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Remimazolam was first approved in 2020 as a general anesthetic for adults and still does not have pediatric labeling. Our study will be the first pilot program that administers remimazolam as an adjunct to a general endotracheal anesthetic in children. Between August 2020 and December 2022, electronic medical records were collected for all children who received remimazolam during anesthesia. The remimazolam dosing regimen was extrapolated from the adult package insert, with intravenous induction doses of 12 mg/kg/h administered until the desired effect was achieved. Subsequent infusions were given at a rate of 1–2 mg/kg/h, accompanied by intermittent boluses of 0.2 mg/kg, with all dosing adjustments made according to the anesthesiologist’s clinical discretion. A total of 418 children (mean 4.6 yrs, 68.7% ASA 1 and 2) underwent surgeries which averaged 81.2 min. A total of 75.2% of patients had greater than a 20% change (increase or decrease) in MAP (lowest or highest) from baseline, and 203 (49.3%) patients had greater than a 30% change (increase or decrease) in MAP (lowest or highest) from baseline. A total of 5% received ephedrine to treat unanticipated hemodynamic variability. Discharge criteria were met within an average of 13.8 min after arrival at the post-anesthesia care unit. Remimazolam may offer the benefits of rapid recovery following general endotracheal anesthesia. The risk of hemodynamic variability which necessitates and responds to ephedrine should be anticipated.

Starch is stored temporarily in the leaves during the day but degraded during the night. In this study, we investigated the relationship between diurnal changes in starch content in rice leaf blades and the mRNA levels of β-amylase genes. In addition to the known plastid-type β-amylases OsBAM2 and OsBAM3, OsBAM4, and OsBAM5 were also identified as plastid targeted proteins. In the leaf blades, starch contents, which reached its maximum at the end of day, showed two periods of marked decrease: from 18:00 to 21:00 and from 24:00 to 6:00. The expression of OsBAM2, OsBAM3, OsBAM4, and OsBAM5 was maintained at a low level from 18:00 to 21:00 but increased strongly after midnight. Furthermore, β-amylase activity gradually increased after 21:00, reaching a maximum during the early morning. These results suggest that in rice leaf blades, β-amylase plays an important role in starch degradation by being highly active from midnight to dawn.

Dynamic morphological changes of intracellular organelles are often regulated by protein phosphorylation or dephosphorylation. Phosphorylation modulates stereospecific interactions among structured proteins, but how it controls molecular interactions among unstructured proteins and regulates their macroscopic behaviours remains unknown. Here we determined the cell cycle-specific behaviour of Ki-67, which localizes to the nucleoli during interphase and relocates to the chromosome periphery during mitosis. Mitotic hyperphosphorylation of disordered repeat domains of Ki-67 generates alternating charge blocks in these domains and increases their propensity for liquid–liquid phase separation (LLPS). A phosphomimetic sequence and the sequences with enhanced charge blockiness underwent strong LLPS in vitro and induced chromosome periphery formation in vivo. Conversely, mitotic hyperphosphorylation of NPM1 diminished a charge block and suppressed LLPS, resulting in nucleolar dissolution. Cell cycle-specific phase separation can be modulated via phosphorylation by enhancing or reducing the charge blockiness of disordered regions, rather than by attaching phosphate groups to specific sites., タンパク質リン酸化による液-液相分離制御のしくみを解明 --細胞内非膜型オルガネラの構築原理の解明へ--. 京都大学プレスリリース. 2022-05-12.

DNA compaction is required for the condensation and resolution of chromosomes during mitosis, but the relative contribution of individual chromatin factors to this process is poorly understood. We developed a physiological, cell-free system using high-speed Xenopus egg extracts and optical tweezers to investigate real-time mitotic chromatin fiber formation and force-induced disassembly on single DNA molecules. Compared to interphase extract, which compacted DNA by ~60%, metaphase extract reduced DNA length by over 90%, reflecting differences in whole-chromosome morphology under these two conditions. Depletion of the core histone chaperone ASF1, which inhibits nucleosome assembly, decreased the final degree of metaphase fiber compaction by 29%, while depletion of linker histone H1 had a greater effect, reducing total compaction by 40%. Compared to controls, both depletions reduced the rate of compaction, led to more short periods of decompaction, and increased the speed of force-induced fiber disassembly. In contrast, depletion of condensin from metaphase extract strongly inhibited fiber assembly, resulting in transient compaction events that were rapidly reversed under high force. Altogether, these findings support a speculative model in which condensin plays the predominant role in mitotic DNA compaction, while core and linker histones act to reduce slippage during loop extrusion and modulate the degree of DNA compaction.

