Spontaneous Atomic-Scale Polar Skyrmions and Merons on a SrTiO3 (001) Surface: Defect Engineering for Emerging Topological Orders.

The emergence of nontrivial topological order in condensed matter has been attracting a great deal of attention owing to its promising technological applications in novel functional nanodevices. In ferroelectrics, the realization of polar topological order at an ultimately small scale is extremely challenging due to the lack of chiral interaction and the critical size of the ferroelectricity. Here, we break through these limitations and demonstrate that the ultimate atomic-scale polar skyrmion and meron (∼2 nm) can be induced by engineering oxygen vacancies on the SrTiO3 (001) surface based on first-principles calculations. The paraelectric-to-antiferrodistortive phase transition leads to a novel topological transition from skyrmion to meron, indicating phase-topology correlations. We also discuss accumulating and driving polar skyrmions based on the oxygen divacancy model; these results and the recent discovery of defect engineering techniques suggest the possibility of arithmetic operations on topological numbers through the natural self-organization and diffusion features of oxygen vacancies.

Mechanical Rippling for Diverse Ferroelectric Topologies in Otherwise Nonferroelectric SrTiO_{3} Nanofilms.

Polar topological structures such as skyrmions and merons have become an emerging research field due to their rich functionalities and promising applications in information storage. Up to now, the obtained polar topological structures are restricted to a few limited ferroelectrics with complex heterostructures, limiting their large-scale practical applications. Here, we circumvent this limitation by utilizing a nanoscale ripple-generated flexoelectric field as a universal means to create rich polar topological configurations in nonpolar nanofilms in a controllable fashion. Our extensive phase-field simulations show that a rippled SrTiO_{3} nanofilm with a single bulge activates polarizations that are stabilized in meron configurations, which further undergo topological transitions to Néel-type and Bloch-type skyrmions upon varying the geometries. The formation of these topologies originates from the curvature-dependent flexoelectric field, which extends beyond the common mechanism of geometric confinement that requires harsh energy conditions and strict temperature ranges. We further demonstrate that the rippled nanofilm with three-dimensional ripple patterns can accommodate other unreported modulated phases of ferroelectric topologies, which provide ferroelectric analogs to the complex spin topologies in magnets. The present study not only unveils the intriguing nanoscale electromechanical properties but also opens exciting opportunities to design various functional topological phenomena in flexible materials.

Emergent ultrasmall multiferroics in paraelectric perovskite oxide by hole polarons.

Ultimately small multiferroics with coupled ferroelectric and ferromagnetic order parameters have drawn considerable attention for their tremendous technological potential. Nevertheless, these ferroic orders inevitably disappear below the critical size of several nanometers in conventional ferroelectrics or multiferroics. Here, based on first-principles calculations, we propose a new strategy to overcome this limitation and create ultrasmall multiferroic elements in otherwise nonferroelectric CaTiO3 by engineering the interplay of oxygen octahedral rotations and hole polarons, though both of them are generally believed to be detrimental to ferroelectricity. It is found that the hole doped in CaTiO3 spontaneously forms a localized polaronic state. The lattice distortions associated with a hole polaron interacting with the intrinsic oxygen octahedral rotations in CaTiO3 effectively break the inversion symmetry and create atomic-scale ferroelectricity beyond the critical size limitation. The hole polaron also causes highly localized magnetism attributed to the associated spin-polarized electric state and thus manifests as a multiferroic polaron. Moreover, the hole polaron exhibits high hopping mobility accompanied by rich switching of polarization and magnetic directions, indicating strong magnetoelectric coupling with a mechanism dissimilar from that of conventional multiferroics. The present work provides a new mechanism to engineer inversion symmetry and opens avenues for designing unusual multifunctional materials.

Electronic strengthening mechanism of covalent Si via excess electron/hole doping.

Brittle fracture of a covalent material is ultimately governed by the strength of the electronic bonds. Recently, attempts have been made to alter the mechanical properties including fracture strength by excess electron/hole doping. However, the underlying mechanics/mechanism of how these doped electrons/holes interact with the bond and changes its strength is yet to be revealed. Here, we perform first-principles density-functional theory calculations to clarify the effect of excess electrons/holes on the bonding strength of covalent Si. We demonstrate that the bond strength of Si decreases or increases monotonically in correspondence with the doping concentration. Surprisingly, change to the extent of 30-40% at the maximum feasible doping concentration could be observed. Furthermore, we demonstrated that the change in the covalent bond strength is determined by the bonding/antibonding state of the doped excess electrons/holes. In summary, this work explains the electronic strengthening mechanism of covalent Si from a quantum mechanical point of view and provides valuable insights into the electronic-level design of strength in covalent materials.

