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A pheochromocytoma is a malignant tumor with metastatic potential. Moreover, the cardiovascular effects of abnormal amounts of catecholamines resulting from pheochromocytoma impact prognosis. Resection of the primary tumor is useful for reducing catecholamine production; however, the significance of resection of metastases remains unclear. Herein, we report a case in which multiple lung resections for metastases from pheochromocytoma were performed 5 years after primary tumor resection. Complete resection of 6 pulmonary lesions was achieved, maintaining reduced catecholamine levels and blood pressure without any sign of recurrence for a year.

Summary: Ischemia and pathological angiogenesis in retinal vascular diseases cause serious vision-related problems. However, the transcriptional regulators of vascular repair remain unidentified. Thus, the factors and mechanisms involved in angiogenesis must be elucidated to develop approaches for restoring normal blood vessels. Here, we investigated the effects of the stress response activating transcription factor 3 (ATF3) on angiogenesis and vascular regeneration in vitro and in vivo. ATF3 was expressed specifically in retinal vascular endothelial cells (ECs) during vascular development. Vascular endothelial growth factor stimulation upregulated ATF3 expression in cultured ECs. The downregulated ATF3 expression in ECs caused the deterioration of vascular network formation in vitro and in vivo. Moreover, ATF3 deletion in a model of oxygen-induced retinopathy inhibited retinal vascular repair but not pathological neovascularization. Transcriptome analysis confirmed that high ATF3 expression upregulated the expression of angiogenesis-related genes in ECs. ATF3 may aid vascular repair therapy in retinal vascular diseases.

Objective: The exact relationship between fibroblast growth factor 2 (FGF2) and choroidal neovascularization (CNV) remains unclear. In this study, using optical coherence tomography angiography (OCTA) and FGF2-tg mice which are transgenic mice with a rhodopsin promoter/FGF2 gene fusion, we aimed to investigate the dynamics of FGF2's role in angiogenesis over time. Methods: We developed laser-induced CNV models of FGF2-tg and wild-type (WT) mice and then separated them into two groups using different laser photocoagulation (PC) conditions. The first group received 3 intense PC shots (1st PC) altogether (one-time PC group), while the other group received 3 intense PC shots (1st PC) followed by 6 additional weak PC shots (2 nd PC) on the 7th day after 1st PC (two-times PC group). Results: Using OCTA to observe vessel changes within the same individual over time, there was no difference in the timing of vessel transition from the CNV development phase to the CNV regression phase between FGF2-tg and WT mice in the one-time PC group. In contrast, the neovascular vessels in the two-times PC group of FGF2-tg mice were maintained at least 28 days post-2nd PC without regression. In addition, mature vessels surrounded by PDGFRβ positive pericytes and α-SMA positive smooth muscle cells were observed. Real-time qPCR showed a substantial increase in apelin mRNA expression in the one-time PC group of FGF2-tg, rather than VEGF-A (p

ABSTRACT Patients with borderline pulmonary hypertension (PH) often experience shortness of breath or exacerbation of PH during exercise, known as exercise‐induced PH. However, the pathogenesis of exercise‐induced post‐capillary PH (post‐EIPH) and its treatment strategies remain unclear. Recent guidelines and consensus documents have highlighted the benefits of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors in heart failure and chronic kidney disease (CKD). This study aimed to investigate the effects of SGLT2 inhibitors in patients with post‐EIPH and CKD. This single‐center prospective cohort study enroled 10 patients with CKD (age, 68 years; female, 60%) who exhibited post‐EIPH between 1 July 2022 and 31 December 2023. Post‐EIPH was defined as a pulmonary capillary wedge pressure (PCWP)/cardiac output (CO) slope > 2 and peak PCWP during exercise ≥ 25 mmHg measured by catheterization. The patients received SGLT2 inhibitor treatment for 6 months. At rest, patients with post‐EIPH had borderline‐PH (21.5 ± 1.8 mmHg), with preserved left and right ventricular function. SGLT2 inhibitors treatment significantly reduced the PCWP/CO slope during exercise (3.9 ± 1.2 vs. 2.4 ± 1.2 mmHg/L/min, p = 0.013) and improved the 6‐min walking distance (489.9 ± 80.2 vs. 568.3 ± 91.9 m, p = 0.014). Magnetic resonance imaging revealed a lower left ventricular global longitudinal strain in patients with post‐EIPH, which was increased by SGLT2 inhibitor treatment (−13.8 ± 2.0 vs. −17.3 ± 2.0%, p = 0.003). SGLT2 treatment inhibitors mitigated post‐EIPH hemodynamic abnormalities and exercise intolerance, suggesting their potential as its therapeutic option.

Sudachitin, a member of the flavonoid family, reportedly improves glucose metabolism after long-term administration, but details of the underlying mechanisms are unknown. We found that Sudachitin approximately doubles insulin secretion under high glucose concentrations in mouse pancreatic islets and MIN6 cells. When Sudachitin was orally administered to mice, early-phase insulin secretion was increased and a 30 % reduction in blood glucose levels was demonstrated 30 min after glucose loading. Insulin tolerance tests also showed Sudachitin to increase systemic insulin sensitivity. Additionally, we observed that Sudachitin raised intracellular cAMP levels in pancreatic islets. Phosphodiesterase (PDE) activity assays revealed Sudachitin to inhibit PDE activity and computer simulations predicted a high binding affinity between PDEs and Sudachitin. These findings suggest that Sudachitin enhances both insulin secretion and insulin sensitivity via an increase in intracellular cAMP resulting from PDE inhibition. These insights may facilitate understanding the mechanisms underlying the regulation of glucose metabolism by Sudachitin and other isoflavones.

