A possible function of Nik-related kinase in the labyrinth layer of delayed delivery mouse placentas.

In mice and humans, Nik-related protein kinase (Nrk) is an X-linked gene that encodes a serine/threonine kinase belonging to GCK group 4. Nrk knockout (Nrk KO) mice exhibit delayed delivery, possibly due to defective communication between the Nrk KO conceptus and its mother. However, the mechanism of delayed labor remains largely unknown. Here, we found that in pregnant mothers with the Nrk KO conceptus, the serum progesterone (P4) and placental lactogen (PL-2) concentrations in late pregnancy were higher than those in the wild type. Moreover, we demonstrated that Nrk is expressed in trophoblast giant cells (TGCs) and syncytiotrophoblast-2 (SynT-2) in the labyrinth layer of the mouse placenta. In the human placenta, NRK is also expressed in Syn-T in villi. Both human Syn-T and mouse TGCs of the labyrinth layer are present within fetal tissues that are in direct contact with the maternal blood. The labyrinth layer of the Nrk KO conceptus was gigantic, with enlarged cytoplasm and Golgi bodies in the TGCs. To investigate the function of Nrk in the labyrinth layer, a differentially expressed gene (DEG) analysis was performed. The DEG analysis revealed that labor-promoting factors, such as prostaglandins, were decreased, and pregnancy-maintaining factors, such as the prolactin family and P4 receptor, were increased. These findings suggest that the Nrk KO mice exhibit delayed delivery owing to high P4 concentrations caused by the hypersecretion of pregnancy-maintaining factors, such as PL-2, from the placenta.

Dopaminergic Signaling in the Nucleus Accumbens Modulates Stress-Coping Strategies during Inescapable Stress.

Maladaptation to stress is a critical risk factor in stress-related disorders, such as major depression and post-traumatic stress disorder (PTSD). Dopamine signaling in the nucleus accumbens (NAc) has been shown to modulate behavior by reinforcing learning and evading aversive stimuli, which are important for the survival of animals under environmental challenges such as stress. However, the mechanisms through which dopaminergic transmission responds to stressful events and subsequently regulates its downstream neuronal activity during stress remain unknown. To investigate how dopamine signaling modulates stress-coping behavior, we measured the subsecond fluctuation of extracellular dopamine concentration and pH using fast scanning cyclic voltammetry (FSCV) in the NAc, a postsynaptic target of midbrain dopaminergic neurons, in male mice engaged in a tail suspension test (TST). The results revealed a transient decrease in dopamine concentration and an increase in pH levels when the animals changed behaviors, from being immobile to struggling. Interestingly, optogenetic inhibition of dopamine release in NAc, potentiated the struggling behavior in animals under the TST. We then addressed the causal relationship of such a dopaminergic transmission with behavioral alterations by knocking out both the dopamine receptors, i.e., D1 and D2, in the NAc using viral vector-mediated genome editing. Behavioral analyses revealed that male D1 knock-out mice showed significantly more struggling bouts and longer struggling durations during the TST, while male D2 knock-out mice did not. Our results therefore indicate that D1 dopaminergic signaling in the NAc plays a pivotal role in the modulation of stress-coping behaviors in animals under tail suspension stress.SIGNIFICANCE STATEMENT The tail suspension test (TST) has been widely used as a despair-based behavioral assessment to screen the antidepressant so long. Despite its prevalence in the animal studies, the neural substrate underlying the changes of behavior during the test remains unclear. This study provides an evidence for a role of dopaminergic transmission in the modulation of stress-coping behavior during the TST, a despair test widely used to screen the antidepressants in rodents. Taking into consideration the fact that the dopamine metabolism is upregulated by almost all antidepressants, a part of which acts directly on the dopaminergic transmission, current results would uncover the molecular mechanism through which the dopaminergic signaling mediates antidepressant effect with facilitation of the recovery from the despair-like behavior in the TST.

Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain.