Condensin-mediated loop extrusion is now considered as the main driving force of mitotic chromosome assembly. Recent experiments have shown, however, that a class of mutant condensin complexes deficient in loop extrusion can assemble chromosome-like structures inXenopusegg extracts, although these structures are somewhat different from those assembled by wild-type condensin complexes. In the absence of topoisomerase II (topo II), the mutant condensin complexes produce an unusual round-shaped structure termed a ‘bean’, which consists of a DNA-dense central core surrounded by a DNA-sparse halo. The mutant condensin complexes accumulate in the core whereas histones are more concentrated in the halo than in the core. We consider that this peculiar structure serves as a model system to study how DNA entanglements, nucleosomes, and condensin functionally crosstalk with each other. To gain insight into how the bean structure is formed, here we construct a theoretical model. Our theory predicts that the core is formed by attractive interactions between mutant condensin complexes whereas the halo is stabilized by the energy reduction through the selective accumulation of nucleosomes. The formation of the halo increases the elastic free energy due to the DNA entanglement in the core, but the latter free energy is compensated by condensin complexes that suppress the assembly of nucleosomes.

We investigated the synthesis and herbicidal activity of 23 toxoflavin analogs, 1a–w, in which aromatic rings (R) were introduced into the C-3 position. In paddy field conditions, 1k (R=2-CF(3)–C(6)H(4)) and 1w (R=2-thienyl) showed excellent herbicidal activity. Under upland field conditions, we found that toxoflavin analogs 1a (R=C(6)H(5)), 1n (R=2-CH(3)O–C(6)H(4)), and 1p (R=4-CH(3)O–C(6)H(4)) exhibited wide herbicidal spectrum against Echinochloa crus-galli (L) var. crus-galli (ECHCG), Chenopodium album, and Amaranthus viridis (AMAVI). The analog with the 2-fluoro group on benzene ring 1b also showed high herbicidal activity against both ECHCG and AMAVI.

In vertebrates, condensin I and condensin II cooperate to assemble rod-shaped chromosomes during mitosis. Although the mechanism of action and regulation of condensin I have been studied extensively, our corresponding knowledge of condensin II remains very limited. By introducing recombinant condensin II complexes into Xenopus egg extracts, we dissect the roles of its individual subunits in chromosome assembly. We find that one of two HEAT subunits, CAP-D3, plays a crucial role in condensin II-mediated assembly of chromosome axes, whereas the other HEAT subunit, CAP-G2, has a very strong negative impact on this process. The structural maintenance of chromosomes ATPase and the basic amino acid clusters of the kleisin subunit CAP-H2 are essential for this process. Deletion of the C-terminal tail of CAP-D3 increases the ability of condensin II to assemble chromosomes and further exposes a hidden function of CAP-G2 in the lateral compaction of chromosomes. Taken together, our results uncover a multilayered regulatory mechanism unique to condensin II, and provide profound implications for the evolution of condensin II.

What is known and objective The distribution of tacrolimus (TAC), an immunosuppressant used during cord blood transplantation (CBT)-one of the haematopoietic stem cell transplantations, to red blood cell (RBC) is approximately 90% in whole blood. In CBT patients, the total RBC count shows dramatic fluctuation due to conditioning before transplantation, including anticancer agents and total body irradiation, as well as RBC transfusions during the treatment period. Therefore, the amount of TAC in whole blood may show wide variation. However, therapeutic drug monitoring (TDM) of TAC has been performed based on the whole blood concentration. In this study, to contribute to TDM of TAC in CBT, we performed the population pharmacokinetic (PPK) analysis of TAC in 56 CBT patients and investigated the factors that affected the concentration of TAC, focusing the variation of RBC count. Method A one-compartment model was applied to the observed whole blood TAC concentrations, and a PPK analysis was conducted with a non-linear mixed effect model. Results and discussion Our final PPK model indicated good robustness and accuracy. In addition, haemoglobin (Hb) level was an influential covariate on Vd, which was expressed as Vd(L) = 91.4 × (Hb/8.2)(-1.07) . What is new and conclusion In this study, our results showed the necessity for the Hb level monitoring during TDM of TAC in CBT patients and provided useful information for improving TDM strategy of TAC.

