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The present study investigated the expression and role of ROR2 in small cell lung cancer (SCLC). To examine the expression of ROR2, 27 surgically resected SCLC tissue samples were immunostained for ROR2. Sixteen tissue samples were positive and some showed intratumor heterogeneity in staining intensity. The heterogeneity of ROR2 expression was also observed in tumor tissues from a PDX model of SCLC, in which there were cells with high ROR2 expression (ROR2

Gyrification patterns reflect early neurodevelopment and could be highly heritable. While some discrepant results have been reported, the most consistent finding was that patients with obsessive-compulsive disorder showed altered gyrification patterns in the orbitofrontal cortex. Nevertheless, no study has investigated the alterations in gyrification in unaffected first-degree relatives of patients with obsessive-compulsive disorder. We measured local gyrification by the FreeSurfer software in 23 unaffected first-degree relatives of patients with obsessive-compulsive disorder and 52 healthy control participants. We explored differences in the local gyrification index using vertex-wise whole-brain analysis and a region of interest-based approach in the medial and lateral orbitofrontal cortex. There was no significant difference in the local gyrification index between the 2 groups in the vertex-wise whole-brain analysis. Region of interest analyses showed that, compared with healthy controls, first-degree relatives showed significantly reduced local gyrification index in the left medial and lateral orbitofrontal cortex. A negative correlation was observed between the reduced local gyrification index in lateral orbitofrontal cortex and the subclinical anxiety scores of first-degree relatives. Our results showed that first-degree relatives of patients with obsessive-compulsive disorder had an altered local gyrification index in the orbitofrontal cortex. Especially, reduced local gyrification index in lateral orbitofrontal cortex associated with subclinical anxiety symptom could be a potential neurodevelopmental marker for the illness onset.

Neuroendocrine (NE) differentiation has been histochemically detected in normal and cancer tissues and cells. Immunohistochemical analyses have provided a more detailed understanding of NE biology and pathology. Pulmonary NE cells are a rare lung epithelial type, and small cell carcinoma of the lung (SCLC) is a high-grade NE tumor. Pulmonary NE and SCLC cells share common mechanisms for NE differentiation. Neural or NE cell lineage-specific transcription factors, such as achaete-scute homologue 1 (Ascl1) and insulinoma-associated protein 1 (INSM1), are crucial for the development of pulmonary NE cells, and NE differentiation is influenced by the balance between Ascl1 and the suppressive neural transcription factor, hairy-enhancer of split 1, a representative target molecule of the Notch signaling pathway. In this review, we discuss the importance of Ascl1 and INSM1 in identifying pulmonary NE and SCLC cells and introduce Ascl1-related molecules detected by comparative RNA-sequence analyses. The molecular classification of SCLC based on the expression of lineage-specific transcription or co-transcription factors, including ASCL1, NEUROD1, POU2F3, and YAP1, was recently proposed. We attempted to characterize these 4 SCLC subtypes using integrated immunohistochemical studies, which will provide insights into the molecular characteristics of these subtypes and clarify the inter- and intratumor heterogeneities of SCLC.

Previous studies have suggested that specific fronto-striatal circuits are associated with impaired motor response inhibition in patients with obsessive-compulsive disorder (OCD) and their relatives. However, no study has investigated the underlying resting-state network associated with motor response inhibition in the unaffected first-degree relatives of patients with OCD. We measured motor response inhibition using stop-signal task, and obtained resting-state fMRI in 23 first-degree relatives and 52 healthy control participants. We explored the group differences in the functional network from seed regions-of-interest (ROIs) associated with motor response inhibition abilities. We used the inferior frontal gyrus (IFG) and pre-supplementary motor area (pre-SMA) as seed-ROIs. A significant group difference was observed in functional connectivity between the pre-SMA and inferior parietal lobule. In the relative group, reduced functional connectivity between these areas was associated with a longer stop-signal reaction time. Additionally, relatives showed significantly greater functional connectivity between the IFG and SMA, precentral, and postcentral areas. Our results could provide new insights into the resting-state neural activity of the pre-SMA underlying impaired motor response inhibition of unaffected first-degree relatives. In addition, our results suggested that relatives have an altered connectivity of the sensorimotor region, similar to that of patients with OCD shown in previous literature.

