Characterization of patients with major psychiatric disorders with AMPA receptor positron emission tomography.

Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [11C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [11C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [11C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [11C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology.

Five nucleotides found in RCTG motifs are essential for post-fertilization methylation imprinting of the H19 ICR in YAC transgenic mice.

Genomic imprinting at the mouse Igf2/H19 locus is controlled by the H19 ICR, within which paternal allele-specific DNA methylation originating in sperm is maintained throughout development in offspring. We previously found that a 2.9 kb transgenic H19 ICR fragment in mice can be methylated de novo after fertilization only when paternally inherited, despite its unmethylated state in sperm. When the 118 bp sequence responsible for this methylation in transgenic mice was deleted from the endogenous H19 ICR, the methylation level of its paternal allele was significantly reduced after fertilization, suggesting the activity involving this 118 bp sequence is required for methylation maintenance at the endogenous locus. Here, we determined protein binding to the 118 bp sequence using an in vitro binding assay and inferred the binding motif to be RCTG by using a series of mutant competitors. Furthermore, we generated H19 ICR transgenic mice with a 5-bp substitution mutation that disrupts the RCTG motifs within the 118 bp sequence, and observed loss of methylation from the paternally inherited transgene. These results indicate that imprinted methylation of the H19 ICR established de novo during the post-fertilization period involves binding of specific factors to distinct sequence motifs within the 118 bp sequence.

Perioperative complications and cost of posterior decompression with fusion in thoracic spine for ossification of the posterior longitudinal ligament and ossification of the ligamentum flavum -a comparative study using a national inpatient database.

BACKGROUND: Although posterior decompression with fusion (PDF) are effective for treating thoracic myelopathy, surgical treatment has a high risk of various complications. There is currently no information available on the perioperative complications in thoracic ossification of the longitudinal ligament (T-OPLL) and thoracic ossification of the ligamentum flavum (T-OLF). We evaluate the perioperative complication rate and cost between T-OPLL and T-OLF for patients underwent PDF. METHODS: Patients undergoing PDF for T-OPLL and T-OLF from 2012 to 2018 were detected in Japanese nationwide inpatient database. One-to-one propensity score matching between T-OPLL and T-OLF was performed based on patient characteristics and preoperative comorbidities. We examined systemic and local complication rate, reoperation rate, length of hospital stays, costs, discharge destination, and mortality after matching. RESULTS: In a total of 2,660 patients, 828 pairs of T-OPLL and T-OLF patients were included after matching. The incidence of systemic complications did not differ significantly between the T-OPLL and OLF groups. However, local complications were more frequently occurred in T-OPLL than in T-OLF groups (11.4% vs. 7.7% P = 0.012). Transfusion rates was also significantly higher in the T-OPLL group (14.1% vs. 9.4%, P = 0.003). T-OPLL group had longer hospital stay (42.2 days vs. 36.2 days, P = 0.004) and higher medical costs (USD 32,805 vs. USD 25,134, P < 0.001). In both T-OPLL and T-OLF, the occurrence of perioperative complications led to longer hospital stay and higher medical costs. While fewer patients in T-OPLL were discharged home (51.6% vs. 65.1%, P < 0.001), patients were transferred to other hospitals more frequently (47.5% vs. 33.5%, P = 0.001). CONCLUSION: This research identified the perioperative complications of T-OPLL and T-OLF in PDF using a large national database, which revealed that the incidence of local complications was higher in the T-OPLL patients. Perioperative complications resulted in longer hospital stays and higher medical costs.

Efficacy and safety of intravenous ketamine treatment in Japanese patients with treatment-resistant depression: A double-blind, randomized, placebo-controlled trial.

