Social memory deficit caused by dysregulation of the cerebellar vermis.

Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar activity affects social functions remains unclear. We selectively increased the excitability of molecular layer interneurons (MLIs) to suppress Purkinje cell firing in the mouse cerebellar vermis. Chemogenetic perturbation of MLIs impaired SRM without affecting sociability, anxiety levels, motor coordination or object recognition. Optogenetic interference of MLIs during distinct phases of a social recognition test revealed the cerebellar engagement in the retrieval, but not encoding, of social information. c-Fos mapping after the social recognition test showed that cerebellar manipulation decreased brain-wide interregional correlations and altered network structure from medial prefrontal cortex and hippocampus-centered to amygdala-centered modules. Anatomical tracing demonstrated hierarchical projections from the central cerebellum to the social brain network integrating amygdalar connections. Our findings suggest that the cerebellum organizes the neural matrix necessary for SRM.

Direct microwave energy input on a single cation for outstanding selective catalysis.

Microwave (MW)-driven catalytic systems are attracting attention not only as an aggressive electrification strategy of the chemical industry but also as creating a unique catalytic reaction field that conventional equilibrium heating cannot achieve. This study unlocked direct and selective heating of single alkali metal cations in the pores of aluminosilicate zeolites under MW. Selectively heated Cs+ cations in FAU zeolite exhibited selective CH4 combustion performance, that is, COx generation at the heated Cs+ cations selectively occurred while side reactions in the low-temperature gas phase were suppressed. The Cs-O pair distribution function revealed by synchrotron-based in situ x-ray total scattering gave us direct evidence of peculiar displacement induced by MW, which was consistent with the results of molecular dynamics simulation mimicking MW heating. The concept of selective monoatomic heating by MW is expected to open a next stage in "microwave catalysis" science by providing physicochemical insights into "microwave effects."

An adaptive behavioral control motif mediated by cortical axo-axonic inhibition.

Genetically defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our understanding of the scope and nature of their specific contributions. Here we reveal that the chandelier cell (ChC), an interneuron type that specializes in inhibiting the axon-initial segment (AIS) of pyramidal neurons, establishes cortical microcircuits for organizing neural coding through selective axo-axonic synaptic plasticity. We found that organized motor control is mediated by enhanced population coding of direction-tuned premotor neurons, with tuning refined through suppression of irrelevant neuronal activity. ChCs contribute to learning-dependent refinements by providing selective inhibitory control over individual pyramidal neurons rather than global suppression. Quantitative analysis of structural plasticity across axo-axonic synapses revealed that ChCs redistributed inhibitory weights to individual pyramidal neurons during learning. These results demonstrate an adaptive logic of the inhibitory circuit motif responsible for organizing distributed neural representations. Thus, ChCs permit efficient cortical computation in a targeted cell-specific manner.

An adaptive behavioral control motif mediated by cortical axo-axonic inhibition.

Neural circuits are reorganized with specificity during learning. Genetically-defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our understanding of the scope and nature of their specific contributions to learning. Here we reveal that the chandelier cell (ChC), an interneuron type that specializes in inhibiting the axon-initial segment (AIS) of pyramidal neurons, establishes cortical microcircuits for organizing neural coding through selective axo-axonic synaptic plasticity. We find that organized motor control is mediated by enhanced population coding of direction-tuned premotor neurons, whose tuning is refined through suppression of irrelevant neuronal activity. ChCs are required for learning-dependent refinements via providing selective inhibitory control over pyramidal neurons rather than global suppression. Quantitative analysis on structural plasticity of axo-axonic synapses revealed that ChCs redistributed inhibitory weights to individual pyramidal neurons during learning. These results demonstrate an adaptive logic of the inhibitory circuit motif responsible for organizing distributed neural representations. Thus, ChCs permit efficient cortical computation in a target cell specific manner, which highlights the significance of interneuron diversity.

Ferroelectric Ionic Molecular Crystals with Significant Plasticity and a Low Melting Point: High Performance in Hot-Pressed Polycrystalline Plates and Melt-Grown Crystalline Sheets.

