphocyte-C-reactive protein ratio were 715.2 (110–2,607) preoperatively and 6,095.2 (1,612.3–14,431.8) postoperatively (p = 0.0214). The median survival of the entire cohort was 60.4 months. The 3-year survival rates for R0 + R1 and R2 cases were 83% and 24% (p = 0.018), respectively. Univariate analysis showed that R2 resection and low postoperative lymphocyte-C-reactive protein ratio were associated with poor prognosis. Conclusions: Oophorectomy for ovarian metastasis from colorectal cancers was safely performed. It improved the patients' symptoms and nutritional status and may result in improved prognosis. [ABSTRACT FROM AUTHOR]

Many massive quiescent galaxies have been discovered at z > 2 thanks to multiwavelength deep and wide surveys; however, substantial deep near-infrared spectroscopic observations are needed to constrain their star formation histories statistically. Here, we present a new technique to select quiescent galaxies with a short quenching time-scale (≤0.1 Gyr) at z ∼ 2 photometrically. We focus on a spectral break at ∼1600 Å that appears for such fast-quenching galaxies ∼1 Gyr after quenching when early A-type stars go out, but late A-type stars still live. This spectral break at z ∼ 2 is similar to a Lyman break at z ∼ 4. We construct a set of colour criteria for z ∼ 2 fast-quenching galaxies on g − r versus r − i and i − J versus J − H or |$\rm {\it i}-[3.6]$| versus |$\rm [3.6]-[4.5]$| colour diagrams, which are available with the existing and/or future wide imaging surveys, by simulating various model galaxy spectra and test their robustnesses using the COSMOS2020 catalogue. Galaxies with photometric and/or spectroscopic redshifts z ∼ 2 and low specific star formation rates are successfully selected using these colours. The number density of these fast-quenching galaxy candidates at z ∼ 2 suggests that massive galaxies not so far above the star formation main sequence at z  = 3–4 should be their progenitors. [ABSTRACT FROM AUTHOR]