Nonmagnetic framboid and associated iron nanoparticles with a space-weathered feature from asteroid Ryugu.

Extraterrestrial minerals on the surface of airless Solar System bodies undergo gradual alteration processes known as space weathering over long periods of time. The signatures of space weathering help us understand the phenomena occurring in the Solar System. However, meteorites rarely retain the signatures, making it impossible to study the space weathering processes precisely. Here, we examine samples retrieved from the asteroid Ryugu by the Hayabusa2 spacecraft and discover the presence of nonmagnetic framboids through electron holography measurements that can visualize magnetic flux. Magnetite particles, which normally provide a record of the nebular magnetic field, have lost their magnetic properties by reduction via a high-velocity (>5 km s-1) impact of a micrometeoroid with a diameter ranging from 2 to 20 µm after destruction of the parent body of Ryugu. Around these particles, thousands of metallic-iron nanoparticles with a vortex magnetic domain structure, which could have recorded a magnetic field in the impact event, are found. Through measuring the remanent magnetization of the iron nanoparticles, future studies are expected to elucidate the nature of the nebular/interplanetary magnetic fields after the termination of aqueous alteration in an asteroid.

Comparison of large-volume 3D reconstruction using plasma FIB-SEM and X-ray CT.

We demonstrated large-volume three-dimensional (3D) reconstruction using plasma focused ion beam - scanning electron microscopy (PFIB-SEM). We successfully reconstructed a 750 µm (W) × 143 µm (H) × 310 µm (D) volume at a resolution of 200 nm/pix from 1,550 SEM backscattered electron images of a Li-ion battery cathode sheet. The PFIB-SEM system was found to be capable of acquiring and reconstructing larger volume 3D datasets than X-ray computed tomography, and with higher resolution and contrast.

Efficacy of Erenumab for Migraine Prevention in Japanese Patients with Episodic and Chronic Migraine: Results of a Post-Hoc Pooled Analysis.

INTRODUCTION: Erenumab, a fully human monoclonal antibody against the calcitonin gene-related peptide receptor, is approved in Japan for the prevention of adult migraine. This post-hoc analysis evaluated the efficacy of erenumab in Japanese patients with low-frequency episodic migraine (LFEM) versus those with high-frequency episodic migraine (HFEM) and chronic migraine (CM). METHODS: A pooled analysis of data from the 24-week double-blind treatment phases (DBTPs) of phase 2 and 3 studies evaluated the efficacy of once-monthly erenumab 70 mg in Japanese patients. Patients were categorized into subgroups by monthly migraine days (MMD): LFEM and HFEM/CM. The main efficacy outcomes were change from baseline in MMD, acute migraine-specific medication treatment days (MSMD), and six-item Headache Impact Test (HIT-6™) scores. RESULTS: Patients with migraine (n = 532) were included in the analysis (LFEM, n = 215; HFEM, n = 215; CM, n = 102). Overall, mean age was 44 years, 86.5% were female, and 63.3-88.2% had used or were taking migraine preventive treatment at baseline. Throughout the DBTP, the placebo-adjusted mean change from baseline in MMD, MSMD, and HIT-6 scores with erenumab was similar across LFEM and HFEM/CM subgroups. The proportion of patients achieving at least 50% or 75% reduction from baseline in MMD and MSMD was similar across migraine frequency groups. Reduction in MMD moderately correlated with improvement in HIT-6 scores in the LFEM and HFEM/CM groups. Furthermore, the proportion of patients converting from HFEM/CM to LFEM during the DBTP was higher in the erenumab group than in the placebo. CONCLUSION: In Japanese patients with different migraine frequencies, erenumab treatment resulted in significant improvements in MMD, MSMD, and headache impact. This pooled analysis of data from phase 2 and 3 studies increases confidence that erenumab is efficacious in patients with high MMD, which is associated with increased disability.

Long-term efficacy and safety of erenumab in Japanese patients with episodic and chronic migraine: results from a 28-week open-label treatment period of a randomised trial.

