RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis.

Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.

Nodeless electron pairing in CsV3Sb5-derived kagome superconductors.

The newly discovered kagome superconductors represent a promising platform for investigating the interplay between band topology, electronic order and lattice geometry1-9. Despite extensive research efforts on this system, the nature of the superconducting ground state remains elusive10-17. In particular, consensus on the electron pairing symmetry has not been achieved so far18-20, in part owing to the lack of a momentum-resolved measurement of the superconducting gap structure. Here we report the direct observation of a nodeless, nearly isotropic and orbital-independent superconducting gap in the momentum space of two exemplary CsV3Sb5-derived kagome superconductors-Cs(V0.93Nb0.07)3Sb5 and Cs(V0.86Ta0.14)3Sb5-using ultrahigh-resolution and low-temperature angle-resolved photoemission spectroscopy. Remarkably, such a gap structure is robust to the appearance or absence of charge order in the normal state, tuned by isovalent Nb/Ta substitutions of V. Our comprehensive characterizations of the superconducting gap provide indispensable information on the electron pairing symmetry of kagome superconductors, and advance our understanding of the superconductivity and intertwined electronic orders in quantum materials.

Publisher Correction: A weak topological insulator state in quasi-one-dimensional bismuth iodide.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A weak topological insulator state in quasi-one-dimensional bismuth iodide.

The major breakthroughs in understanding of topological materials over the past decade were all triggered by the discovery of the Z2-type topological insulator-a type of material that is insulating in its interior but allows electron flow on its surface. In three dimensions, a topological insulator is classified as either 'strong' or 'weak'1,2, and experimental confirmations of the strong topological insulator rapidly followed theoretical predictions3-5. By contrast, the weak topological insulator (WTI) has so far eluded experimental verification, because the topological surface states emerge only on particular side surfaces, which are typically undetectable in real three-dimensional crystals6-10. Here we provide experimental evidence for the WTI state in a bismuth iodide, ß-Bi4I4. Notably, the crystal has naturally cleavable top and side planes-stacked via van der Waals forces-which have long been desirable for the experimental realization of the WTI state11,12. As a definitive signature of this state, we find a quasi-one-dimensional Dirac topological surface state at the side surface (the (100) plane), while the top surface (the (001) plane) is topologically dark with an absence of topological surface states. We also find that a crystal transition from the ß-phase to the α-phase drives a topological phase transition from a nontrivial WTI to a normal insulator at roughly room temperature. The weak topological phase-viewed as quantum spin Hall insulators stacked three-dimensionally13,14-will lay a foundation for technology that benefits from highly directional, dense spin currents that are protected against backscattering.

Puddle formation and persistent gaps across the non-mean-field breakdown of superconductivity in overdoped (Pb,Bi)2Sr2CuO6+δ.

The cuprate high-temperature superconductors exhibit many unexplained electronic phases, but the superconductivity at high doping is often believed to be governed by conventional mean-field Bardeen-Cooper-Schrieffer theory1. However, it was shown that the superfluid density vanishes when the transition temperature goes to zero2,3, in contradiction to expectations from Bardeen-Cooper-Schrieffer theory. Our scanning tunnelling spectroscopy measurements in the overdoped regime of the (Pb,Bi)2Sr2CuO6+δ high-temperature superconductor show that this is due to the emergence of nanoscale superconducting puddles in a metallic matrix4,5. Our measurements further reveal that this puddling is driven by gap filling instead of gap closing. The important implication is that it is not a diminishing pairing interaction that causes the breakdown of superconductivity. Unexpectedly, the measured gap-to-filling correlation also reveals that pair breaking by disorder does not play a dominant role and that the mechanism of superconductivity in overdoped cuprate superconductors is qualitatively different from conventional mean-field theory.

Robust Weak Topological Insulator in the Bismuth Halide Bi_{4}Br_{2}I_{2}.

