A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation.

Vitamin K, primarily known for its roles in coagulation and bone metabolism, has recently been implicated in neuroprotection and neuronal differentiation, particularly via its bioactive form, menaquinone-4 (MK-4). Here, we synthesized 12 vitamin K compounds with retinoic acid-conjugated side chains and methyl ester modifications to enhance neuroactive properties. Among these, compound demonstrated superior stability, robust transcriptional activation via steroid and xenobiotic receptor and retinoic acid receptor, and efficient induction of neuronal differentiation in mouse neural progenitor cells.

Urinary prostaglandin D and E metabolites are elevated with disease severity in patients with Fukuyama congenital muscular dystrophy.

Treatment approaches are lacking for Fukuyama congenital muscular dystrophy (FCMD), the second most common type of pediatric muscular dystrophy after Duchenne muscular dystrophy (DMD) in the Japanese population. Recent studies demonstrating the involvement of prostaglandin (PG) D in DMD progression has led to the development of novel inhibitors targeting hematopoietic PGD synthase. This study aimed to determine the role of PGD in FCMD etiology in 42 patients with FCMD and 77 healthy age-matched individuals.

Direct photoreception by pituitary endocrine cells regulates hormone release and pigmentation.

The recent discovery of nonvisual photoreceptors in various organs has raised expectations for uncovering their roles and underlying mechanisms. In this work, we identified a previously unrecognized hormone-releasing mechanism in the pituitary of the Japanese rice fish (medaka) induced by light. Ca imaging analysis revealed that melanotrophs, a type of pituitary endocrine cell that secretes melanocyte-stimulating hormone, robustly increase the concentration of intracellular Ca during short-wavelength light exposure.

Successful skipping of abnormal pseudoexon by antisense oligonucleotides in vitro for a patient with beta-propeller protein-associated neurodegeneration.

Pathogenic variants in WDR45 on chromosome Xp11 cause neurodegenerative disorder beta-propeller protein-associated neurodegeneration (BPAN). Currently, there is no effective therapy for BPAN. Here we report a 17-year-old female patient with BPAN and show that antisense oligonucleotide (ASO) was effective in vitro.

V180I genetic Creutzfeldt-Jakob disease: Severe degeneration of the inferior olivary nucleus in an autopsied patient with identification of the M2T prion strain.

Genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation (V180I gCJD) is the most common type of gCJD in Japan, characterized by an older age at onset, slower progression, and moderate to severe cortical degeneration with spongiform changes and sparing of the brainstem and cerebellum. Degeneration of the inferior olivary nucleus (IO) is rarely observed in patients with CJD but is known to occur in fatal familial insomnia (FFI) and MM2-thalamic-type sporadic CJD (sCJD-MM2T) involving type 2 prion protein (M2T prion). Here we report on an 81-year-old Japanese woman who initially developed depressive symptoms followed by progressive cognitive impairment, myoclonus, and hallucinations and died after a clinical course of 23 months.

Correction: Noguchi et al. PCR-Based Screening of Spinal Muscular Atrophy for Newborn Infants in Hyogo Prefecture, Japan. 2022, , 2110.

The authors wish to make the following correction to this paper [...

Synthesis of new vitamin K derivatives with a ketone group at the C-1' position of the side chain and their conversion to menaquinone-4.

Prior to being utilized in the body, dietary vitamin K homologues are converted to menaquinone-4 (MK-4) by cleavage of the side chain part followed by prenylation. We predicted that the prenylation would occur due to the electron deficiency at the C-1' position of the allyl moiety. Therefore, as an alternative method to make the C-1' position electron-deficient, a new vitamin K derivative was synthesized by introducing a ketone group, and its conversion to MK-4 was investigated.

Preventive or promotive effects of polymorphic heterozygosity on the onset of prion disease.

The polymorphic heterozygosity of at codon 129 or 219 prevents the onset of sporadic Creutzfeldt-Jakob disease (sCJD). We investigated the association between polymorphic genotypes at codon 129 or 219 and comprehensive prion disease onset using non-CJD as a reference. EK heterozygotes at codon 219, versus EE homozygotes, showed a preventive effect on the extensive prion diseases-sCJD, genetic CJD (gCJD) with V180I or M232R mutation, and Gerstmann-Straussler-Scheinker disease with P102L mutation.

A point mutation in GPI-attachment signal peptide accelerates the development of prion disease.

A missense variant from methionine to arginine at codon 232 (M232R) of the prion protein gene accounts for ~ 15% of Japanese patients with genetic prion diseases. However, pathogenic roles of the M232R substitution for the induction of prion disease have remained elusive because family history is usually absent in patients with M232R. In addition, the clinicopathologic phenotypes of patients with M232R are indistinguishable from those of sporadic Creutzfeldt-Jakob disease patients.

PCR-Based Screening of Spinal Muscular Atrophy for Newborn Infants in Hyogo Prefecture, Japan.

Spinal muscular atrophy (SMA) is a common devastating neuromuscular disorder, usually involving homozygous deletion of the gene. Newly developed drugs can improve the motor functions of infants with SMA when treated in the early stage. To ensure early diagnosis, newborn screening for SMA (SMA-NBS) via PCR-based genetic testing with dried blood spots (DBSs) has been spreading throughout Japan.

Stability and Oligomerization of Mutated SMN Protein Determine Clinical Severity of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disease characterized by defects of lower motor neurons. Approximately 95% of SMA patients are homozygous for () gene deletion, while ~5% carry an intragenic mutation. Here, we investigated the stability and oligomerization ability of mutated SMN1 proteins.

Parkinson's disease with a typical clinical course of 17 years overlapped by Creutzfeldt-Jakob disease: an autopsy case report.