Management of Hypervascular Retained Products of Conception With Massive Bleeding.

Retained products of conception (RPOC) could be a factor for massive postpartum hemorrhage; however, a management protocol is yet to be established. Performing a surgical intervention is controversial due to the potential for natural healing. Herein, we report the management of a hypervascular RPOC case with massive bleeding. Abortion was performed in a 40-year-old patient with gravida 2 and para 0, at 20 weeks and five days of gestation following the detection of Down's syndrome on prenatal screening. Post-delivery transvaginal ultrasonography identified an intrauterine mass measuring 4cm × 5cm × 5cm. The patient was then followed up in the outpatient department. One month after the abortion, the patient developed abnormal vaginal bleeding. Transvaginal ultrasonography revealed a hypervascular myometrial RPOC with turbulent flow. Although the bleeding stopped upon her admission to our hospital, the patient developed recurrent abnormal vaginal bleeding after nine days of hospitalization, which resulted in a hemoglobin level drop to 5.9 g/dL. CT and MRI scan findings raised the suspicion of hypervascular RPOC or uterine artery pseudoaneurysm. Uterine artery embolization was performed, leading to diminished vascularity in the RPOC, which was confirmed through color Doppler ultrasonography. The remnant placenta was successfully resected hysteroscopically, and a subsequent transvaginal ultrasonography showed a decrease in blood flow. In conclusion, hypervascular RPOC, previously reported as uterine artery pseudoaneurysms, should be considered when detecting hypervascular myometrial lesions in postpartum ultrasonography. Hypervascular RPOC with hemorrhage might benefit from hysteroscopic resection after achieving hemostasis with uterine artery embolization. This case report highlights the potential risks of awaiting spontaneous resolution in large RPOC and suggests that timely surgical intervention is both effective and essential.

[Relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia responding to retreatment with inotuzumab ozogamicin].

A 72-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) was treated with dasatinib (week1: 50 mg/day, week2: 70 mg/day, week3-: 100 mg/day) and prednisolone from June 2017. However, in January 2018, it relapsed with the T315I mutation. Although the treatment was changed to ponatinib 30 mg/day, he experienced a second relapse in June 2018. Following confirmation of CD22 positivity, he was treated with three cycles of inotuzumab ozogamicin (InO), resulting in CR. He was CR for 2.9 years before relapsing for the third time in May 2021. Because the patient was still CD22-positive, InO was given again, and the patient achieved CR at the end of the second cycle. We had a case where re-administering InO was effective as a salvage therapy for relapsed/refractory Ph+ALL (r/r Ph+ALL) in an elderly patient.

Intrinsic Atomic-Scale Antiferroelectric VOF3 Nanowire with Ultrahigh-Energy Storage Properties.

Antiferroelectrics with antiparallel dipoles are receiving tremendous attention for their technological importance and fundamental interest. However, intrinsic one-dimensional (1D) materials harboring antiferroelectric ordering have rarely been reported despite the promise of novel paradigms for miniaturized and high-density electronics. Herein, based on first- and second-principles calculations, we demonstrate the VOF3 atomic wire, exfoliated from an experimentally synthesized yet underexplored 1D van der Waals (vdW) bulk, as a new 1D antiferroelectric material. The energetic, thermal, and dynamic stabilities of the nanowire are confirmed theoretically. Moreover, the temperature-dependent phase transitions and double-hysteresis polarization-field loops are computed for the VOF3 nanowire by constructing the second-principles model. According to the hysteresis loops, high energy densities and efficiencies can be obtained simultaneously at room temperature in the VOF3 nanowire under moderate applied fields. Our identified 1D atomic wire not only expands the family of antiferroelectricity but also holds potential for novel high-power energy storage nanodevices.

Ultrasmall Polar Skyrmions and Merons in SrTiO3 Heterostructures by Polaron Engineering.