We apply a topological material design concept for selecting a bulk topology of 3D crystals by different van der Waals stackings of 2D topological insulator layers, and find a bismuth halide Bi_{4}Br_{2}I_{2} to be an ideal weak topological insulator (WTI) with the largest band gap (∼300 meV) among all the WTI candidates, by means of angle-resolved photoemission spectroscopy (ARPES), density functional theory (DFT) calculations, and resistivity measurements. Furthermore, we reveal that the topological surface state of a WTI is not "weak" but rather robust against external perturbations against the initial theoretical prediction by performing potassium deposition experiments. Our results vastly expand future opportunities for fundamental research and device applications with a robust WTI.

Fermi Surface Nesting Driving the RKKY Interaction in the Centrosymmetric Skyrmion Magnet Gd_{2}PdSi_{3}.

The magnetic skyrmions generated in a centrosymmetric crystal were recently first discovered in Gd_{2}PdSi_{3}. In light of this, we observe the electronic structure by angle-resolved photoemission spectroscopy and unveil its direct relationship with the magnetism in this compound. The Fermi surface and band dispersions are demonstrated to have a good agreement with the density functional theory calculations carried out with careful consideration of the crystal superstructure. Most importantly, we find that the three-dimensional Fermi surface has extended nesting which matches well the q vector of the magnetic order detected by recent scattering measurements. The consistency we find among angle-resolved photoemission spectroscopy, density functional theory, and the scattering measurements suggests the Ruderman-Kittel-Kasuya-Yosida interaction involving itinerant electrons to be the formation mechanism of skyrmions in Gd_{2}PdSi_{3}.

Broken Screw Rotational Symmetry in the Near-Surface Electronic Structure of AB-Stacked Crystals.

We investigate the electronic structure of 2H-NbS_{2} and h-BN by angle-resolved photoemission spectroscopy (ARPES) and photoemission intensity calculations. Although in bulk form, these materials are expected to exhibit band degeneracy in the k_{z}=π/c plane due to screw rotation and time-reversal symmetries, we observe gapped band dispersion near the surface. We extract from first-principles calculations the near-surface electronic structure probed by ARPES and find that the calculated photoemission spectra from the near-surface region reproduce the gapped ARPES spectra. Our results show that the near-surface electronic structure can be qualitatively different from the bulk electronic structure due to partially broken nonsymmorphic symmetries.

Hereditary thrombocythemia due to splicing donor site mutation of THPO in a Japanese family.

Thrombopoietin (THPO) is an essential factor for platelet production. Hereditary thrombocythemia (HT) is caused by a germline mutation of THPO, MPL, or JAK2 and is inherited in an autosomal-dominant manner. We identified a Japanese family with HT due to a point mutation of the splicing donor site of the THPO gene (THPO c.13 + 1G > A). Bone marrow biopsy showed increased megakaryocytes mimicking essential thrombocythemia. One affected family member developed chronic myeloid leukemia. We cloned the mutation and developed mutated and wild type THPO expression vectors. Molecular analysis showed that the mutation causes an exon 3 skipping transcript of THPO that abrogates a suppressive untranslated upstream open reading frame. Although the transcript levels of THPO mRNA were comparable, mutated transcripts were more efficiently translated and THPO protein expression was significantly higher than that of the wild type.

Senso-immunology: the hidden relationship between sensory system and immune system.

The primary sensory neurons involved in pain perception express various types of receptor-type ion channels at their nerve endings. These molecules are responsible for triggering neuronal excitation, translating environmental stimuli into pain signals. Recent studies have shown that acute nociception, induced by neuronal excitation, not only serves as a sensor for signaling life-threatening situations but also modulates our pathophysiological conditions. This modulation occurs through the release of neuropeptides by primary sensory neurons excited by nociceptive stimuli, which directly or indirectly affect peripheral systems, including immune function. Senso-immunology, an emerging research field, integrates interdisciplinary studies of pain and immunology and has garnered increasing attention in recent years. This review provides an overview of the systemic pathophysiological functions regulated by receptor-type ion channels, such as transient receptor potential (TRP) channels in primary sensory neurons, from the perspective of senso-immunology.

Configuration of two cysteine residues in a ring within a stapled Bim peptide affects the secondary structure and apoptotic activity.