AIM: Although the antidepressant effect of ketamine on treatment-resistant depression (TRD) has been frequently reported in North American and European countries, evidence is scarce among the Asian population. We aimed to evaluate the efficacy and safety of intravenous ketamine in Japanese patients with TRD. METHODS: In this double-blind randomized placebo-controlled trial, 34 Japanese patients with TRD were randomized to receive either intravenous ketamine (0.5 mg/kg) or placebo, administered over 40 min, twice a week, for 2 weeks. The primary outcome was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to post-treatment. Secondary outcomes included changes in other depressive symptomatology scores and remission, response, and partial response rates. We also examined the association between baseline clinical demographic characteristics and changes in the MADRS total score. RESULTS: Intention-to-treat analysis indicated no significant difference in the decrease in MADRS total score between the groups (-8.1 ± 10.0 vs -2.5 ± 5.2, t[32] = 2.02, P = 0.052), whereas per-protocol analysis showed a significant reduction in the ketamine group compared to the placebo group (-9.1 ± 10.2 vs -2.7 ± 5.3, t[29] = 2.22, P = 0.034). No significant group differences were observed in other outcomes. Adverse events were more frequent in the ketamine group than in the placebo group, and no serious adverse events were reported. A higher baseline MADRS total score and body mass index were associated with a greater reduction in the MADRS total score. CONCLUSION: Intravenous ketamine outperformed placebo in Japanese patients with TRD who completed the study, suggesting that ketamine could alleviate depressive symptoms of TRD across diverse ethnic populations.

Sphingolipids with 2-hydroxy fatty acids aid in plasma membrane nanodomain organization and oxidative burst.

Plant sphingolipids mostly possess 2-hydroxy fatty acids (HFA), the synthesis of which is catalyzed by FA 2-hydroxylases (FAHs). In Arabidopsis (Arabidopsis thaliana), two FAHs (FAH1 and FAH2) have been identified. However, the functions of FAHs and sphingolipids with HFAs (2-hydroxy sphingolipids) are still unknown because of the lack of Arabidopsis lines with the complete deletion of FAH1. In this study, we generated a FAH1 mutant (fah1c) using CRISPR/Cas9-based genome editing. Sphingolipid analysis of fah1c, fah2, and fah1cfah2 mutants revealed that FAH1 hydroxylates very long-chain FAs (VLCFAs), whereas the substrates of FAH2 are VLCFAs and palmitic acid. However, 2-hydroxy sphingolipids are not completely lost in the fah1cfah2 double mutant, suggesting the existence of other enzymes catalyzing the hydroxylation of sphingolipid FAs. Plasma membrane (PM) analysis and molecular dynamics simulations revealed that hydroxyl groups of sphingolipid acyl chains play a crucial role in the organization of nanodomains, which are nanoscale liquid-ordered domains mainly formed by sphingolipids and sterols in the PM, through hydrogen bonds. In the PM of the fah1cfah2 mutant, the expression levels of 26.7% of the proteins, including defense-related proteins such as the pattern recognition receptors (PRRs) brassinosteroid insensitive 1-associated receptor kinase 1 and chitin elicitor receptor kinase 1, NADPH oxidase respiratory burst oxidase homolog D (RBOHD), and heterotrimeric G proteins, were lower than that in the wild-type. In addition, reactive oxygen species (ROS) burst was suppressed in the fah1cfah2 mutant after treatment with the pathogen-associated molecular patterns flg22 and chitin. These results indicated that 2-hydroxy sphingolipids are necessary for the organization of PM nanodomains and ROS burst through RBOHD and PRRs during pattern-triggered immunity.

Significance of End-Diastolic Forward Flow in Patients With Repaired Tetralogy of Fallot　- Its Interaction With the Left Ventricular Property and End Organ Damage.

