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Objective This retrospective, single-center study assessed the effects of interferon (IFN)-free treatment of hepatitis C virus (HCV) infection, which has been approved for seven years; calculated the incidence of hepatocellular carcinoma (HCC) after achieving a sustained virologic response (SVR); and elucidated problems with follow-up for surveillance of post-SVR HCC, particularly the impact of the coronavirus disease 2019 (COVID-19) pandemic. Methods We summarized the SVR achievement rate of 286 HCV-infected patients who received 301 IFN-free treatments and analyzed the cumulative incidence of initial HCC and the cumulative continuation rate of follow-up after SVR in the 253 patients who achieved SVR and did not have a history of HCC. Results Among 286 patients who received IFN-free treatments, 14 dropped out, and the 272 remaining patients achieved an SVR after receiving up to third-line treatment. Post-SVR HCC occurred in 18 (7.1%) of the 253 patients without a history of HCC, with a cumulative incidence at 3 and 5 years after SVR of 6.6% and 10.0%, respectively; the incidence of cirrhosis at those time points was 18.2% and 24.6%, respectively.Of the 253 patients analyzed, 58 (22.9%) discontinued follow-up after SVR. Patients who had no experience with IFN-based therapy tended to drop out after SVR. Notably, the number of dropouts per month has increased since the start of the pandemic. Conclusion Currently, IFN-free treatment is showing great efficacy. However, the incidence of HCC after SVR should continue to be monitored. In this study, the COVID-19 pandemic did not affect treatment outcomes, but it may affect surveillance for post-SVR HCC.

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of thymic T-cell precursors. Overexpression of oncogenic transcription factor TAL1 is observed in 40-60% of human T-ALL cases, frequently together with activation of the NOTCH1 and PI3K-AKT pathways. In this study, we performed chemical screening to identify small molecules that can inhibit the enhancer activity driven by TAL1 using the GIMAP enhancer reporter system. Among approximately 3,000 compounds, PIK- 75, a known inhibitor of PI3K and CDK, was found to strongly inhibit the enhancer activity. Mechanistic analysis demonstrated that PIK-75 blocks transcriptional activity, which primarily affects TAL1 target genes as well as AKT activity. TAL1-positive, AKT-activated T-ALL cells were very sensitive to PIK-75, as evidenced by growth inhibition and apoptosis induction, while T-ALL cells that exhibited activation of the JAK-STAT pathway were insensitive to this drug. Together, our study demonstrates a strategy targeting two types of core machineries mediated by oncogenic transcription factors and signaling pathways in T-ALL.

Adult T-cell leukemia/lymphoma (ATL) is a genetically complex hematological malignancy derived from mature T cells. Using an integrative approach, we previously identified genes recurrently associated with super-enhancers in ATL. One of those genes was TP73, a TP53 family gene; however, the roles and function of TP73 and its super-enhancer in ATL pathogenesis are poorly understood. Our study demonstrates that TP73 is highly activated under the control of a super-enhancer in ATL cells but not in normal T cells or other hematological malignancies examined. Full-length TP73 is required for ATL cell maintenance in vitro and in vivo via the regulation of cell proliferation and DNA damage response pathways. Notably, recurrent deletions of TP73 exons 2-3 were observed in a fraction of primary ATL cases that harbored the super-enhancer, while induction of this deletion in cell lines further increased proliferation and mutational burden. Our study suggests that formation of the TP73 intragenic super-enhancer and genetic deletion are likely sequentially acquired in relation to intracellular state of ATL cells, which leads to functional alteration of TP73 that confers additional clonal advantage.

Supplementary Figures 1-5 from Inhibitors of the Proteasome Suppress Homologous DNA Recombination in Mammalian Cells

Proteasome inhibitors are novel antitumor agents against multiple myeloma and other malignancies. Despite the increasing clinical application, the molecular basis of their antitumor effect has been poorly understood due to the involvement of the ubiquitin-proteasome pathway in multiple cellular metabolisms. Here, we show that treatment of cells with proteasome inhibitors has no significant effect on nonhomologous end joining but suppresses homologous recombination (HR), which plays a key role in DNA double-strand break (DSB) repair. In this study, we treat human cells with proteasome inhibitors and show that the inhibition of the proteasome reduces the efficiency of HR-dependent repair of an artificial HR substrate. We further show that inhibition of the proteasome interferes with the activation of Rad51, a key factor for HR, although it does not affect the activation of ATM, γH2AX, or Mre11. These data show that the proteasome-mediated destruction is required for the promotion of HR at an early step. We suggest that the defect in HR-mediated DNA repair caused by proteasome inhibitors contributes to antitumor effect, as HR plays an essential role in cellular proliferation. Moreover, because HR plays key roles in the repair of DSBs caused by chemotherapeutic agents such as cisplatin and by radiotherapy, proteasome inhibitors may enhance the efficacy of these treatments through the suppression of HR-mediated DNA repair pathways. [Cancer Res 2007;67(18):8536–43]