Many reports have shown that stabilization of secondary structure by stapling functional peptides enhances the intracellular bioactivity. However, no report has discussed the correlation between stabilization and biological activity based on the configuration of amino acid residues used as anchors for stapling. To clarify this, we investigated the helix content and apoptotic efficiency of an apoptosis-inducing peptide, Bim, and four stapled Bim peptides containing stapling-related Cys residues introduced with different configurations within the sequence. The results demonstrated that the configuration of Cys residues in stapled Bim peptides affected the secondary structure and intracellular activity of the peptides, and furthermore, there was a correlation between these latter two variables.

Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.

BACKGROUND: In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. METHODS: We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. RESULTS: Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. CONCLUSIONS: This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.

Development and evaluation of a rapid one-step high sensitivity real-time quantitative PCR system for minor BCR-ABL (e1a2) test in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

OBJECTIVE: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.

Anomalous vortex liquid in charge-ordered cuprate superconductors.

The interplay between charge order and d-wave superconductivity in high-[Formula: see text] cuprates remains an open question. While mounting evidence from spectroscopic probes indicates that charge order competes with superconductivity, to date little is known about the impact of charge order on charge transport in the mixed state, when vortices are present. Here we study the low-temperature electrical resistivity of three distinctly different cuprate families under intense magnetic fields, over a broad range of hole doping and current excitations. We find that the electronic transport in the doping regime where long-range charge order is known to be present is characterized by a nonohmic resistivity, the identifying feature of an anomalous vortex liquid. The field and temperature range in which this nonohmic behavior occurs indicates that the presence of long-range charge order is closely related to the emergence of this anomalous vortex liquid, near a vortex solid boundary that is defined by the excitation current in the [Formula: see text] 0 limit. Our findings further suggest that this anomalous vortex liquid, a manifestation of fragile superconductivity with a suppressed critical current density, is ubiquitous in the high-field state of charge-ordered cuprates.

To teach is to learn twice, revisited: a qualitative study of how residents learn through teaching in clinical environments.

BACKGROUND: Teaching helps the teacher's own learning as a professional-as the saying goes, 'to teach is to learn twice'. Near-peer teaching in clinical practice has been shown to contribute to the development of both teaching skills and necessary competencies for doctors. Research on how near-peer teachers learn through their teaching roles has mainly focused on classroom learning. However, understanding how the phenomenon of 'teaching is learning twice' occurs in clinical settings and its influencing factors is important for the development of a quality workplace learning environment. Therefore, this study investigated how residents learn through teaching in clinical practice and the factors influencing this process. METHODS: This study's methodology is based on the constructivist grounded theory from a social constructivist perspective. Several teaching hospitals in Japan were included, and the study participants were post-graduate year 2 residents (PGY2s) from these hospitals. The interviews were recorded, transcribed into text, and analysed by the first author. RESULTS: From January 2016 to July 2022, 13 interviews were conducted with 11 PGY2s from nine educational hospitals. The PGY2s played diverse educational roles in clinical settings and learned competencies as physicians in almost all areas through such roles. We found that knowledge transfer and serving as role models stimulated PGY2s' intrinsic motivation, encouraged reflection on their own experiences, and promoted self-regulated learning. Further, educating about procedural skills and clinical reasoning prompted reflection on their own procedural skills and thought processes. Supporting post-graduate year 1 residents' reflections led to the refinement of PGY2s' knowledge and thought processes through the verbal expression of their learning experiences. Such processes required the formation of a community of practice. Thus, education promoted learning through reflection and clarified the expert images of themselves that PGY2s envisaged. CONCLUSIONS: The study found that residents acquire various physician competencies through multiple processes by teaching as near-peer teachers in clinical settings, that a community of practice must be formed for near-peer teaching to occur in a clinical setting, and that teaching brings learning to those who teach by promoting reflection and helping them envision the professionals they aim to be.

Clinical utility of genomic profiling of AML using paraffin-embedded bone marrow clots: HM-SCREEN-Japan 01.

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3AR822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.

Humoral response to mRNA-based COVID-19 vaccine in patients with immune thrombocytopenia.

