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In materials showing a linear magnetoelectric (ME) effect, unconventional functionalities can be anticipated such as electric control of magnetism and nonreciprocal optical responses. Thus, the search for new linear ME materials is of interest in materials science. Here, using a recently proposed design principle of linear ME materials, which is based on the combination of local structural asymmetry and collinear antiferromagnetism, we demonstrate that an anion-deficient fluorite derivative, Mn3Ta2O8, is a new linear ME material. This is evidenced by the onset of magnetic-field-induced electric polarization in its collinear antiferromagnetic phase below TN = 24 K. Furthermore, we also find an antiferroelectric-like phase transition at TS = 55 K, which is attributable to an off-center displacement of magnetic Mn2+ ions. The present study shows that Mn3Ta2O8 is a rare material that exhibits both ME and antiferroelectric-like transitions. Thus, Mn3Ta2O8 may provide an opportunity to investigate the physics associated with complicated interactions between magnetic (spin) and electric dipole degrees of freedom.

In materials showing a linear magnetoelectric (ME) effect, unconventional functionalities can be anticipated such as electric control of magnetism and nonreciprocal optical responses. Thus, the search for new linear ME materials is of interest in materials science. Here, using a recently proposed design principle of linear ME materials, which is based on the combination of local structural asymmetry and collinear antiferromagnetism, we demonstrate that an anion-deficient fluorite derivative, Mn

Simple Summary Hepatocellular carcinoma is the most common form of liver cancer. The lack of models that resemble actual tumor development in patients, limits the research to improve the diagnosis rate and develop new treatments. This study describes a novel mouse model that involves organoid formation and an implantation technique. This mouse model shares human genetic profiles and factors around the tumor, resembling the actual tumor development in patients. We demonstrate the roles of different cell types around the tumor, in promoting tumor growth, using this model. This model will be useful to understand the tumor developmental process, drug testing, diagnosis, prognosis, and treatment development. Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer. This study aims to develop a new method to generate an HCC mouse model with a human tumor, and imitates the tumor microenvironment (TME) of clinical patients. Here, we have generated functional, three-dimensional sheet-like human HCC organoids in vitro, using luciferase-expressing Huh7 cells, human iPSC-derived endothelial cells (iPSC-EC), and human iPSC-derived mesenchymal cells (iPSC-MC). The HCC organoid, capped by ultra-purified alginate gel, was implanted into the disrupted liver using an ultrasonic homogenizer in the immune-deficient mouse, which improved the survival and engraftment rate. We successfully introduced different types of controllable TME into the model and studied the roles of TME in HCC tumor growth. The results showed the role of the iPSC-EC and iPSC-MC combination, especially the iPSC-MC, in promoting HCC growth. We also demonstrated that liver fibrosis could promote HCC tumor growth. However, it is not affected by non-alcoholic fatty liver disease. Furthermore, the implantation of HCC organoids to humanized mice demonstrated that the immune response is important in slowing down tumor growth at an early stage. In conclusion, we have created an HCC model that is useful for studying HCC development and developing new treatment options in the future.

Maternal immune activation (MIA) contributes to behavioral abnormalities relevant to schizophrenia in adult offspring, although the molecular mechanisms underlying MIA-induced behavioral changes remain unclear. Here we demonstrated that dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane, during juvenile and adolescent stages prevented cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial prefrontal cortex (mPFC) of adult offspring after MIA. Gene set enrichment analysis by RNA sequencing showed that MIA caused abnormal expression of centrosome-related genes in the PFC and hippocampus of adult offspring, and that dietary intake of GF improved these abnormal gene expressions. Particularly, MIA increased the expression of suppressor of fermentation-induced loss of stress resistance protein 1 (Sfi1) mRNA in the PFC and hippocampus of adult offspring, and dietary intake of GF prevented the expression of Sfi1 mRNA in these regions. Interestingly, we found altered expression of SFI1 in the postmortem brains and SFI1 mRNA in hair follicle cells from patients with schizophrenia compared with controls. Overall, these data suggest that centrosome-related genes may play a role in the onset of psychosis in offspring after MIA. Therefore, dietary intake of GF-rich vegetables in high-risk psychosis subjects may prevent the transition to psychosis in young adulthood.

Multinucleated muscle fibers are formed by the fusion of myogenic progenitor cells during embryonic and fetal myogenesis. However, the role of prenatally incorporated myonuclei in the skeletal muscle fibers of adult animals is poorly understood. We demonstrated, using muscle-specific reporter mice, that the prenatal myonuclei remained in the adult soleus muscle, although cardiotoxin injection caused the loss of prenatal myonuclei. Overloading by the tendon transection of synergists failed to induce compensatory hypertrophy in regenerated soleus muscle fibers of adult rats, whereas unloading by tail suspension normally induced the fiber atrophy. Loss of hypertrophying function correlated with the lowered histone acetylation at the transcription start site of Igf1r gene, which was one of the genes that did not respond to the overloading. These parameters were improved by the transplantation of cells harvested from the juvenile soleus muscles of neonatal rats in association with enhanced histone acetylation of Igf1r gene. These results indicated that the presence of prenatal myonuclei was closely related to the status of histone acetylation, which could regulate the responsiveness of muscle fibers to physiological stimuli.