Topological objects with skyrmionic textures in ferroelectrics, i.e., polar skyrmions, are promising technological paradigms in next-generation electronic devices. While breakthrough discoveries of stable polar skyrmions approximately ten nanometers in size have been very recently witnessed in complex systems, such a nontrivial topological order in ferroelectrics inevitably disappears below the ferroelectric critical size of several nanometers. Herein, we propose a strategy to overcome this limitation and achieve ultrasmall and isolated polar skyrmions by engineering excess-electron polarons in otherwise nonferroelectric SrTiO3 heterostructures. Our first-principle calculations demonstrate that a polaron localized at a SrTiO3 surface induces a Neel-type polar skyrmion as small as 1.8 nanometers attributed to the effect of atomic-scale surface roughness. Furthermore, we show that this polar topological structure is tunable by the choice of heterostructures and by the mechanical approach, which undergoes a phase transition to a meron state in the twisted boundary and to an antiskyrmion state in the surface with external shear strain, respectively. Such ultraminiaturization of skyrmions and their transitions unexpectedly unravels the formula of ultrasmall topological orders originating from the interplay between an electron polaron and structural symmetry breaking, which is completely different from the common mechanism of geometric confinement for larger-scale skyrmions. Our results not only provide a mechanism for the exploration of polar skyrmions and their rich topological transitions but also hold potential for ultrahigh-density memories.

Development of Myostatin Inhibitory d-Peptides to Enhance the Potency, Increasing Skeletal Muscle Mass in Mice.

Myostatin is a key negative regulator of skeletal muscle growth, and myostatin inhibitors are attractive tools for the treatment of muscular atrophy. Previously, we reported a series of 14-29-mer peptide myostatin inhibitors, including a potent derivative, MIPE-1686, a 16-mer N-terminal-free l-peptide with three unnatural amino acids and a propensity to form ß-sheets. However, the in vivo biological stability of MIPE-1686 is a concern for its development as a drug. In the present study, to develop a more stable myostatin inhibitory d-peptide (MID), we synthesized various retro-inverso versions of a 16-mer peptide. Among these, an arginine-containing derivative, MID-35, shows a potent and equivalent in vitro myostatin inhibitory activity equivalent to that of MIPE-1686 and considerable stability against biodegradation. The in vivo potency of MID-35 to increase the tibialis anterior muscle mass in mice is significantly enhanced over that of MIPE-1686, and MID-35 can serve as a new entity for the prolonged inactivation of myostatin in skeletal muscle.

Preclinical safety profile of a liver-localized mitochondrial uncoupler: OPC-163493.

Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC24h). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates.

Ultrasmall-Scale Brittle Fracture Initiated from a Dislocation in SrTiO3.

Crystal defects often lead to an intriguing variety of catastrophic failures of materials and determine the mechanical properties. Here we discover that a dislocation, which was believed to be a source of plasticity, leads to brittle fracture in SrTiO3. The fracture mechanism, i.e., bond breaking at the dislocation core triggers crack initiation and subsequent fracture, is elucidated from an atomic view by hybrid quantum and molecular simulations and in situ nanomechanical experiments. The fracture strength of the dislocation-included SrTiO3 was theoretically evaluated to be 8.8-10.7 GPa, which was eminently lower than that of the pristine one (21.7 GPa). The experimental results agree well with the simulated ones. Moreover, the fracture toughness of the ultrasmall crack initiating from the dislocation is quantitatively evaluated. This study reveals not only the role of dislocations in brittle fracture but also provides an in-depth understanding of the fracture mechanism of dislocations at the atomic scale.

Emergence of non-trivial polar topologies hidden in singular stress field in SrTiO3: topological strain-field engineering.

Discovery of non-trivial topological structures in condensed matters holds promise in novel technological paradigms. In contrast to ferromagnetics, where a variety of topological structures such as vortex, meron, and skyrmion have been discovered, only few topological structures can exist in ferroelectrics due to the lack of non-collinear interaction like the Dzyaloshinskii-Moriya interaction in ferromagnetics. Here, we demonstrate that polarization structures with a wide range of topological numbers (winding numbernfrom -3 to +1) can be mechanically excited and designed by the mode-I singular stress field formed near the crack-tip in incipient ferroelectric SrTiO3. Our phase-field simulations based on Ginzburg-Landau theory successfully reveals that the near-tip polar topology is driven by the flexoelectric coupling with intense strain gradient at the tip, while a variety of the far-field topological structures is triggered by a collaboration between the electrostrictive and flexoelectric effects. The strain (gradient) field analysis further shows that the unexpected topological characters are implied in the singular stress field, which develops a variety of polar topologies near the crack tip. Therefore, our work provides a novel insight into the unusual interplay between mechanical- and ferroelectric-topologies, i.e. 'topological strain-field engineering', which paves the way to the mechanical design of functional topologies in the matter.

