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This work presents a continuous volumetric indoor air temperature measurement scheme using PMUTs (piezoelectric micromachined ultrasonic transducers). Advancements as compared to state-of-art works include: (1) 'volumetric' temperature monitoring instead traditional 'pointwise' temperature information; (2) accurate temperature readings spanning an operational distance of 5 m as validated by a commercial thermometer for 3 days; and (3) capable of detecting global average temperature and local temperature events by installing networked/grid PMUT pairs. This innovative sensing technique could be applicable for the precision control of future building/living environments.

This paper reports a 9-meter-long ultrasonic 3D detector based on a packaged lithium niobate PMUTs (piezoelectric micromachined ultrasonic transducers). Compared with the state-of-the-art reports, three distinctive achievements have been demonstrated: (1) high uniformity and wide bandwidth PMUTs by optimized package designs for highly efficient ultrasonic energy transfer; (2) a long-range receiving beamforming detection scheme on a 4×4 PMUT array for up to 9 m detection rang - comparable to the longest reported range via PMUTs; and (3) 3D detection of multiple static/moving objects with the field of view exceeding 50°. As such, this device is valuable for various applications such as obstacle avoidance when both low power consumption and small form factor are desirable, including aerial drones.

Abstract Macaque restricts hepatitis B virus (HBV) infection because its receptor homologue, NTCP (mNTCP), cannot bind preS1 on viral surface. To reveal how mNTCP loses the viral receptor function, we here solve the cryo-electron microscopy structure of mNTCP. Superposing on the human NTCP (hNTCP)-preS1 complex structure shows that Arg158 of mNTCP causes steric clash to prevent preS1 from embedding onto the bile acid tunnel of NTCP. Cell-based mutation analysis confirms that only Gly158 permitted preS1 binding, in contrast to robust bile acid transport among mutations. As the second determinant, Asn86 on the extracellular surface of mNTCP shows less capacity to restrain preS1 from dynamic fluctuation than Lys86 of hNTCP, resulting in unstable preS1 binding. Additionally, presence of long-chain conjugated-bile acids in the tunnel induces steric hindrance with preS1 through their tailed-chain. This study presents structural basis in which multiple sites in mNTCP constitute a molecular barrier to strictly restrict HBV.

Abstract Background There have been several reports showing that heart-related deaths are common in long-term survivors of esophageal cancer after radiation therapy; however, radiotherapy technology is evolving year by year. This study was carried out using the SEER database to determine whether the frequency of mortality from heart disease after radiotherapy has improved over time in patients with esophageal cancer. Methods SEER*Stat statistical software version 8.3.9.2 (National Cancer Institute) was used to perform case listing and data extraction. We reviewed causes of death in 8,297 patients who were treated by radiotherapy without surgery between 2004 and 2015 (radiotherapy group). For comparison with this group, we also reviewed causes of death in 5,149 patients who were treated by surgery without radiotherapy (surgery group). Results In the radiotherapy group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus, for which it was considered that the heart was irradiated with a higher dose, was significantly higher than that in patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.017). However, in the surgery group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus tended to be lower than that in patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.063). The cumulative heart-related death rate in patients treated in 2010–2015 was significantly lower than that in patients treated in 2004–2009 in the radiotherapy group (p = 0.011), although the cumulative heart-related death rate was not significantly different between patients treated in 2010–2015 and patients treated in 2004–2009 in the surgery group (p = 0.90). Conclusions The results suggest that recent advances in radiotherapy have enabled a reduction in radiation-induced heart disease in patients with esophageal cancer.

