A combined small cell lung carcinoma patient with only small cell carcinoma components in mediastinal lymph node metastasis and chondrosarcoma-like components in liver metastasis.

A 69-year-old ex-smoker Japanese man presented with a left mediastinal lymph node and left upper lobe tumour. Bronchoscopic biopsy specimens from the enlarged left mediastinal lymph node and left upper lobe tumour revealed small cell lung carcinoma (SCLC). He was treated with first-line chemotherapy with carboplatin, etoposide, and atezolizumab for four courses and subsequent atezolizumab maintenance therapy. However, his left upper lobe lung tumour only increased in size, and left upper lobectomy revealed combined SCLC (adenocarcinoma and chondrosarcoma-like features). Four months after lobectomy, liver metastasis of chondrosarcoma-like features (similar to pathological findings of the left upper lobe tumour) were observed. Combined SCLC, including sarcomatous components, is rare and poorly responds to chemotherapy. The metastases of combined SCLC in this patient were of only one type of histological component, making diagnosis and treatment difficult. If treatment for SCLC responds inadequately, considering combined SCLC and actively re-examining histological diagnosis is necessary.

Automated neuronal reconstruction with super-multicolour Tetbow labelling and threshold-based clustering of colour hues.

Fluorescence imaging is widely used for the mesoscopic mapping of neuronal connectivity. However, neurite reconstruction is challenging, especially when neurons are densely labelled. Here, we report a strategy for the fully automated reconstruction of densely labelled neuronal circuits. Firstly, we establish stochastic super-multicolour labelling with up to seven different fluorescent proteins using the Tetbow method. With this method, each neuron is labelled with a unique combination of fluorescent proteins, which are then imaged and separated by linear unmixing. We also establish an automated neurite reconstruction pipeline based on the quantitative analysis of multiple dyes (QDyeFinder), which identifies neurite fragments with similar colour combinations. To classify colour combinations, we develop unsupervised clustering algorithm, dCrawler, in which data points in multi-dimensional space are clustered based on a given threshold distance. Our strategy allows the reconstruction of neurites for up to hundreds of neurons at the millimetre scale without using their physical continuity.

Nonlocal Spin Correlation as a Signature of Ising Anyons Trapped in Vacancies of the Kitaev Spin Liquid.

In the Kitaev chiral spin liquid, Ising anyons are realized as Z_{2} fluxes binding Majorana zero modes, which, however, are thermal excitations with finite decay rates. On the other hand, a lattice vacancy traps a Z_{2} flux even in the ground state, resulting in the stable realization of a Majorana zero mode in a vacancy. We demonstrate that spin-spin correlation functions between two vacancy sites exhibit long-range correlation arising from the fractionalized character of Majorana zero modes, in spite of the strong decay of bulk spin correlations. Remarkably, this nonlocal spin correlation does not decrease as the distance between two vacancy sites increases, signaling Majorana teleportation. Furthermore, we clarify that the nonlocal correlation can be detected electrically via the measurement of nonlocal conductance between two vacancy sites, which is straightforwardly utilized for the readout of Majorana qubits. These findings pave the way to the measurement-based quantum computation with Ising anyons trapped in vacancies of the Kitaev spin liquid.

Microglia Are Dispensable for Developmental Dendrite Pruning of Mitral Cells in Mice.

During early development, neurons in the brain often form excess synaptic connections. Later, they strengthen some connections while eliminating others to build functional neuronal circuits. In the olfactory bulb, a mitral cell initially extends multiple dendrites to multiple glomeruli but eventually forms a single primary dendrite through the activity-dependent dendrite pruning process. Recent studies have reported that microglia facilitate synapse pruning during the circuit remodeling in some systems. It has remained unclear whether microglia are involved in the activity-dependent dendrite pruning in the developing brains. Here, we examined whether microglia are required for the developmental dendrite pruning of mitral cells in mice. To deplete microglia in the fetal brain, we treated mice with a colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622, from pregnancy. Microglia were reduced by >90% in mice treated with PLX5622. However, dendrite pruning of mitral cells was not significantly affected. Moreover, we found no significant differences in the number, density, and size of excitatory synapses formed in mitral cell dendrites. We also found no evidence for the role of microglia in the activity-dependent dendrite remodeling of layer 4 (L4) neurons in the barrel cortex. In contrast, the density of excitatory synapses (dendritic spines) in granule cells in the olfactory bulb was significantly increased in mice treated with PLX5622 at postnatal day (P) 6, suggesting a role for the regulation of dendritic spines. Our results indicate that microglia do not play a critical role in activity-dependent dendrite pruning at the neurite level during early postnatal development in mice.