Data for COVID-19 vaccine response in patients with immune thrombocytopenia (ITP) are very limited. In a study of 28 patients with ITP, anti-severe acute respiratory syndrome coronavirus 2 spike antibody titres were measured after vaccination. The seroconversion rate for ITP patients was 91.3%, comparable to that in healthy controls (HCs). However, the antibody titre in ITP patients was significantly lower than that in HCs and declined with ageing. Furthermore, the antibody titre in ITP patients who received a minimum prednisolone dose of at least 5 mg/day at any time-point at or after initial vaccination was lower than that in other patients.

Subclinical minute FLT3-ITD clone can be detected in clinically FLT3-ITD-negative acute myeloid leukaemia at diagnosis.

Recent advances in next-generation sequencing (NGS) have enabled the detection of subclinical minute FLT3-ITD. We selected 74 newly diagnosed, cytogenetically normal acute myeloid leukaemia (AML) samples in which FLT3-ITD was not detected by gel electrophoresis. We sequenced them using NGS and found minute FLT3-ITDs in 19 cases. We compared cases with clinically relevant FLT3-ITD (n = 37), cases with minute FLT3-ITD (n = 19) and cases without detectable FLT3-ITD (n = 55). Molecular characteristics (location and length) of minute FLT3-ITD were similar to those of clinically relevant FLT3-ITD. Survival of cases with minute FLT3-ITD was similar to that of cases without detectable FLT3-ITD, whereas the relapse rate within 1 year after onset was significantly higher in cases with minute FLT3-ITD. We followed 18 relapsed samples of cases with clinically FLT3-ITD-negative at diagnosis. Two of 3 cases with minute FLT3-ITD relapsed with progression to clinically relevant FLT3-ITD. Two of 15 cases in which FLT3-ITD was not detected by NGS relapsed with the emergence of minute FLT3-ITD, and one of them showed progression to clinically relevant FLT3-ITD at the second relapse. We revealed the clonal dynamics of subclinical minute FLT3-ITD in clinically FLT3-ITD-negative AML. Minute FLT3-ITD at the initial AML can expand to become a dominant clone at relapse.

Multipole polaron in the devil's staircase of CeSb.

Rare-earth intermetallic compounds exhibit rich phenomena induced by the interplay between localized f orbitals and conduction electrons. However, since the energy scale of the crystal-electric-field splitting is only a few millielectronvolts, the nature of the mobile electrons accompanied by collective crystal-electric-field excitations has not been unveiled. Here, we examine the low-energy electronic structures of CeSb through the anomalous magnetostructural transitions below the Néel temperature, ~17 K, termed the 'devil's staircase', using laser angle-resolved photoemission, Raman and neutron scattering spectroscopies. We report another type of electron-boson coupling between mobile electrons and quadrupole crystal-electric-field excitations of the 4f orbitals, which renormalizes the Sb 5p band prominently, yielding a kink at a very low energy (~7 meV). This coupling strength is strong and exhibits anomalous step-like enhancement during the devil's staircase transition, unveiling a new type of quasiparticle, named the 'multipole polaron', comprising a mobile electron dressed with a cloud of the quadrupole crystal-electric-field polarization.

Semiconducting Electronic Structure of the Ferromagnetic Spinel HgCr_{2}Se_{4} Revealed by Soft-X-Ray Angle-Resolved Photoemission Spectroscopy.

We study the electronic structure of the ferromagnetic spinel HgCr_{2}Se_{4} by soft-x-ray angle-resolved photoemission spectroscopy (SX-ARPES) and first-principles calculations. While a theoretical study has predicted that this material is a magnetic Weyl semimetal, SX-ARPES measurements give direct evidence for a semiconducting state in the ferromagnetic phase. Band calculations based on the density functional theory with hybrid functionals reproduce the experimentally determined band gap value, and the calculated band dispersion matches well with ARPES experiments. We conclude that the theoretical prediction of a Weyl semimetal state in HgCr_{2}Se_{4} underestimates the band gap, and this material is a ferromagnetic semiconductor.