Emergent Spin-Gapped Magnetization Plateaus in a Spin-1/2 Perfect Kagome Antiferromagnet.

The two-dimensional spin-1/2 kagome Heisenberg antiferromagnet is believed to host quantum spin liquid (QSL) states with no magnetic order, but its ground state remains largely elusive. An important outstanding question concerns the presence or absence of the 1/9 magnetization plateau, where exotic quantum states, including topological ones, are expected to emerge. Here we report the magnetization of a recently discovered kagome QSL candidate YCu_{3}(OH)_{6.5}Br_{2.5} up to 57 T. Above 50 T, a clear magnetization plateau at 1/3 of the saturation moment of Cu^{2+} ions is observed, supporting that this material provides an ideal platform for the kagome Heisenberg antiferromagnet. Remarkably, we found another magnetization plateau around 20 T, which is attributed to the 1/9 plateau. The temperature dependence of this plateau reveals the presence of the spin gap. The observation of 1/9 and 1/3 plateaus highlights the emergence of novel states in quantum spin systems.

Evidence for a finite-momentum Cooper pair in tricolor d-wave superconducting superlattices.

Fermionic superfluidity with a nontrivial Cooper-pairing, beyond the conventional Bardeen-Cooper-Schrieffer state, is a captivating field of study in quantum many-body systems. In particular, the search for superconducting states with finite-momentum pairs has long been a challenge, but establishing its existence has long suffered from the lack of an appropriate probe to reveal its momentum. Recently, it has been proposed that the nonreciprocal electron transport is the most powerful probe for the finite-momentum pairs, because it directly couples to the supercurrents. Here we reveal such a pairing state by the non-reciprocal transport on tricolor superlattices with strong spin-orbit coupling combined with broken inversion-symmetry consisting of atomically thin d-wave superconductor CeCoIn5. We find that while the second-harmonic resistance exhibits a distinct dip anomaly at the low-temperature (T)/high-magnetic field (H) corner in the HT-plane for H applied to the antinodal direction of the d-wave gap, such an anomaly is absent for H along the nodal direction. By carefully isolating extrinsic effects due to vortex dynamics, we reveal the presence of a non-reciprocal response originating from intrinsic superconducting properties characterized by finite-momentum pairs. We attribute the high-field state to the helical superconducting state, wherein the phase of the order parameter is spontaneously spatially modulated.

Charge-neutral fermions and magnetic field-driven instability in insulating YbIr3Si7.

Kondo lattice materials, where localized magnetic moments couple to itinerant electrons, provide a very rich backdrop for strong electron correlations. They are known to realize many exotic phenomena, with a dramatic example being recent observations of quantum oscillations and metallic thermal conduction in insulators, implying the emergence of enigmatic charge-neutral fermions. Here, we show that thermal conductivity and specific heat measurements in insulating YbIr3Si7 reveal emergent neutral excitations, whose properties are sensitively changed by a field-driven transition between two antiferromagnetic phases. In the low-field phase, a significant violation of the Wiedemann-Franz law demonstrates that YbIr3Si7 is a charge insulator but a thermal metal. In the high-field phase, thermal conductivity exhibits a sharp drop below 300 mK, indicating a transition from a thermal metal into an insulator/semimetal driven by the magnetic transition. These results suggest that spin degrees of freedom directly couple to the neutral fermions, whose emergent Fermi surface undergoes a field-driven instability at low temperatures.

Quasiparticle Nodal Plane in the Fulde-Ferrell-Larkin-Ovchinnikov State of FeSe.

The Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) state, characterized by Cooper pairs condensed at finite momentum, has been a long-sought state that remains unresolved in many classes of fermionic systems, including superconductors and ultracold atoms. A fascinating aspect of the FFLO state is the emergence of periodic nodal planes in real space, but its observation is still lacking. Here we investigate the superconducting order parameter at high magnetic fields H applied perpendicular to the ab plane in a high-purity single crystal of FeSe. The heat capacity and magnetic torque provide thermodynamic evidence for a distinct superconducting phase at the low-temperature/high-field corner of the phase diagram. Despite the bulk superconductivity, spectroscopic-imaging scanning tunneling microscopy performed on the same crystal demonstrates that the order parameter vanishes at the surface upon entering the high-field phase. These results provide the first demonstration of a pinned planar node perpendicular to H, which is consistent with a putative FFLO state.