Effective Hand Rearing of Neonatal Mice for Developmental Studies.

Chronic manipulation in neonatal mice is a technical challenge, but it can achieve greater insights into how mice develop immediately after birth. However, these manipulations can often result in maternal rejection and consequently serious malnourishment and occasional death. Here, we describe a method to effectively hand rear mice to develop normally during the first post-natal week. In our experiments, we were able to negate the feeding deficiencies of anosmic mutant mice when compared to littermate controls. As a result, the delayed neuronal remodeling seen in maternally reared mutant mice was not seen in the hand-reared mutant mice. This methodology is user intensive but can be useful for a broad range of studies either requiring many interventions or one intervention that can result in maternal rejection or being outcompeted by healthy littermates.

Activity-dependent local protection and lateral inhibition control synaptic competition in developing mitral cells in mice.

In developing brains, activity-dependent remodeling facilitates the formation of precise neuronal connectivity. Synaptic competition is known to facilitate synapse elimination; however, it has remained unknown how different synapses compete with one another within a post-synaptic cell. Here, we investigate how a mitral cell in the mouse olfactory bulb prunes all but one primary dendrite during the developmental remodeling process. We find that spontaneous activity generated within the olfactory bulb is essential. We show that strong glutamatergic inputs to one dendrite trigger branch-specific changes in RhoA activity to facilitate the pruning of the remaining dendrites: NMDAR-dependent local signals suppress RhoA to protect it from pruning; however, the subsequent neuronal depolarization induces neuron-wide activation of RhoA to prune non-protected dendrites. NMDAR-RhoA signals are also essential for the synaptic competition in the mouse barrel cortex. Our results demonstrate a general principle whereby activity-dependent lateral inhibition across synapses establishes a discrete receptive field of a neuron.

Spin-Nernst Effect in Time-Reversal-Invariant Topological Superconductors.

We investigate the spin-Nernst effect in time-reversal-invariant topological superconductors, and show that it provides smoking-gun evidence for helical Cooper pairs. The spin-Nernst effect stems from asymmetric, in spin space, scattering of quasiparticles at nonmagnetic impurities, and generates a transverse spin current by the temperature gradient. Both the sign and the magnitude of the effect sensitively depend on the scattering phase shift at impurity sites. Therefore the spin-Nernst effect is uniquely suitable for identifying time-reversal-invariant topological superconducting orders.

Post hoc Correction of Chromatic Aberrations in Large-Scale Volumetric Images in Confocal Microscopy.

Over the last decade, tissue-clearing techniques have expanded the scale of volumetric fluorescence imaging of the brain, allowing for the comprehensive analysis of neuronal circuits at a millimeter scale. Multicolor imaging is particularly powerful for circuit tracing with fluorescence microscopy. However, multicolor imaging of large samples often suffers from chromatic aberration, where different excitation wavelengths of light have different focal points. In this study, we evaluated chromatic aberrations for representative objective lenses and a clearing agent with confocal microscopy and found that axial aberration is particularly problematic. Moreover, the axial chromatic aberrations were often depth-dependent. Therefore, we developed a program that is able to align depths for different fluorescence channels based on reference samples with fluorescent beads or data from guide stars within biological samples. We showed that this correction program can successfully correct chromatic aberrations found in confocal images of multicolor-labeled brain tissues. Our simple post hoc correction strategy is useful to obtain large-scale multicolor images of cleared tissues with minimal chromatic aberrations.

Electric Probe for the Toric Code Phase in Kitaev Materials through the Hyperfine Interaction.

