Field-Free Spin-Orbit Torque Magnetization Switching in a Perpendicularly Magnetized Semiconductor (Ga,Mn)As Single Layer.

Current-induced spin-orbit torque (SOT) in a perpendicularly magnetized single layer has a strong potential to switch the magnetization using an extremely low current density, which is generally 2-3 orders of magnitude smaller than that required for conventional metal bilayer systems. However, an in-plane external magnetic field has to be applied to break the symmetry and achieve deterministic switching. To further enhance the high-density integration and accelerate the practical application of highly efficient SOT magnetic random-access memory (SOT-MRAM) devices, field-free SOT magnetization switching in a ferromagnetic single layer is strongly needed. In a spin-orbit ferromagnet (a ferromagnet with strong spin-orbit interaction) with crystal inversion asymmetry and a multi-domain structure, the internal Dzyaloshinskii-Moriya effective fields are considered to induce field-free switching. Here, combined with strong spin-orbit coupling and a tilted anisotropy axis induced by a nonuniform Mn distribution and a possible magnetocrystalline anisotropy resulting from a slight substrate tilting, we successfully achieve magnetization switching in a spin-orbit ferromagnet (Ga,Mn)As single layer by utilizing SOT without applying any external magnetic field. Our findings help to deeply elucidate the SOT switching mechanism and can advance the development of a highly efficient MRAM with better scalability.

Colossal Magnetoresistive Switching Induced by d0 Ferromagnetism of MgO in a Semiconductor Nanochannel Device with Ferromagnetic Fe/MgO Electrodes.

Exploring potential spintronic functionalities in resistive switching (RS) devices is of great interest for creating new applications, such as multifunctional resistive random-access memory and novel neuromorphic computing devices. In particular, the importance of the spin-triplet state of cation vacancies in oxide materials, which is induced by localized and strong O-2p on-site Coulomb interactions, in RS devices has been overlooked. d0 ferromagnetism sometimes appears due to the spin-triplet state and ferromagnetic Zener's double exchange interactions between cation vacancies, which are occasionally strong enough to make nonmagnetic oxides ferromagnetic. Here, for the first time, anomalous and colossal magneto-RS (CMRS) with very high magnetic field dependence is demonstrated by utilizing an unconventional RS device composed of a Ge nanochannel with all-epitaxial single-crystalline Fe/MgO electrodes. The device shows colossal and unusual behavior as the threshold voltage and ON/OFF ratio strongly depend on a magnetic field, which is controllable with an applied voltage. This new phenomenon is attributed to the formation of d0-ferromagnetic filaments by attractive Mg vacancies due to the spin-triplet states with ferromagnetic double exchange interactions and the ferromagnetic proximity effect of Fe on MgO. The findings will allow the development of energy-efficient CMRS devices with multifield susceptibility.

Electric Field Control of Spin-Orbit Torque Magnetization Switching in a Spin-Orbit Ferromagnet Single Layer.

To achieve a desirable magnitude of spin-orbit torque (SOT) for magnetization switching and realize multifunctional spin logic and memory devices utilizing SOT, controlling the SOT manipulation is vitally important. In conventional SOT bilayer systems, researchers have tried to control the magnetization switching behavior via interfacial oxidization, modulation of spin-orbit effective field, and effective spin Hall angle; however, the switching efficiency is limited by the interface quality. A current-induced effective magnetic field in a single layer of a ferromagnet with strong spin-orbit interactions, the so-called spin-orbit ferromagnet, can be utilized to induce SOT. In spin-orbit ferromagnet systems, electric field application has the potential for manipulating the spin-orbit interactions via carrier concentration modulation. In this work, it is demonstrated that SOT magnetization switching can be successfully controlled via an external electric field using a (Ga, Mn)As single layer. By applying a gate voltage, the switching current density can be solidly and reversibly manipulated with a large ratio of 14.5%, which is ascribed to the successful modulation of the interfacial electric field. The findings of this work help further the understanding of the magnetization switching mechanism and advance the development of gate-controlled SOT devices.

Ultrafast Subpicosecond Magnetization of a 2D Ferromagnet.