Tissue engineers have utilized a variety of three-dimensional (3D) scaffolds for controlling multicellular dynamics and the resulting tissue microstructures. In particular, cutting-edge microfabrication technologies, such as 3D bioprinting, provide increasingly complex structures. However, unpredictable microtissue detachment from scaffolds, which ruins desired tissue structures, is becoming an evident problem. To overcome this issue, we elucidated the mechanism underlying collective cellular detachment by combining a new computational simulation method with quantitative tissue-culture experiments. We first quantified the stochastic processes of cellular detachment shown by vascular smooth muscle cells on model curved scaffolds and found that microtissue morphologies vary drastically depending on cell contractility, substrate curvature, and cell-substrate adhesion strength. To explore this mechanism, we developed a new particle-based model that explicitly describes stochastic processes of multicellular dynamics, such as adhesion, rupture, and large deformation of microtissues on structured surfaces. Computational simulations using the developed model successfully reproduced characteristic detachment processes observed in experiments. Crucially, simulations revealed that cellular contractility-induced stress is locally concentrated at the cell-substrate interface, subsequently inducing a catastrophic process of collective cellular detachment, which can be suppressed by modulating cell contractility, substrate curvature, and cell-substrate adhesion. These results show that the developed computational method is useful for predicting engineered tissue dynamics as a platform for prediction-guided scaffold design.

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also known as WWTR1) are core downstream effectors of the Hippo pathway, which is involved in diverse biological processes. The oncogenic effects of YAP and TAZ in non-small cell lung cancer (NSCLC) have recently been reported; however, their roles in SCLC remain unclear. Immunohistochemistry (IHC) on lung cancer tissues and Western blotting (WB) on lung cancer cell lines were performed to examine the expression of YAP1. Genome editing using CRISPR/Cas9 was then used to knockout the YAP1 gene in the H69AR cell line. An RNA-sequence analysis, gene ontology (GO) analysis, WB, cell counting assay, invasion assays, and xenograft studies were conducted on these cells to investigate the biological roles of YAP1. IHC revealed that insulinoma-associated protein 1 was expressed in most cases (28 out of 32 cases), while only four cases expressed YAP1. The knockout of YAP1 in H69AR cells, a chemically induced SCLC-Y subtype, reduced cell proliferation and invasion capacity and restored drug sensitivity. Xenograft assays revealed that the knockout of YAP1 suppressed cell proliferation. Tumor tissues showed the expression of neuroendocrine markers and a low Ki-67 index. In SCLC, YAP1 plays an important role in biological functions, such as cell proliferation, EMT, drug sensitivity, and neuroendocrine differentiation.

We report an experimental setup for simultaneously measuring specific heat and thermal conductivity in feedback-controlled pulsed magnetic fields of 50 msec duration at cryogenic temperatures. A stabilized magnetic field pulse obtained by the feedback control, which dramatically improves the thermal stability of the setup and sample, is used in combination with the flash method to obtain absolute values of thermal properties up to 37.2 T in the 2 K to 16 K temperature range. We describe the experimental setup and demonstrate the performance of the present method with measurements on single crystal samples of the geometrically frustrated quantum spin-dimer system SrCu$_2$(BO$_3$)$_2$. Our proof-of-principle results show excellent agreement with data taken using a standard steady-state method, confirming the validity and convenience of the present approach., Comment: 9 pages, 7 figures

We have successfully synthesized new Ru4+ double perovskite oxides SrLaInRuO6 and SrLaGaRuO6, which are expected to be a spin–orbit coupled Jeff = 0 Mott insulating ground state. Their magnetic susceptibility is much significant than that expected for a single Ru4+ ion for which exchange coupling with other ions is negligible. Their isothermal magnetization process suggests that there are about 20 percent isolated spins. These origins would be the Ru3+/Ru5+ magnetic defects, while the regular Ru4+ sites remain nonmagnetic. Moreover, SrLaGaRuO6 shows a spin-glass-like magnetic transition at low temperatures, probably caused by isolated spins. The observed spin-glass can be interpreted by the analogy of a dilute magnetic alloy, which can be seen as a precursor to the mobile Jeff = 1 exciton as a dispersive mode as predicted.