BACKGROUND: Although right ventricular (RV) enlargement may affect RV diastolic dysfunction assessed by end-diastolic forward flow (EDFF) in patients with repaired tetralogy of Fallot (TOF), EDFF may also be modified by left ventricular (LV) hemodynamics. We hypothesized that EDFF is affected by LV hemodynamics, not limited to RV diastolic stiffening.Methods and Results: Among 145 consecutive patients with repaired TOF who underwent catheterization, hemodynamic properties in 47 with consistent EDFF and 75 without EDFF were analyzed. Compared with patients without EDFF, those with EDFF had a large RV volume with a high regurgitant fraction. Although cardiac index and central venous pressure (CVP) were similar, contrast injection augmented CVP and LV end-diastolic pressure (EDP) in patients with vs. those without EDFF, suggesting compromised diastolic reserve. In patients with EDFF, the velocity-time integral (VTI) of EDFF was positively correlated with LVEDP and systemic vascular resistance, in addition to RV EDP. EDFF-VTI was correlated with hepatic venous wedge pressure and markers of hepatic dysfunction. Subanalysis of the older (≥6 years) half of the study cohort revealed that EDFF was associated with bi-atrial enlargement independent of RV volume, highlighting the pronounced role of EDFF on the diastolic property in the aged cohort. CONCLUSIONS: EDFF-VTI in patients with repaired TOF reflects RV diastolic dysfunction, affected by the left heart system. EDFF-VTI indicates blood stagnation, which may be attributed to end-organ damage.

Risk factors for recurrence and regrowth of spinal schwannoma.

BACKGROUND: Spinal schwannoma recurs after initial surgery at a rate of 4%-6%, with known risk factors including subtotal resection, multilevel involvement, large tumor size, and malignant histopathology. This study examined risk factors for schwannoma recurrence and residual tumor regrowth. METHODS: Sixty-five patients who underwent resection of spinal schwannoma in our department between July 2010 and December 2018 and were followed up for more than 1 year were retrospectively analyzed for age, sex, follow-up duration, imaging and surgical data, recurrence, reoperation, and Japanese Orthopaedic Association scores before and 1 year after surgery. Patients with postoperative recurrence or residual tumor regrowth of >10% at the final visit (R+ group) were compared with patients without recurrence or regrowth (R- group). Multivariate logistic regression analysis was performed to analyze concurrent effects of risk factors on recurrence and regrowth. RESULTS: The 65 patients (mean age 52.4 years at surgery) had schwannomas involving cervical (n = 14), thoracic (n = 25), and lumbar (n = 26) spinal levels. Mean follow-up duration was 58 months. Location was intradural in 65%, extradural in 17%, and both intradural and extradural in 18%. There were 4 recurrences (6.2%), and the mean interval between surgery and recurrence was 18.8 months. Seven patients (10.8%) experienced regrowth. Comparing group R+ (n = 11) and group R- (n = 54), univariate analysis showed significant differences in Sridhar tumor classification, giant tumor (Sridhar classification II, IVb, and V), left-right and cranial-caudal tumor size, largest diameter, operative time, blood loss, subtotal resection, reoperation, fusion surgery, and follow-up duration. Multivariate logistic regression analysis revealed giant tumor (Sridhar classification types II, IVb, and V) as an independent risk factor for recurrence and regrowth. CONCLUSIONS: This retrospective review of 65 consecutive patients with spinal schwannoma in a single institution demonstrated that 16.9% had recurrence or regrowth, demonstrating that this potential risk should be kept in mind.

Application of a Markovian ancestral model to the temporal and spatial dynamics of cultural evolution on a population network.

Cultural macroevolution concerns a long-term evolutionary process involving transmission of non-genetic or cultural traits between populations as well as birth and death of populations. To understand the spatial dynamics of cultural macroevolution, we present a one-locus model of cultural diffusion in which a cultural trait is transmitted on a network of populations. Borrowing the method of ancestral backward process from population genetics, our model explores the lineage of a trait variant sampled in the present generation to quantify when and where the variant was invented. Mathematical analysis of the model enables us to predict the distribution of cultural age in each population of the network, estimate the frequencies of trait variants originating from given populations, and discuss the time it takes for a trait variant to diffuse between a given pair of populations. We also perform numerical analysis on random scale-free network of populations to investigate the effect of network topology and innovation rate on the age and origin of variants in each population. The result suggests that trait variants are more likely to derive from a population with higher innovation rate. Our numerical analysis also shows that trait variants invented in populations with higher network-centrality values are likely to be maintained at a higher frequency and transmitted to other populations in a shorter time period.

Phosphorylation of Collapsin Response Mediator Protein 1 (CRMP1) at Tyrosine 504 residue regulates Semaphorin 3A-induced cortical dendritic growth.