Strong spin-charge interactions in several ferromagnets are expected to lead to subpicosecond (sub-ps) magnetization of the magnetic materials through control of the carrier characteristics via electrical means, which is essential for ultrafast spin-based electronic devices. Thus far, ultrafast control of magnetization has been realized by optically pumping a large number of carriers into the d or f orbitals of a ferromagnet; however, it is extremely challenging to implement by electrical gating. This work demonstrates a new method for sub-ps magnetization manipulation called wavefunction engineering, in which only the spatial distribution (wavefunction) of s (or p) electrons is controlled and no change is required in the total carrier density. Using a ferromagnetic semiconductor (FMS) (In,Fe)As quantum well (QW), instant enhancement, as fast as 600 fs, of the magnetization is observed upon irradiating a femtosecond (fs) laser pulse. Theoretical analysis shows that the instant enhancement of the magnetization is induced when the 2D electron wavefunctions (WFs) in the FMS QW are rapidly moved by a photo-Dember electric field formed by an asymmetric distribution of the photocarriers. Because this WF engineering method can be equivalently implemented by applying a gate electric field, these results open a new way to realize ultrafast magnetic storage and spin-based information processing in present electronic systems.

Giant Spin-Valve Effect in Planar Spin Devices Using an Artificially Implemented Nanolength Mott-Insulator Region.

Developing technology to realize oxide-based nanoscale planar integrated circuits is in high demand for next-generation multifunctional electronics. Oxide circuits can have a variety of unique functions, including ferromagnetism, ferroelectricity, multiferroicity, superconductivity, and mechanical flexibility. In particular, for spin-transistor applications, the wide tunability of the physical properties due to the presence of multiple oxide phases is valuable for precise conductivity matching between the channel and ferromagnetic electrodes. This feature is essential for realistic spin-transistor operations. Here, a substantially large magnetoresistance (MR) ratio of up to ≈140% is demonstrated for planar-type (La,Sr)MnO3 (LSMO)-based spin-valve devices. This MR ratio is 10-100 times larger than the best values obtained for semiconductor-based planar devices, which have been studied over the past three decades. This structure is prepared by implementing an artificial nanolength Mott-insulator barrier region using the phase transition of metallic LSMO. The barrier height of the Mott-insulator region is only 55 meV, which enables the large MR ratio. Furthermore, a successful current modulation, which is a fundamental functionality for spin transistors, is shown. These results open up a new avenue for realizing oxide planar circuits with unique functionalities that conventional semiconductors cannot achieve.

Room-temperature spin injection from a ferromagnetic semiconductor.

Spin injection using ferromagnetic semiconductors at room temperature is a building block for the realization of spin-functional semiconductor devices. Nevertheless, this has been very challenging due to the lack of reliable room-temperature ferromagnetism in well-known group IV and III-V based semiconductors. Here, we demonstrate room-temperature spin injection by using spin pumping in a BiSb/(Ga,Fe)Sb heterostructure, where (Ga,Fe)Sb is a ferromagnetic semiconductor (FMS) with high Curie temperature (TC) and BiSb is a topological insulator (TI). Despite the very small magnetization of (Ga,Fe)Sb at room temperature (45 emu/cc), we detected spin injection from (Ga,Fe)Sb by utilizing the large inverse spin Hall effect (ISHE) in BiSb. Our study provides the first demonstration of spin injection at room temperature from a FMS.

Giant gate-controlled odd-parity magnetoresistance in one-dimensional channels with a magnetic proximity effect.

According to Onsager's principle, electrical resistance R of general conductors behaves as an even function of external magnetic field B. Only in special circumstances, which involve time reversal symmetry (TRS) broken by ferromagnetism, the odd component of R against B is observed. This unusual phenomenon, called odd-parity magnetoresistance (OMR), was hitherto subtle (< 2%) and hard to control by external means. Here, we report a giant OMR as large as 27% in edge transport channels of an InAs quantum well, which is magnetized by a proximity effect from an underlying ferromagnetic semiconductor (Ga,Fe)Sb layer. Combining experimental results and theoretical analysis using the linearized Boltzmann's equation, we found that simultaneous breaking of both the TRS by the magnetic proximity effect (MPE) and spatial inversion symmetry (SIS) in the one-dimensional (1D) InAs edge channels is the origin of this giant OMR. We also demonstrated the ability to turn on and off the OMR using electrical gating of either TRS or SIS in the edge channels. These findings provide a deep insight into the 1D semiconducting system with a strong magnetic coupling.