Using a high-end mass spectrometry, we screened phosphoproteins and phosphopeptides in four types of Alzheimer's disease (AD) mouse models and human AD postmortem brains. We identified commonly changed phosphoproteins in multiple models and also determined phosphoproteins related to initiation of amyloid beta (Aß) deposition in the mouse brain. After confirming these proteins were also changed in and human AD brains, we put the proteins on experimentally verified protein-protein interaction databases. Surprisingly, most of the core phosphoproteins were directly connected, and they formed a functional network linked to synaptic spine formation. The change of the core network started at a preclinical stage even before histological Aß deposition. Systems biology analyses suggested that phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) by overactivated kinases including protein kinases C and calmodulin-dependent kinases initiates synapse pathology. Two-photon microscopic observation revealed recovery of abnormal spine formation in the AD model mice by targeting a core protein MARCKS or by inhibiting candidate kinases, supporting our hypothesis formulated based on phosphoproteome analysis.

Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1.

DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1). We identified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR.

Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network.

The spinocerebellar ataxia type 7 (SCA7) gene product, Ataxin-7 (ATXN7), localizes to the nucleus and has been shown to function as a component of the TATA-binding protein-free TAF-containing-SPT3-TAF9-GCN5-acetyltransferase transcription complex, although cytoplasmic localization of ATXN7 in affected neurons of human SCA7 patients has also been detected. Here, we define a physiological function for cytoplasmic ATXN7. Live imaging reveals that the intracellular distribution of ATXN7 dynamically changes and that ATXN7 distribution frequently shifts from the nucleus to the cytoplasm. Immunocytochemistry and immunoprecipitation demonstrate that cytoplasmic ATXN7 associates with microtubules (MTs), and expression of ATXN7 stabilizes MTs against nocodazole treatment, while ATXN7 knockdown enhances MT degradation. Interestingly, normal and mutant ATXN7 similarly associate with and equally stabilize MTs. Taken together, these findings provide a novel physiological function of ATXN7 in the regulation of cytoskeletal dynamics, and suggest that abnormal cytoskeletal regulation may contribute to SCA7 disease pathology.

Chronic non-discriminatory social defeat stress during the perinatal period induces depressive-like outcomes in female mice.

Depression is more prevalent in women than in men. Perinatal stress is one of the main risk factors for depression in women. However, there is no suitable female model for perinatal depression that uses the social defeat stress (SDS) paradigm. The standard chronic SDS protocol, which is the most useful method for developing a depression-like model, is effective only in male mice. Thus, this study aimed to characterize a novel SDS method for producing a perinatal depression-like model mouse. We induced chronic SDS in perinatal female mice, wherein chronic non-discriminatory SDS (ND-SDS) was used to induce substantial stress in female mice. The female mice were placed in aggressive ICR mouse cages with sentinel male mice under ND-SDS conditions. Stressed female mice subjected to ND-SDS during the perinatal period efficiently exhibited stress-susceptible phenotypes, such as a social avoidance phenotype and anhedonic behavior, whereas stressed female mice subjected to SDS did not show depressive-like behaviors. These results indicate that chronic ND-SDS in perinatal females could be used to develop a female perinatal depression-like model that can be used to study women's health.

A randomized, placebo-controlled trial evaluating the safety of excessive administration of kaempferol aglycone.

Kaempferol (KMP) is an important flavonoid in many fruits and vegetables. Preclinical studies on KMP have reported its pharmacological effects, including antimicrobial, antioxidant, anti-inflammatory, antitumor, antidiabetic, myocardial protective, and neuroprotective effects. Additionally, some epidemiological studies have revealed a negative association between the consumption of KMP-containing foods and the risk of developing several disorders, such as cancer and cardiovascular diseases. Thus, although a large body of literature has demonstrated the benefits of KMP supplementation, there are no reports of clinical trials evaluating the safety of KMP aglycone administration or KMP aglycone-rich food consumption. The purpose of this study was to evaluate the safety of a high dose of KMP aglycone by administrating KMP aglycone-containing supplements to healthy adults. This study had a randomized, double-blind, placebo-controlled design and a 4-week duration. Participants were randomly allocated to the KMP (n = 24) or placebo (n = 24) group. For 4 weeks, the KMP group received a capsule containing 50-mg KMP daily, a dose approximately five times higher than the estimated human dietary intake. The placebo group received a capsule containing cornstarch-based powder daily. The general toxicity parameters were evaluated by examining the characteristics of the participants, hematological and blood biochemical parameters, general urinalysis, qualitative urine tests, and adverse events. No clinical changes were observed in anthropometric and blood pressure measurements or blood and urine parameters in the KMP group compared to those in the placebo group. Furthermore, no adverse events owing to KMP aglycone administration occurred. The study results revealed that the consumption of 50-mg KMP aglycone daily for 4 weeks is safe in healthy adults.