Bendamustine plays an especially important role as a treatment for non-Hodgkin lymphoma (NHL). However, patients administered bendamustine alone or in combination with rituximab (BR) may experience drug-associated skin toxicities that can profoundly impact their health-related QOL through both physical discomfort and psychological distress. Moreover, worsening skin symptoms may lead to dose reduction or termination in the management of cancer chemotherapy. We retrospectively investigated patient backgrounds and pretreatment characteristics from medical records of NHL patients treated with bendamustine alone or BR therapy and identified predictive factors for skin toxicities at the start of chemotherapy. Patients were eligible for the study if they were 20 years older, diagnosed with NHL, and received bendamustine alone or BR therapy at the Department of Hematology, Kobe City Medical Center General Hospital, between April 1, 2011, and March 31, 2018. This study included 95 patients with newly diagnosed or refractory or relapsed NHL. Multivariate stepwise logistic regression analysis with backward selection revealed that baseline non-prior chemotherapy (odds ratio (OR), 15.72; 95% confidence interval (CI), 4.24-83.13, p < 0.001) was a significant factor influencing the occurrence of skin toxicity. Our results demonstrated that non-prior chemotherapy was a significant risk factor for skin toxicities in patients with NHL receiving bendamustine alone or BR therapy. No patient experience serious side effects of grade 3 or higher and that bendamustine is very useful as a first-line treatment.

Chemorefractory ovarian cancer has limited therapeutic options. Hence, new types of treatment including neoantigen-specific immunotherapy need to be investigated. Neoantigens represent promising targets for personalized cancer immunotherapy. We here describe the clinical and immunological effects of a neoantigen peptide-loaded DC-based immunotherapy in a patient with recurrent and chemoresistant ovarian cancer. A 71-year-old female patient with chemorefractory ovarian cancer and malignant ascites received intranodal vaccination of DCs loaded with four neoantigen peptides that were predicted by our immunogenomic pipeline. Following four rounds of vaccinations with this therapy, CA-125 levels were remarkably declined and tumor cells in the ascites were also decreased. Concordantly, the tumor-related symptoms such as respiratory discomfort improved without any adverse reactions. The reactivity against one HLA-A2402-restricted neoantigen peptide derived from a mutated PPM1 F protein was detected in lymphocytes from peripheral blood by IFN-γ ELISPOT assay. Furthermore, the neoantigen (PPM1 F mutant)-specific TCRs were detected in the tumor-infiltrating T lymphocytes post-vaccination. Our results showed that vaccination with intranodal injection of neoantigen peptide-loaded DCs may have clinical and immunological impacts on cancer treatment.

Biological soil disinfestation (BSD) is biotechnology to control soil-borne plant pathogens based on the anaerobic-reducing environment in soil and the functions of indigenous microbes. A new sustainable agricultural technology, the GET system, which produces and recovers methane as renewable energy from paddy fields, has a structure and principles similar to those of BSD technology. To confirm the potential of the GET system as BSD technology, the microbial community structures in the GET system were analyzed using next-generation sequencing. Thirty-four phyla were detected: 31 bacterial and 3 archaeal.

Condensin I is a five-subunit protein complex that is central to mitotic chromosome assembly in eukaryotic cells. Despite recent progress, its molecular mechanisms of action remain to be fully elucidated. By using Xenopus egg extracts as a functional assay, we find that condensin I complexes harboring mutations in its kleisin subunit CAP-H produce chromosomes with confined axes in the presence of topoisomerase IIα (topo IIα) and highly compact structures (termed “beans”) with condensin-positive central cores in its absence. The bean phenotype depends on the SMC ATPase cycle and can be reversed by subsequent addition of topo IIα. The HEAT repeat subunit CAP-D2, but not CAP-G, is essential for the bean formation. Notably, loop extrusion activities of the mutant complexes cannot explain the chromosomal defects they exhibit in Xenopus egg extracts, implying that a loop extrusion–independent mechanism contributes to condensin I–mediated chromosome assembly and shaping. We provide evidence that condensin–condensin interactions underlie these processes.

An important and often researched area of management science is mathematical modeling of a supply chain. Competitive situations can occur in supply chains owing to the involvement of multiple decision makers (players) that independently decide their behaviors. To investigate competitive supply chain networks, a supply chain network equilibrium (SCNE) model was proposed. Recently, particular attention has been paid to risk management of a supply chain. In equilibrium models, it is vital to consider players’ decisions and interdependence relations. Thus, we consider competitive supply chain networks with uncertainties in the other players’ strategies. In the proposed model, each player cannot know exactly the other players’ strategies, and they decide their strategy using the minimax principle (that is, assuming the worst case). We call it the robust SCNE model. We formulate the robust SCNE model as a variational inequality problem (VIP) in which the set associated with the VIP is constructed by second-order cone constraints. We show the existence and uniqueness of the equilibrium under mild assumptions. In addition, we give, in a special case, some relations between players’ strategies in the equilibrium and magnitudes of uncertainties. Finally, some numerical results are provided.