Acute severe alcohol-induced bronchial asthma.

We report the case of a severe bronchial asthma attack 15 minutes after the ingestion of food containing small amounts of alcohol. Although an ethanol inhalation test was negative, an acetaldehyde inhalation test was positive. Furthermore, it was discovered that the patient was homozygous for a mutation of the aldehyde dehydrogenase-2 (ALDH-2) gene. We subsequently diagnosed his attack as acute severe alcohol-induced asthma. Since bronchial asthma patients who are homozygous for mutant ALDH-2 genes are susceptible to acute severe alcohol-induced asthma attacks, strict clinical attention is thought a necessity.

Identification of another actin-related protein (Arp) 2/3 complex binding site in neural Wiskott-Aldrich syndrome protein (N-WASP) that complements actin polymerization induced by the Arp2/3 complex activating (VCA) domain of N-WASP.

Neural Wiskott-Aldrich syndrome protein (N-WASP) is an essential regulator of actin cytoskeleton formation via its association with the actin-related protein (Arp) 2/3 complex. It is believed that the C-terminal Arp2/3 complex-activating domain (verprolin homology, cofilin homology, and acidic (VCA) or C-terminal region of WASP family proteins domain) of N-WASP is usually kept masked (autoinhibition) but is opened upon cooperative binding of upstream regulators such as Cdc42 and phosphatidylinositol 4,5-bisphosphate (PIP2). However, the mechanisms of autoinhibition and association with Arp2/3 complex are still unclear. We focused on the acidic region of N-WASP because it is thought to interact with Arp2/3 complex and may be involved in autoinhibition. Partial deletion of acidic residues from the VCA portion alone greatly reduced actin polymerization activity, demonstrating that the acidic region contributes to Arp2/3 complex-mediated actin polymerization. Surprisingly, the same partial deletion of the acidic region in full-length N-WASP led to constitutive activity comparable with the activity seen with the VCA portion. Therefore, the acidic region in full-length N-WASP plays an indispensable role in the formation of the autoinhibited structure. This mutant contains WASP-homology (WH) 1 domain with weak affinity to the Arp2/3 complex, leading to activity in the absence of part of the acidic region. Furthermore, the actin comet formed by the DeltaWH1 mutant of N-WASP was much smaller than that of wild-type N-WASP. Partial deletion of acidic residues did not affect actin comet size, indicating the importance of the WH1 domain in actin structure formation. Collectively, the acidic region of N-WASP plays an essential role in Arp2/3 complex activation as well as in the formation of the autoinhibited structure, whereas the WH1 domain complements the activation of the Arp2/3 complex achieved through the VCA portion.

Requirement of the basic region of N-WASP/WAVE2 for actin-based motility.

WASP family proteins activate nucleation by the Arp2/3 complex, inducing rapid actin polymerization in vitro. Although the C-terminal portion of WASP family proteins (VCA) activates nucleation by the Arp2/3 complex in pure systems, we find that this fragment lacks activity in cell extracts. Thus, polystyrene beads coated with VCA did not move in brain cytosol, while beads coated with N-WASP or WAVE2 did move. The basic clusters between the WH1 domain and the CRIB domain of N-WASP were critical for movement since beads coated with N-WASP or WAVE2 constructs missing the basic clusters (Delta basic) also did not move. Furthermore, VCA and N-WASP/WAVE2 Delta basic constructs were much less able than wild-type N-WASP and WAVE2 to induce actin polymerization in cytosol. All of the proteins, with or without the basic domain, were potent activators of nucleation by purified Arp2/3 complex.

A novel neural Wiskott-Aldrich syndrome protein (N-WASP) binding protein, WISH, induces Arp2/3 complex activation independent of Cdc42.