OBJECTIVES: To evaluate the 1-year efficacy and safety of once-monthly erenumab 70 mg following a 24-week double-blind treatment period (DBTP) of a phase III randomised study of Japanese patients with episodic migraine (EM) or chronic migraine (CM). DESIGN: Multicentre open-label study. SETTING: A total of 41 centres in Japan. PARTICIPANTS: Patients completing the DBTP continued into the 28-week open-label treatment period (OLTP). 254 of 261 (97.3%) randomised patients continued into the OLTP; 244 (93.5%) completed treatment. INTERVENTIONS: Once-monthly subcutaneous erenumab 70 mg. MAIN OUTCOME MEASURES: Changes from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication treatment days (MSMD) reported via patient eDiary; proportion of ≥50% and ≥75% responders in MMD reduction from baseline; incidence and exposure-adjusted incidence of treatment-emergent adverse events (TEAEs). RESULTS: At week 24 of the DBTP, the mean (SE) change from baseline in MMD for the erenumab group was -3.8 (0.4) days (EM, -3.0 (0.4); CM, -5.2 (0.8)); in MSMD, -2.6 (0.4) days (EM, -2.1 (0.4); CM, -3.4 (0.7)). At the end of the OLTP (52 weeks postbaseline), the mean (SE) change from baseline in MMD was -4.7 (0.3) days (EM, -3.4 (0.3); CM, -6.9 (0.6)); in MSMD, -3.3 (0.3) days (EM, -2.4 (0.3); CM, -4.6 (0.5)). The proportion of ≥50% responders for MMD reduction in the erenumab group was 34.1% at week 24; 44.4% at week 52. The exposure-adjusted incidence of TEAEs was 219.7 per 100 patient-years during the OLTP (DBTP, 251.0 for the erenumab group). The most common TEAEs during the OLTP were nasopharyngitis, constipation and influenza. No new safety concerns were identified. CONCLUSIONS: Erenumab treatment was associated with reduced migraine frequency in Japanese patients with EM or CM for up to 1 year. Overall safety results from the OLTP were consistent with DBTP results. TRIAL REGISTRATION NUMBER: NCT03812224.

Visualization of nanoscale magnetic domain states in the asteroid Ryugu.

In the samples collected from the asteroid Ryugu, magnetite displays natural remanent magnetization due to nebular magnetic field, whereas contemporaneously grown iron sulfide does not display stable remanent magnetization. To clarify this counterintuitive feature, we observed their nanoscale magnetic domain structures using electron holography and found that framboidal magnetites have an external magnetic field of 300 A m-1, similar to the bulk value, and its magnetic stability was enhanced by interactions with neighboring magnetites, permitting a disk magnetic field to be recorded. Micrometer-sized pyrrhotite showed a multidomain magnetic structure that was unable to retain natural remanent magnetization over a long time due to short relaxation time of magnetic-domain-wall movement, whereas submicron-sized sulfides formed a nonmagnetic phase. These results show that both magnetite and sulfide could have formed simultaneously during the aqueous alteration in the parent body of the asteroid Ryugu.

An unusual case of fatal hypothermia involving topical diphenhydramine.

PURPOSE: Diphenhydramine is an antihistamine drug widely used to alleviate symptoms caused by allergies and the common cold. Diphenhydramine-involved fatalities have been reported in the past but usually involving overdose by ingestion. We report a peculiar case of fatal hypothermia during non-winter season involving topical diphenhydramine. METHODS: A 23-year-old male with no known preexisting medical conditions was found dead in the bathroom of his apartment with a small amount of running water on his back. Postmortem examinations and toxicological analysis on blood and urine were performed. RESULTS: Color difference was apparent between the right and left cardiac blood. Wischnewski spots were observed in the gastric mucosa. Histological examination revealed no obvious findings that could attribute to serious cardiovascular events. Drug screening by gas chromatograph-tandem mass spectrometry (GC/MS/MS) detected diphenhydramine in blood and urine. Further quantification revealed the postmortem concentrations to be 0.44 µg/mL in blood and 2500 µg/mL in urine. CONCLUSIONS: The cause of death was determined to be hypothermia. Diphenhydramine-induced drowsiness and possible intrinsic cardiac factor may have led to prolonged impaired consciousness, preventing his ability to escape from the running cold water leading to hypothermia and death.