Collapsin response mediator proteins (CRMPs) have been identified as mediating proteins of repulsive axon guidance cue Semaphorin-3A (Sema3A). Phosphorylation of CRMPs plays a crucial role in the Sema3A signaling cascade. It has been shown that Fyn phosphorylates CRMP1 at Tyrosine 504 residue (Tyr504); however, the physiological role of this phosphorylation has not been examined. We found that CRMP1 was the most strongly phosphorylated by Fyn among the five members of CRMPs. We confirmed Tyr504 phosphorylation of CRMP1 by Fyn. Immunocytochemistry of mouse dorsal root ganglion (DRG) neurons showed that phosphotyrosine signal in the growth cones was transiently increased in the growth cones upon Sema3A stimulation. Tyr504-phosphorylated CRMP1 also tended to increase after Sema3A simulation. Ectopic expression of a single amino acid mutant of CRMP1 replacing Tyr504 with phenylalanine (CRMP1-Tyr504Phe) suppressed Sema3A-induced growth cone collapse response in chick DRG neurons. CRMP1-Tyr504Phe expression in mouse hippocampal neurons also suppressed Sema3A but not Sema3F-induced growth cone collapse response. Immunohistochemistry showed that Tyr504-phosphorylated CRMP1 was present in the cell bodies and in the dendritic processes of mouse cortical neurons. CRMP1-Tyr504Phe suppressed Sema3A-induced dendritic growth of primary cultured mouse cortical neurons as well as the dendritic development of cortical pyramidal neurons in vivo. Fyn± ; Crmp1± double heterozygous mutant mice exhibited poor development of cortical layer V basal dendrites, which was the similar phenotype observed in Sema3a-/- , Fyn-/- , and Crmp1-/- mice. These findings demonstrate that Tyr504 phosphorylation of CRMP1 by Fyn is an essential step of Sema3A-regulated dendritic development of cortical pyramidal neurons. (247 words).

Activity-induced secretion of semaphorin 3A mediates learning.

The semaphorin family is a well-characterized family of secreted or membrane-bound proteins that are involved in activity-independent neurodevelopmental processes, such as axon guidance, cell migration, and immune functions. Although semaphorins have recently been demonstrated to regulate activity-dependent synaptic scaling, their roles in Hebbian synaptic plasticity as well as learning and memory remain poorly understood. Here, using a rodent model, we found that an inhibitory avoidance task, a hippocampus-dependent contextual learning paradigm, increased secretion of semaphorin 3A in the hippocampus. Furthermore, the secreted semaphorin 3A in the hippocampus mediated contextual memory formation likely by driving AMPA receptors into hippocampal synapses via the neuropilin1-plexin A4-semaphorin receptor complex. This signaling process involves alteration of the phosphorylation status of collapsin response mediator protein 2, which has been characterized as a downstream molecule in semaphorin signaling. These findings implicate semaphorin family as a regulator of Hebbian synaptic plasticity and learning.

Stool preparation under anaerobic conditions contributes to retention of obligate anaerobes: potential improvement for fecal microbiota transplantation.