Quasi-zero-dimensional antiferromagnets with weakly coupled clusters of multiple spins can provide an excellent platform for exploring exotic quantum states of matter. Here, we report the synthesis and the characterization of a copper-based insulating antiferromagnet, K(NbO)Cu4(PO4)4. Single-crystal X-ray diffraction measurements reveal that the crystal structure belongs to the tetragonal space group P4/nmm, in which Cu2+ ions align to form a quasi-two-dimensional layer of spin-1/2 coupled square tetramers. The structure is quasi-isostructural to recently reported magnetoelectric antiferromagnets, A(TiO)Cu4(PO4)4 (A = Ba, Sr, and Pb) with the P4212 space group. Despite their structural similarities, whereas the antiferromagnetic transition in A(TiO)Cu4(PO4)4 produces conventional anomalies in magnetization and heat capacity, that in K(NbO)Cu4(PO4)4 has several unusual features such as an upturn in magnetic susceptibility and a very weak specific heat anomaly that corresponds to a spin entropy release as small as 3%. These results indicate that the magnetism of K(NbO)Cu4(PO4)4 is far different from that of A(TiO)Cu4(PO4)4 and suggest that the ground state is very close to a quantum nonmagnetic singlet state. The origin of the distinct magnetism in K(NbO)Cu4(PO4)4 is discussed in terms of structural modifications of a Cu4O12 unit forming a square tetramer. Our study demonstrates that the present material family, represented by an extended chemical formula A(BO)Cu4(PO4)4 (AB = KNb, BaTi, SrTi, and PbTi), has broad chemical controllability of their magnetism. This makes this system an attractive material platform to study the physics of quantum spin-1/2 coupled square tetramers.

Observation of a quantum spin liquid (QSL) state is one of the most important goals in condensed-matter physics, as well as the development of new spintronic devices that support next-generation industries. The QSL in two dimensional quantum spin systems is expected to be due to geometrical magnetic frustration, and thus a kagome-based lattice is the most probable playground for QSL. Here, we report the first experimental results of the QSL state on a square-kagome quantum antiferromagnet, KCu6AlBiO4(SO4)5Cl. Comprehensive experimental studies via magnetic susceptibility, magnetisation, heat capacity, muon spin relaxation (μSR), and inelastic neutron scattering (INS) measurements reveal the formation of a gapless QSL at very low temperatures close to the ground state. The QSL behavior cannot be explained fully by a frustrated Heisenberg model with nearest-neighbor exchange interactions, providing a theoretical challenge to unveil the nature of the QSL state., There exist many theoretical models of frustrated quantum magnetism, most of which lack convincing experimental realisations. Here the authors combine several experimental methods to argue that KCu6AlBiO4(SO4)5Cl behaves as a square-kagome-lattice quantum Heisenberg antiferromagnet.

ASCL1 is one of the master transcription factors of small cell lung carcinoma (SCLC). To investigate the significance of ASCL1 in pulmonary neuroendocrine carcinoma, we performed 2 comparative RNA-seq studies between H69 (ASCL1-positive, classical type SCLC) and H69AR (ASCL1-negative, variant type SCLC) and between ASCL1-transfected A549 adenocarcinoma cell lines (A549(ASCL1+) cell lines) and A549(control) cell lines. RNA-seq analyses revealed that 940 genes were significantly different between the H69 and H69AR cell lines, and 728 between the A549(ASCL1+) and A549(control) cell lines. In total, 120 common genes between these analyses were selected as candidate ASCL1-related genes, and included genes with various cellular functions, such as neural development, secretion, growth, and morphology. Their expression degrees in three classical and two variant SCLC cell lines, two A549(ASCL1+) and two A549(control) cell lines were subjected to quantitative PCR analyses. Since the candidate ASCL1-related genes were strongly expressed in the classical SCLC and A549(ASCL1+) cell lines and more weakly expressed in the variant SCLC and A549(control) cell lines, the ASCL1-related 7 molecules INSM1, ISL1, SYT4, KCTD16, SEZ6, MS4A8, and COBL were further selected. These molecules suggested diverse functions for A549(ASCL1+): INSM1 and ISL1 are transcription factors associated with neuroendocrine differentiation, while SYT4, KTCD16, and SEZ6 may be related to neurosecretory functions and MS4A8 and COBL to cell growth and morphology. An immunohistochemistry of these seven molecules was performed on lung carcinoma tissues and the xenotransplanted tumors of A549(ASCL1+), and they were preferentially and positively stained in ASCL1-postive tumor tissues.