Atmospheric carbonyl sulfide (COS) has received increasing attention as a potential tracer for investigating the global carbon cycle. Owing to the irreversible photosynthetic absorption of COS, changes in the atmospheric COS mole fraction can be related to terrestrial gross primary production. However, the instability of COS in high-pressure cylinders has hampered the accurate determination of atmospheric COS. Here, we report a dynamic dilution method for generating reference gas mixtures containing COS at ambient levels (ca. 500 pmol mol−1). Our method combined a dynamic dilution system employing a high-accuracy mass flow measurement system and a dry reference gas mixture prepared gravimetrically as a parent gas mixture containing a micromole-per-mole level of COS filled in a high-pressure aluminium cylinder. The storage stability of COS at this level was experimentally validated for three gravimetrically prepared dry reference gases over a period of more than 1 decade. We evaluated the dilution performance of the developed method using a gravimetric parent gas mixture containing approximately 1 µmol mol−1 of COS and chlorodifluoromethane (HCFC-22). Excellent repeatability (0.2 % for COS and 0.4 % for HCFC-22 in terms of relative standard deviation; RSD), reproducibility (COS: 0.1 %; HCFC-22: 0.3 %), and dilution linearity (R2>0.99 for both COS and HCFC-22) were obtained and were corroborated by the nearly constant ratio of the normalized gas chromatography–mass spectrometry (GC/MS) response of COS to HCFC-22. The dilution accuracy was examined by comparing the determined HCFC-22 mole fractions in a dynamically diluted parent gas mixture from a mass flow rate measurement system and GC/MS calibrated using a gravimetrically diluted parent gas mixture. The mole fractions of HCFC-22 from these two methods agreed within an acceptable difference of approximately 2 pmol mol−1, validating the dilution accuracy of the developed method. By re-evaluating the experimental data, we determined the mole fractions of COS and HCFC-22 in an ambient-air-based reference gas mixture, with relative standard deviations of 0.1 % for COS and 0.3 % for HCFC-22. These results demonstrated that the developed method can accurately generate reference gas mixtures containing COS at ambient levels, which we expect will support long-term observations of atmospheric COS.

Abstract Purpose To determine the causes of benign hepaticojejunostomy strictures (BHSs) after pancreaticoduodenectomy (PD) and the outcome of endoscopic retrograde cholangiography (ERC) treatment for BHSs. Methods A total of 175 patients who underwent PD between January 2013 and December 2020 and who were followed up for at least 1 year were included. Preoperative data, operative outcomes, and postoperative courses were compared between the BHS group and the group of patients who did not develop stenosis during follow-up (non-BHS group). The course of treatment in the BHS group was also examined. Results BHS occurred in 13 of 175 patients (7.4%). Multivariate analysis of the BHS and non-BHS groups revealed that male sex (OR; 3.753, 95% CI; 1.029–18.003, P = 0.0448) and a preoperative bile duct diameter less than 8.8 mm (OR; 7.51, 95% CI; 1.75–52.40, P = 0.0053) were independent risk factors for the development of BHS. In the BHS group, all patients underwent ERC using enteroscopy. The success rate of the ERC approach to the bile duct was 92.3%. Plastic stents were inserted in 6 patients, and metallic stents were inserted in 3 patients. The median observation period since the last ERC was 17.9 months, and there was no recurrence of stenosis in any of the 13 patients. Conclusions Patients with narrow bile ducts are at greater risk of BHS after PD. Recently, BHS after PD has been treated with ERC-related procedures, which may reduce the burden on patients.

Background: The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear. Methods: This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association. Results: Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1–5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45–0.77) and at 6 months (RR = 0.49, 95 % CI 0.36–0.68). , Reduced risks of eczema were also observed at 2–5 (RR = 0.52, 95 % CI 0.37–0.73) and 3–5 years of age (RR = 0.50 95 % CI 0.35–0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations. Conclusions: Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts.

