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Abstract Near-seafloor concentrated gas hydrates (GHs) containing large amounts of methane have been identified at various gas chimney sites. Although understanding the spatial distribution of GHs is fundamental for assessing their dissociation impact on aggravating global warming and resource potential, the spatial distribution of GHs within gas chimneys remains unclear. Here, we estimate the subseafloor distribution of GHs at a gas chimney site in the Japan Sea using marine electrical resistivity tomography data. The resulting two-dimensional subseafloor resistivity structure shows high anomalies (10–100 Ωm) within seismically inferred gas chimneys. As the resistivity anomalies are aligned with high amplitude seismic reflections and core positions recovering GHs, we interpret the resistivity anomalies are near-seafloor concentrated GH deposits. We also detect various distribution patterns of the high resistivity anomalies including 100-m wide and 40-m thick anomaly near the seafloor and 500-m wide anomaly buried 50 m below the seafloor, suggesting that GHs are heterogeneously distributed. Therefore, considering such heterogeneous GH distribution within gas chimneys is critical for in-depth assessments of GH environmental impacts and energy resources.

It is well known that the friction coefficient of viscoelastic solids against the drive speed exhibits a bell shape. In previous theoretical studies on viscoelastic friction, we can find two origins for the bell shape. One is due to the material response (i.e., the bell-shaped rheology of viscoelastic solids), and the other is due to the mechanical response (i.e., the vertical lift of the counter surface with asperities). Although these two origins do not contradict each other, their relationship seems unclear. This paper theoretically examines the friction coefficient for the steady sliding contact between a rigid probe and a viscoelastic foundation exhibiting the standard linear solid viscoelasticity. Capitalizing on the strength of the simple model, we successfully find the complete set of dimensionless numbers and master curves describing the velocity dependence of the friction coefficient. Comparing them with the dimensionless numbers and master curves for the Kelvin-Voigt viscoelasticity, we clarify two origins for the bell-shaped velocity-dependent friction coefficient and their relationship.

Abstract A 76‐year‐old woman with cT1bN2M1b stage IVA spindle cell carcinoma of the right lower lobe of the lung, no driver gene mutation, and programmed death ligand 1

Recent advances in computational methods have enabled realistic numerical simulations for the sliding friction of viscoelastic solids (e.g., rubber friction by the finite element method in the macroscale and soft matter friction by the molecular dynamics method in the nanoscale). However, the factor analysis of accumulated numerical results is generally not easy as their models include many system parameters. Here we theoretically examine the sliding friction with the minimum number of system parameters: the sliding friction between a rigid probe of various shapes and a viscoelastic foundation that consists of the Kelvin-Voigt elements. The analytical solutions for the master curves of the friction coefficient are described by using dimensionless numbers under two boundary conditions (i.e., a constant indentation depth and a constant contact load). Based on the analytical solutions, we discuss how the bell-shaped velocity dependence of the friction coefficient appears under a constant contact load without bell-shaped rheology: The keys are the vertical lift of the probe and the change in the inlet slope due to the vertical lift. The analytical solutions (exact and approximate) obtained here would help the factor analysis to some extent for several numerical simulations in computer-aided science and engineering.

Abstract The Aira caldera, located in southern Kyushu, Japan, originally formed 100 ka, and its current shape reflects the more recent 30 ka caldera-forming eruptions (hereafter, called the AT eruptions). This study aimed to delineate the detailed two-dimensional (2D) seismic velocity structure of the Aira caldera down to approximately 15 km, by means of the travel-time tomography analysis of the seismic profile across the caldera acquired in 2017 and 2018. A substantial structural difference in thickness in the subsurface low-velocity areas in the Aira caldera between the eastern and western sides, suggest that the Aira caldera comprises at least two calderas, identified as the AT and Wakamiko calderas. The most interesting feature of the caldera structure is the existence of a substantial high-velocity zone (HVZ) with a velocity of more than 6.8 km/s at depths of about 6–11 km beneath the central area of the AT caldera. Because no high ratio of P- to S-wave velocity zones in the depth range were detected from the previous three-dimensional velocity model beneath the AT caldera region, we infer that the HVZ is not an active magma reservoir but comprises a solidified and cool remnant. In addition, a poorly resolved low-velocity zone around 15 km in depth suggests the existence of a deep active magma reservoir. By superimposing the distribution of the known pressure sources derived from the observed ground inflation and the volcanic earthquake distribution onto the 2D velocity model, the magma transportation path in the crust was imaged. This image suggested that the HVZ plays an important role in magma transportation in the upper crust. Moreover, we estimated that the AT magma reservoir in the 30 ka Aira caldera-forming eruptions has the total volume of 490 km3 DRE and is distributed in a depth range of 4–11 km. Graphical Abstract

Abstract Viral cell‐free DNA (cfDNA) in plasma has been widely evaluated for detecting cancer and monitoring disease in virus‐associated tumors. We investigated whether the amount of cfDNA of human T‐cell leukemia virus type 1 (HTLV‐1) correlates with disease state in adult T‐cell leukemia‐lymphoma (ATL). HTLV‐1 cfDNA in aggressive ATL was significantly higher than that in indolent ATL and asymptomatic carriers. Notably, patients with lymphoma type represented higher HTLV‐1 cfDNA amount than chronic and smoldering subtypes, though they had no abnormal lymphocytes in the peripheral blood. HTLV‐1 cfDNA can be a universal biomarker that reflects the expansion of ATL clones.