Some preceding studies have provided evidence that hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitors have therapeutic potential against tubular interstitial fibrosis (TIF). Recently, transformation of renal interstitial fibroblasts (RIFs) into α-smooth muscle actin-positive myofibroblasts with loss of their hypoxia-inducible erythropoietin (EPO) expression has been hypothesized as the central mechanism responsible for TIF with renal anemia (the RIF hypothesis). These reports have suggested that HIF-PH inhibitors may suppress TIF via suppressing transformation of RIFs. However, the direct effect of HIF-PH inhibitors on transformation of RIFs has not been demonstrated because there has been no appropriate assay system. Here, we established a novel in vitro model of the transformation of RIFs. This model expresses key phenotypic changes such as transformation of RIFs accompanied by loss of their hypoxia-inducible EPO expression, as proposed by the RIF hypothesis. Using this model, we demonstrated that JTZ-951, a newly developed HIF-PH inhibitor, stabilized HIF protein in RIFs, suppressed transformation of RIFs, and maintained their hypoxia-inducible EPO expression. JTZ-951 also suppressed the expression of FGF2, FGF7, and FGF18, which are upregulated during transformation of RIFs. Furthermore, expression of Fgf2, Fgf7, and Fgf18 was correlated with TIF in an animal model of TIF. We also demonstrated that not only FGF2, which is a well-known growth-promoting factor, but also FGF18 promoted proliferation of RIFs. These data suggest that JTZ-951 has therapeutic potential against TIF with renal anemia. Furthermore, FGF2, FGF7, and FGF18, which faithfully reflect the anti-TIF effects of JTZ-951, have potential as TIF biomarkers.

Spin-1/2 maple leaf lattice antiferromagnets are expected to show interesting phenomena originating from frustration effects and quantum fluctuations. We report the hydrothermal synthesis of a powder sample of bluebellite Cu$_6$IO$_3$(OH)$_{10}$Cl as a first potential candidate. Magnetization and heat capacity measurements reveal moderate frustration with a Curie-Weiss temperature of $-35$ K, and a magnetic transition at $T_N$ = 17 K. Surprisingly, the magnetic susceptibility and heat capacity above $T_N$ are well reproduced by the Bonner-Fisher model, which suggests that a one-dimensional spin correlation with a magnetic interaction of 25 K occurs in the apparently two-dimensional lattice. This emergent one-dimensionality cannot be explained by orbital ordering or dimensional reduction due to geometrical frustration. We believe that there is an unknown mechanism to cause one-dimensionality in the spin-1/2 maple leaf lattice antiferromagnet.

Magnetic properties of an antiferromagnetic double perovskite oxide ${\mathrm{Ba}}_{2}{\mathrm{CaReO}}_{6}$, where ${\mathrm{Re}}^{6+}$ $(5{d}^{1})$ ions with large spin-orbit coupling are arranged on the face-centered-cubic lattice, are investigated using pulsed high magnetic field up to 66 T. Magnetization and magnetostriction measurements have revealed a magnetic field-induced phase transition at around 50 T. The phase transition accompanies a jump of magnetization and longitudinal magnetostriction of approximately $2\ifmmode\times\else\texttimes\fi{}{10}^{--4}$ with the change of power-law behavior, indicating sizable coupling between the electronic degrees of freedom and the lattice. The high-field phase exhibits a magnetic moment approximately 0.2 ${\ensuremath{\mu}}_{\mathrm{B}}$, which is close to the values observed in $5{d}^{1}$ double perovskite oxides with noncollinear magnetic structure. We argue that ${\mathrm{Ba}}_{2}{\mathrm{CaReO}}_{6}$ is an antiferromagnet that sits close to the phase boundary between the collinear and noncollinear phases, providing the target material for investigating the interplay between spin-orbital entangled electrons and magnetic field.