BACKGROUND: Fecal microbiota transplantation (FMT) in patients with ulcerative colitis has shown variable efficacy depending on the protocol used. A previous randomized controlled trial reported that anaerobic preparation of donor stool contributes to improved efficacy. Despite the suggestion that viable obligate anaerobes would be decreased through aerobic handling, there have been only a limited number of reports on how these aerobic or anaerobic procedures affect the composition of viable microbiota in the fecal slurries used for FMT. METHODS: We adopted 16S and 23S rRNA-targeted reverse transcription-quantitative polymerase chain reaction to quantify viable bacteria in fecal slurries. This study utilized specific primers designed to detect obligate anaerobes (including Clostridium coccoides group, C. leptum subgroup, Bacteroides fragilis group, Bifidobacterium, Atopobium cluster, and Prevotella) and facultative anaerobes (including total lactobacilli, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus). We then calculated the ratio change (RC) between before and after mixing, and compared the resulting values between anaerobic-prep and aerobic-prep in samples fixed immediately after blending (RCAn0 vs. RCAe0) and in samples maintained (under anaerobic or aerobic conditions) for 1 h after blending (RCAn1 vs. RCAe1). RESULTS: For most obligate anaerobes, the median RC tended to be less than 1, indicating that the number of obligate anaerobes was decreased by the blending procedure. However, in samples maintained for 1 h after blending, anaerobic-prep counteracted the decrease otherwise seen for the C. coccoides group and B. fragilis groups (P < 0.01 for both). The C. leptum subgroup also tended to show higher RC by anaerobic-prep than by aerobic-prep, although this effect was not statistically significant. Among facultative anaerobes, Enterobacteriaceae, Enterococcus, and Staphylococcus showed median RC values of more than 1, indicating that these organisms survived and even grew after mixing. Moreover, oxygen exposure had no significant influence on the survival of the facultative anaerobes. CONCLUSIONS: The conditions under which the blending procedure was performed affected the proportion of live anaerobes in fecal slurries. The obligate anaerobes tended to be decreased by blending processes, but anaerobic-prep significantly mitigated this effect. Anaerobic-prep may improve the efficacy of FMT by permitting the efficient transfer of obligate anaerobes to patients with ulcerative colitis.

Translational medicine of the glutamate AMPA receptor.

Psychiatric and neurological disorders severely hamper patient's quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has only made slow progress. This is due to limited evidence on the biological basis of these disorders in humans. Synapses are essential structural units of neurotransmission, and neuropsychiatric disorders are considered as "synapse diseases". Thus, a translational approach with synaptic physiology is crucial to tackle these disorders. Among a variety of synapses, excitatory glutamatergic synapses play central roles in neuronal functions. The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a principal component of glutamatergic neurotransmission; therefore, it is considered to be a promising translational target. Here, we review the limitations of current diagnostics and therapeutics of neuropsychiatric disorders and advocate the urgent need for the promotion of translational medicine based on the synaptic physiology of AMPAR. Furthermore, we introduce our recent translational approach to these disorders by targeting at AMPARs.

[A Case of Primary Acinic Cell Carcinoma of the Breast].

Acinic cell carcinoma(ACC)is an invasive malignancy primarily characterized by proliferation of tumor cells that resemble acinar cells of the salivary glands and pancreas. ACC of the mammary glands is rare. We report a case of primary ACC of the breast. Two masses were revealed in the left mammary gland of a 57-year-old woman who visited our hospital through screening mammography. The lesions were identified as synchronous multiple breast carcinoma of 2 different histological types; ACC and tubulolobular carcinoma. For treatment, left mastectomy and sentinel lymph node biopsy were performed, followed by postoperative chemotherapy and endocrine therapy. Hematoxylin-eosin staining of ACC revealed abundant acinar- like structures formed by tumor cells with prominent eosinophilic granules in the cytoplasm. Immunostaining was positive for S-100 protein, α1-antichymotrypsin, α1-antitrypsin, and lysozyme. The tumor cells were negative for estrogen, progesterone, and HER2 receptors, which indicated that they had a triple-negative phenotype. Although primary ACC of the breast is regarded as low-grade triple-negative breast carcinoma with a favorable prognosis, further accumulation of cases may be needed to elucidate the biological features of ACC and investigate appropriate therapeutic strategies.

Novel synaptic plasticity enhancer drug to augment functional recovery with rehabilitation.

PURPOSE OF REVIEW: Stroke is a devastating illness which severely attenuates quality of life because of paralysis. Despite recent advances in therapies during acute phase such as thrombolytic therapy, clinical option to intervene the process of rehabilitation is limited. No pharmacological intervention that could enhance the effect of rehabilitation has not been established. Recent articles, which are summarized in the review article, reported novel small compound which accelerates training-dependent motor function recovery after brain damage. RECENT FINDINGS: A novel small compound, edonerpic maleate, binds to collapsin response mediator protein 2 (CRMP2) and enhance synaptic plasticity leading to the acceleration of rehabilitative training-dependent functional recovery after brain damage in rodent and nonhuman primate. The clinical trial to test this effect in human is now ongoing. Future preclinical and clinical studies will delineate the potentials of this compound. SUMMARY: A novel CRMP2-binding small compound, edonerpic maleate, accelerates motor function recovery after brain damage in rodent and nonhuman primate.