Abstract Mt. Ontake is an active volcano in central Japan where phreatic eruption activity is prominent. A shallow subsurface structure in the summit region of this volcano has been scarcely studied despite its importance. Our study examines the structure from three seismic analyses: a typical P-wave velocity from the semblance of the vertical propagation of intermediate-depth earthquakes (IDEs), a layered velocity model from P- and S-wave arrival times of shallow volcanic earthquakes, and a pseudoreflection profile from the autocorrelation functions of the IDEs. Our results consistently indicate the presence of three layers, which are interpreted as younger (> 0.1 Ma) and older (0.39–0.78 Ma) eruptive deposits and the basement. A comparison of the structure with hypocentres and deformation sources suggests fluid migration controlled by the structure. Graphical Abstract

ABSTRACT Antibody screening tests for human T-cell leukemia virus type 1 (HTLV-1) are performed based on methods such as chemiluminescent enzyme immunoassay (CLEIA), chemiluminescence immunoassay (CLIA), electrochemiluminescence immunoassay, and particle agglutination (PA). Espline HTLV-I/II, a commercially available, easy-to-use, and rapid immunochromatographic antibody test (IC), was developed for situations where expensive instruments and laboratory equipment are not available. In this report, we compared the performance of IC with the above existing tests using diverse samples derived from asymptomatic HTLV-1 carriers and patients with HTLV-1-associated diseases in collaboration with 11 Japanese institutes. We found that IC detected HTLV-1 infection in all samples from HTLV-1-associated diseases, including adult T-cell leukemia, HTLV-1-associated myelopathy, and HTLV-1 uveitis (200/200). The sensitivity of IC compared with CLIA, CLEIA, and PA was 99.2% (363/366), 100% (241/241), and 100% (47/47), respectively, and the specificity was 99.4% (994/1000), 100% (60/60), and 100% (40/40), respectively. The positive and negative predictive values of IC were 99.7% [95% confidence interval (CI): 99.12–99.92] and 99.5% (95% CI: 98.82–99.75), respectively. However, IC had difficulty in correctly judging samples that were diagnosed as seroreactive in other first screening tests but negative by a confirmatory test; for example, of 612 confirmed negative samples that were CLIA seroreactive, 332 samples were IC positive. These results confirmed that IC has sufficient sensitivity and specificity as a screening test for HTLV-1, although, like the other screening tests, it also requires a confirmatory test to determine HTLV-1 infection correctly. IMPORTANCE The World Health Organization estimated that 5–10 million people are infected with human T-cell leukemia virus type 1 (HTLV-1). This number is likely to be underestimated because reliable endemic data are available for only approximately 1.5 billion people worldwide. The point-of-care test is a powerful tool for the easy and quick detection of infections without the requirement for expensive instruments and laboratory equipment. Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test that was evaluated in this study, might significantly advance our understanding of the global epidemiology of HTLV-1 infection.

Abstract We applied a novel method of passive seismic reflection imaging to actual local earthquake data collected by a dense seismic network in the Kanto region, Japan. This method, which implements reverse time migration (RTM), is based on the cross-correlation of wavefields that are extrapolated forward and backward in time from receiver locations using passively observed seismic records. Using multiple reflections between the Earth’s surface and subsurface boundaries, internal structures are imaged using many earthquakes without well-defined source information. The objective of this case study is to evaluate the possibility of acquiring seismic reflection images of the deep crustal structure by applying the RTM-based method using P-wave reflections in the earthquake data collected by a dense seismic network. The P-wave reflection profile along a 191-km-long pseudo-survey line down to a 100 km depth is obtained using the seismic records of hundreds of local earthquakes observed at 72 receiver stations. A P-wave velocity model for RTM imaging is extracted from an existing 3D model obtained by seismic tomography in a previous study. The resulting image shows several continuous reflectors at depths of 15–70 km. These reflectors correspond to the spatially variable velocity and suggest deep structures related to dual plate subduction in this region. Two eastward-dipping reflectors imaged at depths of 15–50 km are likely the top and bottom surfaces of the crust of the Philippine Sea slab, and the westward-dipping reflector at depths of 50–70 km implies the top surface of the Pacific slab. The en-échelon reflectors at depths of 15–20 km may be reflective boundaries between the upper and lower crust in the overlying Okhotsk plate. Our case study results confirm the possibility of obtaining profiles at higher resolutions than are typically obtained by earthquake-based seismic tomography and of imaging at depths beyond the limits of artificially controlled-source seismic surveys. Further implementation of the RTM-based imaging method will improve its potential use for subsurface imaging and monitoring from dense passive seismic data. Graphical Abstract

Integrating RAISING and CLOVA, an effective method for detection and monitoring clonal integration of viruses and viral vectors is presented.

Abstract We conducted waveform inversions of an ultra-long-period (~ 240-s) event associated with the phreatic eruption of Mount Kusatsu–Shirane on January 23, 2018. We used broadband seismic and tilt records from three stations surrounding the eruption site. The horizontal components of the broadband seismic records were severely contaminated by tilt motions. We applied a waveform inversion algorithm to account for both the translational and tilt motions. To reduce the number of free parameters, we assumed a tensile crack source and conducted grid searches for the centroid location and orientation of the crack. The results showed a rapid inflation of 105 m3 of the crack, followed by a slow deflation starting 8–11 s prior to the onset of the eruption. The source location and crack orientation were not uniquely determined. The most likely source is a north–south-opening sub-vertical crack near the eruptive craters. This ultra-long-period event may represent volcanic fluid migration from depth to the surface through a vertical crack during the eruption. Graphical abstract

Abstract Autocorrelation functions (ACFs) of vertically incident seismic waves are used to image subsurface reflectors. However, the reflection responses derived from ACFs usually contain many false signals. We present a method to quantify the errors in ACFs and extract true reflectors with high reliability. We estimated the errors for each earthquake at each station as follows. We calculated the amplitude of the observed waveform within the noise window and generated 1000 random noise traces that have this amplitude. By subtracting the random noise traces from the observed waveform, we created 1000 candidate earthquake waveforms. We computed the ACF for each of the 1000 waveforms and calculated the ensemble average and standard deviation of the 1000 different ACF amplitudes at each lag time. Then, we applied weighted stacking to the ACFs of many earthquakes to obtain the reflection response at the station. We calculated the standard deviation of the weighted stack to estimate errors in the reflection response. We evaluated the method by applying it to seismic data from the metropolitan area of Japan. The subsurface structure of the study area has been studied extensively and consists of a strong velocity discontinuity between sedimentary and basement layers. Following our method, the discontinuity was imaged as a clear reflector with an amplitude that was substantially greater than three times the standard deviation, which corresponds to statistical significance at the 99% confidence level. At other depths where reflectors are not expected to be present, the amplitudes of the peaks were less than or close to three times the standard deviation. The signal of the discontinuity was clearly visible at frequencies below 10 Hz and was less prominent at higher frequencies. Graphical Abstract