The Kitaev model is a remarkable spin model with gapped and gapless spin liquid phases, which are potentially realized in iridates and α-RuCl_{3}. In the recent experiment of α-RuCl_{3}, the signature of a nematic transition to the gapped toric code phase, which breaks the C_{3} symmetry of the system, has been observed through the angle dependence of the heat capacity. We here propose a mechanism by which the nematic transition can be detected electrically. This is seemingly impossible because J_{eff}=1/2 spins do not have an electric quadrupole moment (EQM). However, in the second-order perturbation, the virtual state with a nonzero EQM appears, which makes the nematic order parameter detectable by nuclear magnetic resonance and Mössbauer spectroscopy. The purely magnetic origin of the EQM is different from conventional electronic nematic phases, allowing the direct detection of the realization of Kitaev's toric error-correction code.

BMPR-2 gates activity-dependent stabilization of primary dendrites during mitral cell remodeling.

Developing neurons initially form excessive neurites and then remodel them based on molecular cues and neuronal activity. Developing mitral cells in the olfactory bulb initially extend multiple primary dendrites. They then stabilize single primary dendrites while eliminating others. However, the mechanisms underlying selective dendrite remodeling remain elusive. Using CRISPR-Cas9-based knockout screening combined with in utero electroporation, we identify BMPR-2 as a key regulator for selective dendrite stabilization. Bmpr2 knockout and its rescue experiments show that BMPR-2 inhibits LIMK without ligands and thereby permits dendrite destabilization. In contrast, the overexpression of antagonists and agonists indicates that ligand-bound BMPR-2 stabilizes dendrites, most likely by releasing LIMK. Using genetic and FRET imaging experiments, we demonstrate that free LIMK is activated by NMDARs via Rac1, facilitating dendrite stabilization through F-actin formation. Thus, the selective stabilization of primary dendrites is ensured by concomitant inputs of BMP ligands and neuronal activity.

Arranging Diamagnetic Particles in a Modulated Magnetic Field Originating in Microelectromechanical Systems Compatible with an Integrated Circuit upon Halbach Array Magnet.

In this study, we attempted to expand the applicability of the mechanism for arranging diamagnetic particles in a modulated magnetic field. A Halbach array magnet was prototyped as a portable device for generating a high magnetic field. Despite the magnet being palm-size with dimensions of 50 × 50 × 20 mm, the magnetic field is 1.31 T at 1 mm from the surface. Additionally, an Si substrate on which an Fe thin film is formed and patterned to be compatible with the integrated circuit (IC)-utilizing the microelectromechanical systems process technology-is prototyped as a tool to generate a modulated magnetic field. Regarding the deposition condition of the Fe thin film, holes with diameters of 30 µm are arranged in an array at intervals of 60 µm, and the thickness is approximately 0.5 µm. Finally, a particle magnetic-adsorption experiment was conducted using the prototypes. The diamagnetic particles (diameter: 25 µm) dispersed in the paramagnetic surrounding medium were observed to be arranged in the hole portions. This result indicates that the microparticles are absorbed in their arbitrary positions by the modulated magnetic field. In the end, we succeeded in achieving the portability and implementation on IC for the particle arrangement magnetic mechanism.

Chiral Higgs Mode in Nematic Superconductors.

Nematic superconductivity with spontaneously broken rotation symmetry has recently been reported in doped topological insulators, M_{x}Bi_{2}Se_{3} (M=Cu, Sr, Nb). Here we show that the electromagnetic (EM) response of these compounds provides a spectroscopy for bosonic excitations that reflect the pairing channel and the broken symmetries of the ground state. Using quasiclassical Keldysh theory, we find two characteristic bosonic modes in nematic superconductors: the nematicity mode and the chiral Higgs mode. The former corresponds to the vibrations of the nematic order parameter associated with broken crystal symmetry, while the latter represents the excitation of chiral Cooper pairs. The chiral Higgs mode softens at a critical doping, signaling a dynamical instability of the nematic state towards a new chiral ground state with broken time reversal and mirror symmetry. Evolution of the bosonic spectrum is directly captured by EM power absorption spectra. We also discuss contributions to the bosonic spectrum from subdominant pairing channels to the EM response.

Effects of cognitive remediation on cognitive and social functions in individuals with schizophrenia.