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening. However, functional roles of local brain circadian clocks in memory performance remains unclear. Here, we show that hippocampal clock controlled by the circadian-dependent transcription factor BMAL1 regulates time-of-day retrieval profile. Inducible transgenic dominant negative BMAL1 (dnBMAL1) expression in mouse forebrain or hippocampus disrupted retrieval of hippocampal memories at Zeitgeber Time 8–12, independently of retention delay, encoding time and Zeitgeber entrainment cue. This altered retrieval profile was associated with downregulation of hippocampal Dopamine-cAMP signaling in dnBMAL1 mice. These changes included decreases in Dopamine Receptors (D1-R and D5-R) and GluA1-S845 phosphorylation by PKA. Consistently, pharmacological activation of cAMP-signals or D1/5Rs rescued impaired retrieval in dnBMAL1 mice. Importantly, GluA1 S845A knock-in mice showed similar retrieval deficits with dnBMAL1 mice. Our findings suggest mechanisms underlying regulation of retrieval by hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation., The neural mechanisms that lead to a relative deficit in memory retrieval in the afternoon are unclear. Here, the authors show that the circadian - dependent transcription factor BMAL1 regulates retrieval through dopamine and glutamate receptor phosphorylation.

Although transplantation is the only definitive treatment for liver cirrhosis, there remains a shortage of donors, necessitating that novel treatments be developed. We aimed to establish a liver fibrosis model in Macaca fascicularis that can help accelerate preclinical research. Liver fibrosis was induced by administering thioacetamide (TAA) and carbon tetrachloride (CCl4). Analysis of residual liver function and fibrosis progression was based on clinical indices, such as the Child–Pugh score or fibrotic markers, besides histology. TAA-induced marked fibrosis, whereas CCl4 did not induce fibrosis. Concerning residual liver function, both of TAA and CCl4 worsened the indices of the Child–Pugh score, but only the TAA model increased the retention ratio of indocyanine green. The TAA-induced fibrosis model in Macaca fascicularis worsens fibrosis and residual liver function, mimicking Child–Pugh grade B. Given that our model was evaluated by clinical indices, it could be applicable to preclinical research.

Patients with severe Wernicke–Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation., Graphical abstract PTD mice showed deficits in hippocampus-dependent memory and loss of neurons and spines in the hippocampus.

We investigated the low-energy incommensurate (IC) magnetic fluctuations in Sr$_2$RuO$_4$ by the high-resolution inelastic neutron scattering measurements and random phase approximation (RPA) calculations. We observed a spin resonance with energy of $\hbar\omega_\text{res}=0.56$~meV centered at a characteristic wavevector $\mathbf{Q}_\text{res}=(0.3, 0.3, 0.5)$. The resonance energy corresponds well to the superconducting gap $2\Delta=0.56$~meV estimated by the tunneling spectroscopy. The spin resonance shows the $L$ modulation with a maximum at around $L = 0.5$. The $L$ modulated intensity of the spin resonance and our RPA calculations indicate that the superconducting gaps regarding the quasi-one-dimensional $\alpha$ and $\beta$ sheets at the Fermi surfaces have the horizontal line nodes. These results may set a strong constraint on the pairing symmetry of Sr$_2$RuO$_4$. We also discuss the implications on possible superconducting order parameters., Comment: arXiv admin note: substantial text overlap with arXiv:1904.01234

Transplantation of liver organoids has been investigated as a treatment alternative to liver transplantation for chronic liver disease. Transportal approach can be considered as a method of delivering organoids to the liver. It is important to set the allowable organoid amount and verify translocation by intraportal transplantation. We first examined the transplantation tolerance and translocation of porcine fetal liver-derived allogeneic organoids using piglets. Fetal liver-derived organoids generated from the Kusabira Orange-transduced pig were transplanted to the 10-day-old piglet liver through the left branch of the portal vein. All recipients survived without any observable adverse events. In contrast, both local and main portal pressures increased transiently during transplantation. In necropsy samples, Kusabira Orange-positive donor cells were detected primarily in the target lobe of the liver and partly in other areas, including the lungs and brain. As we confirmed the transplantation allowance by porcine fetal liver-derived organoids, we performed intraportal transplantation of human-induced pluripotent stem cell (iPSC)-derived liver organoid, which we plan to use in clinical trials, and portal pressure and translocation were investigated. Human iPSC-derived liver organoids were transplanted into the same 10-day-old piglet. Portal hypertension and translocation of human iPSC-derived liver organoids to the lungs were observed in one of two transplanted animals. Translocation occurred in the piglet in which patent ductus venosus (PDV) was observed. Therefore, a 28-day-old piglet capable of surgically ligating PDV was used, and after the PDV was ligated, human iPSC-derived liver organoids with the amount of which is scheduled in clinical trials were transplanted. This procedure inhibited the translocation of human iPSC-derived liver organoids to extrahepatic sites without no portal hypertension. In conclusion, human iPSC-derived liver organoids can be safely transplanted through the portal vein. Ligation of the ductus venosus prior to transplantation was effective in inhibiting extrahepatic translocation in newborns and infants.