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged

HTLV-1 is an oncovirus causing ATL and other inflammatory diseases such as HAM/TSP and HU in about 5% of infected individuals. It is also known that HTLV-1-infected cells maintain a disease-free, immortalized, latent state throughout the lifetimes of about 95% of infected individuals. We believe that the stable maintenance of disease-free infected cells in the carrier is an intrinsic characteristic of HTLV-1 that has been acquired during its evolution in the human life cycle. We speculate that the pathogenesis of the virus is ruled by the orchestrated functions of viral proteins. In particular, the regulation of Rex, the conductor of viral replication rate, is expected to be closely related to the viral program in the early active viral replication followed by the stable latency in HTLV-1 infected T cells. HTLV-1 and HIV-1 belong to the family Retroviridae and share the same tropism, e.g., human CD4+ T cells. These viruses show significant similarities in the viral genomic structure and the molecular mechanism of the replication cycle. However, HTLV-1 and HIV-1 infected T cells show different phenotypes, especially in the level of virion production. We speculate that how the activity of HTLV-1 Rex and its counterpart HIV-1 Rev are regulated may be closely related to the properties of respective infected T cells. In this review, we compare various pathological aspects of HTLV-1 and HIV-1. In particular, we investigated the presence or absence of a virally encoded “regulatory valve” for HTLV-1 Rex or HIV-1 Rev to explore its importance in the regulation of viral particle production in infected T cells. Finally, wereaffirm Rex as the key conductor for viral replication and viral pathogenesis based on our recent study on the novel functional aspects of Rex. Since the activity of Rex is closely related to the viral replication rate, we hypothesize that the “regulatory valve” on the Rex activity may have been selectively evolved to achieve the “scenario” with early viral particle production and the subsequent long, stable deep latency in HTLV-1 infected cells.

Characterising the clonal architecture of Adult T-cell leukemia-lymphoma (ATL) remains crucial. Here, the authors develop a capture-based sequencing panel and use deep DNA and single cell RNA sequencing and report distinct genomic and transcriptomic features associated with subclonal evolution.

Abstract We analyze temporal variations in the travel times of both P and S waves (Vp and Vs) for 14 months at Toyohashi (central Japan) with a continuously operating vibration source that could efficiently produce both P and S waves. Seismic waves produced by the source, which is called the accurately controlled routinely operated signal system (ACROSS), are recorded by three nearby seismic stations, and the travel time variation at each station is estimated using the transfer function calculated from the recorded data. Long-term variations in Vp and Vs are observed and can be interpreted by the change in fluid saturation and crack density of the subsurface rocks. The variation in fluid saturation and crack density are consistent with that in the groundwater level, which is measured at the station nearest to the ACROSS. Short-term responses to rainfalls are observed at the station nearest to the ACROSS system; the interpretation of the changes in crack density and saturation is inconsistent with the ground water observation, partly owing to the initial response to rainfall. This can be interpreted as an air–water mixture within pores or cracks on a fine scale.

Abstract Background Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

Abstract Wnt5a is a ligand of the non-canonical Wnt signaling pathway involved in cell differentiation, motility, and inflammatory response. Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive T-cell malignancies caused by infection of human T-cell leukemia virus type1 (HTLV-1). Among subtypes of ATL, acute-type ATL cells are particularly resistant to current multidrug chemotherapies and show remarkably high cell-proliferative and invasive phenotypes. Here we show a dramatic increase of WNT5A gene expression in acute-type ATL cells compared with those of indolent-type ATL cells. Treatment with IWP-2 or Wnt5a-specific knockdown significantly suppressed cell growth of ATL-derived T-cell lines. We demonstrated that the overexpression of c-Myb and FoxM1 was responsible for the synergistic activation of the WNT5A promoter. Also, a WNT5A transcript variant without the exon4 (the ΔE4-WNT5A mRNA), encoding ΔC-Wnt5 (1-136aa of 380aa), is overexpressed in acute-type ATL cells. The ΔC-Wnt5a is secreted extracellularly and enhances cellular migration/invasion to a greater extent compared with wildtype (WT)-Wnt5a. Moreover, the ΔC-Wnt5a secretion was not suppressed by IWP-2, indicating that this mutant Wnt5a is secreted via a different pathway from the WT-Wnt5a. Taken together, synergistic overexpression of the ΔC-Wnt5a by c-Myb and FoxM1 may be responsible for the malignant phenotype of acute-type ATL cells.

This study provides evidence of the enhancement of the oxygen reduction reaction (ORR) activity of Pt/C and Pd-core Pt-shell catalysts upon ionic liquid modification. Under high potential at 1.15 V (vs. reversible hydrogen electrode), the lower coverage of the oxide species on the Pt surface modified with [7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD)][bis(trifluoromethylsulfonyl)imide (NTf2)] ionic liquid (IL) was confirmed by electrochemical analysis. Operando X-ray absorption spectra (XAS) of the ionic liquid-modified Pd-core Pt-shell catalyst displayed smaller 5d orbital vacancies than the naked catalyst. Shrinkage of Pt-Pt bond length was also displayed, indicating the suppression of oxidation. Thus, we conclude that the IL-modified systems are effective in avoiding the adsorption of oxide species on the Pt surface and improving the oxygen reduction activity.