We identified a novel adaptor protein that contains a Src homology (SH)3 domain, SH3 binding proline-rich sequences, and a leucine zipper-like motif and termed this protein WASP interacting SH3 protein (WISH). WISH is expressed predominantly in neural tissues and testis. It bound Ash/Grb2 through its proline-rich regions and neural Wiskott-Aldrich syndrome protein (N-WASP) through its SH3 domain. WISH strongly enhanced N-WASP-induced Arp2/3 complex activation independent of Cdc42 in vitro, resulting in rapid actin polymerization. Furthermore, coexpression of WISH and N-WASP induced marked formation of microspikes in Cos7 cells, even in the absence of stimuli. An N-WASP mutant (H208D) that cannot bind Cdc42 still induced microspike formation when coexpressed with WISH. We also examined the contribution of WISH to a rapid actin polymerization induced by brain extract in vitro. Arp2/3 complex was essential for brain extract-induced rapid actin polymerization. Addition of WISH to extracts increased actin polymerization as Cdc42 did. However, WISH unexpectedly could activate actin polymerization even in N-WASP-depleted extracts. These findings suggest that WISH activates Arp2/3 complex through N-WASP-dependent and -independent pathways without Cdc42, resulting in the rapid actin polymerization required for microspike formation.

Enhancement of branching efficiency by the actin filament-binding activity of N-WASP/WAVE2.

The actin-related protein (Arp) 2/3 complex is an essential regulator of de novo actin filament formation. Arp2/3 nucleates the polymerization of actin and creates branched actin filaments when activated by Arp2/3-complex activating domain (VCA) of Wiskott-Aldrich syndrome proteins (WASP family proteins). We found that the branching of actin filaments on pre-existing ADP filaments mediated by the Arp2/3 complex is twice as efficient when Arp2/3 was activated by wild-type neural WASP (N-WASP) or WASP-family verprolin-homologous protein (WAVE) 2 than when activated by the VCA domain alone. By contrast, there was no difference between wild-type N-WASP or WAVE2 and VCA in the branching efficiency on de novo filaments, which are thought to consist mainly of ADP-phosphate filaments. This increased branching efficiency on ADP filaments is due to the basic region located in the center of N-WASP and WAVE2, which was found to associate with ADP actin filaments. Actin filaments and phosphatidylinositol bisphosphate (PIP2) associate with N-WASP at different sites. This association of N-WASP and WAVE2 with actin filaments enhanced recruitment of Arp2/3 to the pre-existing filaments, presumably leading to efficient nucleation and branch formation on pre-existing filaments. These data together suggest that the actin filament binding activity of N-WASP and WAVE2 in the basic region increases the number of barbed ends created on pre-existing filaments. Efficient branching on ADP filaments may be important for initiation of actin-based motility.

IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling.

Neural Wiskott-Aldrich syndrome protein (N-WASP) functions in several intracellular events including filopodium formation, vesicle transport and movement of Shigella frexneri and vaccinia virus, by stimulating rapid actin polymerization through the Arp2/3 complex. N-WASP is regulated by the direct binding of Cdc42 (refs 7, 8), which exposes the domain in N-WASP that activates the Arp2/3 complex. A WASP-related protein, WAVE/Scar, functions in Rac-induced membrane ruffling; however, Rac does not bind directly to WAVE, raising the question of how WAVE is regulated by Rac. Here we demonstrate that IRSp53, a substrate for insulin receptor with unknown function, is the 'missing link' between Rac and WAVE. Activated Rac binds to the amino terminus of IRSp53, and carboxy-terminal Src-homology-3 domain of IRSp53 binds to WAVE to form a trimolecular complex. From studies of ectopic expression, we found that IRSp53 is essential for Rac to induce membrane ruffling, probably because it recruits WAVE, which stimulates actin polymerization mediated by the Arp2/3 complex.

Two tandem verprolin homology domains are necessary for a strong activation of Arp2/3 complex-induced actin polymerization and induction of microspike formation by N-WASP.