New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493.

We serendipitously found a mitochondrial uncoupler (mUncoupler), compound 1, in the process of screening for inhibitors of a gene product related to calorie restriction (CR) and longevity. Compound 1 has a unique 4-cyano-1,2,3-triazole structure which is different from any known mUncoupler and ameliorated HbA1c in Zucker diabetic fatty (ZDF) rats. However, its administration at high doses was not tolerated in an acute toxicity test in rats. We therefore tried to optimize cyanotriazole compound 1 and convert it into an agent that could be safely administered to patients with diabetes mellitus (DM) or metabolic disorders. Considering pharmacokinetic (PK) profiles, especially organ distribution targeting the liver and avoiding the brain, as well as acute toxicities and pharmacological effects of the derivatives, various conversions and substitutions at the 5-position on the cyanotriazole ring were carried out. These optimizing processes improved PK profiles and effectiveness, and acute toxicities became negligible even at high doses. We finally succeeded in developing an optimized compound, OPC-163493, as a liver-localized/targeted mUncoupler.

High accuracy tracking reveals how small conservation areas can protect marine megafauna.

Space use estimates can inform conservation management but relaying high-accuracy locations is often not straightforward. We used Fastloc-GPS Argos satellite tags with the innovation of additional data relay via a ground station (termed a "Mote") to record high volumes (typically >20 locations per individual per day) of high accuracy tracking data. Tags were attached in the Chagos Archipelago (Indian Ocean) in 2018-2019 to 23 immature turtles of two species for which there have been long-standing conservation concerns: 21 hawksbill turtles (Eretmochelys imbricata) and two green turtles (Chelonia mydas). Over long tracking durations (mean 227.6 d per individual), most turtles moved very little. For example, 17 of 21 hawksbill turtles remained continuously in the lagoon where they were equipped, with 95% and 50% utilization distributions (UDs) averaging only 1.03 and 0.18 km2 , respectively. Many individuals, and both species, could use the same small spaces, i.e., individuals did not maintain unique home ranges. However, three hawksbill turtles travelled hundreds of kilometers from the tagging site. Our results show that, for some large marine vertebrates, even small protected areas of only a few square kilometers can encompass the movements of a large proportion of individuals over long periods. High accuracy tracking may likewise reveal the details of space use for many other animals that move little and/or use important focal areas and where previous low-accuracy tracking techniques have tended to overestimate space use.

Strategic structure-activity relationship study on a follistatin-derived myostatin inhibitory peptide.

Myostatin, a negative regulator of muscle mass is a promising target for the treatment of muscle atrophic diseases. The novel myostatin inhibitory peptide, DF-3 is derived from the N-terminal α-helical domain of follistatin, which is an endogenous inhibitor of myostatin and other TGF-ß family members. It has been suggested that the optimization of hydrophobic residues is important to enhance the myostatin inhibition. This study describes a structure-activity relationship study focused on hydrophobic residues of DF-3 and designed to obtain a more potent peptide. A methionine residue in DF-3, which is susceptible to oxidation, was successfully converted to homophenylalanine in DF-100, and a new derivative DF-100, with four amino acid substitutions in DF-3 shows twice the potent inhibitory ability as DF-3. This report provides a new platform of a 14-mer peptide muscle enhancer.

Correction: Two-dimensional polar metal of a PbTe monolayer by electrostatic doping.

Correction for 'Two-dimensional polar metal of a PbTe monolayer by electrostatic doping' by Tao Xu et al., Nanoscale Horiz., 2020, 5, 1400-1406, DOI: .

Beyond conventional nonlinear fracture mechanics in graphene nanoribbons.