Immune-Mediated Non-Infectious Periaortitis After Aortic Graft Replacement Surgery: A Case Report Highlighting the Need for Immunosuppressive Therapy.

BACKGROUND A non-infectious inflammatory reaction against replaced aortic graft for aortic dissection often manifests as fever, malaise, and peri-graft effusion. It usually lasts less than 1 month and subsides spontaneously without immunosuppressive treatment. CASE REPORT A 49-year-old man underwent ascending aorta and total arch replacement for acute thoracic aortic dissection. He had fever, malaise, nausea, and elevated serum C-reactive protein for 1 month postoperatively. Pathological examination of the aorta revealed no aortitis, and repeated blood cultures were negative. We also noted periaortic graft fluid collection, and a small amount of pleural and pericardial effusions. We suspected post-pericardiotomy syndrome. Colchicine and prednisolone were administered, with an excellent clinical response. Three weeks after discontinuation of a 7-week prednisolone treatment, the same symptoms recurred and gradually worsened. Prednisolone was restarted 6 months after the first surgery, with good clinical response. Thereafter, he developed left-sided weakness and dysarthria, being diagnosed as ischemic stroke. Contrast-enhanced computed tomography revealed fluid collection with contrast leak around the aortic grafts, suggesting peel dehiscence, and thrombus formation in anastomotic pseudoaneurysm. He underwent surgical repair. He was diagnosed with non-infectious periaortitis, likely due to an immune reaction to the grafts, based on an excellent clinical response to immunosuppressive therapy. CONCLUSIONS We report a case of non-infectious periaortitis around a thoracic aortic graft, probably with an immune-mediated mechanism, requiring immunosuppressive treatment. When fever persists after aortic graft replacement surgery, non-infectious periaortitis should be considered and immunosuppressive treatment should be considered to prevent critical complications of anastomotic pseudoaneurysm and graft dehiscence.

Neural mechanisms underlying uninstructed orofacial movements during reward-based learning behaviors.

During reward-based learning tasks, animals make orofacial movements that globally influence brain activity at the timings of reward expectation and acquisition. These orofacial movements are not explicitly instructed and typically appear along with goal-directed behaviors. Here, we show that reinforcing optogenetic stimulation of dopamine neurons in the ventral tegmental area (oDAS) in mice is sufficient to induce orofacial movements in the whiskers and nose without accompanying goal-directed behaviors. Pavlovian conditioning with a sensory cue and oDAS elicited cue-locked and oDAS-aligned orofacial movements, which were distinguishable by a machine-learning model. Inhibition or knockout of dopamine D1 receptors in the nucleus accumbens inhibited oDAS-induced motion but spared cue-locked motion, suggesting differential regulation of these two types of orofacial motions. In contrast, inactivation of the whisker primary motor cortex (wM1) abolished both types of orofacial movements. We found specific neuronal populations in wM1 representing either oDAS-aligned or cue-locked whisker movements. Notably, optogenetic stimulation of wM1 neurons successfully replicated these two types of movements. Our results thus suggest that accumbal D1-receptor-dependent and -independent neuronal signals converge in the wM1 for facilitating distinct uninstructed orofacial movements during a reward-based learning task.

Knock-down of PQBP1 impairs anxiety-related cognition in mouse.

PQBP1 (polyglutamine tract-binding protein 1) is a causative gene for a relatively frequent X-linked syndromic and non-syndromic mental retardation (MR). To analyze behavioral abnormalities of these patients from molecular basis, we developed a knock-down (KD) mouse model. The KD mice possess a transgene expressing 498 bp double-strand RNA that is endogenously cleaved to siRNA suppressing PQBP1 efficiently. After confirming that PQBP1 is selectively suppressed to nearly 50% of the control mice, we performed behavioral analyses of PQBP1-KD mice. The KD mice possessed normal ability in ordinary memory tests including water-maze test, whereas they showed abnormal anxiety-related behavior in light/dark exploration test and open-field test and showed obvious declines of anxiety-related cognition in the repetitive elevated plus maze or novel object recognition test. Correspondingly, we found c-fos upregulation and histone H3 acetylation after behavior tests were declined in neurons of amygdala, prefrontal cortex and hippocampus. Furthermore, we found that 4-phenylbutyric acid, an HDAC inhibitor, efficiently improved expression of these genes and rescued the abnormal phenotypes in adult PQBP1-KD mice. These results suggested that PQBP1 dysfunction in regulating gene expression might underlie the abnormal behavior and cognition of PQBP1-KD mice and that the recovery of expression of such PQBP1 target genes might improve the symptoms in adult patients.