Flow structure in a three-dimensionally connected dual elbow is visualized using a 1/15-scale experimental apparatus simulating the 1st and 2nd elbows of JSFR cold-leg piping. A matched refractive-index PIV measurement clarifies that a low-velocity region formed on the inner wall side of the 1st elbow develops toward the 2nd elbow. This low-velocity region consists of the following two ones: a flow separation region accompanied mainly with the generation and disappearance of transverse vortices, and a velocity recovery region that has longitudinal vortices with strong unsteadiness. These longitudinal vortices exist as twin vortices in the time-averaged flow field, and their dynamic characteristics highly depend on high-velocity creeping flows generated in the 1st elbow that flow into the velocity recovery region through the side walls. Since the velocity recovery region reaches the 2nd elbow, the geometry of the 2nd elbow has a significant impact on the characteristics of the vortex shedding in the velocity recovery region. On the other hand, obvious flow separation is not observed in the 2nd elbow, whereas high-velocity flow with intense velocity fluctuation is confirmed on the inner wall side. Furthermore, the unsteady vortices shed from the velocity recovery region are transferred to the central area of the 2nd elbow while growing significantly. The visualization of the secondary elbow shortly after the 2nd elbow clarifies that a strong swirling flow is formed in the 2nd elbow. These flow structures are due to the distorted flow formed in the 1st elbow and the shape effect of the 2nd elbow.

The NiFe-based planar-type magnetic tunnel junction was fabricated. The patterned NiFe thin film of 10 nm thickness was covered with an insulating Al-oxide layer. The channel width was 2 µm. The nano-oxidation technique using an atomic force microscope was used in order to form a tunnel barrier of the junction. The current-voltage characteristic of the junction exhibited a rectifying curve, which indicated that the nanowires of NiFe-oxide acted as the potential barrier. Equivalent values for the barrier height and barrier width of 1.75 eV and 1.5 nm were deduced from the Simmons’ formula, respectively.  2008 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.

To utilize data of Radar rain gauge in prediction for snowfall disttibution a model was proposed In this model, a calculation of wind field on arbitrary terrain is included. The accuracy of the prediction model are examined by comparisons with field data of hourly measurements of snow fall at seven sites, maximum snow depth distribution in dam depth basin and dam inflow.

Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.

Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1 −/− ) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1 −/− mice. In addition, HSF1 −/− mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid–neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1 −/− mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.

A 70-year-old woman with a 6-year history of seropositive rheumatoid arthritis (RA) and asymptomatic interstitial lung disease (ILD) began taking etanercept for ongoing arthritis despite treatment with methotrexate (MTX) and bucillamine. MTX was discontinued before introduction of etanercept. She developed lung injury 8 weeks after starting etanercept. Etanercept was discontinued and oral prednisolone 40 mg/day was begun, and her clinical findings gradually improved. Lung injury, although rare, is a recently noticed, potentially fatal adverse effect of all 3 licensed biological anti-tumor necrosis factor (TNF) agents. We recommend caution in the use of anti-TNF agents in elderly RA patients with preexisting ILD.

Background Previous studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). However, previous studies have also shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors. In this study, to understand the roles of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing alpha-CaMKII in the forebrain and analyzed their behavioral phenotypes. Results We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/-) heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression. Conclusion Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects aggressive behavior.

From the measurements of sound velocity and density of a solution of carboxymethyl cellulose and carboxymethyl dextran, the hydration numbers of these materials were evaluated as a function of the degree of substitution, that is, the average number of CH 2 COONa groups in a glucose unit. The hydration numbers of both carboxymethyl cellulose and carboxymethyl dextran increase with the degree of substitution. The increment of the hydration numbers for both samples is ca. 6.6 per degree of substitution and is interpreted in terms of the increase of the hydrophilic CH 2 COONa group in a glucose unit. A slight difference exists between the hydration numbers of carboxymethyl cellulose and carboxymethyl dextran.