We report a 69-year-old female who was a human T-cell leukemia virus type 1 carrier and exhibited a unique clinical course of developing three hematological malignancies within a short period: diffuse large B-cell lymphoma (DLBCL), chronic myelomonocytic leukemia (CMMoL), and acute myeloid leukemia (AML). Although the blast cells in AML showed typical morphological and immunophenotypical features of acute promyelocytic leukemia (APL), it did not harbor RARα gene fusion and thus initially diagnosed as APL-like leukemia (APLL). The patient developed heart failure with a fulminant clinical course and died soon after the diagnosis of APLL. Retrospective analysis with whole-genome sequencing detected a chromosomal rearrangement between KMT2A and ACTN4 gene loci both in CMMoL and APLL samples, but not in the DLBCL sample. Therefore, CMMoL and APLL were considered to be derived from the same clone with KMT2A translocation associated with prior immunochemotherapy. However, KMT2A rearrangement is rarely found in CMMoL in general and ACTN4 is also a rare partner of KMT2A translocation. Thus, this case did not follow typical transformational process of CMMoL or KMT2A-rearranged leukemia. Importantly, additional genetic alterations, including NRAS G12 mutation, were found in APLL, but not in CMMoL samples, suggesting that they might contribute to leukemic transformation. This report highlights the diverse effects of KMT2A translocation and NRAS mutation on the transformation of hematological cells as well as the importance of upfront sequencing analysis to detect genetic backgrounds for a better understanding of therapy-related leukemia.

Novel DNA-based structures with the ability to encapsulate nanoscale molecules, such as proteins, can be applied to a wide range of areas, including reaction fields and micro/nano drug carriers. DNA-functionalized nanoparticle (DNA-NP) colloidal crystals have emerged as a new class of programmable DNA-based structures harboring metal nanoparticles with improved mechanical properties. The encapsulation of guest molecules into empty spaces in lattice structures is theoretically possible. However, due to the lack of a strategy for versatile encapsulation of guest molecules, the feasibility of nanoscale encapsulation by DNA-NP crystals is unclear. In this study, we developed DNA-functionalized gold nanoparticle (DNA-AuNP) crystals with tunable interparticle spacing for molecular encapsulation. We demonstrated that the modification of DNA-AuNP crystals with functional moieties, that is, biotin molecules, was effective in retaining molecules in the crystals. The crystallinities before and after encapsulation of the molecules were confirmed using small-angle X-ray scattering. We also succeeded in encapsulating CRISPR/Cas9 ribonucleoproteins into DNA-AuNP crystals by harnessing their affinity for target molecules. These findings demonstrated the potential use of metal-DNA hybrid crystals as carriers for direct protein delivery

Several molecular salts exhibit organic deliquescence in response to organic vapors.

Air-stable single-component ambipolar organic semiconductors that conduct both holes and electrons are highly desired but have been rarely realized. Neutral nickel bis(dithiolene) complexes are promising candidates that fulfill the stringent electronic requirements of shallow HOMO levels and deep LUMO levels, which can reduce the carrier injection barrier to overcome the work function of gold electrodes and ensure air stability. However, most nickel bis(dithiolene) analogs that have been characterized as ambipolar semiconductors have twisted molecular structures that hinder the effective intermolecular interactions required for carrier conduction. To address this issue, we synthesized planar alkoxy-substituted nickel bis(dithiolene) analogs that facilitate dense packing with effective intermolecular interactions. Remarkably, changing the methoxy substituents to ethoxy or propoxy groups led to a dramatic change in the packing mode, from one-dimensional to herringbone-like, while maintaining effective intermolecular interactions. These materials overcome the usual trade-off between crystallinity and solubility; they are highly crystalline, even in their film forms, and are highly soluble in organic solvents. They are therefore readily solution-processable to form semiconducting layers with well-defined and well-ordered structures in field-effect transistors. Devices based on these compounds exhibited efficient ambipolar characteristics, even after several months of exposure to air, achieving high carrier mobilities of up to 10