Synergetic Enhancement of Light-Matter Interaction by Nonlocality and Band Degeneracy in ZnO Thin Films.

This study aims to reveal the full potential of ZnO as an ultrafast photofunctional material. Based on nonlocal response theory to incorporate the spatially inhomogeneous quality of the samples coupled with experimental observations of linear and nonlinear optical responses, we establish the ultrafast radiative decay of excitons in ZnO thin films that reaches the speed of excitonic dephasing at room temperature in typical semiconductors at a couple tens of femtoseconds. The consistency between the observed delay-time dependence of the transient-grating signals and the theoretical prediction reveals that the ultrafast radiative decay is due to the synergetic effects of the giant light-exciton interaction volume and the radiative coupling between multicomponent excitons.

Cultural and evolutionary dynamics with best-of-k learning when payoffs are uncertain.

Social learning not only takes the form of random copying of other individuals, but also involves learners' choice of what to learn or from whom to learn. Best-of-k learning refers to a kind of success-biased social learning strategy in which a learner randomly samples k exemplars from the population and imitates the most "successful" one, or the one gaining the highest payoff. While it is intuitive that best-of-k learning can promote the spread of superior variants and thereby enable cumulative cultural evolution, a previous mathematical analysis has shown that it may sometimes result in maladaptive cultural evolution when the payoffs associated with cultural variants vary stochastically. If so, best-of-k learners may be selectively disfavored and in the long run replaced by unbiased learners, who simply copy someone chosen at random. Here we develop new mathematical models that are more simplified and mathematically tractable than the previous model to achieve a fuller analysis of cultural and evolutionary dynamics involving best-of-k learning and stochastic payoffs. We find that best-of-k learning, unlike unbiased learning, can facilitate the invasion of an on average inferior variant that sometimes gives a very high payoff, destabilize a population fixed with a variant that is on average superior but occasionally results in a very low payoff, and maintain cultural polymorphism at equilibrium. Considering gene-culture coevolution of learning rules and cultural variants, under the assumption that social learning is always faithful, it is shown that a population of best-of-k learners at the culturally polymorphic state can always be invaded by unbiased learners and eventually converges to a culturally monomorphic state. Nonetheless, we show that best-of-k learning can be stable against invasion by unbiased learning if social learning is sometimes combined with individual learning.

Neonatal isolation augments social dominance by altering actin dynamics in the medial prefrontal cortex.

Social separation early in life can lead to the development of impaired interpersonal relationships and profound social disorders. However, the underlying cellular and molecular mechanisms involved are largely unknown. Here, we found that isolation of neonatal rats induced glucocorticoid-dependent social dominance over nonisolated control rats in juveniles from the same litter. Furthermore, neonatal isolation inactivated the actin-depolymerizing factor (ADF)/cofilin in the juvenile medial prefrontal cortex (mPFC). Isolation-induced inactivation of ADF/cofilin increased stable actin fractions at dendritic spines in the juvenile mPFC, decreasing glutamate synaptic AMPA receptors. Expression of constitutively active ADF/cofilin in the mPFC rescued the effect of isolation on social dominance. Thus, neonatal isolation affects spines in the mPFC by reducing actin dynamics, leading to altered social behavior later in life.

Comparison of emotional processing assessed with fear conditioning by interpersonal conflicts in patients with depression and schizophrenia.