All WASP family proteins share a common C terminus that consists of the verprolin homology domain (V), cofilin homology domain (C), and acidic region (A), through which they activate Arp2/3 complex-induced actin polymerization. In this study, we characterized the Arp2/3 complex-mediated actin polymerization activity of VCA fragments of all of the WASP family proteins: WASP, N-WASP, WAVE1, WAVE2, and WAVE3. All of the VCA fragments stimulated the nucleating activity of Arp2/3 complex. Among them, N-WASP VCA, which possesses two tandem V motifs, had a more potent activity than other VCA proteins. The chimeric protein experiments revealed that the V motif was more important to the activation potency than the CA region; two V motifs were required for full activity of N-WASP. COS7 cells overexpressing N-WASP form microspikes in response to epidermal growth factor. However, when a chimeric protein in which the VCA region of N-WASP is replaced with WAVE1 VCA was overexpressed, microspike formation was suppressed. Interestingly, when the N-WASP VCA region was replaced with WAVE1 VCA, having two V motifs, this chimeric protein could induce microspike formation. These results indicate that strong activation of Arp2/3 complex by N-WASP is mainly caused by its two tandem V motifs, which are essential for actin microspike formation.

[Asthma death among adults in Japan 1995-1997. Analysis of 295 cases reported questionnaires sent to hospitals with more than 100 beds. Asthma Death Investigation Committee].

To clarify recent trends in adult asthma mortality, the Asthma Death Investigation Committee of Japan studied the clinical characteristics of 295 patients who died of asthma between 1995 and 1997. Males were slightly more than females among the death cases. Approximately half of the patients ranged in age from 60 to 79 years. Tendency to increase of death among young male adults continued. One third of the patient deaths involved the asphyxic type, while status asthmaticus was the cause death in 21.9%. Half of the asthmatics died in hospitals or emergency rooms, and places where the fatal attacks occurred were mainly patients' houses. The main cause fatal asthma attacks was respiratory infection, followed by fatigue, stress, and discontinuation of medication. Most of the patients were classified moderate or severe type of asthma 1 month before death. Histories of life-threatening attacks and hospitalization due to severe attacks, irregular visits to the hospital, low compliance, and insufficiency of corticosteroid treatment were suggested as the main risk factors in adult asthma deaths.

Profilin is required for sustaining efficient intra- and intercellular spreading of Shigella flexneri.

The ability of Shigella to mediate actin-based motility within the host cell is a prominent pathogenic feature of bacillary dysentery. The ability is dependent on the interaction of VirG with neural Wiskott-Aldrich syndrome protein (N-WASP), which in turn mediates recruitment of Arp2/3 complex and several actin-related proteins. In the present study, we show that profilin I is essential to the rapid movement of Shigella in epithelial cells, for which the capacity of profilin to interact with G-actin and N-WASP is critical. In COS-7 cells overexpressing either mutated profilin H119E, which failed to bind G-actin, or H133S, which is unable to interact with poly-l-proline, Shigella motility was significantly inhibited. Similarly, depletion of profilin from Xenopus egg extracts resulted in a decrease in bacterial motility that was completely rescued by adding back profilin I but not H119E or H133S. In COS-7 cells overexpressing a N-WASP mutant lacking the proline-rich domain (Deltap) unable to interact with profilin, the actin tail formation of intracellular Shigella was inhibited. In N-WASP-depleted extracts, addition of Deltap but not full-length N-WASP was unable to restore the bacterial motility. Furthermore, in a plaque formation assay with Madin-Darby canine kidney cell monolayers infected by Shigella, Madin-Darby canine kidney cells stably expressing H119E, H133S, or Deltap reduced the bacterial cell-to-cell spreading. These results indicate that profilin I associated with N-WASP is an essential host factor for sustaining efficient intra- and intercellular spreading of Shigella.

Compensatory head posture changes in patients with obstructive sleep apnea.