Objective: Oncological feasibility of segmentectomy for internal non–small cell lung cancer (NSCLC) has not been assessed adequately. We assessed the oncological feasibility of segmentectomy for inner-located NSCLC by investigating surgical margins and patient prognosis after undergoing the procedure. Methods: Of the 3555 patients who underwent resection for lung cancer between 2013 and 2019 at our institution, 659 patients who underwent segmentectomy for clinical stage 0 to stage1A NSCLC were included in this study. Patients were separated into 2 groups according to whether the tumor was in the inner or outer third of the lung area. Clinical characteristics and prognoses were retrospectively compared between the groups. Results: Of the included 659 cases, 183 (27.8%) were inner-located, and 476 (72.2%) had outer-located NSCLC. The surgical margin was significantly shorter in the inner-located group than in the outer group (median, 16 vs 25 mm; P

Abstract Aims The pathophysiology of pulmonary hypertension (PH) due to left‐sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left‐sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)–soluble guanylate cyclase–cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. Methods and results This was a single‐centre, retrospective study with a median follow‐up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty‐four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: −2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all‐cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27–14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. Conclusions Patients with Group 2 PH were tolerant of the inhaled NO test. NO‐induced PAWP is a novel prognostic indicator.

Abstract Dry eye syndrome (DES) is a chronic ocular disease that induces epithelial damage to the cornea by decreasing tear production and quality. Adequate treatment options have not been established for severe DES such as Sjogren’s syndrome due to complicated pathological conditions. To solve this problem, we focused on the conditioned medium of human adipose-derived mesenchymal stem cells (hAdMSC-CM), which have multiple therapeutic properties. Here, we showed that hAdMSC-CM suppressed Benzalkonium Chloride (BAC)-induced cytotoxicity and inflammation in human corneal epithelial cells (hCECs). In addition, hAdMSC-CM increased the expression level and regulated the localisation of barrier function-related components, and improved the BAC-induced barrier dysfunction in hCECs. RNA-seq analysis and pharmacological inhibition experiments revealed that the effects of hAdMSC-CM were associated with the TGFβ and JAK-STAT signalling pathways. Moreover, in DES model rats with exorbital and intraorbital lacrimal gland excision, ocular instillation of hAdMSC-CM suppressed corneal epithelial damage by improving barrier dysfunction of the cornea. Thus, we demonstrated that hAdMSC-CM has multiple therapeutic properties associated with TGFβ and JAK-STAT signalling pathways, and ocular instillation of hAdMSC-CM may serve as an innovative therapeutic agent for DES by improving corneal barrier function.

Gas sensors based on ambipolar carbon nanotube (CNT) field-effect transistors with various amounts of CNTs were fabricated by dielectrophoretic assembly. The nitrogen dioxide (NO2) gas response and recovery properties of the transistors were measured to investigate the effect of CNT amount on gas response. For the device with a small amount of CNTs, responses from the CNT bulk and CNT/electrode contacts were observed. For devices with a large amount of CNTs, in which a network-like structure of CNTs was observed near the electrodes, an increased current in both electron and hole conduction regions was observed compared with that for the device with a small amount of CNTs. The increased current in the electron conduction region rapidly decreased during recovery. This response is consistent with that of CNT/CNT X-type contacts, which have a high resistance before NO2 adsorption. Equivalent circuits of CNT channels with CNT/CNT contacts were developed, allowing the transistor behavior to be qualitatively discussed. Evaluation of time constants revealed that CNT/electrode contacts and CNT/CNT X-type contacts exhibited high NO2 adsorption and desorption rates, respectively.

Objective: Retinal vein occlusion (RVO) can lead to visual impairment, but the development of collateral vessels can sometimes mitigate significant damage. This study aimed to investigate the relationship between collateral vessels and hypertension, the most common underlying condition associated with RVO, by comparing spontaneously hypertensive rats (SHRs) and wild-type Wister rats (WWRs). We also examined the differences between WWRs and SHRs in terms of sphingosine 1-phosphate receptor 1 (S1PR1) expression and its product nitric oxide synthase 3 (NOS3) expression, which are involved in the formation of collateral vessels after vascular occlusion. Methods: Laser photocoagulation (PC) was used to occlude one randomly selected retinal vein in WWRs and SHRs, and the area surrounding the occluded vessel was examined using optical coherence tomography angiography. If reperfusion of the occluded vessel occurred within 2 weeks, the vessel was re-occluded repeatedly by PC. The number of eyes with successfully occluded vessels accompanied by collateral vessels was recorded. Then, WWRs and SHRs were divided into the following four groups: 1) control (no treatment), 2) vehicle (20% DMSO), 3) S1PR1 agonist (2 mg/mL SEW2871), and 4) S1PR1 antagonist (0.25 mg/mL VPC 23019) groups. The drugs were administered intravitreally in all groups except the control. The number of laser shots required for successful RVO was recorded. Histological evaluation and quantitative real-time PCR of S1PR1 and NOS3 were performed to elucidate the mechanisms underlying collateral vessel formation. Results: The proportion of eyes achieving successful vein occlusion was lower in SHRs (4/12 eyes, 33.3%) than in WWRs (8/10 eyes, 80%, p = 0.043). NOS3 expression at 6 h after PC was significantly higher in WWRs than in SHRs (p = 0.021). In WWRs treated with SEW2871, vein occlusion failed in 7 of 10 eyes (70%). The expression of NOS3 was significantly higher in the SEW2871 treatment group than in the untreated group (p

This study focuses on the combustion timing control in hydrogen mixed combustion of a spark ignition gas engine. Especially, we examined the effect of hydrogen mixed ratio and air excess ratio on the combustion feature under same engine conditions. The 50% mass fraction burning timing (MFB50T) is within the specified range under MBT condition, independent of hydrogen mixed ratio and air excess ratio. We also examined the combustion phase estimation method using the existing sensor of the engine. The MFB50T can be estimated by the peak timing of angle speed.

Abstract Peptidoglycan for elongation in Escherichia coli is synthesized by the Rod complex, which includes RodZ. Although various mutant strains of the Rod complex have been isolated, the relationship between the activity of the Rod complex and the overall physical and chemical structures of the peptidoglycan have not been reported. We constructed a RodZ mutant, termed RMR, and analyzed the growth rate, morphology, and other characteristics of cells producing the Rod complexes containing RMR. The growth and morphology of RMR cells were abnormal, and we isolated suppressor mutants from RMR cells. Most of the suppressor mutations were found in components of the Rod complex, suggesting that these suppressor mutations increase the integrity and/or the activity of the Rod complex. We purified peptidoglycan from wild‐type, RMR, and suppressor mutant cells and observed their structures in detail. We found that the peptidoglycan purified from RMR cells had many large holes and different compositions of muropeptides from those of WT cells. The Rod complex may be a determinant not only for the whole shape of peptidoglycan but also for its highly dense structure to support the mechanical strength of the cell wall.