Among ferroelectric crystals based on small molecules, plastic/ferroelectric crystals are currently receiving particular attention because they can be used as bulk polycrystals. Herein, we show that an ionic molecular ferroelectric crystal, guanidinium tetrafluoroborate, exhibits significant malleability and multiaxial ferroelectricity despite the absence of a plastic crystal phase. Powder samples of this crystal can be processed into transparent bulk crystalline plates either by press-forming or by melt-growing. The plates show high ferroelectric performance and related properties, demonstrating the largest hitherto reported spontaneous polarization for bulk polycrystals of small-molecule-based ferroelectrics. Owing to the ready availability of large-scale materials and processability into various bulk crystalline forms, this ferroelectric crystal represents a highly promising functional material that will boost research on diverse applications as bulk crystals.

Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial.

PURPOSE: The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety. PATIENTS AND METHODS: Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point. RESULTS: The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; P = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% v 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% v 11%, respectively). CONCLUSION: In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

Neuromodulatory control of inhibitory network arborization in the developing postnatal neocortex.

Interregional neuronal communication is pivotal to instructing and adjusting cortical circuit assembly. Subcortical neuromodulatory systems project long-range axons to the cortex and affect cortical processing. However, their roles and signaling mechanisms in cortical wiring remain poorly understood. Here, we explored whether and how the cholinergic system regulates inhibitory axonal ramification of neocortical chandelier cells (ChCs), which control spike generation by innervating axon initial segments of pyramidal neurons. We found that acetylcholine (ACh) signaling through nicotinic ACh receptors (nAChRs) and downstream T-type voltage-dependent calcium (Ca2+) channels cell-autonomously controls axonal arborization in developing ChCs through regulating filopodia initiation. This signaling axis shapes the basal Ca2+ level range in varicosities where filopodia originate. Furthermore, the normal development of ChC axonal arbors requires proper levels of activity in subcortical cholinergic neurons. Thus, the cholinergic system regulates inhibitory network arborization in the developing neocortex and may tune cortical circuit properties depending on early-life experiences.

National survey of hepatobiliary and pancreatic surgery in hemophilia patients in Japan.

BACKGROUND: Approximately 8300 hemophiliacs are registered in Japan, but no comprehensive reports on hepatobiliary and pancreatic surgery (HBPS) have been conducted. This report investigates the current status of HPBS in hemophilia patients in Japan. METHODS: The subjects were hemophiliac patients seen between January 1 2007, and December 31 2017, at facilities participating in this study among the facilities for performing high-difficulty cases nationwide designated by the Japanese Society for HBPS. A retrospective examination of short-term outcomes in 49 cases was conducted to assess patient background, disease, surgical procedure, and complications. RESULTS: The types of hemophilia were A: 43 cases, B: four cases, and von Willebrand disease: two cases (hemophilia severity: mild 32, moderate seven, severe 10). The target malignant diseases for surgery were hepatocellular carcinoma (HCC) in 20 cases, intrahepatic cholangiocellular carcinoma (CCC) in four cases, combined HCC-CCC in two cases, hilar CCC in two cases, and pancreatic cancer in four cases. As for the surgical procedure, limited resection (subsegmentectomy and partial hepatectomy) was performed in 16 cases of HCC even with normal liver function tests. Pancreaticoduodenectomy and distal pacreatectomy were performed for pancreatic cancers as in the standard procedure. Postoperative complications were postoperative bleeding in two cases after hepatectomy and one after pancreatectomy in one case. When compared with Japanese National Clinical Data base, the complication rates after hepatectomy and pancreatectomy were not conspicuous in hemophilic patients. CONCLUSIONS: As long as they are performed in qualified centers, complication rate is not increased in hemophilic patients undergoing HBPS.

First demonstration of a C + L band CDC-ROADM with a simple node configuration using multiband switching devices.