Owing to a finite and single-atom-thick two-dimensional structure, graphene nanostructures such as nanoribbons possess outstanding physical properties and unique size-dependent characteristics due to nanoscale defects, especially for mechanical properties. Graphene nanostructures characteristically exhibit strong nonlinearity in deformation and the defect brings about an extremely localized singular stress field of only a few nanometers, which might lead to unique fracture properties. Fundamental understanding of their fracture properties and criteria is, however, seriously underdeveloped and limited to the level of continuum mechanics and linear elasticity. Here, we demonstrate the breakdown of continuum-based fracture criteria for graphene nanoribbons due to the strong nonlinearity and discreteness of atoms emerging with decreasing size and identify the critical sizes for these conventional criteria. We further propose an energy-based criterion considering atomic discrete nature, and show that it can successfully describe the fracture beyond the critical sizes. The complete clarification of fracture criterion for nonlinear graphene with nanoscale singularity contributes not only to the reliable design of graphene-based nanodevices but also to the elucidation of the extreme dimensional limit in fracture mechanics.

Two-dimensional polar metal of a PbTe monolayer by electrostatic doping.

Polar metals characterized by the simultaneous coexistence of a polar structure and metallicity have been a long-sought goal due to the promise of novel electronic devices. Developing such materials at low dimensions remains challenging since both conducting electrons and reduced dimensions are supposed to quench the polar state. Here, based on first-principles calculations, we report the discovery of a non-centrosymmetric polar structure in two-dimensional (2D) metallic materials with electrostatic doping, even though ferroelectricity is unconventional at the atomic scale. We revealed that the PbTe monolayer is intrinsically ferroelectric with pronounced out-of-plane electric polarization originating from its non-centrosymmetric buckled structure. Moreover, the polar distortions can be preserved with carrier doping in the monolayer, which further enables the doped PbTe monolayer to act as a 2D polar metal. With an effective Hamiltonian extracted from the parametrized energy space, we found that the special elastic-polar mode interaction is of great importance for the existence of robust polar instability (i.e., soft phonon mode associated with polar distortion) in the doped system. The application of this doping strategy is not specific to the present crystal, but is rather general to other 2D ferroelectrics to bring about the fascinating non-centrosymmetric metallic state. Our findings thus change the conventional knowledge in 2D materials and will facilitate the development of multifunctional materials in low dimensions.

Ab Initio Study of Ferroelectric Critical Size of SnTe Low-Dimensional Nanostructures.

Beyond a ferroelectric critical thickness of several nanometers existed in conventional ferroelectric perovskite oxides, ferroelectricity in ultimately thin dimensions was recently discovered in SnTe monolayers. This discovery suggests the possibility that SnTe can sustain ferroelectricity during further low-dimensional miniaturization. Here, we investigate a ferroelectric critical size of low-dimensional SnTe nanostructures such as nanoribbons (1D) and nanoflakes (0D) using first-principle density-functional theory calculations. We demonstrate that the smallest (one-unit-cell width) SnTe nanoribbon can sustain ferroelectricity and there is no ferroelectric critical size in the SnTe nanoribbons. On the other hand, the SnTe nanoflakes form a vortex of polarization and lose their toroidal ferroelectricity below the surface area of 4 × 4 unit cells (about 25 Å on one side). We also reveal the atomic and electronic mechanism of the absence or presence of critical size in SnTe low-dimensional nanostructures. Our result provides an insight into intrinsic ferroelectric critical size for low-dimensional chalcogenide layered materials.

Conservation and Enforcement Capacity index (CECi): Integrating human development, economy, and marine turtle status.

Human societies are closely linked to their ecological environments. Natural ecosystems and wildlife populations are often in better condition in countries with healthy, educated and economically prosperous populations compared to countries with lower health and literacy conditions, and depressed economies. In the latter countries, these socio-economic factors can compromise government's capacity to manage their natural resources. Thus, the conservation capacity of a government is likely to play key role in the protection of threatened species, such as marine turtles. This paper aims: (1) to evaluate the conservation capacity and enforcement within the 58 Regional Management Units (RMUs) of the seven species of marine turtles throughout the world, and (2) to develop a proxy that predicts the conservation status of RMUs. We developed a Conservation and Enforcement Capacity index (CECi) by integrating the following indices: (a) the economic level and, (b) the Human Development Index (HDI) of each country, plus (c) the risks and threats in the RMUs. We used the conservation status of 15 RMUs recently assessed by the International Union for Conservation of Nature - IUCN to predict the conservation status of the 43 RMUs without updated IUCN categorisation. CECi values ranged from 0 to 1, where lower values represent a better capacity for implementation of conservation initiatives. We found that using our multi-index model, we predicted the status of 33 of 58 RMUs, 57% of which may be of threatened conservation status due to their high CECi values. This study highlighted how socio-economic aspects may impact conservation of endangered species.