BackgroundHuman T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM) is a neuroinflammatory disease, causing various neurological symptoms, including motor, sensory, and bladder and bowel dysfunctions. This study was designed to reveal the impact of HAM and related symptoms on health-related quality of life (HRQoL).MethodsWe analyzed the Short Form-36 (SF-36) and clinical data of 538 patients with HAM registered in the HAM-net, a nationwide patient registry for HAM in Japan. HRQoL was evaluated using the SF-6D (a health state utility value calculated from the SF-36) and eight SF-36 subscales. A general liner model was used to estimate the impact of major HAM-related symptoms, including gait dysfunction, sensory disturbance in the legs (pain and numbness), urinary dysfunction, and constipation, on the SF-6D and SF-36 subscale scores.ResultsThe mean age and disease duration were 62.0 and 16.5 years, respectively. Of the patients, 73.2% needed walking aid; 42.7 and 67.1% had leg pain and numbness, respectively; 92.1% had urinary dysfunction; and 77.9% had constipation. The mean SF-6D score was 0.565, which was significantly lower than the national average (0.674 in the 60–69 years age group; p < 0.001), exceeding the minimal important difference (0.05–0.1). All the major symptoms were significantly associated with a decrease in the SF-6D score. The SF-36 subscale scores were significantly lower than the national standard of 50 (p ≤ 0.001), except for mental health (MH). Gait dysfunction was associated with lower scores in physical functioning (PF), limitations on role functioning because of physical health, bodily pain, general health perception (GH), vitality (VT), and social functioning; however, no association was observed between gait dysfunction and limitations on role functioning because of emotional problems and MH. Meanwhile, sensory disturbance in the legs was associated with a decrease in scores in all subscales. Urinary dysfunction was associated with worse PF, GH, VT, and MH. Constipation was associated only with PF.ConclusionHRQoL of patients with HAM was worse than that of the general population and was associated with all major symptoms. Thus, patients should be comprehensively managed to achieve better HRQoL.

Introduction: The third ventricular tumor is one of the most difficult lesions to approach. However, if a cavum septum pellucidum (CSP) and cavum vergae (CV) are present, approaching the tumor might be easier by exploiting them. Here, we describe the achievement of a favorable outcome in treating a patient with third ventricular tumor with CSP and CV using an anterior transcallosal interforniceal approach for tumor removal. Case description: A 52-year-old woman presented with acute hydrocephalus symptoms. Head imaging revealed a tumor filling the third ventricle and protruding into the right lateral ventricle through the right foramen of Monro. We also confirmed the presence of CSP and CV. After ventricular drainage, we performed a craniotomy to remove the tumor via an anterior transcallosal interforniceal approach. Almost all of the intraventricular tumor was removed easily without any complications, such as memory impairment. Conclusion: If CSP and CV are present, an anterior transcallosal interforniceal approach can be safely and effectively used to remove a third ventricular tumor.

Abstract Background The reliable diagnosis of human T-cell leukemia virus type 1 (HTLV-1) infection is important, particularly as it can be vertically transmitted by breast feeding mothers to their infants. However, current diagnosis in Japan requires a confirmatory western blot (WB) test after screening/primary testing for HTLV-1 antibodies, but this test often gives indeterminate results. Thus, this collaborative study evaluated the reliability of diagnostic assays for HTLV-1 infection, including a WB-based one, along with line immunoassay (LIA) as an alternative to WB for confirmatory testing. Results Using peripheral blood samples from blood donors and pregnant women previously serologically screened and subjected to WB analysis, we analyzed the performances of 10 HTLV-1 antibody assay kits commercially available in Japan. No marked differences in the performances of eight of the screening kits were apparent. However, LIA determined most of the WB-indeterminate samples to be conclusively positive or negative (an 88.0% detection rate). When we also compared the sensitivity to HTLV-1 envelope gp21 with that of other antigens by LIA, the sensitivity to gp21 was the strongest. When we also compared the sensitivity to envelope gp46 by LIA with that of WB, LIA showed stronger sensitivity to gp46 than WB did. These findings indicate that LIA is an alternative confirmatory test to WB analysis without gp21. Therefore, we established a novel diagnostic test algorithm for HTLV-1 infection in Japan, including both the performance of a confirmatory test where LIA replaced WB on primary test-reactive samples and an additional decision based on a standardized nucleic acid detection step (polymerase chain reaction, PCR) on the confirmatory test-indeterminate samples. The final assessment of the clinical usefulness of this algorithm involved performing WB analysis, LIA, and/or PCR in parallel for confirmatory testing of known reactive samples serologically screened at clinical laboratories. Consequently, LIA followed by PCR (LIA/PCR), but neither WB/PCR nor PCR/LIA, was found to be the most reliable diagnostic algorithm. Conclusions Because the above results show that our novel algorithm is clinically useful, we propose that it is recommended for solving the aforementioned WB-associated reliability issues and for providing a more rapid and precise diagnosis of HTLV-1 infection.

All-solid-state fluoride-ion batteries (FIBs) using metal/metal fluorides are expected to be the next generation of storage batteries because they exhibit high volumetric energy densities by utilizing multielectron reactions, compared to the current lithium-ion batteries. However, method of fabricating a composite electrode for all-solid-state fluoride-ion batteries has not yet been established. A fabrication method for a composite electrode that disperses the active material and solid electrolyte is required. To approach this problem, in this study, we employed a high-pressure torsion (HPT) method, in which an active material, solid electrolyte, and conductive agent can be mixed with size reduction, as a new process and prepared Cu (active material)/PbSnF4 (solid electrolyte)/acetylene black (conductive agent) cathode composites. The crystalline sizes of Cu and PbSnF4 were significantly reduced. The apparent grain boundary resistance was also reduced owing to the more homogeneous distribution in the cathode composites after HPT processing. These structural and morphological changes led to high electrochemical performances, compared to a cathode composite without HPT.

HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Recent studies have addressed several long-standing uncertainties about HU. HTLV-1-related diseases are known to be caused mainly through vertical transmission (mother-to-child transmission), but emerging HTLV-1 infection by horizontal transmission (such as sexual transmission) has become a major problem in metropolitan areas, such as Tokyo, Japan. Investigation in Tokyo showed that horizontal transmission of HTLV-1 was responsible for HU with severe and persistent ocular inflammation. The development of ATL and HAM is known to be related to a high provirus load and hence involves a long latency period. On the other hand, factors contributing to the development of HU are poorly understood. Recent investigations revealed that severe HU occurs against a background of Graves’ disease despite a low provirus load and short latency period. This review highlights the recent knowledge on HU and provides an update on the topic of HU in consideration of a recent nationwide survey.