While ultrahigh-baud-rate optical signals are effective for extending the transmission distance of large capacity signals, they also reduce the number of wavelengths that can be arranged in a band because of their wider bandwidth. This reduces the flexibility of optical path configuration in reconfigurable optical add/drop multiplexing (ROADM) networks. Particularly in colorless, directionless and contentionless (CDC)-ROADM, the effect reduces the add/drop ratio at a node. Multiband ROADM systems are an effective countermeasure for overcoming this issue, but they make the node configuration more complicated and its operation more difficult. In this paper, we analyze the challenges of C + L band CDC-ROADM and show that optical switch devices that operate over multiple bands are effective in meeting them. For this purpose, we built a C + L band CDC-ROADM node based on C + L band wavelength-selective switches and multicast switches and confirmed its effectiveness experimentally. In particular, to simplify the node configuration, we propose a reduction in the number of optical amplifiers used for node loss compensation and experimentally verify its feasibility.

IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype.

The most prominent structural hallmark of the mammalian neocortical circuitry is the layer-based organization of specific cell types and synaptic inputs. Accordingly, cortical inhibitory interneurons (INs), which shape local network activity, exhibit subtype-specific laminar specificity of synaptic outputs. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that Immunoglobulin Superfamily member 11 (IgSF11) homophilic adhesion proteins are preferentially expressed in one of the most distinctive IN subtypes, namely, chandelier cells (ChCs) that specifically innervate axon initial segments of pyramidal neurons (PNs), and their synaptic laminar target. Loss-of-function experiments in either ChCs or postsynaptic cells revealed that IgSF11 is required for ChC synaptic development in the target layer. While overexpression of IgSF11 in ChCs enlarges ChC presynaptic boutons, expressing IgSF11 in nontarget layers induces ectopic ChC synapses. These findings provide evidence that synapse-promoting adhesion proteins, highly localized to synaptic partners, determine the layer-specific synaptic connectivity of the cortical IN subtype.

Analysis of filtration behavior using integrated column chromatography followed by virus filtration.

We evaluated filtration behavior and virus removal capability for a monoclonal antibodies (mAb) and plasma IgG under constant flow rate directly following flow-through column chromatography in an integrated process. mAb solution with quantified host cell protein (HCP) content processed in flow-through mode on in-series mixed-mode AEX and modified CEX columns connected to the Planova BioEX filter (pool-less) achieved HCP logarithmic reduction value (LRV) of 2.3 and 93.9% protein recovery, demonstrating comparable or higher HCP LRV with high protein recovery compared to previous reports. For 5-15 mg/ml plasma IgG run to 100 L/m2 , similar filtration behavior was achieved for flux of 10-100 LMH, and lower flux runs remained well below the maximum operating pressure, suggesting that higher throughput in continuous processing is achievable. Comparison of fit of plasma IgG and mAb filtration behavior to four blocking models showed little differences but slightly better fit to the cake filtration model. Viral clearance of the filtration step tested by in-line spiking X-MuLV or MVM into purified plasma IgG following the chromatography step showed robust removal at low flux. Integrating the Planova BioEX filter into continuous processes with column chromatography can achieve efficient downstream processing with reduced footprint and process time.

Size effect of the guest cation on the AlO4 framework in aluminate sodalite-type oxides M8[Al12O24](SO4)2 (M = Sr2+ and Ca2+) in the I43m phase.

Sr8[Al12O24](SO4)2 (SAS) and Ca8[Al12O24](SO4)2 (CAS) are members of the aluminate sodalite-type oxides with the general chemical formula M8[Al12O24](XO4)2 (M2+ is the guest cation and XO42- is the guest anion). To discuss the role of the guest cations (M2+ = Sr2+ and Ca2+) on the rotation of AlO4 in the oxygen tetrahedral framework in the I43m phase, the crystal structure parameters and the probability density function of the guest ions in SAS and CAS have been investigated via synchrotron radiation X-ray powder diffraction by considering Gram-Charlier expansions. The interatomic distances between the M2+ and O2- ions evaluated from the maximum positions in the probability density distribution are almost equal to the sum of the ideal ionic radii of the M2+ and O2- ions. This result suggests that the geometry of the AlO4 tetrahedral framework and the fluctuation of the guest ions are mainly caused by steric effects between the M2+ and O2- ions.