Giant spin-to-charge conversion at an all-epitaxial single-crystal-oxide Rashba interface with a strongly correlated metal interlayer.

The two-dimensional electron gas (2DEG) formed at interfaces between SrTiO3 (STO) and other oxide insulating layers is promising for use in efficient spin-charge conversion due to the large Rashba spin-orbit interaction (RSOI). However, these insulating layers on STO prevent the propagation of a spin current injected from an adjacent ferromagnetic layer. Moreover, the mechanism of the spin-current flow in these insulating layers is still unexplored. Here, using a strongly correlated polar-metal LaTiO3+δ (LTO) interlayer and the 2DEG formed at the LTO/STO interface in an all-epitaxial heterostructure, we demonstrate giant spin-to-charge current conversion efficiencies, up to ~190 nm, using spin-pumping ferromagnetic-resonance voltage measurements. This value is the highest among those reported for all materials, including spin Hall systems. Our results suggest that the strong on-site Coulomb repulsion in LTO and the giant RSOI of LTO/STO may be the key to efficient spin-charge conversion with suppressed spin-flip scattering. Our findings highlight the hidden inherent possibilities of oxide interfaces for spin-orbitronics applications.

Serology suggests adequate safety measures to protect healthcare workers from COVID-19 in Shiga Prefecture, Japan.

Healthcare workers (HCWs), especially frontline workers against coronavirus disease 2019 (COVID-19), are considered to be risky because of occupational exposure to infected patients. This study evaluated the correlation between seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies among HCWs and the implementation of personal protective equipment (PPE) & infection prevention and control (IPC). We recruited 1237 HCWs from nine public COVID-19-designated hospitals in Shiga Prefecture, central Japan, between 15-26 February 2021. All participants answered a self-administered questionnaire and provided blood samples to evaluate SARS-CoV-2 antibodies. A total of 22 cases (1·78%) were seropositive among the 1237 study participants. An unavoidable outbreak of SARS-CoV-2 had occurred at the terminal care unit of one hospital, before identifying and securely isolating this cluster of cases. Excluding with this cluster, 0·68% of HCWs were suspected to have had previous SARS-CoV-2 infections. Binomial logistic regression from individual questionnaires and seropositivity predicted a significant correlation with N95 mask implementation under aerosol conditions (p = 8.63e-06, aOR = 2.47) and work duration in a red zone (p = 2.61e-04, aOR = 1.99). The institutional questionnaire suggested that IPC education was correlated with reduced seropositivity at hospitals. Seroprevalence and questionnaire analyses among HCWs indicated that secure implementation of PPE and re-education of IPC are essential to prevent SARS-CoV-2 infection within healthcare facilities. Occupational infections from SARS-CoV-2 in healthcare settings could be prevented by adhering to adequate measures and appropriate use of PPE. With these measures securely implemented, HCWs should not be considered against as significantly risky or dirty by local communities.

Clinical evaluation of [18F]pitavastatin for quantitative analysis of hepatobiliary transporter activity.

It is widely accepted that uptake and efflux transporters on clearance organs play crucial roles in drug disposition. Although in vitro transporter assay system can identify the intrinsic properties of the target transporters, it is not so easy to precisely predict in vivo pharmacokinetic parameters from in vitro data. Positron emission tomography (PET) imaging is a useful tool to directly assess the activity of drug transporters in humans. We recently developed a practical synthetic method for fluorine-18-labeled pitavastatin ([18F]PTV) as a PET probe for quantitative evaluation of hepatobiliary transport. In the present study, we conducted clinical PET imaging with [18F]PTV and compared the pharmacokinetic properties of the probe for healthy subjects with or without rifampicin pretreatment. Rifampicin pretreatment significantly suppressed the hepatic maximum concentration and biliary excretion of the probe to 52% and 34% of the control values, respectively. Rifampicin treatment markedly decreased hepatic uptake clearance (21% of the control), and moderately canalicular efflux clearance with regard to hepatic concentration (52% of the control). These results demonstrate that [18F]PTV is a useful probe for clinical investigation of the activities of hepatobiliary uptake/efflux transporters in humans.