Annulative coupling of vinylboronic esters: aryne-triggered 1,2-metallate rearrangement.

A stereoselective annulative coupling of a vinylboronic ester ate-complex with arynes producing cyclic borinic esters has been developed. An annulation reaction that proceeded through the formation of two C-C bonds and a C-B bond was realized by exploiting a 1,2-metallate rearrangement of boronate triggered by the addition of a vinyl group to the strained triple bond of an aryne. The generated aryl anion would then cyclize to a boron atom to complete the annulation cascade. The annulated borinic ester could be converted to boronic acids and their derivatives by oxidation, halogenation, and cross-coupling. Particularly, halogenation and Suzuki-Miyaura coupling proceeded in a site-selective fashion and produced highly substituted alkylboronic acid derivatives.

Early onset of efficacy with erenumab for migraine prevention in Japanese patients: Analysis of two randomized, double-blind, placebo-controlled studies.

PURPOSE: In two 24-week migraine prevention studies in Japan, erenumab was associated with significantly greater reductions in migraine frequency versus placebo over Weeks 13-24 (primary endpoint). This post hoc analysis evaluated the onset of efficacy within the first 4 weeks after the initiation of erenumab from the 24-week double-blind periods of these studies. METHODS: Placebo-adjusted differences in least squares mean (LSM) change from baseline in weekly migraine days (WMD) were assessed weekly in each study and by migraine type (episodic (EM]/chronic [CM]) (Study 20170609). RESULTS: A total of 407 patients from Study 20120309 (70 mg: N = 135; 140 mg: N = 136; placebo: N = 136) and 261 patients from Study 20170609 ([EM] 70 mg: N = 78; placebo: N = 81; [CM] 70 mg: N = 52; placebo: N = 50) were included. For Study 20120309, onset of efficacy was observed as early as Week 1 in favor of erenumab versus placebo. Placebo-adjusted differences in LSM (95% confidence interval [CI]) change from baseline in WMD at Week 1 were -0.38 (-0.71 to -0.05; p = .022) and -0.49 (-0.82 to -0.16; p = .004) in favor of erenumab 70 and 140 mg, respectively. For Study 20170609, significant placebo-adjusted differences were observed with erenumab 70 mg at Week 1 in patients with EM (LSM [95% CI]: -0.55 [-0.97 to -0.12; p = .012]), and at Week 2 in patients with CM (LSM [95% CI]: -0.81 [-1.53 to -0.09; p = .028]) and for the overall population (LSM [95% CI]: -0.71 [-1.09 to -0.33; p < .001]). CONCLUSIONS: Erenumab treatment significantly reduced WMD compared with placebo. Onset of erenumab efficacy occurred as early as Week 1 in patients with migraine.

Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial.

BACKGROUND: These subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) ("failed-yes" and "failed-no" subgroups) and with/without concomitant preventive treatment ("concomitant preventive-yes" and "concomitant preventive-no" subgroups). METHODS: Overall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4-6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated. RESULTS: Of the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4-6 (treatment difference versus placebo [95% CI], failed-yes: - 1.9 [- 3.3, - 0.4]; failed-no: - 1.4 [- 2.6, - 0.3]; concomitant preventive-yes: - 1.7 [- 3.3, 0.0]; concomitant preventive-no: - 1.6 [- 2.6, - 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup. CONCLUSION: Erenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment. TRIAL REGISTRATION: Clinicaltrials.gov . NCT03812224. Registered January 23, 2019.

Erenumab treatment for migraine prevention in Japanese patients: Efficacy and safety results from a Phase 3, randomized, double-blind, placebo-controlled study.