Coronavirus disease (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was reported in Wuhan of China in December 2019. The world is still in a state of pandemic owing to COVID-19. COVID-19 vaccines help our bodies develop immunity against the virus that causes COVID-19 without having to get the illness. Herein, we describe a rare case of a critical disorder, hemophagocytic lymphohistiocytosis (HLH), in a patient with nephritic sclerosis associated with hypertension, following mRNA COVID-19 vaccination. HLH is a life-threatening hyperinflammatory syndrome caused by aberrantly activated macrophages and cytotoxic T cells that may rapidly progress to terminal multiple organ failure.An 85-year-old Japanese woman with chronic renal failure and hypertension was included in this study. Routine laboratory investigations provided the following results: white blood cell (WBC) count, 4.6 × 109/L; hemoglobin (Hb), 8.1 g/dL; platelet count, 27 × 109/L; blood urea nitrogen 48.9 mg/dL, and serum creatinine 3.95 mg/dL. The patient developed malaise, vomiting, and persistent high fever (up to 39.7°C) on the 12th day after receiving the second dose of the vaccine. Initial evaluation revealed neutropenia. The total WBC count was 0.40 × 109/L (Neutrophils 0, Lymphocytes 240/μ, blast 0%); Hb 9.0 g/dL, platelet count 27 × 109/L; and, C Reactive Protein 9.64 mg/dL.Further tests showed hyperferritinemia (serum ferritin 2284.4 μg/L). Bone marrow examination revealed haemophagocytosis. A provisional diagnosis of HLH associated with the Comirnaty® vaccination was made based on the HLH-2004 diagnostic criteria.The patient was treated with granulocyte colony-stimulating factor and 500 mg methylprednisolone.A significant improvement was observed in the patient's condition; the abnormal laboratory results resolved gradually, and the patient was discharged.This case serves to create awareness among clinicians that HLH is a rare complication of COVID-19 vaccination and should be considered, especially in patients with a history of chronic renal failure and hypertension.

The present study investigated the potential of bemegride as a pharmacological activation agent that elicits epileptiform discharges (EDs) in interictal electroencephalogram (EEG) recordings in dogs. Four laboratory dogs with idiopathic epilepsy and four without epilepsy were included. The dogs were anesthetized using sevoflurane during EEG recordings. Bemegride was administered intravenously and repeatedly until EDs were enhanced or induced, or until the maximum dose (20 mg/kg) had been administered. Bemegride activated EDs in all dogs with epilepsy. These EDs predominantly occurred in each dog’s spontaneous irritative zones, which were identified without the administration of bemegride. EDs occurred after the administration of bemegride in 50% of dogs without epilepsy. The dose required for activation was significantly lower in dogs with epilepsy (median; 7.3 mg/kg) than in those without (median; 19.7 mg/kg) (p = 0.0294). The only suspected adverse effect associated with the administration of bemegride was vomiting in two dogs after awakening from anesthesia. There were no other adverse effects, including seizures. The present results demonstrated the potential of bemegride as a safe and effective pharmacological activation agent of EDs in anesthetized dogs with epilepsy and provided more options for the diagnosis and therapeutic planning of epilepsy, including presurgical evaluations, in dogs.

Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of D4Z4 repeats on chromosome 4q (FSHD1). Mutations in theSMCHD1gene are linked to both minor cases with no prominent repeat loss (FSHD2) and severe cases of FSHD1. Abnormal upregulation of the transcription factor DUX4, encoded in theD4Z4repeat, is believed to play a central role in FSHD. However, defining the disease mechanism has been hampered by the heterogeneity of patient-derived cells, difficulty to detect DUX4 in patient myocytes, and limited animal models because D4Z4 repeats are primate-specific. To overcome these limitations, we engineered isogenic human skeletal myoblast lines with D4Z4 and/orSMCHD1mutations. We found a highly synergistic effect of double mutations on triggering two key disease processes, D4Z4 heterochromatin disruption and cross-stimulation of DUX4 targets, such as histone H3.X/Y and LEUTX transcription factor. Thus, engineered human myocyte models provide unique insights into the molecular mechanisms underpinning FSHD.TeaserFSHD mutations cause D4Z4 heterochromatin disruption and feedforward DUX4 network activation.