First-in-human assessment of the novel LAT1 targeting PET probe 18F-FIMP.

In the first-in-human PET study, we evaluated the biodistribution and tumor accumulation of the novel PET probe, (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP), which targets the tumor-related L-type amino acid transporter 1 (LAT1), and compared it with L-[methyl-11C]methionine (11C-MET) and 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG). 18F-FIMP biodistribution was revealed by whole-body and brain scans in 13 healthy controls. Tumor accumulation of 18F-FIMP was evaluated in 7 patients with a brain tumor, and compared with those of 11C-MET and 18F-FDG. None of the subjects had significant problems due to probe administration, such as adverse effects or abnormal vital signs. 18F-FIMP was rapidly excreted from the kidneys to the urinary bladder. There was no characteristic physiological accumulation in healthy controls. 18F-FIMP PET resulted in extremely clear images in patients with suspected glioblastoma compared with 11C-MET and 18F-FDG. 18F-FIMP could be a useful novel PET probe for LAT1-positive tumor imaging including glioblastoma.

Elemental Topological Dirac Semimetal α-Sn with High Quantum Mobility.

α-Sn provides an ideal avenue to investigate novel topological properties owing to its rich diagram of topological phases and simple elemental material structure. Thus far, however, the realization of high-quality α-Sn remains a challenge, which limits the understanding of its quantum transport properties and device applications. Here, epitaxial growth of α-Sn on InSb (001) with the highest quality thus far is presented. The studied samples exhibit unprecedentedly high quantum mobilities of both the surface state (30 000 cm2 V-1 s-1 ), which is ten times higher than the previously reported values, and the bulk heavy-hole state (1800 cm2 V-1 s-1 ), which is never obtained experimentally. These excellent features allow quantitative characterization of the nontrivial interfacial and bulk band structure of α-Sn via a thorough investigation of Shubnikov-de Haas oscillations combined with first-principles calculations. The results firmly identify that α-Sn grown on InSb (001) is a topological Dirac semimetal (TDS). Furthermore, a crossover from the TDS to a 2D topological insulator and a subsequent phase transition to a trivial insulator when varying the thickness of α-Sn are demonstrated. This work indicates that α-Sn is an excellent model system to study novel topological phases and a prominent material candidate for topological devices.

Ferromagnetism and giant magnetoresistance in zinc-blende FeAs monolayers embedded in semiconductor structures.

Material structures containing tetrahedral FeAs bonds, depending on their density and geometrical distribution, can host several competing quantum ground states ranging from superconductivity to ferromagnetism. Here we examine structures of quasi two-dimensional (2D) layers of tetrahedral Fe-As bonds embedded with a regular interval in a semiconductor InAs matrix, which resembles the crystal structure of Fe-based superconductors. Contrary to the case of Fe-based pnictides, these FeAs/InAs superlattices (SLs) exhibit ferromagnetism, whose Curie temperature (TC) increases rapidly with decreasing the InAs interval thickness tInAs (TC ∝ tInAs-3), and an extremely large magnetoresistance up to 500% that is tunable by a gate voltage. Our first principles calculations reveal the important role of disordered positions of Fe atoms in the establishment of ferromagnetism in these quasi-2D FeAs-based SLs. These unique features mark the FeAs/InAs SLs as promising structures for spintronic applications.

Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress.