Microplastics (MP) encompass not only plastic products but also paint particles. Marine microdebris, including MP, was retrieved from five sampling stations spanning Nagasaki-Goto island and was classified into six types, primarily consisting of MP (A), Si-based (B), and Cu-based (C) paint particles. Type-A particles, i.e., MP, were exceedingly small, with 74% of them having a long diameter of 25 µm or less. The vertical distribution of type C, containing cuprous oxide, exhibited no depth dependence, with its dominant size being less than 7 μm. It was considered that the presence of type C was associated with a natural phenomenon of MP loss. To clarify this, polypropylene (PP) samples containing cuprous oxide were prepared, and their accelerated degradation behavior was studied using a novel enhanced degradation method employing a sulfate ion radical as an initiator. Infrared spectroscopy revealed the formation of a copper soap compound in seawater. Scanning electron microscopy/energy-dispersive X-ray spectroscopy analysis indicated that the chemical reactions between Cl− and cuprous oxide produced Cu+ ions. The acceleration of degradation induced by the copper soap formed was studied through the changes in the number of PP chain scissions, revealing that the presence of type-C accelerated MP degradation.

Abstract Microscopic colitis (MC) is a chronic inflammatory bowel disease that is characterized by nonbloody watery diarrhea. The epidemiology in Japan differs from that in Europe and the United States, but little information is available from epidemiological surveys of MC in Japan. This study aimed to provide a new hypothesis regarding the factors associated with MC by using the Japanese Adverse Drug Event Report (JADER) database. “Colitis microscopic” (preferred term code: 10056979) cases entered into the JADER database between 2004 and 2021 were analyzed. Of the 246,997 cases in the JADER database, 161 cases were observed to be associated with MC. A Weibull analysis revealed that the median onset duration of MC (interquartile range) was 72.5 (36.0‒125.5) days in lansoprazole users and 116.0 (60.3‒1089.0) days in aspirin users. A multiple logistic regression analysis revealed that MC was significantly associated with the female sex, as well as ages ≥ 60 years and drugs including lansoprazole, aspirin, and nicorandil. A subset analysis revealed that MC was positively associated with obesity in female cases. Our study cannot demonstrate a causal inference between MC and each drug; however, the findings suggest that MC was associated with nicorandil as well as with lansoprazole and aspirin.

How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.

Background: Simultaneously modulating individual neural oscillation and cortical excitability may be important for enhancing communication between the primary motor cortex and spinal motor neurons, which plays a key role in motor control. However, it is unknown whether individualized beta-band oscillatory transcranial direct current stimulation (otDCS) enhances corticospinal oscillation and excitability. Objective: This study investigated the effects of individualized beta-band otDCS on corticomuscular coherence (CMC) and corticospinal excitability in healthy individuals. Methods: In total, 29 healthy volunteers participated in separate experiments. They received the following stimuli for 10 min on different days: 1) 2-mA otDCS with individualized beta-band frequencies, 2) 2-mA transcranial alternating current stimulation (tACS) with individualized beta-band frequencies, and 3) 2-mA transcranial direct current stimulation (tDCS). The changes in CMC between the vertex and tibialis anterior (TA) muscle and TA muscle motor-evoked potentials (MEPs) were assessed before and after (immediately, 10 min, and 20 min after) stimulation on different days. Additionally, 20-Hz otDCS for 10 min was applied to investigate the effects of a fixed beta-band frequency on CMC. Results: otDCS significantly increased CMC and MEPs immediately after stimulation, whereas tACS and tDCS had no effects. There was a significant negative correlation between normalized CMC changes in response to 20-Hz otDCS and the numerical difference between the 20-Hz and individualized CMC peak frequency before the stimulation. Conclusions: These findings suggest that simultaneous modulation of neural oscillation and cortical excitability is critical for enhancing corticospinal communication. Individualized otDCS holds potential as a useful method in the field of neurorehabilitation.

Growth promotion through application of ultrafine bubbles (UFBs) was observed in several crop species grown under suboptimal conditions. In the current study, mitigation of osmotic stress through polyethylene glycol 6000 (PEG6000) was analyzed in soybean seedlings to assess the effects of UFB on plants under soil drought stress. In no-nutrient conditions, growth suppression due to osmotic stress was increasingly mitigated by UFB application as stress intensity increased. Shoot biomass of UFB-treated plants (at all examined PEG6000 concentrations) exceeded to that of the absolute control. Production of superoxide radicals (O2−) under osmotic stress was 1.5-fold higher than that in the control, whereas that in UFB-treated plant showed a similar level as the absolute control. The reduction of O2− through treatment with UFB may help mitigate osmotic stress. In conclusion, this study quantitatively showed that UFB was effective in reducing osmotic stress in soybean seedlings.