Individuals with schizophrenia exhibit cognitive impairments, which are related to impairments in social functions. This study investigated the effects of cognitive remediation on cognitive, social, and daily living impairment. Participants were individuals with schizophrenia between 20 and 60 years old (N = 44). Participants were randomly assigned to two groups: a cognitive remediation intervention group and a non-intervention control group. The control group was provided with conventional drug therapy and either day care or occupational therapy. The intervention group was provided with the "neuropsychological educational approach to cognitive remediation" developed by Medalia and co-workers. We assessed cognitive functions using the brief assessment of cognition in schizophrenia (BACS), and evaluated social and daily living functions using the global assessment of functioning (GAF) scale. Significant group by time interaction effects indicated that verbal memory, working memory, attention, and executive function showed significantly greater improvement at post-intervention for the intervention group than the control group. Social and daily living function also improved in the intervention group and improvements were maintained one year after intervention. These preliminary findings indicate that the combination of cognitive remediation and psychiatric rehabilitation is effective for facilitating improvements in cognitive function and social and daily living functions in individuals with schizophrenia.

Negative Thermal Magnetoresistivity as a Signature of a Chiral Anomaly in Weyl Superconductors.

We propose that the chiral anomaly of Weyl superconductors gives rise to negative thermal magnetoresistivity induced by emergent magnetic fields, which are generated by vortex textures of order parameters or lattice strain. We establish this scenario by combining the argument based on Berry curvatures and the quasiclassical theory of the Eilenberger equation with quantum corrections arising from inhomogeneous structures. It is found that the chiral anomaly contribution of the thermal conductivity exhibits characteristic temperature dependence, which can be a smoking-gun signature of this effect.

Duplication and Variation in the Major Histocompatibility Complex Genes in Blakiston's Fish Owl, Bubo blakistoni.

The major histocompatibility complex (MHC) includes many genes that are essential for the adaptive immune system, and variation in the antigen binding site (ABS) is related to resistance against pathogens. In the present study, quantitative real-time PCR indicated a larger number of MHC gene copies in the endangered population of Blakiston's fish owl (Bubo blakistoni) than in five other owl species, and massively parallel pyrosequencing detected more MHC class IIß per individual alleles in B. blakistoni than in the other species. A chromosomal fluorescence in situ hybridization (FISH) analysis showed that the MHC class I and class IIß loci are closely linked on a single pair of microchromosomes, indicating that the MHC genes were tandemly duplicated in a limited chromosomal region. Because B. blakistoni has twice as many MHC genes as its sister species, the tawny fish owl (Bubo flavipes), the duplication of MHC genes occurred after these species diverged by speciation. A Bayesian molecular phylogenetic analysis showed that the DAB1 and DAB2 lineages of MHC class IIß alleles from various strigid species each formed a separate clade, indicating that the two allelic lineages preceded the radiation of Strigidae and evolved as paralogs. By contrast, the ABS sequences did not form distinct clades between DAB1 and DAB2 alleles but were intermixed, presumably due to gene conversion. Despite the low diversity of alleles per locus, B. blakistoni had many lineages of MHC class IIß alleles. Gene duplication increases variation in the MHC genes in this species, and could have facilitated adaptation in small populations.

Distorted Coarse Axon Targeting and Reduced Dendrite Connectivity Underlie Dysosmia after Olfactory Axon Injury.

The glomerular map in the olfactory bulb (OB) is the basis for odor recognition. Once established during development, the glomerular map is stably maintained throughout the life of an animal despite the continuous turnover of olfactory sensory neurons (OSNs). However, traumatic damage to OSN axons in the adult often leads to dysosmia, a qualitative and quantitative change in olfaction in humans. A mouse model of dysosmia has previously indicated that there is an altered glomerular map in the OB after the OSN axon injury; however, the underlying mechanisms that cause the map distortion remain unknown. In this study, we examined how the glomerular map is disturbed and how the odor information processing in the OB is affected in the dysosmia model mice. We found that the anterior-posterior coarse targeting of OSN axons is disrupted after OSN axon injury, while the local axon sorting mechanisms remained. We also found that the connectivity of mitral/tufted cell dendrites is reduced after injury, leading to attenuated odor responses in mitral/tufted cells. These results suggest that existing OSN axons are an essential scaffold for maintaining the integrity of the olfactory circuit, both OSN axons and mitral/tufted cell dendrites, in the adult.

Torsional Chiral Magnetic Effect in a Weyl Semimetal with a Topological Defect.