Activation of proprotein convertase in the mouse habenula causes depressive-like behaviors through remodeling of extracellular matrix.

The lateral habenula (LHb) attracts a growing interest as a regulator of monoaminergic activity which were frequently reported to be defective in depression. Here we found that chronic social defeat stress (CSDS) increased production of pro-inflammatory cytokines in LHb associated with mobilization of monocytes and remodeling of extracellular matrix by increased matrix metalloproteinase (MMP) activity. RNA-seq analysis identified proprotein convertase Pcsk5 as an upstream regulator of MMP activation, with upregulation in LHb neurons of mice with susceptibility to CSDS. PCSK5 facilitated motility of microglia in vitro by converting inactive pro-MMP14 and pro-MMP2 to their active forms, highlighting its role in mobilization of microglia and monocytes in neuroinflammation. Suppression of Pcsk5 expression via small interfering RNA (siRNA) ameliorated depressive-like behaviors and pathological mobilization of monocytes in mice with susceptibility to CSDS. PCSK5-MMPs signaling pathway could be a target for development of the antidepressants targeting the inflammatory response in specific brain regions implicated in depression.

Antidepressant effect of the translocator protein antagonist ONO-2952 on mouse behaviors under chronic social defeat stress.

In preclinical models, it has been reported that social defeat stress activates microglial cells in the CNS. Translocator protein 18 kDa (TSPO) is a mitochondrial protein expressed on microglia in the CNS that has been proposed to be a useful biomarker for brain injury and inflammation. We hypothesized that a TSPO antagonist, ONO-2952, would inhibit the neuroinflammation induced by microglial hyperactivation and associated depressive-like behaviors. An in vitro analysis showed that ONO-2952 suppressed the release of pro-inflammatory cytokines and mitochondrial reactive oxygen species in cultured microglia stimulated by lipopolysaccharide. In mice submitted to chronic social defeat stress, microglia predominantly expressed TSPO in limbic areas implicated in depressive-like behaviors, including the amygdala, ventral hippocampus and nucleus accumbens, in which an increase in the production of pro-inflammatory cytokines in vivo were associated. Treating animals with ONO-2952 during chronic social defeat stress ameliorated impairments in social avoidance and anxiety-like behaviors and suppressed pro-inflammatory cytokine production, suggesting that ONO-2952 exerted an anti-stress effect in this animal model of depression. Thus, targeting TSPO as a candidate for the development of antidepressants that reduce susceptibility to chronic stress could pave the way toward therapeutic interventions for relapse prophylaxis in depression.

Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice.

Peripheral lipopolysaccharide (LPS) injection induces systemic inflammation through the activation of the inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK)/NF-κB signaling pathway, which promotes brain dysfunction resulting in conditions including anorexia. LPS-mediated reduction of food intake is associated with activation of NF-κB signaling and phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. We recently reported phospholipase C-related catalytically inactive protein (PRIP) as a new negative regulator of phosphatidylinositol 3-kinase/AKT signaling. AKT regulates the IKK/NF-κB signaling pathway; therefore, this study aimed to investigate the role of PRIP/AKT signaling in LPS-mediated neuroinflammation-induced anorexia. PRIP gene (Prip1 and Prip2) knockout (Prip-KO) mice intraperitoneally (ip) administered with LPS exhibited increased anorexia responses compared with wild-type (WT) controls. Although few differences were observed between WT and Prip-KO mice in LPS-elicited plasma pro-inflammatory cytokine elevation, hypothalamic pro-inflammatory cytokines were significantly upregulated in Prip-KO rather than WT mice. Hypothalamic AKT and IKK phosphorylation and IκB degradation were significantly increased in Prip-KO rather than WT mice, indicating further promotion of AKT-mediated NF-κB signaling. Consistently, hypothalamic STAT3 was further phosphorylated in Prip-KO rather than WT mice. Furthermore, suppressor of cytokine signaling 3 (Socs3), a negative feedback regulator for STAT3 signaling, and cyclooxogenase-2 (Cox2), a candidate molecule in LPS-induced anorexigenic responses, were upregulated in the hypothalamus in Prip-KO rather than WT mice. Pro-inflammatory cytokines were upregulated in hypothalamic microglia isolated from Prip-KO rather than WT mice. Together, these findings indicate that PRIP negatively regulates LPS-induced anorexia caused by pro-inflammatory cytokine expression in the hypothalamus, which is mediated by AKT-activated NF-κB signaling. Importantly, hypothalamic microglia participate in this PRIP-mediated process. Elucidation of PRIP-mediated neuroinflammatory responses may provide novel insights into the pathophysiology of many brain dysfunctions.