IntroductionNeuromuscular electrical stimulation (NMES) induces neural plasticity of the central nervous system (CNS) and improves motor function in patients with CNS lesions. However, the extended stimulus duration of NMES reduces its clinical applicability. Transcutaneous spinal direct current stimulation (tsDCS), which increases afferent input, may enhance the effects and reduce the stimulus duration of NMES. This study investigated the excitability of the motor cortex, somatosensory cortex, and spinal motor neurons after the combined stimulation of NMES and tsDCS.MethodsAmong the 55 participants in this study, 24 were allocated to experiment 1, 15 to experiment 2, and 16 to experiment 3. They received intervention for 20 min on different days: (1) NMES combined with tsDCS (NMES + tsDCS), (2) NMES combined with sham tsDCS (NMES + sham tsDCS), and (3) sham NMES combined with tsDCS (sham NMES + tsDCS). NMES was delivered to the right common peroneal nerve at 25 Hz with the intensity at 120% of the motor threshold. For tsDCS, the cathodal electrode was positioned on the thoracic 10th–12th vertebral levels, and the anodal electrode was located on the right shoulder. The stimulus intensity was 2.5 mA. In experiment 1, motor evoked potentials (MEPs) and short-latency intracortical inhibition (SICI) were measured by transcranial magnetic stimulation up to 60 min after stimulation. The spinal motor neurons’ excitability was assessed by recording the posterior root muscle reflex (PRMR) induced via transcutaneous spinal cord stimulation in experiment 2, and the primary somatosensory cortex excitability was evaluated by recording the somatosensory evoked potentials (SEPs) in experiment 3 up to 15 min after stimulation.ResultsCompared to before the stimulation, NMES + tsDCS significantly increased MEP for 60 min or more, and significantly decreased SICI immediately after. Conversely contrast, the PRMR significantly decreased immediately after, and SEPs were unchanged.DiscussionThese results suggest that simultaneous afferent inputs from different stimulus positions critically induce primary motor cortex plasticity. The combined stimulation of NMES with tsDCS may facilitate the development of a new neurorehabilitation technique.

Introduction Masked obesity (MO) is defined as a normal body mass index (BMI) with a high body fat percentage (%BF), and is associated with the onset of lifestyle-related diseases. However, little is known about the current status of MO. Therefore, we investigated the relationship of MO to physical characteristics and lifestyle habits among Japanese university students. Methods Between 2011 and 2019, we conducted a survey of 10,168 males and 4,954 females with BMI within the normal range (18.5 ≤ BMI < 25 kg/m2). MO was defined as %BF ≥ 20% in males and %BF ≥ 30% in females. Students completed a questionnaire containing items about lifestyle habits. Systolic and diastolic blood pressures were measured, and hypertension was defined as systolic above 140 mmHg and/or diastolic blood pressure above 90 mmHg. A multivariate logistic regression analysis was performed to evaluate the relationships as follows: the relationship of masked obesity to self-reported lifestyle habits, ideal body image, and anthropometric measures; the relationship between hypertension and body indices. Results The proportion of students with MO in 2019 was 13.4% in males and 25.8% in females, and the proportion of females increased over time. MO was associated with desire for weight loss (odds ratio, 95% confidence interval: 1.76, 1.53–2.02), intake of five macronutrients (0.79, 0.67–0.93), rice and wheat intakes (1.22, 1.01–1.47), sleep duration of < 7hr (0.85, 0.74–0.98), and exercise habit (0.71, 0.63–0.81) in males; and with balanced diet intake (0.79, 0.64–0.99) and exercise habit (0.65, 0.51–0.82) in females. There was a significant association of MO with hypertension in males (1.29, 1.09–1.53). Conclusion The percentage of female students with MO increased during the study period, and in males, MO may be a risk factor for hypertension. These results suggest that intervention for MO is needed in Japanese university students.

Ultrafine bubbles (UFBs) exhibit a number of unique physical characteristics; however, reports on plant growth enhancement by UFB application are controversial. Here, we report experiments conducted to test whether UFB technology effectively promotes plant growth. We analyzed the effects of three experimental factors: water (UFB addition), hypoxia (aeration), and fluid movement (stirring) on the growth of soybean seedlings cultured hydroponically under low and high nutrition levels in a controlled environment room under artificial lighting for 8 days. When no nutrients were supplied, positive UFB water effects were evident, but low nutrition reduced UFB water-mediated growth enhancement and high nutrition totally obliterated any growth enhancement by UFB water. We concluded that UFB water-induced growth enhancement was effective and significant under nutrient deficit stress but no growth enhancement was observed, and even negative effects were evident, under favorable plant growth conditions.

We discovered that the ignition area of a planar dielectric barrier discharge gradually extends beyond the area of the opposite electrode when the ambient temperature increases. Even with the opposite electrode the sectional area of which is less than 1 mm2, the discharge eventually ignites over the area of 225 mm2 at ca. 800 K. Several investigations indicate that the creeping discharge occurring around the opposite electrode is not the cause for the extension phenomenon.

Quasielastic neutron scattering (QENS) and neutron powder diffraction of the complex transition metal hydrides Li_{5}MoH_{11} and Li_{6}NbH_{11} were measured in a temperature range of 10–300 K to study their structures and dynamics, especially the dynamics of the hydrogen atoms. These hydrides contain unusual ninefold H-coordinated complex ions (MoH_{9}^{3−} or NbH_{9}^{4−}) and hydride ions (H^{−}). A QENS signal appeared >150 K due to the relaxation of H atoms. The intermediate scattering functions derived from the QENS spectra are well fitted by a stretched exponential function called the Kohlrausch-Williams-Watts functions with a small stretching exponent β ≈ 0.3–0.4, suggesting a wide relaxation time distribution. The Q dependence of the elastic incoherent structure factor is reproduced by the rotational diffusion of MH_{9} (M=Mo or Nb) anions. The results are well supported by a van Hove analysis for the motion of H atoms obtained using first-principles molecular dynamics calculations. We conclude that the wide relaxation time distribution of the MH_{9} rotation is due to the positional disorder of the surrounding Li ions and a unique rotation with MH_{9} anion deformation (pseudorotation).

Previous research into the effects of ultrafine bubbles (UFB) on plant growth have been contradictory. To facilitate the resolution of these contradictions, the aim of the present study was to clarify the interspecific differences in growth responses among cereal/leguminous species under different levels of UFB concentrations. Seedlings of six species were grown hydroponically with three different UFB concentrations and two levels of plant nutrition to evaluate biomass and elongation growth. UFB growth promotion under zero-nutrition occurred in all species. Interspecific differences were noted in response to differing UFB concentration levels. Rice and soybean had higher above-ground biomass production at both low and high concentrations. Conversely, other crops exhibited promoted growth at only one of the concentrations. Negative effects occurred in full nutrient conditions except for root elongation. This study demonstrated that growth-promoting effects with UFB depended on the crop species being tested and the concentration of UFB used.