We propose a torsional response raised by a lattice dislocation in Weyl semimetals akin to a chiral magnetic effect; i.e., a fictitious magnetic field arising from a screw or edge dislocation induces a charge current. We demonstrate that, in sharp contrast to the usual chiral magnetic effect that vanishes in real solid state materials, the torsional chiral magnetic effect exists even for realistic lattice models, which implies the experimental detection of the effect via superconducting quantum interference device or nonlocal resistivity measurements in Weyl semimetal materials.

Super-Resolution Mapping of Neuronal Circuitry With an Index-Optimized Clearing Agent.

Super-resolution imaging deep inside tissues has been challenging, as it is extremely sensitive to light scattering and spherical aberrations. Here, we report an optimized optical clearing agent for high-resolution fluorescence imaging (SeeDB2). SeeDB2 matches the refractive indices of fixed tissues to that of immersion oil (1.518), thus minimizing both light scattering and spherical aberrations. During the clearing process, fine morphology and fluorescent proteins were highly preserved. SeeDB2 enabled super-resolution microscopy of various tissue samples up to a depth of >100 µm, an order of magnitude deeper than previously possible under standard mounting conditions. Using this approach, we demonstrate accumulation of inhibitory synapses on spine heads in NMDA-receptor-deficient neurons. In the fly medulla, we found unexpected heterogeneity in axon bouton orientations among Mi1 neurons, a part of the motion detection circuitry. Thus, volumetric super-resolution microscopy of cleared tissues is a powerful strategy in connectomic studies at synaptic levels.

Spatial and temporal variation at major histocompatibility complex class IIB genes in the endangered Blakiston's fish owl.

INTRODUCTION: Quantifying intraspecific genetic variation in functionally important genes, such as those of the major histocompatibility complex (MHC), is important in the establishment of conservation plans for endangered species. The MHC genes play a crucial role in the vertebrate immune system and generally show high levels of diversity, which is likely due to pathogen-driven balancing selection. The endangered Blakiston's fish owl (Bubo blakistoni) has suffered marked population declines on Hokkaido Island, Japan, during the past several decades due to human-induced habitat loss and fragmentation. We investigated the spatial and temporal patterns of genetic diversity in MHC class IIß genes in Blakiston's fish owl, using massively parallel pyrosequencing. RESULTS: We found that the Blakiston's fish owl genome contains at least eight MHC class IIß loci, indicating recent gene duplications. An analysis of sequence polymorphism provided evidence that balancing selection acted in the past. The level of MHC variation, however, was low in the current fish owl populations in Hokkaido: only 19 alleles were identified from 174 individuals. We detected considerable spatial differences in MHC diversity among the geographically isolated populations. We also detected a decline of MHC diversity in some local populations during the past decades. CONCLUSIONS: Our study demonstrated that the current spatial patterns of MHC variation in Blakiston's fish owl populations have been shaped by loss of variation due to the decline and fragmentation of populations, and that the short-term effects of genetic drift have counteracted the long-term effects of balancing selection.

Recent fragmentation of the endangered Blakiston's fish owl (Bubo blakistoni) population on Hokkaido Island, Northern Japan, Revealed by Mitochondrial DNA and Microsatellite Analyses.

INTRODUCTION: Blakiston's fish owl (Bubo blakistoni) was previously widespread on Hokkaido Island, Japan, but is now distributed only in limited forest areas. The population size on Hokkaido decreased during the 20th century due to reduction and fragmentation of the owl's habitat. To elucidate temporal and spatial changes in population structure and genetic diversity, we analyzed 439 individuals collected over the last 100 years. RESULTS: We detected a population bottleneck and fragmentation event indicated by mitochondrial DNA (mtDNA) haplotype and microsatellite analyses. The lowest value for effective population size, which was estimated by moment and temporal methods from microsatellite data, occurred in the 1980s. Five haplotypes were found in the mtDNA control region; most haplotypes were previously widespread across Hokkaido, but have become fixed in separate areas after the bottleneck period. Genetic differentiation among local populations, as indicated by both mtDNA and microsatellite data, likely arose through population fragmentation. CONCLUSIONS: The owl population may have been divided into limited areas due to loss of habitats via human activities, and have lost genetic variability within the local populations through inbreeding. Our mtDNA and microsatellite data show that genetic diversity decreased in local populations, indicating the importance of individuals moving between areas for conservation of this species on Hokkaido.