T cells infected with human T-cell leukemia virus type 1 (HTLV-1) acquire various abnormalities during a long latent period and transform into highly malignant adult T-cell leukemia-lymphoma (ATL) cells. This can be described as “clonal evolution”, in which a single clone evolves into ATL cells after overcoming various selective pressures in the body of the infected individuals. Many studies have shown that the genome and epigenome contain a variety of abnormalities, which are reflected in gene expression patterns and define the characteristics of the disease. The latest research findings suggest that epigenomic disorders are thought to begin forming early in infection and evolve into ATL through further changes and accentuation as they progress. Genomic abnormalities profoundly affect clonal dominance and tumor cell characteristics in later events. ATL harbors both genomic and epigenomic abnormalities, and an accurate understanding of these can be expected to provide therapeutic opportunities.

Crack initiation and propagation in carbon fiber-reinforced plastic (CFRP) was observed in situ under the application of an opening load using nanoscopic synchrotron radiation X-ray computed tomography (nanoscopic SR X-CT) at a high spatial resolution of ∼50 nm. Two datasets of reconstructed and segmented images were produced in typical regions, namely in the thin and thick epoxy regions where the resin thickness between the adjacent carbon fibers was small and large, respectively. This novel study presents the first non-destructive three-dimensional (3D) visualization of resin deformation behavior around crack tips, and provides a valuable and unique insight for the future design of CFRPs.

Adult T cell leukemia-lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with the human T cell leukemia virus type I (HTLV-I) retrovirus. ATL carries a dismal prognosis. ATL classifies into four subtypes (acute, lymphoma, chronic, and smoldering) which display different clinical features, prognosis and response to therapy, hence requiring different clinical management. Smoldering and chronic subtypes respond well to antiretroviral therapy using the combination of zidovudine (AZT) and interferon-alpha (IFN) with a significant prolongation of survival. Conversely, the watch and wait strategy or chemotherapy for these indolent subtypes allies with a poor long-term outcome. Acute ATL is associated with chemo-resistance and dismal prognosis. Lymphoma subtypes respond better to intensive chemotherapy but survival remains poor. Allogeneic hematopoietic stem cell transplantation (HSCT) results in long-term survival in roughly one third of transplanted patients but only a small percentage of patients can make it to transplant. Overall, current treatments of aggressive ATL are not satisfactory. Prognosis of refractory or relapsed patients is dismal with some encouraging results when using lenalidomide or mogamulizumab. To overcome resistance and prevent relapse, preclinical or pilot clinical studies using targeted therapies such as arsenic/IFN, monoclonal antibodies, epigenetic therapies are promising but warrant further clinical investigation. Anti-ATL vaccines including Tax peptide-pulsed dendritic cells, induced Tax-specific CTL responses in ATL patients. Finally, based on the progress in understanding the pathophysiology of ATL, and the risk-adapted treatment approaches to different ATL subtypes, treatment strategies of ATL should take into account the host immune responses and the host microenvironment including HTLV-1 infected non-malignant cells. Herein, we will provide a summary of novel treatments of ATL in vitro, in vivo, and in early clinical trials.

Japan has been running a nationwide antenatal human T-cell leukemia virus type-1 (HTLV-1) antibody screening program since 2010 for the prevention of HTLV-1 mother-to-child transmission. As part of the program, pregnant women are invited to take an HTLV-1 antibody screening test, usually within the first 30 weeks of gestation, during regular pregnancy checkups. Pregnant women tested positive on the antibody screening test undergo a confirmatory test, either western blotting or line immunoassay. In indeterminate case, polymerase chain reaction (PCR) is used as a final test to diagnose infection. Pregnant women tested positive on a confirmatory or PCR test are identified as HTLV-1 carriers. As breastfeeding is a predominant route of postnatal HTLV-1 mother-to-child transmission, exclusive formula feeding is widely used as a postnatal preventive measure. Although there is insufficient evidence that short-term breastfeeding during ≤3 months does not increase the risk of mother-to-child transmission compared to exclusive formula feeding, this feeding method is considered if the mother is eager to breastfeed her child. However, it is important that mothers and family members fully understand that there is an increase in the risk of mother-to-child transmission when breastfeeding would be prolonged. As there are only a few clinical studies on the protective effect of frozen-thawed breastmilk feeding on mother-to-child transmission of HTLV-1, there is little evidence to recommend this feeding method. Further study on the protective effects of these feeding methods are needed. It is assumed that the risk of anxiety or depression may increase in the mothers who selected exclusive formula feeding or short-term breastfeeding. Thus, an adequate support and counseling for these mothers should be provided. In addition to raising public awareness of HTLV-1 infection, epidemiological data from the nationwide program needs to be collected and analyzed. In most cases, infected children are asymptomatic, and it is necessary to clarify how these children should be followed medically.

Adult T-cell leukemia/leukemia (ATLL) is an aggressive peripheral T-cell malignancy, caused by infection with the human T-cell leukemia virus type 1 (HTLV-1). We have recently shown that cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is specifically and consistently overexpressed in ATLL cells, and functions as a novel cell surface marker. In this study, we first show that a soluble form of CADM1 (sCADM1) is secreted from ATLL cells by mainly alternative splicing. After developing the Alpha linked immunosorbent assay (AlphaLISA) for sCADM1, we showed that plasma sCADM1 concentrations gradually increased during disease progression from indolent to aggressive ATLL. Although other known biomarkers of tumor burden such as soluble interleukin-2 receptor α (sIL-2Rα) also increased with sCADM1 during ATLL progression, multivariate statistical analysis of biomarkers revealed that only plasma sCADM1 was selected as a specific biomarker for aggressive ATLL, suggesting that plasma sCADM1 may be a potential risk factor for aggressive ATLL. In addition, plasma sCADM1 is a useful marker for monitoring response to chemotherapy as well as for predicting relapse of ATLL. Furthermore, the change in sCADM1 concentration between indolent and aggressive type ATLL was more prominent than the change in the percentage of CD4+CADM1+ ATLL cells. As plasma sCADM1 values fell within normal ranges in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with higher levels of serum sIL-2Rα, a measurement of sCADM1 may become a useful tool to discriminate between ATLL and other inflammatory diseases, including HAM/TSP.