Poorly differentiated adenocarcinoma of colorectal carcinoma (CRC) is a rare condition with poor prognosis. Here, we describe the case of a 69-year-old man who underwent laparoscopic low anterior resection and was pathologically diagnosed with stage IIIA CRC. At 10 months post-operation, he developed fever and loss of appetite. Laboratory examination revealed fibrin degradation products > 120.0 µg/dL and D-dimer > 60.0 µg/dL. Bone marrow (BM) examination showed malignant epithelioid infiltrate with CK20 and CDX2 expression, leading to a diagnosis of disseminated carcinomatosis of bone marrow, which is rare in CRC and indicates widespread disease is throughout the body. Furthermore, immunohistochemistry indicated the predominant expression of receptor activator of nuclear factor κB ligand (RANKL) in CRC and BM tissues. Thus, RANKL expression, which is known to indicate metastatic behavior of cancer cells, in CRC may play a critical role in promoting osteoclast formation, which has been associated with the pathogenesis of BM lesions.

Single-cell RNA-seq (scRNA-seq) has revolutionized modern genomics, but the large size of myotubes and myofibers has restricted use of scRNA-seq in skeletal muscle. For the study of muscle, single-nucleus RNA-seq (snRNA-seq) has emerged not only as an alternative to scRNA-seq, but as a novel method providing valuable insights into multinucleated cells such as myofibers. Nuclei within myofibers specialize at junctions with other cell types such as motor neurons. Nuclear heterogeneity plays important roles in certain diseases such as muscular dystrophies. We survey current methods of high-throughput single cell and subcellular resolution transcriptomics, including single-cell and single-nucleus RNA-seq and spatial transcriptomics, applied to satellite cells, myoblasts, myotubes and myofibers. We summarize the major myonuclei subtypes identified in homeostatic and regenerating tissue including those specific to fiber type or at junctions with other cell types. Disease-specific nucleus populations were found in two muscular dystrophies, FSHD and Duchenne muscular dystrophy, demonstrating the importance of performing transcriptome studies at the single nucleus level in muscle.

In this paper, we survey on reaction automata theory to model and analyze the biochemical behaviors of vital reactions occurring in nature. Inspired by two notions of a reaction system initiated by Ehrenfeucht and Rozenberg in 2007 and of a multiset, reaction automata (RAs) have been proposed as computing models for accepting string languages. Given an input sequence of symbols, an RA performs its computation process as follows: at every time of receiving an input symbol, it changes the current configuration (represented by a multiset) by applying reaction rules to the multiset in a prescribed manner, for which two kinds of application manners are considered: the maximally parallel manner and the (usual) sequential manner. An RA functions as an extended finite automaton in which multisets play a role of (unbounded number of) states and the state transition is performed by applying reaction rules. We show that the computational powers of RAs are Turing universal in both manners of rule applications. The relationship between the space-bounded variants of RA and the Chomsky hierarchy is also discussed. Further, we discuss the notion of chemical reaction automata, which is a simplified variant of RAs with reaction rules that are free from inhibitor functioning. We complete this survey with a variety of related models of computing together with future research topics.

Considering the personality traits of racehorses (e.g., flightiness, anxiety, and affability) is considered essential to improve training efficiency and decrease accident frequency, especially when retraining for a second career that may involve contact with inexperienced personnel after retiring from racing. Studies on human personality-related genes are frequently conducted; however, such studies are rare in horses because a consistent methodology for personality evaluation is lacking. Using the recently published whole genome variant database of 101 Thoroughbred horses, we compared horse genes orthologous to human genes related to the Big Five personality traits, and identified 18 personality-related candidate genes in horses. These genes include 55 variants that involve non-synonymous substitutions that highly impact the encoded protein. Moreover, we evaluated the allele frequencies and functional impact on the proteins in terms of the difference in molecular weights and hydrophobicity levels between reference and altered amino acids. We identified 15 newly discovered genes that may affect equine personality, but their associations with personality are still unclear. Although more studies are required to compare genetic and behavioral information to validate this approach, it may be useful under limited conditions for personality evaluation.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2020-05-24, 資料番号: PA2120018000