Omi / HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington's disease.

Selective vulnerability of neurons is a critical feature of neurodegenerative diseases, but the underlying molecular mechanisms remain largely unknown. We here report that Omi/HtrA2, a mitochondrial protein regulating survival and apoptosis of cells, decreases selectively in striatal neurons that are most vulnerable to the Huntington's disease (HD) pathology. In microarray analysis, Omi/HtrA2 was decreased under the expression of mutant huntingtin (htt) in striatal neurons but not in cortical or cerebellar neurons. Mutant ataxin-1 (Atx-1) did not affect Omi/HtrA2 in any type of neuron. Western blot analysis of primary neurons expressing mutant htt also confirmed the selective reduction of the Omi/HtrA2 protein. Immunohistochemistry with a mutant htt-transgenic mouse line and human HD brains confirmed reduction of Omi/HtrA2 in striatal neurons. Overexpression of Omi/HtrA2 by adenovirus vector reverted mutant htt-induced cell death in primary neurons. These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology.

Age-dependent change of HMGB1 and DNA double-strand break accumulation in mouse brain.

HMGB1 is an evolutionarily conserved non-histone chromatin-associated protein with key roles in maintenance of nuclear homeostasis; however, the function of HMGB1 in the brain remains largely unknown. Recently, we found that the reduction of nuclear HMGB1 protein level in the nucleus associates with DNA double-strand break (DDSB)-mediated neuronal damage in Huntington's disease [M.L. Qi, K. Tagawa, Y. Enokido, N. Yoshimura, Y. Wada, K. Watase, S. Ishiura, I. Kanazawa, J. Botas, M. Saitoe, E.E. Wanker, H. Okazawa, Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases, Nat. Cell Biol. 9 (2007) 402-414]. In this study, we analyze the region- and cell type-specific changes of HMGB1 and DDSB accumulation during the aging of mouse brain. HMGB1 is localized in the nuclei of neurons and astrocytes, and the protein level changes in various brain regions age-dependently. HMGB1 reduces in neurons, whereas it increases in astrocytes during aging. In contrast, DDSB remarkably accumulates in neurons, but it does not change significantly in astrocytes during aging. These results indicate that HMGB1 expression during aging is differentially regulated between neurons and astrocytes, and suggest that the reduction of nuclear HMGB1 might be causative for DDSB in neurons of the aged brain.

Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice.

Patients with major depressive disorder have elevated peripheral inflammation; the degree of this increase correlates with the severity of the disorder. Chronic psychological stress increases pro-inflammatory cytokines and promotes microglial activation, leading to stress vulnerability. Epigenetics, including DNA methylation and histone modification, are also related to the pathophysiology of major depressive disorder. Sodium butyrate (SB), a histone deacetylase inhibitor, exerts an antidepressant effect by altering gene expression in the hippocampus. In this study, we investigated whether lipopolysaccharide (LPS)-induced depressive-like behaviors in mice are affected by the repeated treatment with SB. Intraperitoneal injection of LPS (5 mg/kg) induced cytokines and ionized calcium-binding adaptor molecule 1(Iba1), a marker of microglial activation, in the hippocampus. It also increased the immobility time in a forced swim test, without changing locomotion. Repeated treatment with SB reduced LPS-induced alterations. These findings suggested that epigenetic regulation exist in hippocampal microglial activation, and is involved in depressive-like behaviors associated with neuro-inflammation. Further, using cDNA microarray analyses, we examined whether LPS and SB treatment affected the microglial gene profiles. Our results indicated 64 overlapping genes, between LPS-increased genes and SB-decreased genes. Among these genes, EF hand calcium binding domain 1 was a particularly distinct candidate gene. Altogether, our findings indicated that microglial activation mediated through epigenetic regulation may be involved in depressive-like behaviors. In addition, we demonstrated the effect of SB on gene information in hippocampal microglia under neuroinflammatory conditions.