Nanoscale structural analysis of Pb(Mg1/3Nb2/3)O3.

The determination of local atomic structure at nanoscale for inhomogeneous systems is challenging. The local arrangement of atoms needs to be studied to understand the local or short-range order structures for disordered materials with a lack of long-range order periodicity. Pair distribution function (PDF) analysis is a technique, that is used to study the short-range order structure of materials: this technique is based on the evaluation of local atomic arrangement using synchrotron and neutron sources. An attempt was made to determine the local arrangement at 20 nm-scale for a typical relaxor ferroelectric material, Pb(Mg1/3Nb2/3)O3(PMN). The PDF technique was employed owing to the limited structural coherence in this disordered material. It was determined that there are three types of structures depending on the distance. A glass-like network structure was observed as a short-range order structure owing to the large off-center shift of lead atoms. With an increase in distance, the structure of PMN changed from rhombohedral to cubic. Using the above-mentioned approach, we elucidated the process of local structure averaging.

Author Correction: Butterfly-shaped magnetoresistance in triangular-lattice antiferromagnet Ag2CrO2.

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

Butterfly-shaped magnetoresistance in triangular-lattice antiferromagnet Ag2CrO2.

Spintronic devices using antiferromagnets (AFMs) are promising candidates for future applications. Recently, many interesting physical properties have been reported with AFM-based devices. Here we report a butterfly-shaped magnetoresistance (MR) in a micrometer-sized triangular-lattice antiferromagnet Ag2CrO2. The material consists of two-dimensional triangular-lattice CrO2 layers with antiferromagnetically coupled S = 3/2 spins and Ag2 layers with high electrical conductivity. The butterfly-shaped MR appears only when the magnetic field is applied perpendicularly to the CrO2 plane with the maximum MR ratio (≈15%) at the magnetic ordering temperature. These features are distinct from those observed in conventional magnetic materials. We propose a theoretical model where fluctuations of partially disordered spins with the Ising anisotropy play an essential role in the butterfly-shaped MR in Ag2CrO2.

[A Case of Primary Gastric Adenocarcinoma with Enteroblastic Differentiation(GAED)].

Gastric adenocarcinoma with enteroblastic differentiation(GAED)is a rare disease that is classified as a special type in the 15th edition Japanese Classification of Gastric Carcinoma. GAED is considered to have a poor prognosis. We report about a 76-year-old man with GAED who presented with complaints of poor appetite and weight loss. He was suspected of having gastric cancer based on ultrasonography and computed tomography findings and was referred to our hospital by his home doctor. Upper gastrointestinal endoscopy revealed a gastric cancer in the lesser curvature of the gastric antrum. Distal gastrectomy was performed. Histopathology showed a moderately differentiated adenocarcinoma with a clear cytoplasm. Immunostaining was positive for Sal-like protein 4(SALL4)and negative for α-fetoprotein(AFP). The patient was diagnosed as having GAED. Vascular and lymphatic invasion were not observed. He was discharged on the 9th day after surgery. At 5 months postoperatively, he was treated with adjuvant chemotherapy, and no recurrence was noted. GAED is a rare disease with a poor prognosis. We report this case and discuss relevant literature.

Antiferroelectric to Antiferroelectric-Relaxor Phase Transition in Calcium Strontium Sulfoaluminate.

Structural phase transitions of calcium strontium sulfoaluminate series, (Ca1-xSrx)8[AlO2]12(SO4)2 ((CS)AS-x) with x = 0.80-1.00, are systematically investigated by powder X-ray diffraction, dielectric measurements, and pyroelectric measurements, to clarify a phase diagram of (CS)AS-x (x = 0.80-1.00). A pure strontium sulfoaluminate, (CS)AS-1.00, is found to undergo three phase transitions, which take place successively on cooling from a prototypical cubic phase with the symmetry of Im3̅m. Though the room-temperature phase of (CS)AS-1.00 was previously reported to be of polar Pcc2, the pyroelectric measurements clarified a nonpolar character of the crystal symmetry. The dielectric measurements suggest a possibility of an antiferroelectric ground state of (CS)AS-x in the Sr-rich compositions. As x decreases, the ground state changes to a short-range-ordered state, implying a unique phase transition from the antiferroelectric state to the antiferroelectric-relaxor state. The present study provides an intriguing playground for designing new ferro/antiferroelectric materials.

Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer: The ACHIEVE Phase 3 Randomized Clinical Trial.

Importance: Oxaliplatin-based chemotherapy is associated with debilitating peripheral sensory neuropathy (PSN) for patients with stage III colon cancer. Objective: To assess disease-free survival (DFS) and long-lasting PSN in patients treated with 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. Design, Setting, and Participants: An open-label, multicenter, phase 3 randomized clinical trial of 1313 Asian patients with stage III colon cancer was conducted investigating the noninferiority of 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. From August 1, 2012, to June 30, 2014, participants were randomized to the 2 treatment groups. Data were analyzed from July 2017 to June 2018. Interventions: Patients were randomized to receive 3 or 6 months of adjuvant chemotherapy. The choice of chemotherapy regimen, with the drugs modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX), was at the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was DFS. Secondary end points included the evaluation of PSN for up to 3 years and overall survival. Results: Of the 1313 patients (651 were women and mean age was 66 [range, 28-85] years) enrolled and randomized, 22 were not treated because 10 were unable to begin treatment within 2 weeks of enrollment, 7 withdrew their consent, and 5 were not treated for various other reasons. Of 1291 patients treated (650 in the 3-month arm and 641 in the 6-month arm), 969 (75%) received the chemotherapy drug CAPOX. The hazard ratio (HR) for DFS of the 3-month arm compared with the 6-month arm was 0.95 (95% CI, 0.76-1.20). Hazard ratios were 1.07 (95% CI, 0.71-1.60) and 0.90 (95% CI, 0.68-1.20) for the drugs mFOLFOX6 and CAPOX, and 0.81 (95% CI, 0.53-1.24) and 1.07 (95% CI, 0.81-1.40) for patients with low-risk disease (TNM classification stages T1-3 and N1) and high-risk disease (stages T4 or N2), respectively. The rates of any grade of PSN lasting for 3 years in the 3-month vs 6-month treatment arms were 9.7% vs 24.3% (P < .001). Incidence of PSN lasting for 3 years was significantly lower for patients treated with CAPOX than for patients treated with mFOLFOX6 in both the 3-month (7.9% vs 15.7%; P = .04) and 6-month arms (21.0% vs 34.1%; P = .02). Conclusions and Relevance: The incidence of long-lasting PSN was significantly lower for 3 months than for 6 months of therapy, and significantly lower for treatment with the drug CAPOX than with mFOLFOX6. Since the shortened therapy duration did not compromise outcomes, a 3-month course of CAPOX may be the most appropriate treatment option, particularly for patients with low-risk disease. Trial Registration: UMIN Clinical Trials Registry: UMIN000008543.

In Vivo Single-Cell Genotyping of Mouse Cortical Neurons Transfected with CRISPR/Cas9.

CRISPR/Cas-based technologies have revolutionized genetic approaches to addressing a wide range of neurobiological questions. The ability of CRISPR/Cas to introduce mutations into target genes allows us to perform in vivo loss-of-function experiments without generating genetically engineered mice. However, the lack of a reliable method to determine genotypes of individual CRISPR/Cas-transfected cells has made it impossible to unambiguously identify the genetic cause of their phenotypes in vivo. Here, we report a strategy for single-cell genotyping in CRISPR/Cas-transfected neurons that were phenotypically characterized in vivo. We show that re-sectioning of cortical slices and subsequent laser microdissection allow us to isolate individual CRISPR/Cas-transfected neurons. Sequencing of PCR products containing a CRISPR/Cas-targeted genomic region in single reference neurons provided genotypes that completely correspond with those deduced from their target protein expression and phenotypes. Thus, our study establishes a powerful strategy to determine the causality between genotypes and phenotypes in CRISPR/Cas-transfected neurons.