Electronic-state modulation utilizing the electrostatic properties and dynamics of hydrogen-bonding (H-bonding) protons is an effective strategy for realizing novel electron–proton-coupled functionalities. However, material developments based on this strategy have been limited to a few π-electron systems; thus, the realization of solid-state electron–proton-coupled functionalities is challenging. Here, we successfully synthesized new crystals based on nickel catecholdithiolene complexes, which are d/π-electron systems with H-bonds, exhibiting various deprotonation/oxidation states brought about via solution processes. In these crystals, unique three-dimensional framework or two-dimensional sheet structures are formed by intermolecular H-bonds between the complexes, including anionic [O–H⋯O]− H-bonds (dO⋯O ∼ 2.59 A), which were advantageous for proton transfer in solid states. Importantly, detailed analyses revealed that the nickel complexes in the crystals were in various oxidation/deprotonation states. Accordingly, the magnetic properties changed from paramagnetic to non-magnetic with the oxidation of the complexes through proton-coupled electron transfer in solution processes. Density functional theory calculations revealed that the d/π electronic states of the nickel complexes in each crystal are significantly modulated depending on the deprotonation/oxidation states. We propose a possible mechanism for the oxidation-coupled deprotonation of the nickel complex, where various oxidation/deprotonation states can be obtained as crystals and controlled by recrystallization conditions, which is realized by the characteristic d/π-conjugation property and (de)protonation/redox activity of the nickel catecholdithiolene complex. The findings provide a further possibility to construct d/π-electron–proton-coupled collective functionalities based on this complex, together with significant insights for exploring novel electron–proton-coupled functionalities in the solid state.

Propagation of a H2-added strained laminar CH4/air flame in a rich-to-lean stratified mixture is numerically studied. The back-support effect, which is known to enhance the consumption speed of a flame propagating into a leaner mixture compared to that into a homogeneous mixture, is evaluated. A new method is devised to characterize unsteady reactant-to-reactant counterflow flames under transiently decreasing equivalence ratio, in order to elucidate the influence of flow strain on the back-support effect. In contrast to the conventional reactant-to-product configurations, the current configuration is more relevant to unsteady stratified flames back-supported by their own combustion products. Moreover, since H2 distribution downstream of the flame is known to play a crucial role in back-supported CH4/air flames, the influence of H2 addition in the upstream mixture is examined. The results suggest that a larger strain rate leads to a larger equivalence ratio gradient at the reaction zone through increased flow divergence, which amplifies the back-support. Meanwhile, since H2 addition in the upstream mixture does not affect the downstream H2 content, the relative increase in the consumption speed, i.e. the back-support, is suppressed with larger H2 addition. Especially, when the upstream H2 content decreases with the equivalence ratio, the H2 preferentially diffuses toward the unburned gas, which mitigates H2 accumulation in the preheat zone and further weakens the back-support.

Caregivers of dogs with epilepsy experience severe stress due to unpredictable seizures. Hence, they feel the need for a better management strategy. A seizure detection system (SDS), which can identify seizures and provide notifications to caregivers immediately, is required to address this issue. The current study aimed to establish a wearable automatic SDS using acceleration data and the Mahalanobis distance and to preliminarily investigate its feasibility among dogs. A generalized tonic–clonic seizure (GTCS) was targeted because it is the most common type of seizure and can have serious consequences (i.e., status epilepticus). This study comprised three phases. First, the reference datasets of epileptic and non-epileptic activities were established using acceleration data of GTCSs in 3 dogs and daily activities in 27 dogs. Second, the GTCS-detecting algorithm was created using the reference datasets and was validated using other acceleration data of GTCSs in 4 epileptic dogs and daily activities in 27 dogs. Third, a feasibility test of the SDS prototype was performed in three dogs with epilepsy. The algorithm was effective in identifying all acceleration data of GTCSs as seizures and all acceleration data of daily activities as non-seizure activities. Dogs with epilepsy were monitored with the prototype for 48–72 h, and three GTCSs were identified. The prototype detected all GTCSs accurately. A false positive finding was not obtained unless the accelerometer was displaced. Hence, a method that can detect epileptic seizures, particularly GTCSs, was established. Nevertheless, further large-scale studies must be conducted before the method can be commercialized.

Proton-electron-coupled reactions, specifically proton-coupled electron transfer (PCET), in biological and chemical processes have been extensively investigated for use in a wide variety of applications, including energy conversion and storage. However, the exploration of the functionalities of the conductivity, magnetism, and dielectrics by proton-electron coupling in molecular materials is challenging. Dynamic and static proton-electron-coupled functionalities are to be expected. This feature article highlights the recent progress in the development of functionalities of dynamic proton-electron coupling in molecular materials. Herein, single-unit conductivity by self-doping, quantum spin liquid state coupled with quantum fluctuation of protons, switching of conductivity and magnetism triggered by the disorder-order transition of deuterons, and their external responses under pressure and in the presence of an electric field are introduced. In addition, as for the functionalities of proton-d/π-electron coupling in metal dithiolene complexes, magnetic switching with multiple PCET and vapochromism induced by electron transfer through hydrogen-bond (H-bond) formation is introduced experimentally and theoretically. We also outlined the basic and applied issues and potential challenges for development of proton-electron-coupled molecular materials, functionalities, and devices.