Evaluation of refractive correction for standard automated perimetry in eyes wearing multifocal contact lenses.

AIM: To evaluate the refractive correction for standard automated perimetry (SAP) in eyes with refractive multifocal contact lenses (CL) in healthy young participants. METHODS: Twenty-nine eyes of 29 participants were included. Accommodation was paralyzed in all participants with 1% cyclopentolate hydrochloride. SAP was performed using the Humphrey SITA-standard 24-2 and 10-2 protocol under three refractive conditions: monofocal CL corrected for near distance (baseline); multifocal CL corrected for distance (mCL-D); and mCL-D corrected for near vision using a spectacle lens (mCL-N). Primary outcome measures were the foveal threshold, mean deviation (MD), and pattern standard deviation (PSD). RESULTS: The foveal threshold of mCL-N with both the 24-2 and 10-2 protocols significantly decreased by 2.2-2.5 dB (P<0.001), while that of mCL-D with the 24-2 protocol significantly decreased by 1.5 dB (P=0.0427), as compared with that of baseline. Although there was no significant difference between the MD of baseline and mCL-D with the 24-2 and 10-2 protocols, the MD of mCL-N was significantly decreased by 1.0-1.3 dB (P<0.001) as compared with that of both baseline and mCL-D, with both 24-2 and 10-2 protocols. There was no significant difference in the PSD among the three refractive conditions with both the 24-2 and 10-2 protocols. CONCLUSION: Despite the induced mydriasis and the optical design of the multifocal lens used in this study, our results indicated that, when the dome-shaped visual field test is performed with eyes with large pupils and wearing refractive multifocal CLs, distance correction without additional near correction is to be recommended.

Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1.

YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions. We found that expression of YAPdeltaC during development, but not adulthood, rescued neurodegeneration phenotypes of mutant ataxin-1 knock-in (Atxn1-KI) mice. YAP/YAPdeltaC interacted with RORα via the second WW domain and served as co-activators of its transcriptional activity. YAP/YAPdeltaC formed a transcriptional complex with RORα on cis-elements of target genes and regulated their expression. Both normal and mutant Atxn1 interacted with YAP/YAPdeltaC, but only mutant Atxn1 depleted YAP/YAPdeltaC from the RORα complex to suppress transcription on short timescales. Over longer periods, mutant Atxn1 also decreased RORα in vivo. Genetic supplementation of YAPdeltaC restored the RORα and YAP/YAPdeltaC levels, recovered YAP/YAPdeltaC in the RORα complex and normalized target gene transcription in Atxn1-KI mice in vivo. Collectively, our data suggest that functional impairment of YAP/YAPdeltaC by mutant Atxn1 during development determines the adult pathology of SCA1 by suppressing RORα-mediated transcription.

A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation.

Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression. Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels. Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggest that KDM5C mutations are causal to XLID. Furthermore, our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes.

Water-Permeable Dialysis Membranes for Multi-Layered Microdialysis System.

This paper presents the development of water-permeable dialysis membranes that are suitable for an implantable microdialysis system that does not use dialysis fluid. We developed a microdialysis system integrating microfluidic channels and nanoporous filtering membranes made of polyethersulfone (PES), aiming at a fully implantable system that drastically improves the quality of life of patients. Simplicity of the total system is crucial for the implantable dialysis system, where the pumps and storage tanks for the dialysis fluid pose problems. Hence, we focus on hemofiltration, which does not require the dialysis fluid but water-permeable membranes. We investigated the water permeability of the PES membrane with respect to the concentrations of the PES, the additives, and the solvents in the casting solution. Sufficiently, water-permeable membranes were found through in vitro experiments using whole bovine blood. The filtrate was verified to have the concentrations of low-molecular-weight molecules, such as sodium, potassium, urea, and creatinine, while proteins, such as albumin, were successfully blocked by the membrane. We conducted in vivo experiments using rats, where the system was connected to the femoral artery and jugular vein. The filtrate was successfully collected without any leakage of blood inside the system and it did not contain albumin but low-molecular-weight molecules whose concentrations were identical to those of the blood. The rat model with renal failure showed 100% increase of creatinine in 5 h, while rats connected to the system showed only a 7.4% increase, which verified the effectiveness of the proposed microdialysis system.