Calcium/calmodulin-dependent protein kinase IIα heterozygous knockout mice show electroencephalogram and behavioral changes characteristic of a subpopulation of schizophrenia and intellectual impairment.

Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity.

5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome.

Background: Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia.

Increased levels of a pro-inflammatory IgG receptor in the midbrain of people with schizophrenia.

Background: There is growing evidence that neuroinflammation may contribute to schizophrenia neuropathology. Elevated pro-inflammatory cytokines are evident in the midbrain from schizophrenia subjects, findings that are driven by a subgroup of patients, characterised as a "high inflammation" biotype. Cytokines trigger the release of antibodies, of which immunoglobulin G (IgG) is the most common.

Characterisation of a novel KRAS G12C inhibitor ASP2453 that shows potent anti-tumour activity in KRAS G12C-mutated preclinical models.

Background: KRAS is one of the most frequently mutated oncogenes in various cancers, and several novel KRAS G12C direct inhibitors are now in clinical trials. Here, we characterised the anti-tumour efficacy of ASP2453, a novel KRAS G12C inhibitor, in preclinical models of KRAS G12C-mutated cancer.

Methods: We evaluated the in vitro and in vivo activity of ASP2453, alone or in combination with targeted agents and immune checkpoint inhibitors, in KRAS G12C-mutated cancer cells and xenograft models.

Virtual clinical trial simulations for a novel KRAS inhibitor (ASP2453) in non-small cell lung cancer.

KRAS is a small GTPase family protein that relays extracellular growth signals to cell nucleus. KRAS mutations lead to constitutive proliferation signaling and are prevalent across human cancers. ASP2453 is a novel, highly potent, and selective inhibitor of KRAS .

Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion.

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD.

Gamma power abnormalities in a Fmr1-targeted transgenic rat model of fragile X syndrome.

Fragile X syndrome (FXS) is characteristically displayed intellectual disability, hyperactivity, anxiety, and abnormal sensory processing. Electroencephalography (EEG) abnormalities are also observed in subjects with FXS, with many researchers paying attention to these as biomarkers. Despite intensive preclinical research using Fmr1 knock out (KO) mice, an effective treatment for FXS has yet to be developed.

Calcium Imaging in Drug Discovery for Psychiatric Disorders.

The past 5 years have seen a sharp increase in the number of studies using calcium imaging in behaving rodents. These studies have helped identify important roles for individual cells, brain regions, and circuits in some of the core behavioral phenotypes of psychiatric disorders, such as schizophrenia and autism, and have characterized network dysfunction in well-established models of these disorders. Since rescuing clinically relevant behavioral deficits in disease model mice remains a foundation of preclinical CNS research, these studies have the potential to inform new therapeutic approaches targeting specific cell types or projections, or perhaps most importantly, the network-level context in which neurons function.

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect).

Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methotrexate in Patients with Rheumatoid Arthritis.

Background: Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate.

Objective: The objective of this study was to investigate potential drug-drug interactions of peficitinib with methotrexate and the short-term safety of coadministration.

Enhancing Clinical Trials Through Synergistic Gamma Power Analysis.

While the etiology of many neuropsychiatric disorders remains unknown, increasing evidence suggests that aberrant sensory processing plays a central role. For this class of disorders, which are characterized by affective, cognitive, and behavioral symptoms, electroencephalography remains the dominant tool for providing insight into the physiological and molecular underpinnings of the disease state and predicting the effectiveness of investigational new drugs. Within the spectrum of electrical activity present in the CNS, high-frequency oscillations in the gamma band are frequently altered in these patient populations.

A drug-drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers.

Purpose: Peficitinib is an oral pan-Janus kinase inhibitor for the treatment of rheumatoid arthritis. Co-administration of peficitinib with metformin, a type 2 diabetes therapy, can occur in clinical practice. Hepatic and renal uptake of metformin is mediated by organic cation transporter 1 (OCT1) and OCT2, respectively, and its renal excretion by multidrug and toxin extrusion 1 (MATE1) and MATE2-K.

Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates.

Better understanding of the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here, we use RNA sequencing, cell imaging, and lineage tracing of mouse and human in vitro NSCs and monkey brain sections to model the generation of cortical neuronal fates. We show that conserved signaling mechanisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons.

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects.

Background And Objective: Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects.

Methods: In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo.

Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk.

Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data.

Pharmacokinetics and Immunogenicity of ASP0113 in CMV-Seronegative Dialysis Patients and CMV-Seronegative and -Seropositive Healthy Subjects.