Repetitive peripheral magnetic stimulation (rPMS) may improve motor function following central nervous system lesions, but the optimal parameters of rPMS to induce neural plasticity and mechanisms underlying its action remain unclear. We examined the effects of rPMS over wrist extensor muscles on neural plasticity and motor performance in 26 healthy volunteers. In separate experiments, the effects of rPMS on motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), direct motor response (M-wave), Hoffmann-reflex, and ballistic wrist extension movements were assessed before and after rPMS. First, to examine the effects of stimulus frequency, rPMS was applied at 50, 25, and 10 Hz by setting a fixed total number of stimuli. A significant increase in MEPs of wrist extensors was observed following 50 and 25 Hz rPMS, but not 10 Hz rPMS. Next, we examined the time required to induce plasticity by increasing the number of stimuli, and found that at least 15 min of 50 and 25 Hz rPMS was required. Based on these parameters, lasting effects were evaluated following 15 min of 50 or 25 Hz rPMS. A significant increase in MEP was observed up to 60 min following 50 and 25 Hz rPMS; similarly, an attenuation of SICI and enhancement of ICF were also observed. The maximal M-wave and Hoffmann-reflex did not change, suggesting that the increase in MEP was due to plastic changes at the motor cortex. This was accompanied by increasing force and electromyograms during wrist ballistic extension movements following 50 and 25 Hz rPMS. These findings suggest that 15 min of rPMS with 25 Hz or more induces an increase in cortical excitability of the relevant area rather than altering the excitability of spinal circuits, and has the potential to improve motor output.

This study tackles the task of swarm robotics, where robots explore the environment to detect targets. When a robot detects a target, the robot must be connected with a base station via intermediate relay robots for wireless communication. Our previous results confirmed that Lévy flight outperformed the usual random walk for exploration strategy in an indoor environment. This paper investigated the search performance of swarm crawler robots with Lévy flight on target detection problems in large environments through a series of real robots’ experiments. The results suggest that the swarm crawler robots with Lévy flight succeeded in the target’s discovery in the indoor environment with a 100% success rate, and were able to find several targets in a given time in the outdoor environment. Thus, we confirmed that target exploration in a large environment would be possible by crawler robots with Lévy flight and significant variances in the detection rate among the positions to detect the outdoor environment’s target.

We investigate estimation methods of aerodynamic coefficients for a ball in sports by using characteristic quantities of its trajectory. One method is based on the quantities representing the whole shape of trajectory while the other utilizes local quantities such as curvature and/or torsion. In the former, the flight distance and the maximum height are measured, and the motion equation predicts numerical values of these quantities with measured initial conditions and preset aerodynamic coefficients. Then the optimal combination of the aerodynamic coefficients is determined by minimizing the error between the measured and estimated values of the characteristic quantities. This method is applied to estimate drag and lift coefficients of a soccer ball in back-spinning, and the result shows that the averaged values of CD and CL are 0.205 and 0.237, respectively. In the latter method, the expressions between the aerodynamic coefficients and the geometrical quantities of trajectory are derived, which suggests that the piecewise quadratic interpolation on a trajectory provides the aerodynamic coefficients. This method enables to locally estimate the coefficients, and therefore clarifies the variation of the coefficients along a trajectory. Measured data for a table tennis ball is analyzed with the method and we obtain successfully the drag and lift coefficients in flight condition. The results indicate the qualitative difference of spinning effect in drag and lift coefficients.

Piwi proteins are part of a superfamily of Argonaute proteins, which are one of the core components of the RNA silencing pathway in many eukaryotes. Piwi proteins are thought to repress the transposon expression both transcriptionally and post-transcriptionally. Recently, Drosophila melanogaster Piwi was recently reported to associate with chromatin and to interact directly with the Heterochromatin Protein 1 (HP1a). However, similar interactions have not been reported in other higher eukaryotes. Here we show that silkworm Piwi proteins interact with HP1s in the nucleus. The silkworm, Bombyx mori, has two Piwi proteins, Ago3 and Siwi, and two typical HP1 proteins, HP1a and HP1b. We found that HP1a plays an important role in the interaction between Ago3/Siwi and HP1b in the ovary-derived BmN4 cell line. We also found that Ago3/Siwi regulates the transcription in an HP1-dependent manner. These results suggest that silkworm Piwi proteins function as a chromatin regulator in collaboration with HP1a and HP1b.

In hematologic oncology, acute myeloid leukemia (AML) presents a significant challenge due to its complex genetic landscape and resistance to conventional therapies. Despite advances in treatment, including intensive chemotherapy and hematopoietic stem cell transplantation (HSCT), the prognosis for many patients with AML remains poor. Recently, immunotherapy has emerged as a promising approach to improve outcomes by augmenting existing treatments. Natural killer (NK) cells, a subset of innate lymphoid cells, have garnered attention for their potent cytotoxic capabilities against AML cells. In this review, we discuss the role of NK cells in AML immunosurveillance, their dysregulation in patients with AML, and various therapeutic strategies leveraging NK cells in AML treatment. We explore the challenges and prospects associated with NK cell therapy, including approaches to enhance NK cell function, overcome immune evasion mechanisms, and optimize treatment efficacy. Finally, we emphasize the importance of further research to validate and refine patient-first NK cell-based immunotherapies for AML., (© 2024. Japanese Society of Hematology.)

Acute myeloid leukemia (AML) is a hematologic malignancy that frequently relapses, even if remission can be achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic cells from immune surveillance. Currently, there is no effective immunotherapy for AML because of the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and determine the therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 cases of AML indicated that the survival of patients with high expression of CD112 was shorter than that of patients with low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhanced the expression of cytotoxicity-related genes, thus overcoming the inhibitory activity of TIGIT. Between CD155 and CD112, CD112 is an especially important target for natural killer (NK)-cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also discovered that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, our findings suggest that the levels of expression of these molecules are potential prognostic markers in AML.