The human retrovirus human T-cell leukemia virus type I (HTLV-1) infects human T cells by vertical transmission from mother to child through breast milk or horizontal transmission through blood transfusion or sexual contact. Approximately 5% of infected individuals develop adult T-cell leukemia/lymphoma (ATL) with a poor prognosis, while 95% of infected individuals remain asymptomatic for the rest of their lives, during which time the infected cells maintain a stable immortalized latent state in the body. It is not known why such a long latent state is maintained. We hypothesize that the role of functional proteins of HTLV-1 during early infection influences the phenotype of infected cells in latency. In eukaryotic cells, a mRNA quality control mechanism called nonsense-mediated mRNA decay (NMD) functions not only to eliminate abnormal mRNAs with nonsense codons but also to target virus-derived RNAs. We have reported that HTLV-1 genomic RNA is a potential target of NMD, and that Rex suppresses NMD and stabilizes viral RNA against it. In this study, we aimed to elucidate the molecular mechanism of NMD suppression by Rex using various Rex mutant proteins. We found that region X (aa20–57) of Rex, the function of which has not been clarified, is required for NMD repression. We showed that Rex binds to Upf1, which is the host key regulator to detect abnormal mRNA and initiate NMD, through this region. Rex also interacts with SMG5 and SMG7, which play essential roles for the completion of the NMD pathway. Moreover, Rex selectively binds to Upf3B, which is involved in the normal NMD complex, and replaces it with a less active form, Upf3A, to reduce NMD activity. These results revealed that Rex invades the NMD cascade from its initiation to completion and suppresses host NMD activity to protect the viral genomic mRNA.

After integration to the human genome as a provirus, human T-cell leukemia virus type 1 (HTLV-1) utilizes host T cell gene expression machinery for viral replication. The viral RNA-binding protein, Rex, is known to transport unspliced/incompletely spliced viral mRNAs encoding viral structural proteins out of the nucleus to enhance virus particle formation. However, the detailed mechanism of how Rex avoids extra splicing of unspliced/incompletely spliced viral mRNAs and stabilizes them for effective translation is still unclear. To elucidate the underlying molecular mechanism of Rex function, we comprehensively analyzed the changes in gene expression and splicing patterns in Rex-overexpressing T cells. In addition, we identified 81 human proteins interacting with Rex, involved in transcription, splicing, translation, and mRNA quality control. In particular, Rex interacts with NONO and SFPQ, which play important roles in the regulation of transcription and splicing. Accordingly, expression profiles and splicing patterns of a wide variety of genes are significantly changed in Rex-expressing T cells. Especially, the level of vPD-L1 mRNA that lacks the part of exon 4, thus encodes soluble PD-L1 was significantly increased in Rex-expressing cells. Overall, by integrated analysis of these three datasets, we showed for the first time that Rex intervenes the host gene expression machinery throughout the pathway, probably to escort viral unstable mRNAs from transcription (start) to translation (end). Upon exerting its function, Rex may alter the expression level and splicing patterns of various genes, thus influencing the phenotype of the host cell.

Abstract We discovered a secular change in the travel time of direct S-waves over a 10-year observation period by means of continuous operation of an artificial and stable seismic source, called Accurately Controlled Routinely Operated Signal System (ACROSS), which is deployed in the central part of Japan along the Nankai Trough. We used 13 High Sensitivity Seismograph Network Japan (Hi-net) stations around the ACROSS source to monitor the temporal variation in travel time. Green’s functions were calculated for each station daily from March 29, 2007, through October 30, 2017. Secular advance in the temporal variation in travel time was seen for the whole operation period, in addition to a steplike delay associated with the 2011 Tohoku earthquake. We estimated the rate of secular change and the amount of coseismic step by modeling the transfer function of S-waves with a linear trend and the coseismic step of the 2011 Tohoku earthquake. Distance dependences of the travel time changes can be explained as a combination of common bias and dispersion for each station, for both the secular and coseismic changes. This can be interpreted as a randomly distributed change in seismic velocity over the range of the observation region. An azimuthal dependence exists for both changes and shows larger changes in the NE–SW direction than in the NW–SE direction from the ACROSS source.

The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients. Based on SciClone analysis, the ATL samples showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to nine clusters. The average number of clusters was six across samples, but the number of clusters differed among different samples. Of these ATL samples, 94% had more than two clusters. Aggressive ATL cases had slightly more clonal clusters than indolent types, indicating the presence of ITH during earlier stages of disease. The known significantly mutated genes in ATL were frequently clustered together and possibly coexisted in the same clone. IRF4, CCR4, TP53, and PLCG1 mutations were almost clustered in subclones with a moderate variant allele frequency (VAF), whereas HLA-B, CARD11, and NOTCH1 mutations were clustered in subclones with lower VAFs. Taken together, these results show that ATL displays a high degree of ITH and a complex subclonal structure. Our findings suggest that clonal/subclonal architecture might be a useful measure for prognostic purposes and personalized assessment of the therapeutic response.

Abstract Background Human T cell leukemia virus type 1 (HTLV-1) causes adult T cell leukemia (ATL) in a proportion of infected individuals after a long latency period. Development of ATL is a multistep clonal process that can be investigated by monitoring the clonal expansion of HTLV-1-infected cells by isolation of provirus integration sites. The clonal composition (size, number, and combinations of clones) during the latency period in a given infected individual has not been clearly elucidated. Methods We used high-throughput sequencing technology coupled with a tag system for isolating integration sites and measuring clone sizes from 60 clinical samples. We assessed the role of clonality and clone size dynamics in ATL onset by modeling data from high-throughput monitoring of HTLV-1 integration sites using single- and multiple-time-point samples. Results From four size categories analyzed, we found that big clones (B; 513–2048 infected cells) and very big clones (VB; >2048 infected cells) had prognostic value. No sample harbored two or more VB clones or three or more B clones. We examined the role of clone size, clone combination, and the number of integration sites in the prognosis of infected individuals. We found a moderate reverse correlation between the total number of clones and the size of the largest clone. We devised a data-driven model that allows intuitive representation of clonal composition. Conclusions This integration site-based clonality tree model represents the complexity of clonality and provides a global view of clonality data that facilitates the analysis, interpretation, understanding, and visualization of the behavior of clones on inter- and intra-individual scales. It is fully data-driven, intuitively depicts the clonality patterns of HTLV-1-infected individuals and can assist in early risk assessment of ATL onset by reflecting the prognosis of infected individuals. This model should assist in assimilating information on clonal composition and understanding clonal expansion in HTLV-1-infected individuals.