We have successfully synthesized new Ru

We have investigated the low-temperature magnetism of sodium superoxide (NaO2), in which spin, orbital, and lattice degrees of freedom are closely entangled. The magnetic susceptibility shows anomalies at T1 = 220 K and T2 = 190 K, which correspond well to the structural phase transition temperatures, and a sudden decrease below T3 = 34 K. At 4.2 K, the magnetization shows a clear stepwise anomaly around 30 T with a large hysteresis. In addition, the muon spin relaxation experiments indicate no magnetic phase transition down to T = 0.3 K. The inelastic neutron scattering spectrum exhibits magnetic excitation with a finite energy gap. These results confirm that the ground state of NaO2 is a spin-singlet state. To understand this ground state in NaO2, we performed Raman scattering experiments. All the Raman-active libration modes expected for the marcasite phase below T2 are observed. Furthermore, we find that several new peaks appear below T3. This directly evidences the low crystal symmetry, namely, the presence of the phase transition at T3.We conclude that the singlet ground state of NaO2 is due to the spin-Peierls instability.

We present a model compound with a spin-1/2 spatially anisotropic frustrated square lattice, in which three antiferromagnetic interactions and one ferromagnetic interaction are competing. We observe an unconventional gradual increase in the low-temperature magnetization curve reminiscent of the quantum critical behavior between gapped and gapless phases. In addition, the specific heat and electron spin resonance signals indicate one-dimensional characteristics. These results demonstrate quantum critical behavior associated with one dimensionalization caused by frustrated interactions in the spin-1/2 spatially anisotropic square lattice., Comment: 6 pages, 4 figures

Manipulating topological spin textures is a key for exploring unprecedented emergent electromagnetic phenomena. Whereas switching control of magnetic skyrmions, e.g., the transitions between a skyrmion-lattice phase and conventional magnetic orders, is intensively studied towards development of future memory device concepts, transitions among spin textures with different topological orders remain largely unexplored. Here we develop a series of chiral magnets MnSi1−xGex, serving as a platform for transitions among skyrmion- and hedgehog-lattice states. By neutron scattering, Lorentz transmission electron microscopy and high-field transport measurements, we observe three different topological spin textures with variation of the lattice constant controlled by Si/Ge substitution: two-dimensional skyrmion lattice in x = 0–0.25 and two distinct three-dimensional hedgehog lattices in x = 0.3–0.6 and x = 0.7–1. The emergence of various topological spin states in the chemical-pressure-controlled materials suggests a new route for direct manipulation of the spin-texture topology by facile mechanical methods., Manipulating topological spin textures are demanded for future spintronic devices, but knowledge about phase transitions among different spin textures remain limited. Here, Fujishiro and Kanazawa et al. report chemical-pressure-controlled phase transitions between different topological spin textures in chiral magnets MnSi1−xGex.

Search for a new quantum state of matter emerging in a crystal is one of recent trends in condensed matter physics. For magnetic materials, geometrical frustration and high magnetic field are two key ingredients to realize it: a conventional magnetic order is possibly destroyed by competing interactions (frustration) and is replaced by an exotic state that is characterized in terms of quasiparticles, that are magnons, and the magnetic field can control the density and chemical potential of the magnons. Here we show that a synthetic copper mineral, Cd-kapellasite, comprising a kagome lattice made of corner-sharing triangles of Cu2+ ions carrying spin-1/2 exhibits an unprecedented series of fractional magnetization plateaux in ultrahigh magnetic fields up to 160 T, which may be interpreted as crystallizations of emergent magnons localized on the hexagon of the kagome lattice. Our observation reveals a novel type of particle physics realized in a highly frustrated magnet., Comment: 9 pages, 10 figures