Induced pluripotent stem cells (iPSCs) hold significant promise for numerous applications in regenerative medicine, disease modeling, and drug discovery. However, the conventional workflow for iPSC generation, with cells grown under two-dimensional conditions, presents several challenges, including the need for specialized scientific skills such as morphologically assessing and picking colonies and removing differentiated cells during the establishment phase. Furthermore, maintaining established iPSCs in three-dimensional culture systems, while offering scalability, necessitates an enzymatic dissociation step for their further growth in a complex and time-consuming protocol. In this study, we introduce a novel approach to address these challenges by reprogramming somatic cells grown under three-dimensional conditions as spheres using a bioreactor, thereby eliminating the need for two-dimensional culture and colony picking. The iPSCs generated in this study were maintained under three-dimensional conditions simply by transferring spheres to the next bioreactor, without the need for an enzymatic dissociation step. This streamlined method simplifies the workflow, reduces technical variability and labor, and paves the way for future advancements in iPSC research and its wider applications.

3β-Hydroxysteroid dehydrogenases (3β-HSDs) catalyze the oxidative conversion of delta (5)-ene-3-beta-hydroxy steroids and ketosteroids. Human 3β-HSD type 2 (HSD3B2) is predominantly expressed in gonadal and adrenal steroidogenic cells for producing all classes of active steroid hormones. Mutations in HSD3B2 gene cause a rare form of congenital adrenal hyperplasia with varying degree of salt wasting and incomplete masculinization, resulting from reduced production of corticoids and androgens. Therefore, evaluation of the HSD3B2 enzymatic activity in both pathways for each steroid hormone production is important for accurately understanding and diagnosing this disorder. Using progesterone receptor (PR)- and androgen receptor (AR)-mediated transactivation, we adapted a method that easily evaluates enzymatic activity of HSD3B2 by quantifying the conversion from substrates [pregnenolone (P5) and dehydroepiandrosterone (DHEA)] to (progesterone and androstenedione). HEK293 cells were transduced to express human HSD3B2, and incubated medium containing P5 or DHEA. Depending on the incubation time with HSD3B2-expressing cells, the culture media progressively increased luciferase activities in CV-1 cells, transfected with the PR/AR expression vector and progesterone-/androgen-responsive reporter. Culture media from human and other mammalian HSD3B1-expressing cells also increased the luciferase activities. HEK293 cells expressing various missense mutations in the HSD3B2 gene revealed the potential of this system to evaluate the relationship between the enzymatic activities of mutant proteins and patient phenotype.

Abstract The current monochromatic beam mode (i.e., uHDR irradiation mode) of the scanned carbon-ion beam lacks a dedicated dose monitor, making the beam control challenging. We developed and characterized a dedicated dose monitor for uHDR-scanned carbon-ion beams. Furthermore, a simple measurable dose rate (dose rate per spot (DRspot)) was suggested by using the developed dose monitor and experimentally validating quantities relevant to the uHDR scanned carbon-ion beam. A large plane-parallel ionization chamber (IC) with a smaller electrode spacing was used to reduce uHDR recombination effects, and a dedicated operational amplifier was manufactured for the uHDR-scanned carbon-ion beam. The dose linearity of the IC was within ± 1% in the range of 1.8–12.3 Gy. The spatial inhomogeneity of the dose response of the IC was ± 0.38% inside the ± 40-mm detector area, and a systematic deviation of approximately 2% was measured at the edge of the detector. uHDR irradiation with beam scanning was tested and verified for different doses at the corresponding dose rates (in terms of both the average dose rate and DRspot). We confirmed that the dose monitor can highlight the characteristics (i.e., dose, dose rate, and dose profile) of uHDR-scanned carbon-ion beams at several dose levels in the monochromatic beam mode.

Abstract Methane (CH4) emission reduction to limit warming to 1.5 °C can be tracked by analyzing CH4 concentration and its isotopic composition (δ 13C, δD) simultaneously. Based on reconstructions of the temporal trends, latitudinal, and vertical gradient of CH4 and δ13C from 1985 to 2020 using an atmospheric chemistry transport model, we show (1) emission reductions from oil and gas exploitation (ONG) since the 1990s stabilized the atmospheric CH4 growth rate in the late 1990s and early 2000s, and (2) emissions from farmed animals, waste management, and coal mining contributed to the increase in CH4 since 2006. Our findings support neither the increasing ONG emissions reported by the EDGARv6 inventory during 1990–2020 nor the large unconventional emissions increase reported by the GAINSv4 inventory since 2006. Total fossil fuel emissions remained stable from 2000 to 2020, most likely because the decrease in ONG emissions in some regions offset the increase in coal mining emissions in China.