Lentinula edodes secretes laccase (Lcc: EC 1.10.3.2), an industrially useful enzyme. In this study, we introduced and expressed the L. edodes Lcc gene, lcc1, driven by L. edodes glyceraldehyde-3-phosphate dehydrogenase gene promoter into L. edodes. The resulting transformants showed 2-fold Lcc activity than that of the host strain, and expression of the recombinant lcc1 was confirmed by RT-PCR.

The trapped field properties during pulsed-field magnetization (PFM) have been investigated numerically using three different assumptions relating to the J c( B , T ) characteristics (Jirsa, Kim, and Bean models) and compared with experimental results. The trapped field properties using the Jirsa model with the so-called “peak effect,” in which a realistic J c( B , T ) is assumed, rather than the Kim model, result in a more realistic numerical simulation. The trapped field properties using a Kim model with a monotonically decreasing J c( B ) also show similar results to those using the Jirsa model. The trapped field properties using a Bean model, for which J c is independent of magnetic field, are not necessarily enhanced because of a larger temperature rise. The numerical results suggest it is necessary to fabricate REBaCuO bulks with J c( B , T ) characteristics with moderate magnetic field and temperature dependences to enhance the trapped field by PFM.

The characteristics of copper (Cu) isotropic dry etching using a hydrogen-based plasma generated at 13.3 kPa (100 Torr) were improved dramatically by simply introducing a moderate amount of N2 gas into the process atmosphere. A maximum Cu etch rate of 2.4 μm/min was obtained by nitrogen addition at a H2 mixture ratio (CH2) of 0.9 and an input power of 70 W. The etch rate for the optimally N2-added plasma was 8 times higher than that for the pure H2 plasma. The Cu etch rate increased with increasing input power. The maximum etch rate reached 3.1 μm/min at an input power of 100 W and a CH2 of 0.9. The surface roughness of the etched copper decreased as a result of optimum N2 addition. Furthermore, N2 addition also improved the etch selectivity between Cu and SiO2 such that the selectivity ratio reached 190. Finally, selective etching of a trench-patterned Si wafer with an electroplated Cu layer was demonstrated.

Background/aim Neoantigens are tumor-specific antigens that emerge due to gene mutations in tumor cells, and are highly antigenic epitopes that escape central immune tolerance in the thymus, making cancer vaccine therapy a desirable option. Patients and methods Tumor neoantigens were predicted in 17 patients with advanced cancer. They were resistant to the standard treatment regime, and their synthetic peptides were pulsed to the patient's monocyte-derived dendritic cells (DCs), and administered to the patient's lymph nodes via ultrasound. Results Some patients showed sustained tumor shrinkage after this treatment, while some did not respond, showing no ELISpot reaction. Although the number of mutations and the predicted neoantigen epitopes differed between patients, the clinical effect depended more on the presence or absence of an immune response after vaccination rather than the number of neoantigens. Conclusion Intranodal neoantigen peptide-pulsed DC vaccine administration therapy has clinical and immunological efficacy and safety.

BackgroundThe preoperative distinction between uncomplicated and complicated appendicitis is important to determine the appropriate treatments, such as antibiotics, surgery, or interval appendectomy. Computed tomography (CT) plays an important role; however, combining clinical and imaging factors may make preoperative evaluation more reliable. This study evaluated and analyzed cases and the usefulness of several preoperative factors and clinical scoring models to detect complicated appendicitis.MethodsA total of 203 patients preoperatively diagnosed with acute appendicitis at our facility were included. Complicated appendicitis was defined as appendicitis with gangrene, perforated appendix, and/or abscess formation. Preoperative factors were collected from published clinical scoring models; patient information, symptoms, signs, results of laboratory tests, and findings of CT. Factors were analyzed using a chi-squared test and the Mann-Whitney U test.ResultsThe preoperative factors were compared between 151 uncomplicated and 52 complicated appendicitis patients. The significant factors were age ≥40, duration of symptoms >24 hours, body temperature ≥37.3°C, high levels of CRP, findings in CT scan (appendix diameter ≥10 mm, stranding of the adjacent fat, presence of fluid collection, and suspicion of abscess or perforation). We also evaluated the usefulness of clinical scoring models for the detection of complicated appendicitis and found the Appendicitis Inflammatory Response score and two prediction models (Atema score and Imaoka score) showed significance (p< 0.05). High serum CRP level was significantly associated with complicated appendicitis (p< 0.001), and the predicted existence rates of complicated appendicitis were 52.7% for serum CRP level ≥50mg/L, 74.4% for ≥100mg/L, and 82.6% for ≥150mg/L.ConclusionThe results demonstrated several preoperative factors and clinical scoring models to increase suspicion of complicated appendicitis. Specifically, high serum levels of CRP may be a useful factor in predicting complicated appendicitis prior to surgery when supported by clinical findings and imaging; however, further research is needed.