Abstract: Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops along a carcinogenic process involving 5 or more genetic events in infected cells. The lifetime incidence of ATL among HTLV-1–infected individuals is approximately 5%. Although epidemiologic studies have revealed risk factors for ATL, the molecular mechanisms that determine the fates of carriers remain unclear. A better understanding of clonal composition and related longitudinal dynamics would clarify the process of ATL leukemogenesis and provide insights into the mechanisms underlying the proliferation of a malignant clone. Genomic DNA samples and clinical information were obtained from individuals enrolled in the Joint Study for Predisposing Factors for ATL Development, a Japanese prospective cohort study. Forty-seven longitudinal samples from 20 individuals (9 asymptomatic carriers and 11 patients with ATL at enrollment) were subjected to a clonality analysis. A method based on next-generation sequencing was used to characterize clones on the basis of integration sites. Relationships were analyzed among clonal patterns, clone sizes, and clinical status, including ATL onset and progression. Among carriers, those exhibiting an oligoclonal or monoclonal pattern with largely expanded clones subsequently progressed to ATL. All indolent patients who progressed to acute-type ATL exhibited monoclonal expansion. In both situations, the major expanded clone after progression was derived from the largest pre-existing clone. This study has provided the first detailed information regarding the dynamics of HTLV-1–infected T-cell clones and collectively suggests that the clonality of HTLV-1–infected cells could be a useful predictive marker of ATL onset and progression.

Summary: Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT has yet been established. We explore epigenome and transcriptome in EZH2WT/WT and EZH2WT/Mu aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome. : A mechanism-based, effective strategy for controlling oncogenic H3K27me3 remains an open question. Yamagishi et al. provide the scientific rationale for dual targeting of EZH1+EZH2 in malignancies overexpressing EZH2, such as ATL, PTCL, and DLBCL, or harboring mutations in histone-modifying genes, as well as in pre-cancerous cells epigenomically perturbed by oncovirus infection. Keywords: EZH1, EZH2, H3K27me3, epigenetic drug, malignant lymphoma, adult T cell leukemia-lymphoma (ATL), HTLV-1, polycomb

Summary: The retrovirus human T-cell leukemia virus type 1 (HTLV-1) integrates into the host DNA, achieves persistent infection, and induces human diseases. Here, we demonstrate that viral DNA-capture sequencing (DNA-capture-seq) is useful to characterize HTLV-1 proviruses in naturally virus-infected individuals, providing comprehensive information about the proviral structure and the viral integration site. We analyzed peripheral blood from 98 naturally HTLV-1-infected individuals and found that defective proviruses were present not only in patients with leukemia, but also in those with other clinical entities. We further demonstrated that clones with defective-type proviruses exhibited a higher degree of clonal abundance than those with full-length proviruses. The frequency of defective-type proviruses in HTLV-1-infected humanized mice was lower than that in infected individuals, indicating that defective proviruses were rare at the initial phase of infection but preferentially selected during persistent infection. These results demonstrate the robustness of viral DNA-capture-seq for HTLV-1 infection and suggest potential applications for other virus-associated cancers in humans. : Katsuya et al. demonstrate that HTLV-1 DNA-capture-seq provides comprehensive information, including the entire viral sequence, integration site, and clonal abundance of infected cells. Infected clones with defective-type proviruses are present in disease states and in asymptomatic carriers, and they proliferate more than full-length proviruses. Keywords: retrovirus, viral oncogenesis, HTLV-1, next-generation sequencing, DNA-capture-seq, viral integration site, clonality analysis, adult T cell leukemia-lymphoma, retroviral latency, HIV-1

Human T-cell leukemia virus type 1 (HTLV-1), the first reported human oncogenic retrovirus, is the etiologic agent of highly aggressive, currently incurable diseases such as adult T-cell leukemia–lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 proteins, including Tax and HBZ, have been shown to have critical roles in HTLV-1 pathogenicity, yet the underlying mechanisms of HTLV-1-driven leukemogenesis are unclear. The frequent disruption of genetic and epigenetic gene regulation in various types of malignancy, including ATL, is evident. In this review, we illustrate a focused range of topics about the establishment of HTLV-1 memory: (1) genetic lesion in the Tax interactome pathway, (2) gene regulatory loop/switch, (3) disordered chromatin regulation, (4) epigenetic lock by the modulation of epigenetic factors, (5) the loss of gene fine-tuner microRNA, and (6) the alteration of chromatin regulation by HTLV-1 integration. We discuss the persistent influence of Tax-dependent epigenetic changes even after the disappearance of HTLV-1 gene expression due to the viral escape from the immune system, which is a remaining challenge in HTLV-1 research. The summarized evidence and conceptualized description may provide a better understanding of HTLV-1-mediated cellular transformation and the potential therapeutic strategies to combat HTLV-1-associated diseases.

Latently infected T lymphocytes are an important barrier toward eliminating a persistent HIV infection. Here we describe an HIV-based recombinant fluorescent-lentivirus referred to as “rfl-HIV” that enables to analyze sense and antisense transcription by means of fluorescence reporter genes. This model virus exhibited similar transcriptional and functional properties of the antisense transcript as observed with a wild type HIV, and largely facilitated the generation of latently-infected T cells clones. We show that latently-infected cells can be divided into two types, those with and those without antisense transcription. Upon addition of latency reversal agents, only the cells that lack antisense transcripts are readily reactivated to transcribe HIV. Thus, antisense transcripts may exhibit a dominant suppressor activity and can lock an integrated provirus into a non-reactivatable state. These findings could have important implications for the development of strategies to eradicate HIV from infected individuals.