Abstract Although increased aerobic glycolysis is common in various cancers, pancreatic ductal adenocarcinoma (PDAC) cells can survive a state of glycolysis suppression. We aimed to identify potential therapeutic targets in glycolysis-suppressed PDAC cells. By screening anticancer metabolic compounds, we identified SP-2509, an inhibitor of lysine-specific histone demethylase 1A (LSD1), which dramatically decreased the growth of PDAC PANC-1 cells and showed an anti-tumoral effect in tumor-bearing mice. The growth of glycolysis-suppressed PANC-1 cells was also inhibited by another LSD1 inhibitor, OG-L002. Similarly, the other two PDAC cells (PK-1 and KLM-1) with suppressed glycolysis exhibited anticancer effects against SP-2509. However, the anticancer effects on PDAC cells were unrelated to LSD1. To investigate how PDAC cells survive in a glycolysis-suppressed condition, we conducted proteomic analyses. These results combined with our previous findings suggested that glucose-starvation causes PDAC cells to enhance mitochondrial oxidative phosphorylation. In particular, mitochondrial fatty acid metabolism was identified as a key factor contributing to the survival of PDAC cells under glycolysis suppression. We further demonstrated that SP-2509 and OG-L002 disturbed fatty acid metabolism and induced lipid droplet accumulation through the impairment of lipophagy, but not bulk autophagy. These findings indicate a significant potential association of lipophagy and anticancer effects in glycolysis-suppressed PDAC cells, offering ideas for new therapeutic strategies for PDAC by dual inhibition of glycolysis and fatty acids metabolism.

Abstract All attempts to identify male-specific growth genes in humans have failed. This study aimed to clarify why men are taller than women. Microarray-based transcriptome analysis of the cartilage tissues of four adults and chondrocytes of 12 children showed that the median expression levels of SHOX, a growth gene in the pseudoautosomal region (PAR), were higher in male samples than in female samples. Male-dominant SHOX expression was confirmed by quantitative RT-PCR for 36 cartilage samples. Reduced representation bisulfite sequencing of four cartilage samples revealed sex-biased DNA methylation in the SHOX-flanking regions, and pyrosequencing of 22 cartilage samples confirmed male-dominant DNA methylation at the CpG sites in the SHOX upstream region and exon 6a. DNA methylation indexes of these regions were positively correlated with SHOX expression levels. These results, together with prior findings that PAR genes often exhibit male-dominant expression, imply that the relatively low SHOX expression in female cartilage tissues reflects the partial spread of X chromosome inactivation into PAR. Altogether, this study provides the first indication that sex differences in height are ascribed, at least in part, to the sex-dependent epigenetic regulation of SHOX. Our findings deserve further validation.

Abstract Objective We retrospectively analyzed breast cancer patients who received adjuvant radiotherapy to determine the incidence of lymphocytopenia and its risk factors. Methods We reviewed 812 patients with breast cancer who received postoperative radiotherapy. Patients were divided into two groups based on the use of chemotherapy, and a generalized linear regression model was used to explore predictive factors for grade 2 or higher lymphocytopenia. We also examined the effect of lymphocytopenia on overall survival. Results Grade 2 or higher lymphocytopenia was observed in 19.4% of patients who did not receive chemotherapy and 45.1% of patients who received chemotherapy. In multivariate analysis, bilateral disease, regional lymph node irradiation, and baseline lymphocytopenia were associated with lymphocytopenia in patients who did not receive cytotoxic chemotherapy. Regional lymph node irradiation, baseline lymphocytopenia, use of antimetabolites, and use of molecular‐targeted agents were associated with lymphocytopenia in patients treated with chemotherapy. In the survival analysis, lymphocytopenia was associated with worse overall survival only in patients treated with cytotoxic chemotherapy (p = 0.039), and not in patients who did not receive chemotherapy (p = 0.77). Conclusion The analysis revealed the incidence and risk factors of lymphocytopenia after postoperative radiotherapy in patients with breast cancer.