The upper airway narrowing and changes in head posture and their relationship with apnea severity in patients with obstructive sleep apnea (OSA) were investigated. In 86 male OSA patients and 37 healthy men, one-night polysomnographic examination was performed and a lateral cephalogram by digital image processing system was taken in each subject. Fifteen variables concerning the upper airway dimensions, area and head postures were measured by using a computer software (NIH Image). The results showed that upper airway dimensions in the OSA group at all levels were significantly smaller than those in the control group and the results hold true when the age and body mass index were well controlled in these two groups. Significant forward inclination of the cervical column was found in the patients with an apnea index (AI) greater than 35 episodes/h. And changes in the head posture variables in the whole study group were significantly correlated with AI and airway dimensions at various levels. It was suggested that there exist significant and extensive upper airway narrowing in OSA patients even in upright position and awake state; And as the apnea severity progresses, patients may assume certain compensatory head postures in an attempt to maintain an adequate airway patency.

[A study of the long-term effectiveness of an outpatient pulmonary rehabilitation program].

Pulmonary rehabilitation is one of the most important components of comprehensive care for patients with significant disability due to chronic respiratory failure. Because pulmonary rehabilitation has not been popular in Japan, the long-term effectiveness of pulmonary rehabilitation has rarely been reported. We therefore examined the long-term effectiveness of an outpatient pulmonary rehabilitation program for patients with chronic respiratory failure. Our program was composed of a once-a-week introduction program for 2 months and a support program that was continued every 4 weeks as long as possible. Thirty stable patients with chronic respiratory failure were enrolled in the program; 21 patients (COPD: 15, lung complications of tuberculosis: 6) completed the 9-week introduction program and the ensuing 6-month support program. Good compliance with the home training regimen was maintained during the period. The introduction program significantly alleviated dyspnea (Fletcher's grade: 3.3 to 3.0, p < 0.01) and improved the data for activity (Spector's score: 5.3 to 5.8, p < 0.01) and 6-minute walking distance (319 to 384 m, p < 0.01). These benefits were sustained during the 6-month support program. We concluded that outpatient pulmonary rehabilitation can alleviate dyspnea and improve the activity and exercise tolerance of patients with chronic respiratory failure, and that the effectiveness of training can be well maintained with a minimal support program.

Distinct roles of profilin in cell morphological changes: microspikes, membrane ruffles, stress fibers, and cytokinesis.

Here we report the functional importance of profilin in various actin-mediated morphological changes using H119E mutant profilin I, which is deficient only in actin binding. In the case of actin-protrusive structures from the plasma membrane, H119E-profilin was shown to suppress the formation of Cdc42-induced actin microspikes and Rac-induced membrane ruffles. Conversely, Rho-induced stress fiber formation seemed to occur independently of H119E-profilin introduction. Furthermore, H119E-profilin blocked cleavage furrow ingression and subsequent adhesion to the substratum during cell division, a process in which actin plays indispensable roles.

Identification of two human WAVE/SCAR homologues as general actin regulatory molecules which associate with the Arp2/3 complex.

WAVE/SCAR protein was identified as a protein which has similarity to WASP and N-WASP, especially in its C terminal. Recently, WAVE/SCAR protein has been shown to cooperate with the Arp2/3 complex, a nucleation core for actin polymerization in vitro. However, in spite of its general function, WAVE/SCAR expression is mainly restricted to the brain, suggesting the existence of related molecule(s). We here identified two human WAVE/SCAR homologues, which cover other organs. We named the original WAVE1 and newly identified ones WAVE2 and WAVE3. WAVE2 had a very wide distribution with strong expression in peripheral blood leukocytes and mapped on chromosome Xp11.21, next to the WASP locus. WAVE3 and WAVE1 had similar distributions. WAVE3 was strongly expressed in brain and mapped on chromosome 13q12. WAVE1 was mapped on chromosome 6q21-22. Ectopically expressed WAVE2 and WAVE3 induced actin filament clusters in a similar manner with WAVE1. These actin cluster formations were suppressed by deletion of their C-terminal VPH (verproline homology)/WH2 (WASP homology 2) domain. Further, WAVE2 and WAVE3 associate with the Arp2/3 complex as does WAVE1. Our identification of WAVE homologues suggests that WAVE family proteins have general function for regulating the actin cytoskeleton in many tissues.