OBJECTIVES: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. Global studies have demonstrated its efficacy in chronic and episodic migraine (EM). Here we report the outcomes from a Phase 3 study of erenumab in Japanese patients with chronic migraine (CM) or EM. METHODS: Japanese patients with EM (<15 headache days/month, including ≥4 migraine days/month) or CM (≥15 headache days/month, including ≥8 migraine days/month) were randomized 1:1 to placebo or erenumab 70 mg once monthly for a 24-week double-blind treatment phase (DBTP). The primary endpoint of change from baseline in mean monthly migraine days (MMD) over months 4, 5, and 6 of the DBTP was compared between erenumab and placebo groups. Secondary efficacy and safety endpoints were also assessed. RESULTS: A total of 261 patients were randomized to placebo (n = 131) or erenumab 70 mg (n = 130); all patients were included in the efficacy and safety analyses. The mean (standard deviation) MMD at baseline was 11.84 (5.70) for the placebo group and 12.40 (5.99) for erenumab 70 mg. The mean (standard error) change in MMD was -1.98 (0.38) for the placebo group (n = 131) and -3.60 (0.38) for erenumab 70 mg (n = 130). The difference in MMD reduction between groups was -1.67 (95% CI: -2.56, -0.78, p < 0.001) for EM and -1.57 (95% CI: -3.39, 0.24, p = 0.089) for CM. Adverse events (AEs) were consistent with earlier studies. The most frequent AEs (placebo, erenumab) were nasopharyngitis (28.2% and 26.9%, respectively), back pain (4.6% and 5.4%), and constipation (0.8% and 4.6%). CONCLUSION: Treatment with erenumab 70 mg once monthly demonstrated favorable efficacy and safety findings in Japanese patients with EM or CM.

[A Case of Multiple Metachronous Metastases from Hepatocellular Carcinoma to Thoracic Spine and Right Adrenal Invading Right Kidney with Tumor Thrombus in the Inferior Vena Cava That Was Treated with Chemotherapy, Radiotherapy, Intravascular Therapy, and Surgery].

For extrahepatic recurrence after primary hepatocellular carcinoma resection, molecular targeted therapy is the first- choice and no consensus is reached on the indication of surgical resection of extrahepatic metastasis. However, when the extrahepatic lesion extends to vena cava, tumor thrombus can cause acute pulmonary embolism that can lead to fatal consequences. Here, we experienced a case of multiple metachronous metastases from hepatocellular carcinoma to thoracic spine and right adrenal invading right kidney with tumor thrombus in the inferior vena cava. Local radiation therapy to thoracic vertebra, molecular targeted therapy, and transcatheter arterial chemoembolization were performed but tumor thrombus still occluded vena cava. Therefore, to prevent pulmonary embolism and to bridge to immunotherapy, right adrenalectomy, right nephrectomy, thrombectomy and replacement of inferior vena cava were performed. The patient remains healthy 6 months after the surgery and still receiving immunochemotherapy.

Contributions of changes in climatology and perturbation and the resulting nonlinearity to regional climate change.

Future changes in large-scale climatology and perturbation may have different impacts on regional climate change. It is important to understand the impacts of climatology and perturbation in terms of both thermodynamic and dynamic changes. Although many studies have investigated the influence of climatology changes on regional climate, the significance of perturbation changes is still debated. The nonlinear effect of these two changes is also unknown. We propose a systematic procedure that extracts the influences of three factors: changes in climatology, changes in perturbation and the resulting nonlinear effect. We then demonstrate the usefulness of the procedure, applying it to future changes in precipitation. All three factors have the same degree of influence, especially for extreme rainfall events. Thus, regional climate assessments should consider not only the climatology change but also the perturbation change and their nonlinearity. This procedure can advance interpretations of future regional climates.

Advanced electron holography techniques for in situ observation of solid-state lithium ion conductors.

Advanced techniques for overcoming problems encountered during in situ electron holography experiments in which a voltage is applied to an ionic conductor are reported. The three major problems encountered were 1) electric-field leakage from the specimen and its effect on phase images, 2) high electron conductivity of damage layers formed by the focused ion beam method, and 3) chemical reaction of the specimen with air. The first problem was overcome by comparing experimental phase distributions with simulated images in which three-dimensional leakage fields were taken into account, the second by removing the damage layers using a low-energy narrow Ar ion beam, and the third by developing an air-tight biasing specimen holder.