Innate immune cells play a key role in inflammation as a source of pro-inflammatory cytokines. However, it remains unclear how innate immunity-mediated inflammation is fine-tuned to minimize tissue damage and assure the host’s survival at the early phase of systemic inflammation. The results of this study with mouse models demonstrate that the supply of monocytes is restricted depending on the magnitude of inflammation. During the acute phase of severe inflammation, monocytes, but not neutrophils, were substantially reduced by apoptosis and the remaining monocytes were dysfunctional in the bone marrow. Monocyte-specific ablation of Casp3/7 prevented monocyte apoptosis but promoted monocyte necrosis in the bone marrow, leading to elevated levels of pro-inflammatory cytokines and the increased mortality of mice during systemic inflammation. Importantly, the limitation of monocyte supply was dependent on pro-inflammatory cytokines in vivo. Consistently, a reduction of monocytes was observed in the peripheral blood during cytokine-release syndrome (CRS) patients, a pathogen-unrelated systemic inflammation induced by chimeric antigen receptor-T cell (CAR-T cell) therapy. Thus, monocytes act as a safety valve to alleviate tissue damage caused by inflammation and ensure host survival, which may be responsible for a primitive immune-control mechanism that does not require intervention by acquired immunity.

We reported a thermal investigation on a photodetector (PD) with a sandwiched structure comprising p-type, intrinsic, and n-type (PIN-PD) layers based on Williams’ thermal model. Simulations and measurements of the photocurrent in the linear region, 3-dB bandwidth and thermal analyses were conducted. We found a good agreement between the measured photocurrent and simulations. The measured linear photocurrent of PIN-PD with $50~\mu \text{m}$ substrate and $0.4~\mu \text{m}$ absorber was 28 mA at -2 V, which was related to the expected RF output power of +13 dBm at 50 GHz. In addition, thermal analyses evaluated the junction temperature corresponding to the specific measured photocurrent, as well as the 431 K for junction breakdown temperature of the fabricated PD samples. This evaluation further predicted that this type of PIN-PD would reach the thermal breakdown point when the photocurrent was 34 mA at -2 V. Furthermore, with the application of AlN flip-chip bonding, the linear and expected maximum photocurrent were improved to 30 mA and 45 mA, respectively. Finally, we predicted the PD temperature and maximum photocurrent of 55 mA using AlN instead of InP as the main substrate.

In this study, we proposed a novel design for fabricating a unitraveling carrier–type photodetector using In0.52Al0.48As as the collector material. The proposed InAlAs photodetector is based on the structure of a conventional unitraveling carrier–type photodetector with an InP collector and is considered to transplant the concept of an avalanche photodetector using the avalanche material InAlAs. Based on the high responsivity of the avalanche photodetector at a high-frequency range, a unitraveling carrier–type photodetector with an avalanche InAlAs collector (10- $\mu \text{m}$ junction diameter) was fabricated. The measured I–V characteristics showed that the proposed photodetector can demonstrate the avalanche effect. The measured 3-dB bandwidths were 43, 26, and 19 GHz at multiplication gains of 1, 2, and 3.5, respectively. Furthermore, the multiplied responsivity (defined as the product of gain and responsivity under the unit gain condition) was >0.6 A/W under the low gain condition (0.187 A/W under the unit gain condition). Furthermore, estimations for the 3-dB bandwidth were discussed, and the experimental results were found to be consistent with the simulation results. The improvements in the proposed photodetector with a 5- $\mu \text{m}$ junction diameter were predicted. We expect the 3-dB bandwidth and responsivity of the proposed photodetector to reach 100 GHz and 0.7 A/W, respectively, with a low multiplication gain.