The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD) indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a block in differentiation and uncontrolled proliferation. FLT3 is a commonly mutated gene found in AML patients. In clinical trials, the presence of a FLT3-ITD mutation significantly correlates with an increased risk of relapse and dismal overall survival. Therefore, activated FLT3 is a promising molecular target for AML therapies. In this study, we have shown that green tea polyphenols including (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin-3-gallate (ECG) suppress the proliferation of AML cells. Interestingly, EGCG, EGC and ECG showed the inhibition of FLT3 expression in cell lines harboring FLT3 mutations. In the THP-1 cells harboring FLT3 wild-type, EGCG showed the suppression of cell proliferation but did not suppress the expression of FLT3 even at the concentration that suppress 100% cell proliferation. Moreover, EGCG-, EGC-and ECG-treated cells showed the suppression of MAPK, AKT and STAT5 phosphorylation. Altogether, we suggest that green tea polyphenols could serve as reagents for treatment or prevention of leukemia harboring FLT3 mutations.

Human T-cell leukemia virus type-1 (HTLV-1) Rex is a viral RNA binding protein. The most important and well-known function of Rex is stabilizing and exporting viral mRNAs from the nucleus, particularly for unspliced/partially-spliced mRNAs encoding the structural proteins essential for viral replication. Without Rex, these unspliced viral mRNAs would otherwise be completely spliced. Therefore, Rex is vital for the translation of structural proteins and the stabilization of viral genomic RNA and, thus, for viral replication. Rex schedules the period of extensive viral replication and suppression to enter latency. Although the importance of Rex in the viral life-cycle is well understood, the underlying molecular mechanism of how Rex achieves its function has not been clarified. For example, how does Rex protect unspliced/partially-spliced viral mRNAs from the host cellular splicing machinery? How does Rex protect viral mRNAs, antigenic to eukaryotic cells, from cellular mRNA surveillance mechanisms? Here we will discuss these mechanisms, which explain the function of Rex as an organizer of HTLV-1 expression based on previously and recently discovered aspects of Rex. We also focus on the potential influence of Rex on the homeostasis of the infected cell and how it can exert its function.

Adenosine 5'-triphosphate (ATP) is the primary energy currency of all living organisms and participates in a variety of cellular processes. Although ATP requirements during viral lifecycles have been examined in a number of studies, a method by which ATP production can be monitored in real-time, and by which ATP can be quantified in individual cells and subcellular compartments, is lacking, thereby hindering studies aimed at elucidating the precise mechanisms by which viral replication energized by ATP is controlled. In this study, we investigated the fluctuation and distribution of ATP in cells during RNA replication of the hepatitis C virus (HCV), a member of the Flaviviridae family. We demonstrated that cells involved in viral RNA replication actively consumed ATP, thereby reducing cytoplasmic ATP levels. Subsequently, a method to measure ATP levels at putative subcellular sites of HCV RNA replication in living cells was developed by introducing a recently-established Förster resonance energy transfer (FRET)-based ATP indicator, called ATeam, into the NS5A coding region of the HCV replicon. Using this method, we were able to observe the formation of ATP-enriched dot-like structures, which co-localize with non-structural viral proteins, within the cytoplasm of HCV-replicating cells but not in non-replicating cells. The obtained FRET signals allowed us to estimate ATP concentrations within HCV replicating cells as ∼5 mM at possible replicating sites and ∼1 mM at peripheral sites that did not appear to be involved in HCV replication. In contrast, cytoplasmic ATP levels in non-replicating Huh-7 cells were estimated as ∼2 mM. To our knowledge, this is the first study to demonstrate changes in ATP concentration within cells during replication of the HCV genome and increased ATP levels at distinct sites within replicating cells. ATeam may be a powerful tool for the study of energy metabolism during replication of the viral genome.

Low-platinum alloy nanowire (NW) catalysts improve the performance of polymer electrolyte membrane fuel cells, but ultrafine PtNi-NW catalysts, particularly those with high Ni content, often experience significant Ni leaching during electrochemical processes. In this study, a Pt-rich surface layer was successfully formed on PtNi NWs through a simple post-annealing process. Pair distribution function (PDF) analysis revealed a Pt surface layer with a face-centered cubic (fcc) structure, along with internal body-centered tetragonal (bct) PtNi and fcc Ni phases. Operando X-ray absorption spectroscopy (XAS), including conventional and high-energy resolution fluorescence detection (HERFD) XAS, was used to investigate the catalysts' electronic states and structural changes under oxygen reduction reaction (ORR) conditions. The results showed that the Pt-rich surface layer of PtNi-NW/C catalysts, with its short Pt--Pt bond lengths, effectively suppresses Pt oxidation at high polarization potentials and restricts Ni leaching, leading to a significant increase in the ORR-specific activity of 2.07 mA cmPt-2, which is a 2.5- and 7-fold activity enhancement compared to Pt-NW/C and commercial Pt/C catalysts. [ABSTRACT FROM AUTHOR]

Li–S batteries have attracted attention as the next-generation secondary batteries. While substantial progress is made in understanding Li–S chemistry at a fundamental level, only a limited number of studies are dedicated to achieving high energy density at the practical pouch cell level. The challenge lies in attaining high-energy-density Li–S batteries under harsh conditions, which involve a minimal amount of electrolyte and a relatively high areal S-loading cathode. This discrepancy creates a substantial gap between fundamental material research and comprehensive cell-level investigations. In this study, it is investigated how the morphology and properties of two carbon materials, namely Ketjen black (KB) and mesoporous carbon nano-dendrites (MCND), influence the composite cathode architecture and determine the performance of Li–S batteries. Unlike KB, MCND allows for a higher sulfur-loading cathode without evident cracks in the composite cathode. This achievement can be attributed to the high porosity, excellent wettability, and high conductivity exhibited during an identical electrode preparation procedure. Furthermore, large-format Li–S pouch cells incorporating MCND/S cathodes are successfully fabricated. These cells demonstrate an energy density surpassing 250 Wh kg−1 and an initial discharge capacity of 3.7 Ah under challenging conditions (S-loading > 5 mg cm−2 and E/S < 3.5 μL mg−1). [ABSTRACT FROM AUTHOR]