Adrenomedullin (AM) is a peptide hormone with multiple physiological functions, which are regulated by its receptor activity-modifying proteins, RAMP2 and RAMP3. We previously reported that AM or RAMP2 knockout (KO) (AM-/-, RAMP2-/-) is embryonically lethal in mice, whereas RAMP3-/- mice are apparently normal. AM, RAMP2, and RAMP3 are all highly expressed in the heart; however, their functions there are not fully understood. Here, we analyzed the pathophysiological functions of the AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2-/- (C-RAMP2-/-) and RAMP3-/- showed no apparent heart failure at base line. After 1 week of transverse aortic constriction (TAC), however, C-RAMP2-/- exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with wild-type mice. Both dP/dtmax and dP/dtmin were significantly reduced in C-RAMP2-/-, indicating reduced ventricular contractility and relaxation. Exposing C-RAMP2-/- cardiomyocytes to isoproterenol enhanced their hypertrophy and oxidative stress compared with wild-type cells. C-RAMP2-/- cardiomyocytes also contained fewer viable mitochondria and showed reduced mitochondrial membrane potential and respiratory capacity. RAMP3-/- also showed reduced systolic function and enhanced fibrosis after TAC, but those only became apparent after 4 weeks. A reduction in cardiac lymphatic vessels was the characteristic feature in RAMP3-/-. These observations indicate the AM-RAMP2 system is necessary for early adaptation to cardiovascular stress through regulation of cardiac mitochondria. AM-RAMP3 is necessary for later adaptation through regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus play separate critical roles in the maintenance of cardiovascular homeostasis against cardiovascular stress.

Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-ß and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-ß and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition.

Quantum transport evidence of Weyl fermions in an epitaxial ferromagnetic oxide.

Magnetic Weyl semimetals have novel transport phenomena related to pairs of Weyl nodes in the band structure. Although the existence of Weyl fermions is expected in various oxides, the evidence of Weyl fermions in oxide materials remains elusive. Here we show direct quantum transport evidence of Weyl fermions in an epitaxial 4d ferromagnetic oxide SrRuO3. We employ machine-learning-assisted molecular beam epitaxy to synthesize SrRuO3 films whose quality is sufficiently high to probe their intrinsic transport properties. Experimental observation of the five transport signatures of Weyl fermions-the linear positive magnetoresistance, chiral-anomaly-induced negative magnetoresistance, π phase shift in a quantum oscillation, light cyclotron mass, and high quantum mobility of about 10,000 cm2V-1s-1-combined with first-principles electronic structure calculations establishes SrRuO3 as a magnetic Weyl semimetal. We also clarify the disorder dependence of the transport of the Weyl fermions, which gives a clear guideline for accessing the topologically nontrivial transport phenomena.

Investigation of the therapeutic mechanism of subthreshold micropulse laser irradiation in retina.

PURPOSE: Subthreshold micropulse laser irradiation has been used for the treatment of retinal edema; however, there are few reports about the mechanism of its therapeutic effect. In this study, we compared threshold short pulse and subthreshold micropulse laser irradiation in mice and investigated their mechanism. METHODS: Nine to 12-week-old male C57BL/6J mice were used in this study. After general anesthesia, threshold short pulse or subthreshold micropulse laser irradiation was performed on the right eye using IQ577. Enucleation was performed 24 h after the laser irradiation, and histological and gene expression analyses were carried out. RESULTS: Coagulation spots and atrophy of the retinal pigment epithelium were observed after threshold short pulse laser irradiation but not after subthreshold micropulse laser irradiation. Twenty-four hours after laser, aquaporin (AQP) 1, 2, 7, and 11 levels were significantly elevated by 1.7- to 3-fold in the threshold short pulse laser group compared with non-treated control group. AQP 3 was increased significantly and prominently by 100-fold. VEGF-A and VEGFR2 were upregulated 1.5- and 2.3-fold, respectively. In the subthreshold micropulse laser group, AQP 3 was increased by 6-fold compared with the non-treated control group. Angiopoietin-1 and the adrenomedullin (AM) receptor CLR were decreased by 0.6-fold and 0.5-fold, respectively. CONCLUSION: Threshold short pulse laser irradiation caused retinal damage and prominent changes in the expression of various genes. Contrarily, subthreshold micropulse laser irradiation did not induce retinal damage; it upregulated AQP 3, which might have improved retinal edema by drainage of subretinal fluid.

High-Mobility 2D Hole Gas at a SrTiO3 Interface.