The transcription factor MYB is a crucial regulator of hematopoietic stem and progenitor cells. However, the nature of lineage-specific enhancer usage of the Myb gene is largely unknown. We identify the Myb −68 enhancer, a regulatory element which marks basophils and mast cells. Using the Myb −68 enhancer activity, we show a population of granulocyte-macrophage progenitors with higher potential to differentiate into basophils and mast cells. Single cell RNA-seq demonstrates the differentiation trajectory is continuous from progenitors to mature basophils in vivo, characterizes bone marrow cells with a gene signature of mast cells, and identifies LILRB4 as a surface marker of basophil maturation. Together, our study leads to a better understanding of how MYB expression is regulated in a lineage-associated manner, and also shows how a combination of lineage-related reporter mice and single-cell transcriptomics can overcome the rarity of target cells and enhance our understanding of gene expression programs that control cell differentiation in vivo.

The human ability to anticipate upcoming behavior not only enables smooth turn transitions but also makes early responses possible, as respondents use a variety of cues that provide for early proje...

Reducing the cycle-to-cycle variation in an engine is a key to expanding the operational limits of high-efficiency engines such as lean-burn engines. The cycle-to-cycle variation of the engine output is caused by unstable combustion and is especially induced by the cycle-to-cycle variation of the in-cylinder flow. This investigation aims to clarify how the cycle-to-cycle variation of in-cylinder flow develops during intake and compression strokes. To achieve this aim, 12 kHz time-resolved particle image velocimetry measurements were conducted on the symmetrical vertical plane in a four-valve, four-stroke optically accessible engine. This study focuses on the relationship between the flow at the plug position at the ignition timing and the flow distribution in the intake and compression stroke. Correlation map analysis reveals this relationship, and some flow distributions are extracted. The fluctuations in the flow distribution induce the cycle-to-cycle variation of the flow direction at the plug position at the ignition timing, the position of the stagnation plane between the intake flow from the intake valves and the upper side of the tumble vortex, the strength of the blowback flow into the intake port generated by the Miller cycle, and the position of the tumble vortex in the late compression stroke. The flow distributions extracted by the correlation map analysis clearly change between cycles. These results also suggest that correlation map analysis is an effective way to elucidate the factors that induce the cycle-to-cycle variation of the in-cylinder flow.

In order to improve thermal efficiency of spark ignition engine under super-lean burn conditions (excess air ratio [Formula: see text]), thermal stratification technique by in-cylinder water injection toward piston surface (stratified water insulated combustion architecture), in which low temperature water vapor layer is formed on the surface, is proposed. From the water spray visualization using the optically accessible engine, injected water is distributed near the piston top surface at ignition timing and thermal stratification can be achieved in the case that water injection timing (SOIw) is set at earlier stage of a compression stroke. In addition, heat flux on the piston surface measured at the same time is reduced by water injection. The 0.5-L single-cylinder engine test at λ = 2.0 at a constant ignition timing also shows that water injection at earlier stage of a compression stroke makes it possible to mitigate knock without significant increase in combustion instability. On the other hand, part of water is distributed near the spark plug at ignition timing with the water injection at SOIw = −60 °ATDC, resulting in unstable combustion. In addition, the engine test at λ = 2.0 and water/fuel ratio(W/F) = 18% shows that knock mitigation by water injection enables spark advance and following combustion enhancement. As a result, combustion period becomes short and cooling loss decreases, followed by the 1.0-pt improvement of gross indicated thermal efficiency. Moreover, the engine can be operated at minimum spark advance for best torque by increasing W/F up to 35%. Finally, stratified water insulated combustion architecture concept is applied at λ = 1.9 with a higher compression ratio of 17, showing that water injection at SOIw = −120 °ATDC and W/F = 50% enables minimum spark advance for best torque operation, and remarkably high gross indicated that thermal efficiency of 52.63% can be achieved with a sufficiently low knock level and coefficient of variation of indicated mean effective pressure.