Background Association between long-term structural changes of grafted bone and outcomes of the implants is not clear. Purpose Morphometrical measurements and implant success were analyzed in subjects of particulate cellular bone and marrow (PCBM) reconstruction of the jawbone. Materials and methods Subjects were 30 implants in 13 patients from a series of 24 PCBM reconstruction cases. The cortical bone thickness and cancellous computed tomography (CT) radiodensity values were retrospectively analyzed from the CT data of 27 subjects. The cumulative success rate of the implants in the PCBM reconstructed cases (pure graft) was compared with that of 127 implants of 56 native bone cases and 42 implants of 28 bone augmentation (partial graft) cases. Results In areas of PCBM reconstruction, cancellous CT radiodensity values were significantly high immediately after the surgery, and subsequently the values became stable. Cortical thickness was significantly increased, but did not reach that of native bone. Implant success rates were statistically not different (P = 0.783) between the native bone (91.3%), the partially grafted bone (95.2%), and the PCBM reconstructed bone (93.3%). Conclusion Implants in pure grafted bone are mainly supported by cancellous bone, because cortical thickness remained thin for a long period of time.

Background It is gradually becoming clear that obsessive-compulsive disorder (OCD) patients have aberrant resting-state large-scale intrinsic networks of cingulo-opercular salience (SN), default mode (DMN), and front-parietal network (FPN). However, it remains unknown whether unaffected first-degree relatives of OCD patients have these alterations as a vulnerability marker to the disorder. Methods We performed resting-state functional magnetic resonance imaging (rsfMRI) scans of 47 medication-free OCD patients, 21 unaffected healthy first-degree relatives of OCD patients, and 62 healthy control (HC) participants. We explored differences between the three groups in the functional connectivity from SN (seeds: anterior-insula (AI) and dorsal anterior cingulate cortex (dACC)), DMN (seeds: medial prefrontal cortex (MPFC) and posterior parietal cortex (PCC)), and FPN (seeds: dorsolateral prefrontal cortex (DLPFC)). Results Compared to HC, both OCD patients and first-degree relatives showed significantly greater functional connectivity between AI and PCC and between DLPFC and the thalamus. Compared to first-degree relatives and HC, OCD patients showed reduced functional connectivity between PCC and DLPFC, and this altered functional connectivity was negatively correlated with anxiety and depressive symptom within OCD group. Conclusions OCD patients and unaffected first-degree relatives of OCD patients showed overlapping alterations in resting state functional connectivity between the regions of SN and DMN and between DLPFC and the thalamus. Our results suggested that alterations between large-scale intrinsic networks and within the dorsal cognitive cortico-striato-thalamo-cortical (CSTC) circuit could represent endophenotype markers of OCD.

When nanometric, noncoplanar spin textures with scalar spin chirality (SSC) are coupled to itinerant electrons, they endow the quasiparticle wavefunctions with a gauge field, termed Berry curvature, in a way that bears analogy to relativistic spin-orbit coupling (SOC). The resulting deflection of moving charge carriers is termed geometrical (or topological) Hall effect. Previous experimental studies modeled this signal as a real-space motion of wavepackets under the influence of a quantum-mechanical phase. In contrast, we here compare the modification of Bloch waves themselves, and of their energy dispersion, due to SOC and SSC. Using the canted pyrochlore ferromagnet Nd$_2$Mo$_2$O$_7$ as a model compound, our transport experiments and first-principle calculations show that SOC impartially mixes electronic bands with equal or opposite spin, while SSC is much more effective for opposite spin band pairs., 14 pages, 4 figures

Zinc finger, myeloproliferative, and mental retardation-type containing 3 (ZMYM3) is a highly conserved protein among vertebrates. Although it promotes DNA repair and moderate histone acetylation, the other functions of ZMYM3 remain unclear. We herein examined the physiological functions of ZMYM3 in human lung cancer using a ZMYM3-knockdown small cell lung cancer (SCLC) cell line. ZMYM3-knockdown SCLC cells grew slowly and the Ki-67 labeling index was lower in ZMYM3-knockdown cells than in mock cells. The subcutaneous tumors that formed after xenotransplantation into immunodeficient mice were slightly smaller in the ZMYM3-knockdown group than in the mock group. Furthermore, public RNA-sequencing data analyses showed similar RNA profiles between ZMYM3 and some cell proliferation markers. These results indicate that ZMYM3 promotes cell proliferation in human lung carcinomas, particularly SCLC.