Varicella-zoster virus (VZV), known for causing chickenpox, establishes latent infections in neural tissues. Reactivation of VZV can lead to herpes zoster (HZ) and various neurological complications. In this report, we present four cases of VZV meningitis and myelitis following amenamevir treatment for HZ dermatitis with positive VZV DNA in cerebrospinal fluid (CSF) revealed by polymerase chain reaction (PCR). Three of them were considered immunocompromised hosts given the fact that two of these patients were taking immunosuppressive drugs for rheumatoid arthritis, and one patient had a history of sigmoid colon cancer (four months after resection). After HZ onset, amenamevir, which has poor CSF transfer, was prescribed for all the patients, and all of them developed central nervous complications by VZV (meningitis in three cases and myelitis in one case) confirmed by PCR. All the patients were treated with acyclovir, which has a higher CSF transfer, and fully recovered. We speculate that amenamevir might have failed to prevent VZV infection in the central nervous system (CNS) and think that consideration should be given to administering acyclovir in preference to amenamevir for ΗΖ patients at high risk of CNS VZV infection, such as immunocompromised hosts., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Tada et al.)

Immunotherapy has attracted considerable attention as a therapeutic strategy for cancers including acute myeloid leukemia (AML). In this study, we found that the development of several aggressive subtypes of AML is slower in Rag2 -/- mice despite the lack of B and T lymphocytes, even compared to the immunologically normal C57BL/6 mice. Furthermore, an orally active p53-activating drug shows stronger antileukemia effect on AML in Rag2 -/- mice than C57BL/6 mice. Intriguingly, Natural Killer (NK) cells in Rag2 -/- mice are increased in number, highly express activation markers, and show increased cytotoxicity to leukemia cells in a coculture assay. B2m depletion that triggers missing-self recognition of NK cells impairs the growth of AML cells in vivo. In contrast, NK cell depletion accelerates AML progression in Rag2 -/- mice. Interestingly, immunogenicity of AML keeps changing during tumor evolution, showing a trend that the aggressive AMLs generate through serial transplantations are susceptible to NK cell-mediated tumor suppression in Rag2 -/- mice. Thus, we show the critical role of NK cells in suppressing the development of certain subtypes of AML using Rag2 -/- mice, which lack functional lymphocytes but have hyperactive NK cells., (© 2023. The Author(s).)

We previously showed that cell-surface CD86 expressed on multiple myeloma (MM) cells contributed to not only tumor growth but also antitumor cytotoxic T-lymphocyte responses mediated by induction of IL-10-producing CD4 + T cells. The soluble form of CD86 (sCD86) was also detected in serum from patients with MM. Thus, to determine whether sCD86 levels are a useful prognostic factor, we investigated the association of serum sCD86 levels with disease progression and prognosis in 103 newly diagnosed patients with MM. Serum sCD86 was detected in 71% of the patients with MM but was only rarely detected in patients with monoclonal gammopathy of undetermined significance and healthy controls, and the level was significantly increased in patients with advanced-stage MM. When we examined differences in clinical characteristics according to the level of serum sCD86, those in the high (≥2.18 ng/mL, n = 38) group exhibited more aggressive clinical characteristics, with shorter overall survival times compared with those in the low (<2.18 ng/mL, n = 65) group. On the other hand, it was difficult to stratify the patients with MM into different risk groups based on the expression levels of cell-surface CD86. The levels of serum sCD86 were significantly correlated with the expression levels of the messenger RNA (mRNA) transcripts of CD86 variant 3, which lack exon 6, resulting in a truncated transmembrane region, and its variant transcripts were upregulated in the high group. Thus, our findings suggest that sCD86 can be easily measured in peripheral blood samples and is a useful prognostic marker in patients with MM., Competing Interests: Conflicts of Interest Disclosure The authors do not have any conflicts of interest to declare in relation to this work., (Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Aim: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400 mg/m 2 for 4 days, but we decided to increase the dosage of Ara-C from the standard to 2 g/m 2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high-dose Ara-C MEAM therapy., Methods: The high-dose Ara-C MEAM protocol consisted of MCNU 300 mg/m 2 on day -7, ETP 200 mg/m 2 on days -6, -5, -4, -3 and Ara-C 2 g/m 2 on day -4 -3, and MEL 140 mg/m 2 on day -2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020., Results: All patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively., Conclusion: The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases., (© 2022 John Wiley & Sons Australia, Ltd.)

Acute myeloid leukemia (AML) relapse is considered to be related to escape from antitumor immunity. Changes in the expression of immune checkpoints, including B7 homolog (H)1 and B7-H2, have been reported to contribute to AML progression. Binding of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) among other immune checkpoints on natural killer (NK) and T cells to CD155/CD112 in tumors is supposed to be inhibitory; however, the mechanism by which changes in CD155 and CD112 expression affect tumor immunity remains unclear. When the increased expression of CD155 and CD112 activates Raf-MEK-ERK pathway and Raf-MEK-ERK pathway is one of the targets of FMS-like tyrosine kinase 3 ( FLT3 ) inhibition. The present study investigated the alterations in CD155 and CD112 expression under FLT3 inhibition (quizartinib and gilteritinib) and studied its effect on NK and T cell cytotoxicity. CD155 and CD112 expression was analyzed using flow cytometry and reverse transcription-quantitative PCR in AML cell lines with or without FLT3 mutation using FLT3 inhibitors. CD155 and CD112 expression was specifically downregulated by FLT3 inhibition in FLT3 -mutated cell lines. Direct cytotoxicity and antibody-dependent cellular cytotoxicity against these cells by NK cells were enhanced. However, the cytotoxicity of γδ T cells with low TIGIT expression compared with NK cells was not enhanced in direct cytotoxicity assay using luciferase luminescence. The analysis of clinical trials from The Cancer Genome Atlas (TCGA) revealed that high CD155 and CD112 expression is associated with poor overall survival. The enhanced cytotoxicity of NK cells against CD155- and CD112-downregulated cells following FLT3 inhibition indicated CD155 and CD112 as possible targets of immunotherapy for AML using FLT3 inhibitors., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kaito et al.)