Advanced electron holography techniques for in situ observation of solid-state lithium ion conductors.

Advanced techniques for overcoming problems encountered during in situ electron holography experiments in which a voltage is applied to an ionic conductor are reported. The three major problems encountered were 1) electric-field leakage from the specimen and its effect on phase images, 2) high electron conductivity of damage layers formed by the focused ion beam method, and 3) chemical reaction of the specimen with air. The first problem was overcome by comparing experimental phase distributions with simulated images in which three-dimensional leakage fields were taken into account, the second by removing the damage layers using a low-energy narrow Ar ion beam, and the third by developing an air-tight biasing specimen holder.

In situ electron holography of electric potentials inside a solid-state electrolyte: Effect of electric-field leakage.

In situ electron holography is used to observe changes of electric-potential distributions in an amorphous lithium phosphorus oxynitride (LiPON) solid-state electrolyte when different voltages are applied. 2D phase images are simulated by integrating the 3D potential distribution along the electron trajectory through a thin Cu/LiPON/Cu region. Good agreement between experimental and simulated phase distributions is obtained when the influence of the external electric field is taken into account using the 3D boundary-charge method. Based on the precise potential changes, the lithium-ion and lithium-vacancy distributions inside the LiPON layer and electric double layers (EDLs) are inferred. The gradients of the phase drops at the interfaces in relation to EDL widths are discussed.

Raftlin Controls Lipopolysaccharide-Induced TLR4 Internalization and TICAM-1 Signaling in a Cell Type-Specific Manner.

The clathrin-dependent endocytic pathway is crucial for endosomal TLR3- and TLR4-mediated Toll-IL-1R domain-containing adaptor molecule-1 (TICAM-1) signaling. TLR4 uses a different signaling platform, plasma membrane and endosomes, for activation of TIRAP-MyD88 and TICAM-2-TICAM-1, respectively. LPS-induced endocytosis of TLR4 is mandatory for TICAM-1-mediated signaling including IFN-ß production. Several molecules/mechanisms such as CD14, clathrin, and phosphatidylinositol metabolism have been reported to act as inducers of TLR4 translocation. However, the molecular mechanism of spatiotemporal regulation of TLR4 signaling remains unresolved. We have previously shown that Raftlin is essential for clathrin-dependent endocytosis of TLR3 ligand in human epithelial cells and myeloid dendritic cells (DCs). In this article, we demonstrate that Raftlin also mediated LPS-induced TLR4 internalization and TICAM-1 signaling in human monocyte-derived DCs and macrophages (Mo-Mϕs). When Raftlin was knocked down, LPS-induced TLR4-mediated IFN-ß promoter activation, but not NF-κB activation, was decreased in HEK293 cells overexpressing TLR4/MD-2 or TLR4/MD-2/CD14. LPS-induced IFN-ß production by monocyte-derived DCs and Mo-Mϕs was significantly decreased by knockdown of Raftlin. Upon LPS stimulation, Raftlin moved from the cytoplasm to the plasma membrane in Mo-Mϕs, where it colocalized with TLR4. Raftlin associated with clathrin-associated adaptor protein-2 in resting cells and transiently bound to TLR4 and clathrin at the cell surface in response to LPS. Thus, Raftlin appears to modulate cargo selection as an accessary protein of clathrin-associated adaptor protein-2 in clathrin-mediated endocytosis of TLR3/4 ligands.

Control of the Metal-Insulator Transition at Complex Oxide Heterointerfaces through Visible Light.

The coupling of the localized surface plasmon resonance of Au nanoparticles is utilized to deliver a visible-light stimulus to control conduction at the LaAlO3 /SrTiO3 interface. A giant photoresponse and the controllable metal-insulator transition are characterized at this heterointerface. This study paves a new route to optical control of the functionality at the heterointerfaces.