[Management of mycobacteriosis in general hospital without isolation ward for tuberculosis patients. 4. Actual status of the management of tuberculosis patients in a university hospital without isolation wards for infectious diseases].

We retrospectively evaluated clinical findings and the actual status of management of 69 tuberculosis patients admitted to the Fujita Health University Hospital, a hospital without isolation wards for infectious diseases, between 1991 and 1994. Forty-nine patients were smear-positive and 22 patients were smear-negative and culture-positive. Twenty-five cases (36.2%) were classified as type II (cavitary) and 29 cases (42.0%) as type III (non-cavitary) according to the GAKKAI classification of findings on chest X-ray films for pulmonary tuberculosis. Physicians in charge did not diagnose twenty-four patients (34.8%) as tuberculosis on admission. Physicians in charge tended not to suspect smear-negative patients of tuberculosis. Most of the patients with cavities on their chest X-ray films were strongly suspected of tuberculosis on admission, but in some of them, tuberculosis was not considered at all. Smear-positive patients with strongly suspected tuberculosis were diagnosed with the disease within three hospital days, while it took about three weeks in patients who were not considered as tuberculosis on admission to be diagnosed as tuberculosis. In the case of smear-negative patients, it took about one month and two months respectively to diagnose the case as tuberculosis. About half (51.1%) of the smear-positive patients were admitted and treated in single-bed rooms while 44.7% were attended in multiple-bed rooms for 11 days before they were transferred to single-bed rooms. When acid-fast bacilli were detected, 57.4% of the smear-positive patients were transferred to hospitals with isolation wards for infectious diseases, while the remaining smear-positive patients were treated in single-bed rooms at the university hospital. About one-third (31.7%) of the smear-negative patients had already left the hospital when specimens were found to be culture positive for tubercle bacilli. In conclusion, it is utmost important for physicians to suspect to tuberculosis for the early diagnosis of the disease.

Cephalometric abnormalities in non-obese and obese patients with obstructive sleep apnoea.

The aim of this work was to comprehensively evaluate the cephalometric features in Japanese patients with obstructive sleep apnoea (OSA) and to elucidate the relationship between cephalometric variables and severity of apnoea. Forty-eight cephalometric variables were measured in 37 healthy males and 114 male OSA patients, who were classed into 54 non-obese (body mass index (BMI) <27 kg x m(-2), apnoea-hypopnoea index (AHI)=25.3+/-16.1 events x h(-1)) and 60 obese (BMI > or = 27 kg x m(-2), AHI=45.6+/-28.0 events h(-1)) groups. Diagnostic polysomnography was carried out in all of the OSA patients and in 19 of the normal controls. The non-obese OSA patients showed several cephalometric defects compared with their BMI-matched normal controls: 1) decreased facial A-P distance at cranial base, maxilla and mandible levels and decreased bony pharynx width; 2) enlarged tongue and inferior shift of the tongue volume; 3) enlarged soft palate; 4) inferiorly positioned hyoid bone; and 5) decreased upper airway width at four different levels. More extensive and severe soft tissue abnormalities with a few defects in craniofacial bony structures were found in the obese OSA group. For the non-obese OSA group, the stepwise regression model on AHI was significant with two bony structure variables as determinants: anterior cranial base length (S-N) and mandibular length (Me-Go). Although the regression model retained only linear distance between anterior vertebra and hyoid bone (H-VL) as an explainable determinant for AHI in the obese OSA group, H-VL was significantly correlated with soft tissue measurements such as overall tongue area (Ton), inferior tongue area (Ton2) and pharyngeal airway length (PNS-V). In conclusion, Japanese obstructive sleep apnoea patients have a series of cephalometric abnormalities similar to those described in Caucasian patients, and that the aetiology of obstructive sleep apnoea in obese patients may be different from that in non-obese patients. In obese patients, upper airway soft tissue enlargement may play a more important role in the development of obstructive sleep apnoea, whereas in non-obese patients, bony structure discrepancies may be the dominant contributing factors for obstructive sleep apnoea.