Introduction: The appearance of erythroblasts (EBLs) in peripheral blood occurs in a variety of serious conditions and has been associated with mortality in critically ill patients. However, the incidence, risk factor, and outcomes of EBLs after cord blood transplantation (CBT) remain unclear., Methods: We have investigated the impact of EBLs on transplant outcomes on 225 adult patients who underwent single-unit CBT at our single institute., Results: The cumulative incidences of EBL ≥200 × 10 6 /L and EBL ≥1000 × 10 6 /L at 60 days after CBT were 17% and 4%, respectively, detected after a median of 35 days and 36.5 days. Multivariate analysis using erythroblastosis as time-dependent covariates demonstrated the significant association of EBL ≥1000 × 10 6 /L, but not EBL ≥200 × 10 6 /L, with the development of grade III-IV acute graft-versus-host disease (GVHD, hazard ratio [HR]: 18.56; P < .001), higher nonrelapse mortality (HR: 13.38; P < .001), and overall mortality (HR: 4.97; P = .001)., Conclusion: These data suggested that higher levels of EBLs were recognized as a significant risk factor for severe acute GVHD and mortality after single-unit CBT. Higher levels of EBLs may serve as a surrogate marker for poor single CBT outcomes., (© 2021 John Wiley & Sons Ltd.)

Background: Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatment of MM, currently known biomarkers of relapse, including serum free-light chains and monoclonal paraproteins, are not associated with genetic changes., Methods: We therefore performed a multicenter study to examine the usefulness of circulating cell-free DNA (cfDNA) present in the peripheral blood (PB) plasma of patients as a biomarker for MM relapse., Results: We identified several driver mutations by combined analysis of next-generation sequencing and existing databases of candidate oncogenes. Furthermore, relapse was detected more sensitively by monitoring the circulating cfDNA with these driver mutations than by conventional serum free-light chain examination., Conclusion: These results suggest the potential utility of cfDNA in the PB plasma of patients as a relevant early biomarker for MM relapse., (© 2021. Japan Society of Clinical Oncology.)

Peripheral blood eosinophilia has been associated with the development of graft-versus-host disease (GVHD) and survival after allogeneic hematopoietic cell transplantation (HCT). However, the impacts of eosinophilia on cord blood transplantation (CBT) outcomes remain unclear. The objective of this study was to examine the associations between eosinophilia and overall survival, relapse incidence, non-relapse mortality, and acute and chronic GVHD after single-unit CBT for adults. We retrospectively analyzed the data for 225 adult patients who received single-unit CBT at our institute between March 2004 and March 2020. The cumulative incidence of eosinophilia, defined as an absolute eosinophil count of ≥500 × 10 6 /L in peripheral blood, was 48.9% (95% confidence interval, 42.2% to 55.2%) at 60 days after CBT. Recipient cytomegalovirus seronegative status and higher cryopreserved cord blood CD34 + cell dose were significantly associated with a higher incidence of eosinophilia after CBT. Among patients who achieved neutrophil recovery, neutrophil recovery was significantly earlier in patient with eosinophilia compared to those without eosinophilia (P = .016). Serum levels of interleukin-5 at 4 weeks were significantly higher in patients with eosinophilia compared with those without eosinophilia (P = .041). Multivariate analysis, in which the development of eosinophilia was treated as a time-dependent covariate, showed that eosinophilia was significantly associated with lower overall mortality (hazard ratio [HR], .58; P = .034) and non-relapse mortality (HR, .41; P = .029), but not relapse incidence or development of acute or chronic GVHD. Our data suggested that early-phase eosinophilia is a predictor of favorable outcomes in adult patients undergoing single-unit CBT., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients., Methods: We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells., Results: The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients., Conclusions: The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

Allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for refractory hematological malignancies. However, there are many treatment-related complications, including organ disorders, graft-versus-host disease (GVHD), and infectious diseases. Furthermore, there are many unclear points regarding central nervous system (CNS) complications, and the prognosis in patients with CNS complications is extremely poor. We herein report a 49-year-old woman who developed CNS-GVHD after a second transplantation for therapy-related myelodysplastic syndrome. CNS-GVHD in this case was refractory to all treatments, including steroids, and progressed. We also present a review of the literature about the symptoms, diagnosis, and treatment of CNS-GVHD.

The signaling lymphocytic activation molecule family 3 (SLAMF3) is highly expressed on plasma cells from patients with multiple myeloma (MM) and induces high malignant potential by ERK signaling mediated via the interaction with adaptor proteins SHP2 and GRB2. This study focused on the single-nucleotide polymorphism (SNP) of the SLAMF3 gene (rs509749, 1804A>G, M602V) in MM. The SNP G allele was a major type, and the frequencies of the GG, GA, and AA genotypes were 61.8%, 29.4%, and 8.8%, respectively, in patients with MM, which was almost the same as in healthy the control group in the Japanese population. Interestingly, patients with GG genotypes had significantly shorter overall survival times than patients with GA/AA genotypes. Consistent with those results, SLAMF3-overexpressing KMS-34 cells with the G allele (V 602 ) had higher cell proliferation potential and were more resistant to anti-MM agents than those with the A allele (M 602 ). When those cells were subcutaneously inoculated into NOG mice, tumor sizes in mice receiving V 602 cells rapidly increased, and survival was significantly shorter than in mice injected with M 602 cells. Furthermore, SLAMF3 V 602 molecules bound more tightly to SHP2 and GRB2, with increased SHP2 and ERK phosphorylation compared with M 602 cells. The mRNA expression of cell cycle-related genes (CCND1 and CCNE1) and anti-apoptotic genes (BCL2L and p21) was increased in V 602 cells compared with M 602 cells. The results thus suggested that the G allele of SLAMF3 SNP rs509749 may be associated with MM disease progression., Competing Interests: Conflict of interest disclosure The authors declare that they have no conflicts of interest., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