Cytomegalovirus (CMV) infection causes significant morbidity and mortality in immunocompromised transplant patients. ASP0113, a first-in-class DNA vaccine containing plasmids encoding CMV phosphoprotein 65 and glycoprotein B (gB), was evaluated in a phase 1b, subject-blinded study in CMV-seropositive (n = 13) and CMV-seronegative (n = 12) healthy and CMV-seronegative dialysis subjects (n = 12) randomized to ASP0113 or placebo. End points included pharmacokinetics, anti-gB antibody levels, phosphoprotein 65-specific T-cell responses measured by ex vivo enzyme-linked immune absorbent spot (ELISpot) assay and 10-day cultured ELISpot and Stat T-cell activation assays, and safety.

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function.

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions.

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects with Normal and Impaired Renal Function.

Background And Objective: This study measured and compared the exposure and safety of peficitinib (ASP015K), a novel oral Janus kinase inhibitor, in subjects with normal and impaired renal function after a single oral, clinically relevant peficitinib dose.

Methods: This was an open-label, parallel-group study conducted at two centres in Japan. Subjects with normal and mildly, moderately, or severely impaired renal function received a single oral dose of peficitinib (one 150 mg tablet) under fasting conditions in a hospital setting.

Conversion of antigen-specific effector/memory T cells into Foxp3-expressing T cells by inhibition of CDK8/19.

A promising way to restrain hazardous immune responses, such as autoimmune disease and allergy, is to convert disease-mediating T cells into immunosuppressive regulatory T (T) cells. Here, we show that chemical inhibition of the cyclin-dependent kinase 8 (CDK8) and CDK19, or knockdown/knockout of the CDK8 or CDK19 gene, is able to induce Foxp3, a key transcription factor controlling T cell function, in antigen-stimulated effector/memory as well as naïve CD4 and CD8 T cells. The induction was associated with STAT5 activation, independent of TGF-β action, and not affected by inflammatory cytokines.

Erratum: Author Correction: Transcriptomic immaturity inducible by neural hyperexcitation is shared by multiple neuropsychiatric disorders.

[This corrects the article DOI: 10.1038/s42003-018-0277-2.].

Transcriptomic immaturity inducible by neural hyperexcitation is shared by multiple neuropsychiatric disorders.

Biomarkers are needed to improve the diagnosis of neuropsychiatric disorders, which are often associated to excitatory/inhibitory imbalances in neural transmission and abnormal maturation. Here, we characterized different disease conditions by mapping changes in the expression patterns of maturation-related genes whose expression was altered by experimental neural hyperexcitation in published studies. This analysis revealed two gene expression patterns: decreases in maturity markers and increases in immaturity markers.

Effective suppression of donor specific antibody production by Cathepsin S inhibitors in a mouse transplantation model.

Donor-specific antibodies (DSA) are a major risk factor for antibody-mediated rejection (ABMR) in solid organ transplantation, and ABMR remains a medical challenge. Therefore, effective anti-ABMR therapies are needed to improve overall graft survival. Cathepsin S (Cat S) is an essential protease for antigen peptide loading onto lysosomal/endosomal major histocompatibility complex (MHC) class II molecules to promote antigen presentation.

Hippocampal Pathophysiology: Commonality Shared by Temporal Lobe Epilepsy and Psychiatric Disorders.

Accumulating evidence points to the association of epilepsy, particularly, temporal lobe epilepsy (TLE), with psychiatric disorders, such as schizophrenia. Among these illnesses, the hippocampus is considered the regional focal point of the brain, playing an important role in cognition, psychosis, and seizure activity and potentially suggesting common etiologies and pathophysiology of TLE and schizophrenia. In the present review, we overview abnormal network connectivity between the dentate gyrus (DG) and the Cornus Ammonis area 3 (CA3) subregions of the hippocampus relative to the induction of epilepsy and schizophrenia.

Schizophrenia-relevant behaviours of female mice overexpressing neuregulin 1 type III.

Elevated levels of the type III (III) isoforms of neuregulin 1 (NRG1) have been observed in the brains of schizophrenia patients that carry NRG1 Hap risk alleles, which is thought to contribute to the aetiology of the disease. We generated transgenic mice with forebrain driven Nrg1 III overexpression (Nrg1 III tg) and previously found that male heterozygous Nrg1 type III tg mice exhibit several schizophrenia-relevant behaviours including social and cognitive deficits as well as impaired sensorimotor gating. A number of mouse models for other Nrg1 isoform types exhibit sex-specific phenotypes yet sex-specific effects of Nrg1 III overexpression had not been evaluated.

Ectopic Mossy Fiber Pathfinding in the Hippocampus Caused the Abnormal Neuronal Transmission in the Mouse Models of Psychiatric Disease.

Appropriate axonal pathfinding is a necessary step for the function of neuronal circuits. The mossy fibers (MFs) in the hippocampus of CaMKIIα heterozygous knockout (CaMKIIα-hKO) psychiatric model mice project onto not only the stratum lucidum but also the stratum oriens region in the CA3, which is a projection pattern distinct from that in normal mice. Thus, we examined the electrophysiological properties of the MF-CA3 connection in this mutant mouse on field recordings and found a lower synaptic connection.