AIM: While emotional processing is implicated in various psychiatric illnesses, its differences among diagnoses are unclear. We compared associative learning of social values in patients with depression and schizophrenia by measuring skin conductance response to interpersonal stimuli. METHODS: We included 20 female outpatients each with depression and schizophrenia. They underwent Pavlovian conditioning experiments in response to a classical aversive sound, and an interpersonal stimulus that was designed to cause aversive social conditioning with actors' faces coupled with negative verbal messages. Multiple regression analysis was performed to examine the associations between the degree of conditioned response and the clinical characteristics of the participants. RESULTS: Conditioned responses during the acquisition phase in both conditions were higher in depression compared to schizophrenia. Patients with depression successfully showed fear conditioning in both conditions, and they exhibited slower extinction in the interpersonal condition. The conditioned response during the extinction phase showed a positive association with Emotion Regulation Questionnaire Expressive Suppression score, and a negative association with the Emotion Regulation Questionnaire Cognitive Reappraisal score and the use of antidepressants. Patients with schizophrenia did not become conditioned in either of the conditions. The Positive and Negative Syndrome Scale Negative Syndrome score was negatively associated with the degree of conditioned response during the acquisition phase in the interpersonal condition. CONCLUSION: Female patients with schizophrenia, especially those who prominently demonstrated negative symptoms, suggested their intrinsic impairments in the associative learning of social context. Antidepressants and adaptive emotional regulation strategy may enhance the extinction learning of aversive social conditioning in depression.

De novo DNA methylation through the 5'-segment of the H19 ICR maintains its imprint during early embryogenesis.

Genomic imprinting is a major monoallelic gene expression regulatory mechanism in mammals, and depends on gamete-specific DNA methylation of specialized cis-regulatory elements called imprinting control regions (ICRs). Allele-specific DNA methylation of the ICRs is faithfully maintained at the imprinted loci throughout development, even in early embryos where genomes undergo extensive epigenetic reprogramming, including DNA demethylation, to acquire totipotency. We previously found that an ectopically introduced H19 ICR fragment in transgenic mice acquired paternal allele-specific methylation in the somatic cells of offspring, whereas it was not methylated in sperm, suggesting that its gametic and postfertilization modifications were separable events. We hypothesized that this latter activity might contribute to maintenance of the methylation imprint in early embryos. Here, we demonstrate that methylation of the paternally inherited transgenic H19 ICR commences soon after fertilization in a maternal DNMT3A- and DNMT3L-dependent manner. When its germline methylation was partially obstructed by insertion of insulator sequences, the endogenous paternal H19 ICR also exhibited postfertilization methylation. Finally, we refined the responsible sequences for this activity in transgenic mice and found that deletion of the 5' segment of the endogenous paternal H19 ICR decreased its methylation after fertilization and attenuated Igf2 gene expression. These results demonstrate that this segment of the H19 ICR is essential for its de novo postfertilization DNA methylation, and that this activity contributes to the maintenance of imprinted methylation at the endogenous H19 ICR during early embryogenesis.

Gut Microbiota Composition Before and After Use of Proton Pump Inhibitors.

BACKGROUND: Recently, problems associated with proton pump inhibitor (PPI) use have begun to surface. PPIs influence the gut microbiota; therefore, PPI use may increase the risk of enteric infections and cause bacterial translocation. In this study, we investigated fecal microbiota composition, fecal organic acid concentrations and pH, and gut bacteria in the blood of the same patients before and after PPI use. METHODS: Twenty patients with reflux esophagitis based on endoscopic examination received 8 weeks of treatment with PPIs. To analyze fecal microbiota composition and gut bacteria in blood and organic acid concentrations, 16S and 23S rRNA-targeted quantitative RT-PCR and high-performance liquid chromatography were conducted. RESULTS: Lactobacillus species were significantly increased at both 4 and 8 weeks after PPI treatment compared with bacterial counts before treatment (P = 0.011 and P = 0.002, respectively). Among Lactobacillus spp., counts of the L. gasseri subgroup, L. fermentum, the L. reuteri subgroup, and the L. ruminis subgroup were significantly increased at 4 and 8 weeks after treatment compared with counts before treatment. Streptococcus species were also significantly increased at 4 and 8 weeks after PPI treatment compared with counts before treatment (P < 0.01 and P < 0.001, respectively). There was no significant difference in the total organic acid concentrations before and after PPI treatment. Detection rates of bacteria in blood before and after PPI treatment were 22 and 28%, respectively, with no significant differences. CONCLUSIONS: Our quantitative RT-PCR results showed that gut dysbiosis was caused by PPI use, corroborating previous results obtained by metagenomic analysis.