Strontium titanate (SrTiO3 or STO) is important for oxide-based electronics as it serves as a standard substrate for a wide range of high-temperature superconducting cuprates, colossal magnetoresistive manganites, and multiferroics. Moreover, in its heterostructures with different materials, STO exhibits a broad spectrum of important physics such as superconductivity, magnetism, the quantum Hall effect, giant thermoelectric effect, and colossal ionic conductivity, most of which emerge in a two-dimensional (2D) electron gas (2DEG) formed at an STO interface. However, little is known about its counterpart system, a 2D hole gas (2DHG) at the STO interface. Here, a simple way of realizing a 2DHG with an ultrahigh mobility of 24 000 cm2 V-1 s-1 is demonstrated using an interface between STO and a thin amorphous FeOy layer, made by depositing a sub-nanometer-thick Fe layer on an STO substrate at room temperature. This mobility is the highest among those reported for holes in oxides. The carrier type can be switched from p-type (2DHG) to n-type (2DEG) by controlling the Fe thickness. This unprecedented method of forming a 2DHG at an STO interface provides a pathway to unexplored hole-related physics in this system and enables extremely low-cost and high-speed oxide electronics.

Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts.

Tumor metastasis is a primary source of morbidity and mortality in cancer. Adrenomedullin (AM) is a multifunctional peptide regulated by receptor activity-modifying proteins (RAMPs). We previously reported that the AM-RAMP2 system is involved in tumor angiogenesis, but the function of the AM-RAMP3 system remains largely unknown. Here, we investigated the actions of the AM-RAMP2 and 3 systems in the tumor microenvironment and their impact on metastasis. PAN02 pancreatic cancer cells were injected into the spleens of mice, leading to spontaneous liver metastasis. Tumor metastasis was enhanced in vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-). By contrast, metastasis was suppressed in RAMP3-/- mice, where the number of podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) was reduced in the periphery of tumors at metastatic sites. Because PDPN-positive CAFs are a hallmark of tumor malignancy, we assessed the regulation of PDPN and found that Src/Cas/PDPN signaling is mediated by RAMP3. In fact, RAMP3 deficiency CAFs suppressed migration, proliferation, and metastasis in co-cultures with tumor cells in vitro and in vivo. Moreover, the activation of RAMP2 in RAMP3-/- mice suppressed both tumor growth and metastasis. Based on these results, we suggest that the upregulation of PDPN in DI-E-RAMP2-/- mice increases malignancy, while the downregulation of PDPN in RAMP3-/- mice reduces it. Selective activation of RAMP2 and inhibition of RAMP3 would therefore be expected to suppress tumor metastasis. This study provides the first evidence that understanding and targeting to AM-RAMP systems could contribute to the development of novel therapeutics against metastasis.

Endogenous Calcitonin Gene-Related Peptide Deficiency Exacerbates Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and M2 Macrophage Accumulation.

Lymphedema is a chronic condition caused by disruption of lymphatic vessels, which often occurs after invasive surgery. Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene (Calca). CGRP was initially identified as a neuropeptide released primarily from sensory nerves and involved in regulating pathophysiological nociceptive pain. However, recent studies have shown CGRP is also released from a variety of other cells and possesses multiple functions. In this study, CGRP knockout (-/-) mice were used to show the actions of endogenous CGRP in postoperative lymphedema. After generating a mouse postoperative tail lymphedema model, the edema was observed to be more severe in CGRP-/- mice than in wild-type mice. Numbers of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)-positive lymphatic capillaries were decreased and lymphatic capillary formation-related factors were down-regulated in CGRP-/- mice. In addition, accumulation of M2 but not M1 macrophages was selectively reduced in the edematous tissue of CGRP-/- mice. Selective depletion of M2 macrophages decreased lymphatic capillary formation and worsened lymphedema in wild-type mice but not CGRP-/- mice, where numbers of M2 macrophages were already diminished. These findings suggest that endogenous CGRP acts to ameliorate postoperative lymphedema by enhancing lymphatic capillary formation and that M2 macrophages play critical roles. CGRP may be a useful therapeutic target for the treatment of postoperative lymphedema.