Dynamical observation of lithium insertion/extraction reaction during charge-discharge processes in Li-ion batteries by in situ spatially resolved electron energy-loss spectroscopy.

All-solid-state Li-ion batteries (LIBs) with solid electrolytes are expected to be the next generation devices to overcome serious issues facing conventional LIBs with liquid electrolytes. However, the large Li-ion transfer resistance at the electrode/solid-electrolyte interfaces causes low power density and prevents practical use. In-situ-formed negative electrodes prepared by decomposing the solid electrolyte Li(1+x+3z)Alx(Ti,Ge)(2-x)Si(3z)P(3-z)O12 (LASGTP) with an excess Li-ion insertion reaction are effective electrodes providing low Li-ion transfer resistance at the interfaces. Prior to our work, however, it had still been unclear how the negative electrodes were formed in the parent solid electrolytes. Here, we succeeded in dynamically visualizing the formation by in situ spatially resolved electron energy-loss spectroscopy in a transmission electron microscope mode (SR-TEM-EELS). The Li-ions were gradually inserted into the solid electrolyte region around 400 nm from the negative current-collector/solid-electrolyte interface in the charge process. Some of the ions were then extracted in the discharge process, and the rest were diffused such that the distribution was almost flat, resulting in the negative electrodes. The redox reaction of Ti(4+)/Ti(3+) in the solid electrolyte was also observed in situ during the Li insertion/extraction processes. The in situ SR-TEM-EELS revealed the mechanism of the electrochemical reaction in solid-state batteries.

One-step synthesis of TiO2 nanorod arrays on Ti foil for supercapacitor application.

Titanium dioxide (TiO2) nanorod arrays grown directly on Ti metal foil were prepared by a facile one-step hydrothermal method, in which the Ti foil serves as both substrate and precursor. The nanorods are tetragonal rutile single crystal with growth orientation along the [001] direction. The electrochemical properties of the TiO2 nanorod arrays were systematically investigated by cyclic voltammetry, galvanostatic charge/discharge and electrochemical impedance spectroscopy using a three-electrode system. As a result, the TiO2 nanorod arrays exhibit good areal specific capacitance and excellent cyclic stability by retaining more than 98% of the initial specific capacitance after 1000 cycles. In addition, a good flexibility of the Ti foil with TiO2 nanorod arrays was demonstrated by the stable electrochemical performance under different bending angles, which indicates that TiO2 nanorod arrays grown on Ti foil could be a promising electrode material for flexible supercapacitor application.

Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells.

Epstein-Barr virus (EBV), a human gammaherpesvirus, establishes a lifelong latent infection in B lymphocytes and epithelial cells following primary infection. Several lines of evidence suggest that exosomes derived from EBV-infected cells are internalized and transfer viral factors, including EBV-encoded latent membrane protein and microRNAs, to the recipient cells. However, the detailed mechanism by which exosomes are internalized and their physiological impact on the recipient cells are still poorly understood. In this study, we visualized the internalization of fluorescently labeled exosomes derived from EBV-uninfected and EBV-infected B cells of type I and type III latency into EBV-negative epithelial cells. In this way, we demonstrated that exosomes derived from all three cell types were internalized into the target cells in a similar fashion. Internalization of exosomes was significantly suppressed by treatment with an inhibitor of dynamin and also by the knockdown of caveolin-1. Labeled exosomes were colocalized with caveolae and subsequently trafficked through endocytic pathways. Moreover, we observed that exosomes derived from type III latency cells upregulated proliferation and expression of intercellular adhesion molecule 1 (ICAM-1) in the recipient cells more significantly than did those derived from EBV-negative and type I latency cells. We also identified the EBV latent membrane protein 1 (LMP1) gene as responsible for induction of ICAM-1 expression. Taken together, our data indicate that exosomes released from EBV-infected B cells are internalized via caveola-dependent endocytosis, which, in turn, contributes to phenotypic changes in the recipient cells through transferring one or more viral factors.