The response of laminar methane/air counterflow premixed flames under sinusoidal equivalence ratio oscillation was investigated numerically. The timescales of the oscillation were chosen to be sufficiently longer than the flame timescale so that the flame responds quasi-steadily. The response of periodically stratified flame (SF) with a detailed reaction mechanism exhibited the “back-support” effect, in that the consumption speed Sc response deviated increasingly from Sc of steady homogeneous flames (HFs) at higher oscillation frequencies. It was shown that even when the imposed oscillation timescale is much longer than the flame timescale, the flame response can still be delayed under a sufficiently large equivalence ratio gradient. Subsequently, the above results were compared with those obtained with a global four-step mechanism that omits back-diffusion radicals into the reaction zone. As a result, SFs with the global mechanism displayed a much smaller back-support effect in both lean and rich mixtures. Further analysis with modified diffusion coefficients revealed the dominant roles of H2 and radical species diffusion in inducing the back-support effect. Contrary to the previous findings, variations in burned gas temperature were found to play a negligible role in modifying Sc. Additionally, the hysteresis of the back-support effect under periodical stratification was found to be more prominent on the richer side because of the presence of a larger H2 pool.

Hydrogen bonding (H-bonding) has long been used for structural regulations. Recently, some examples have been reported where electrical conductivity and magnetism were switched based on direct modulation of electronic states through H-bond. If the application of this strategy is realized to a wide range of functionalities, including optical properties, it will greatly expand the design criteria of functional molecular materials. Here, we report a novel zinc dithiolene complex crystal, which exhibits a new vapochromism induced by electron transfer through H-bonds. This crystal exhibits changes in both visible-light absorption and photoluminescence properties with single-crystal-to-single-crystal (SCSC) transformations caused by methanol or water vapor absorption. Single-crystal structural analysis revealed that the zinc dithiolene complex formed H-bonds with the vapor molecules. Importantly, first-principles calculations based on the periodic crystal structures indicated that the vapochromism in this crystal was solely induced by H-bond formation, not by structural changes. Detailed investigations of the energies and shapes of the crystal orbitals as well as Mulliken population analysis revealed that electron transfer through the H-bonds caused vapochromism in this crystal. The findings provide important insights into the material designs of novel vapochromic materials as well as other stimuli-responsive materials considering the intermolecular H-bonds in the solid-state.

Contains fulltext : 248870.pdf (Publisher’s version ) (Open Access) Facioscapulohumeral muscular dystrophy (FSHD) is the second most common genetic myopathy, characterized by slowly progressing and highly heterogeneous muscle wasting with a typical onset in the late teens/early adulthood [1]. Although the etiology of the disease for both FSHD type 1 and type 2 has been attributed to gain-of-toxic function stemming from aberrant DUX4 expression, the exact pathogenic mechanisms involved in muscle wasting have yet to be elucidated [2-4]. The 2021 FSHD International Research Congress, held virtually on June 24-25, convened over 350 researchers and clinicians to share the most recent advances in the understanding of the disease mechanism, discuss the proliferation of interventional strategies and refinement of clinical outcome measures, including results from the ReDUX4 trial, a phase 2b clinical trial of losmapimod in FSHD [NCT04003974].

Agency refers to the capacity to act and act upon, to initiate and carry out actions either for their own sakes or to influence and affect others. The concept is often invoked in music studies, but the nature and types of actions and agents are defined differently in various research frameworks. This study integrates sociocultural and metaphorical approaches to investigate the interactions between work and performer agencies in the verbal communication and gestural exchanges that take place during ensemble rehearsal. The chapter begins with an overview of current theories of musical agency and traces their implications for research on ensemble music-making. Next, using conversational segments drawn from two empirical case studies of professional string quartets as illustrations, the chapter considers agential roles and ascriptions that are not accounted for in current paradigms. In closing, the chapter explores the theoretical implications of the research outcome and proposes a new critical perspective.