The signaling lymphocytic activation molecule family 3 (SLAMF3) is a member of the immunoglobulin superfamily expressed on T, B, and natural killer cells and modulates the activation and cytotoxicity of these cells. SLAMF3 is also expressed on plasma cells from patients with multiple myeloma (MM), although its role in MM pathogenesis remains unclear. This study found that SLAMF3 is highly and constitutively expressed on MM cells regardless of disease stage and that SLAMF3 knockdown/knockout suppresses proliferative potential and increases drug-induced apoptosis with decreased levels of phosphorylated ERK protein in MM cells. SLAMF3-overexpressing MM cells promote aggressive myeloma behavior in comparison with cytoplasmic domain-truncated SLAMF3 (ΔSLAMF3) cells. SLAMF3 interacts directly with adaptor proteins SH2 domain-containing phosphatase 2 (SHP2) and growth factor receptor bound 2 (GRB2), which also interact with each other. SLAMF3 knockdown, knockout, ΔSLAMF3, and SHP2 inhibitor-treated MM cells decreased phosphorylated ERK protein levels. Finally, serum soluble SLAMF3 (sSLAMF3) levels were markedly increased in advanced MM. Patients with high levels of sSLAMF3 progressed to the advanced stage significantly more often and had shorter progression-free survival times than those with low levels. This study revealed that SLAMF3 molecules consistently expressed on MM cells transmit MAPK/ERK signals mediated via the complex of SHP2 and GRB2 by self-ligand interaction between MM cells and induce a high malignant potential in MM. Furthermore, high levels of serum sSLAMF3 may reflect MM disease progression and be a useful prognostic factor. IMPLICATIONS: SLAMF3 may be a new therapeutic target for immunotherapy and novel agents such as small-molecule inhibitors., (©2020 American Association for Cancer Research.)

Mucosal-associated invariant T (MAIT) cells are a type of innate lymphocyte and recognize riboflavin (vitamin B2) synthesis products presented by MHC-related protein 1. We investigated long-term reconstitution of MAIT cells and its association with chronic graft-versus-host disease (cGVHD) in a cross-sectional cohort of 173 adult patients after allogeneic hematopoietic cell transplantation. According to donor source, the number of MAIT cells significantly correlated with time after cord blood transplantation (CBT) but not with time after bone marrow transplantation or peripheral blood stem cell transplantation. The number of MAIT cells was significantly lower in patients with cGVHD compared with patients without cGVHD. We also examined the association between MAIT cell reconstitution and gut microbiota as evaluated by 16S ribosomal sequencing of stool samples 1 mo post-CBT in 27 adult patients undergoing CBT. The diversity of gut microbiota was positively correlated with better MAIT cell reconstitution after CBT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis indicated that amounts of ribB and ribA genes were significantly higher in the microbiomes of patients with subsequent MAIT cell reconstitution after CBT. In conclusion, long-term MAIT cell reconstitution is dependent on the type of donor source. Our data also unveiled an important role for the interaction of circulating MAIT cells with gut microbiota in humans., (Copyright © 2020 by The American Association of Immunologists, Inc.)

The signaling lymphocytic activation molecule family (SLAMF7; also known as CS1 or CD319) is highly expressed on plasma cells from multiple myeloma (MM) as well as natural killer (NK) cells and is a well-known therapeutic target of elotuzumab. The objective of this study was to evaluate the clinical significance of serum soluble SLAMF7 (sSLAMF7) levels in patients with MM (n=103) and furthermore the impact of sSLMF7 on the antitumor activity of anti-SLAMF7 antibody. Thirty-one percent of MM patients, but not patients with monoclonal gammopathy of undetermined significance and healthy controls, had detectable levels of serum sSLAMF7, which were significantly increased in advanced MM patients. Further, MM in sSLAMF7-postive patients exhibited aggressive clinical characteristics with shorter progression-free survival times in comparison with sSLAMF7-negative patients. In responders to MM therapy, the levels of sSLAMF7 were undetectable or decreased compared with those before treatment. In addition, the anti-SLAMF7 antibody-mediated antibody-dependent cellular cytotoxicity of NK cells against MM cell lines was inhibited by recombinant SLAMF7 protein. Thus, our findings suggest that high concentrations of sSLAMF7, which could transiently suppress the therapeutic effects of elotuzumab, may be a useful indicator of disease progression in MM patients., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

βPix activates Nox1, an O 2 -generating NADPH oxidase, through Rac activation. In this study, we found that S525E mutation of βPix eliminated its Nox1-activating ability in transfected Caco-2 cells. Unexpectedly, affinity for Rac was not diminished but rather enhanced by S525E mutation, and guanine nucleotide exchange factor (GEF) activity was not altered. The N-terminal fragment (amino acids 1-400) showed similar Rac-binding and GEF activity to wild-type βPix. In contrast, the C-terminal fragment (amino acids 408-646) had higher Rac-binding activity, particularly for Rac-GTP, than wild-type βPix, and showed no GEF activity. These data suggest that a second Rac-binding site within the C-terminal region is opened by phosphorylation of Ser-525. The site may bind not only Rac-GDP but also Rac-GTP released from the N-terminal catalytic region, which interrupts Rac-GTP translocation to the membrane where Nox1 resides. If one considers that S340E mutation enhances Nox1 activation (Kaito et al., 2014), the present study suggests that βPix can also play an inhibitory role in O - -generating NADPH oxidase, through Rac activation. In this study, we found that S525E mutation of βPix eliminated its Nox1-activating ability in transfected Caco-2 cells. Unexpectedly, affinity for Rac was not diminished but rather enhanced by S525E mutation, and guanine nucleotide exchange factor (GEF) activity was not altered. The N-terminal fragment (amino acids 1-400) showed similar Rac-binding and GEF activity to wild-type βPix. In contrast, the C-terminal fragment (amino acids 408-646) had higher Rac-binding activity, particularly for Rac-GTP, than wild-type βPix, and showed no GEF activity. These data suggest that a second Rac-binding site within the C-terminal region is opened by phosphorylation of Ser-525. The site may bind not only Rac-GDP but also Rac-GTP released from the N-terminal catalytic region, which interrupts Rac-GTP translocation to the membrane where Nox1 resides. If one considers that S340E mutation enhances Nox1 activation (Kaito et al., 2014), the present study suggests that βPix can also play an inhibitory role in O 2 - production, depending on the sites of phosphorylation., (Copyright © 2017 Elsevier Inc. All rights reserved.)