Abstract Background Intestinal epithelial cells derived from human pluripotent stem cells (hPSCs) are generally maintained and cultured as organoids in vitro because they do not exhibit adhesion when cultured. However, the three-dimensional structure of organoids makes their use in regenerative medicine and drug discovery difficult. Mesenchymal stromal cells are found near intestinal stem cells in vivo and provide trophic factors to regulate stem cell maintenance and proliferation, such as BMP inhibitors, WNT, and R-spondin. In this study, we aimed to use mesenchymal stromal cells isolated from hPSC-derived intestinal organoids to establish an in vitro culture system that enables stable proliferation and maintenance of hPSC-derived intestinal epithelial cells in adhesion culture. Methods We established an isolation protocol for intestinal epithelial cells and mesenchymal stromal cells from hPSCs-derived intestinal organoids and a co-culture system for these cells. We then evaluated the intestinal epithelial cells and mesenchymal stromal cells' morphology, proliferative capacity, chromosomal stability, tumorigenicity, and gene expression profiles. We also evaluated the usefulness of the cells for pharmacokinetic and toxicity studies. Results The proliferating intestinal epithelial cells exhibited a columnar form, microvilli and glycocalyx formation, cell polarity, and expression of drug-metabolizing enzymes and transporters. The intestinal epithelial cells also showed barrier function, transporter activity, and drug-metabolizing capacity. Notably, small intestinal epithelial stem cells cannot be cultured in adherent culture without mesenchymal stromal cells and cannot replaced by other feeder cells. Organoid-derived mesenchymal stromal cells resemble the trophocytes essential for maintaining small intestinal epithelial stem cells and play a crucial role in adherent culture. Conclusions The high proliferative expansion, productivity, and functionality of hPSC-derived intestinal epithelial cells may have potential applications in pharmacokinetic and toxicity studies and regenerative medicine.

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) are associated with poor prognosis and therapy resistance. This study aimed to demonstrate that inhibiting the deubiquitinating enzymes ubiquitin-specific peptidase 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5) (USP14/UCHL5) with b-AP15 or the organogold compound auranofin (AUR) induces apoptosis in the ITD-transformed human leukemia cell line MV4-11 and mononuclear leukocytes derived from patients with FLT3-ITD-positive AML. This study included patients diagnosed with AML at Tokyo Medical and Dental University Hospital between January 2018 and July 2024. Both treatments blocked downstream FLT3 pathway events, with the effects potentiated by USP14 knockdown. Both treatments inhibited FLT3 deubiquitination via K48 and disrupted translation initiation via 4EBP1, a downstream FLT3 target. FLT3 was downregulated in the leukemic cells, with the associated activation of stress-related MAP kinase pathways and increased NF-E2-related factor 2. Furthermore, the overexpression of B-cell lymphoma-extra-large and myeloid cell leukemia-1 prevented the cell death caused by b-AP15 and AUR. These results suggest that inhibiting USP14/UCHL5, which involves multiple regulatory mechanisms, is a promising target for novel therapies for treatment-resistant FLT3-ITD-positive AML.

Dry storage of adsorbent reactors after contaminated water treatment in decommissioning contributes to reducing the risk of contamination spread. In general, the drying process of wet particles involves the simultaneous heat and mass transfers in the particle bed, and the thermal flow becomes complicated. In this study, a simulation model considering the physis involved in the bed, such as the structure of the vessel, the distribution of the initial moisture content, and the resistance of heat and mass transfer, was presented. Predictive calculations of the temperature and moisture content in the drying bed in full-diameter vessel were then performed. In addition, the reproductions of the temperature and the amount of evaporation were confirmed by comparison with the actual measurement results. This model was useful for examining heating methods and predicting drying time. Approximately 100 hours after the start of heating, the adsorbent in contact with the inner surface and bottom of the steel container was dried, and it was thought that it is possible to prevent moisture from coming into contact with the container even during long-time storage. Furthermore, by appropriately setting thermal boundary conditions on the top surface of the packed bed, it was able to improve the prediction accuracy of local moisture content.