This research aims to predict knock occurrences by deep learning using in-cylinder pressure history from experiments and to elucidate the period in pressure history that is most important for knock prediction. Supervised deep learning was conducted using in-cylinder pressure history as an input and the presence or absence of knock in each cycle as a label. The learning process was conducted with and without cost-sensitive approaches to examine the influence of an imbalance in the numbers of knock and non-knock cycles. Without the cost-sensitive approach, the prediction accuracy exceeded 90% and both the precision and the recall were about 70%. In addition, the trade-off between precision and recall could be controlled by adjusting the weights of knock and non-knock cycles in the cost-sensitive approach. Meanwhile, it was found that including the pressure history of the previous cycle did not influence the classification accuracy, suggesting little relationship between the combustion behavior of the previous cycle and knock occurrence in the following cycle. Moreover, learning the pressure history up to 10° CA before a knock improved the classification accuracy, whereas learning it within 10° CA before a knock did not noticeably affect the accuracy. Finally, deep learning was conducted using data, including multiple operating conditions. The present study revealed that deep learning can effectively predict knock occurrences using in-cylinder pressure history.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with poor clinical outcomes. Dysregulated MYC expression, which is associated with protein arginine methyltransferase 5 (PRMT5) dependency, is a recurrent feature of BPDCN. Although recent studies have reported a PRMT5 gene signature in BPDCN patient samples, the role of PRMT5 in BPDCN remains unexplored. Here, we demonstrate that BPDCN is highly sensitive to PRMT5 inhibition. Consistent with the upregulation of PRMT5 in BPDCN, we show that pharmacological inhibition (GSK3326595) of PRMT5 inhibits the growth of the patient-derived BPDCN cell line CAL-1 in vitro and mitigated tumor progression in our mouse xenograft model. Interestingly, RNA-sequencing (RNA-seq) analysis revealed that PRMT5 inhibition increases intron retention in several key RNA methylation genes, including METTL3, which was accompanied by a dose-dependent decrease in METTL3 expression. Notably, the function of cellular m6A RNA modification of METTL3 was also affected by PRMT5 inhibition in CAL-1 cells. Intriguingly, METTL3 depletion in CAL-1 caused a significant increase in interferon (IFN) signaling, which was further elevated upon PRMT5 inhibition. Importantly, we discovered that this increase in IFN signaling attenuated the sensitivity of METTL3-depleted CAL-1 cells to PRMT5 inhibition. Correspondingly, stimulation of IFN signaling via TLR7 agonists weakened CAL-1 cell sensitivity to PRMT5 inhibition. Overall, our findings implicate PRMT5 as a therapeutic target in BPDCN and provide insight into the involvement of METTL3 and the IFN pathway in regulating the response to PRMT5 inhibition.

Muscle groups throughout the body are specialized in function and are specified during development by position specific gene regulatory networks. In developed tissue, myopathies affect muscle groups differently. Facioscapulohumeral muscular dystrophy, FSHD, affects upper body and tibialis anterior (TA) muscles earlier and more severely than others such as quadriceps. To investigate an epigenetic basis for susceptibility of certain muscle groups to disease, we perform DNA methylation and RNA sequencing on primary patient derived myoblasts from TA and quadricep for both control and FSHD2 as well as RNA-seq for myoblasts from FSHD1 deltoid, bicep and TA over a time course of differentiation. We find that TA and quadricep retain methylation and expression differences in transcription factors that are key to muscle group specification during embryogenesis. FSHD2 patients have differences in DNA methylation and expression related to SMCHD1 mutations and FGF signaling. Genes induced specifically in FSHD are more highly expressed in commonly affected muscle groups. We find a set of genes that distinguish more susceptible muscle groups including development-associated TFs and genes involved in WNT signaling. Adult muscle groups therefore retain transcriptional and DNA methylation differences associated with development, which may contribute to susceptibility in FSHD.

AIMS Effects of a proteasome inhibitor, MG-132, on the riboflavin production in Ashbya gossypii were investigated to elucidate the relationship of the riboflavin production with flavoprotein homeostasis. METHODS AND RESULTS The addition of MG-132 to the liquid medium reduced the specific riboflavin production by 79% in A. gossypii at 25 μM after 24 h. The addition of the inhibitor also caused the accumulation of reactive oxygen species and ubiquitinated proteins. These results indicated that MG-132 works in A. gossypii without any genetic engineering and reduces riboflavin production. In the presence of 25 μM MG-132, specific NADH dehydrogenase activity was increased by 1.4-fold compared to DMSO, but specific succinate dehydrogenase (SDH) activity was decreased to 52% compared to DMSO. Additionally, the amount of AgSdh1p (ACR052Wp) was also reduced. Specific riboflavin production was reduced to 22% when 20 mM malonate, a SDH inhibitor, was added to the culture medium. The riboflavin production in heterozygous AgSDH1 gene-disrupted mutant (AgSDH1-/+ ) was reduced to 63% compared to that in wild type. CONCLUSIONS MG-132 suppresses the riboflavin production and SDH activity in A. gossypii. SDH is one of the flavoproteins involved in the riboflavin production in A. gossypii. SIGNIFICANCE AND IMPACT OF THE STUDY This study shows that MG-132 has a negative influence on the riboflavin production and SDH activity in A. gossypii and leads to the elucidation of the connection of the riboflavin production with flavoproteins.