Funder: King Abdulaziz City for Science and Technology; doi: http://dx.doi.org/10.13039/501100004919, Bulk high temperature superconductors based on the rare-earth copper oxides can be used effectively as trapped field magnets capable of generating large magnetic fields. The top-seeded infiltration growth (TSIG) processing technique can provide a more homogeneous microstructure and therefore more uniform superconducting properties than samples grown using conventional melt growth processes. In the present investigation, the properties of bulk, single grain superconductors processed by TSIG and magnetised by the pulsed-field magnetisation technique using a copper-wound solenoid have been studied. A trapped field of ∼3 T has been achieved in a 2-step buffer-assisted TSIG-processed Y-Ba-Cu-O (YBCO) sample at 40 K by magnetising the bulk superconductor completely via a single-pulse magnetisation process. Samples were also subjected to pulsed-field magnetisation at 65 K and by conventional field-cooled magnetisation at 77 K for comparison. Good correlation was observed between the microstructures, critical current densities and trapped field performance of bulk samples fabricated by TSIG and magnetised by pulsed-field and field-cooled magnetisation. The homogeneous distribution of Y2BaCuO5 inclusions within the microstructure of bulk YBCO samples fabricated by the 2-step buffer-assisted TSIG process reduces inhomogeneous flux penetration into the interior of the sample. This, in turn, results in a lower temperature rise of the bulk superconductor during the pulsed-field magnetisation process and a more effective and reliable magnetisation process.

The hybrid trapped field magnet lens (HTFML) is a promising device that is able to concentrate a magnetic field higher than an applied background field continuously, even after removing a background field, which was conceptually proposed by the authors in 2018. We have numerically investigated the HTFML performance, consisting of a REBaCuO cylindrical magnetic lens and REBaCuO trapped field magnet (TFM) cylinder, magnetized by pulsed fields. Single magnetic pulses were applied ranging from B app = 1.5 T to 5.0 T at the operating temperature of T s = 30, 40 and 50 K, and the performance was compared with that of the single REBaCuO TFM cylinder. The HTFML effect was clearly confirmed for the lower B app values. However, for the higher B app values, the trapped field in the magnetic lens bore was nearly equal to or slightly lower than that for the single TFM cylinder because of a weakened lens effect due to magnetic flux penetration into the lens. A temperature rise in the REBaCuO magnetic lens and TFM cylinder was also observed. These results strongly suggest that lowering the temperature of the REBaCuO magnetic lens could enhance the HTFML effect even for higher B app., Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP), Japan Science and Technology Agency (JST), Grant No. VP30218088419 JSPS KAKENHI Grant No.19K05240

Gallbladder polyps are relatively common. Although most gallbladder polyps are benign, some are malignant. Current guidelines state that malignancy should be suspected for polyps ≥ 10 mm in diameter. We clarified the cancer detection rates in accordance with the size distribution of gallbladder polyps, and evaluated the effectiveness of the reported risk factors in predicting malignancy. In this retrospective case–control study, our institutional database was searched to identify patients who underwent laparoscopic cholecystectomy for benign or malignant gallbladder polyps at Sada Hospital, Japan. The chi-squared test was used to analyze the risk factors for malignancy. There were 227 protruding gallbladder lesions. The 206 benign polyps had a diameter of 2–21 mm, while the 21 malignant polyps were 7–60 mm. The cancer detection rates were 16.4% for lesions ≥ 10 mm, 55.9% for lesions ≥ 15 mm, and 94.1% for lesions ≥ 20 mm. Of the benign lesions, cholesterol polyps were the most frequent (50–100%) in all size ranges, even in large lesions (≥ 15 mm). The sessile lesion morphology was significantly more frequent in malignant (60%) than benign lesions (3.4%, p