Background: Late-stage Parkinson's disease (PD) often presents with neuropsychiatric symptoms such as dementia, psychosis, excessive daytime sleepiness, apathy, depression, and anxiety. However, neuropsychiatric symptoms are the cardinal features of Creutzfeldt-Jakob disease (CJD), raising the possibility that CJD may be an overlooked condition when it accompanies late-stage PD.

Case Presentation: We describe a female autopsy case of PD with a typical clinical course of 17 years, in which CJD overlapped with PD during the final year of the patient's life.

Derivatization-assisted enzyme-linked immunosorbent assay for identifying hallucinogenic mushrooms with enhanced sensitivity.

A sensitive immunochemical method for identifying hallucinogenic mushrooms (magic mushrooms) is required for regulating their illicit use. We have previously generated a monoclonal antibody (mAb) that targets psilocin (Psi), the major psychoactive compound in hallucinogenic mushrooms, and developed an enzyme-linked immunosorbent assay (ELISA). However, this ELISA failed to achieve the expected low-picomole-range sensitivity, as a result of insufficient affinity of the mAb to Psi.

Dried Blood Spot Screening System for Spinal Muscular Atrophy with Allele-Specific Polymerase Chain Reaction and Melting Peak Analysis.

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance caused by homozygous deletions. Although SMA has been considered as incurable, newly developed drugs improve life prognoses and motor functions of patients. To maximize the efficacy of the drugs, SMA patients should be treated before symptoms become apparent.

Genetic Creutzfeldt-Jakob disease-M232R with the cooccurrence of multiple prion strains, M1 + M2C + M2T: Report of an autopsy case.

Genetic Creutzfeldt-Jakob disease (gCJD) with a methionine to arginine substitution at codon 232 of the prion protein gene (gCJD-M232R) is rare and has only been reported in Japan. We report an autopsy case of gCJD-M232R showing alleles of codon 129 that were homozygous for methionine and the presence of multiple strains of the protease-resistant, abnormal isoform of prion protein (PrP ), M1 + M2C + M2T. The patient, a 54-year-old Japanese man, died after a clinical course of 21 months characterized by slowly progressive dementia and sleep disturbance.

A Novel System for Spinal Muscular Atrophy Screening in Newborns: Japanese Pilot Study.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by gene deletion/mutation. The drug nusinersen modifies mRNA splicing, increasing the production of the full-length SMN protein. Recent studies have demonstrated the beneficial effects of nusinersen in patients with SMA, particularly when treated in early infancy.

Two distinct prions in fatal familial insomnia and its sporadic form.

Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear.

Immunochemical monitoring of psilocybin and psilocin to identify hallucinogenic mushrooms.

Development of rapid and reliable immunochemical methods for monitoring psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine; Pyb) and psilocin (dephosphorylated metabolite; Psi), the psychoactive compounds contained within hallucinogenic mushrooms (magic mushrooms), is desirable in order to identify these mushrooms and regulate their illicit use. Because no antibody was publicly available for this purpose, we generated two independent monoclonal antibodies (mAbs) against Pyb or Psi, and then developed enzyme-linked immunosorbent assays (ELISAs) by using them. To generate the specific antibodies, novel immunogenic conjugates were prepared by linking Pyb or Psi molecules to carrier proteins by modifying their 2-(N,N-dimethylamino)ethyl side chains.

Clonal array profiling of scFv-displaying phages for high-throughput discovery of affinity-matured antibody mutants.

"Antibody-breeding" approach potentially generates therapeutic/diagnostic antibody mutants with greater performance than native antibodies. Therein, antibody fragments (e.g.

Phosphoethanolamine Elevation in Plasma of Spinal Muscular Atrophy Type 1 Patients.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration or loss of lower motor neurons. The survival of motor neuron (SMN) 1 gene, which produces the SMN protein, has been identified as a responsible gene for the disease. SMN is ubiquitously expressed in any tissue and may play an important role on the metabolism in the human body.

Seeking high-priority mutations enabling successful antibody-breeding: systematic analysis of a mutant that gained over 100-fold enhanced affinity.

"Antibody-breeding" has provided therapeutic/diagnostic antibody mutants with greater performance than native antibodies. Typically, random point mutations are introduced into the V and V domains of parent antibodies to generate diverse libraries of single-chain Fv fragments (scFvs), from which evolved mutants are selected. We produced an scFv against estradiol-17β with 11 amino acid substitutions and a >100-fold improved affinity constant (K = 1.

Study on structure-activity relationship of vitamin K derivatives: Conversion of the naphthoquinone part into another aromatic ring and evaluation of their neuronal differentiation-inducing activity.

We synthesized novel vitamin K derivatives by converting the naphthoquinone group to benzene derivatives and benzoquinone. We evaluated their neuronal differentiation activities to investigate the effect of the quinone moiety on this process. We observed that the 1,4-quinone as well as the side chain part play important roles in neuronal differentiation.

Newborn Screening for Spinal Muscular Atrophy: DNA Preparation from Dried Blood Spot and DNA Polymerase Selection in PCR.

Background: Polymerase chain reaction (PCR) analysis using DNA from dried blood spot (DBS) samples on filter paper is a critical technique for spinal muscular atrophy (SMA) newborn screening. However, DNA extraction from DBS is time-consuming, and elimination of PCR inhibitors from DBS is almost impossible.

Methods: Exon 7 of the two homologous SMA-related genes, survival motor neuron (SMN) 1 and SMN2, of five SMA patients and five controls were amplified by PCR with a punched-out circle of the DBS paper.

Nested PCR Amplification Secures DNA Template Quality and Quantity in Real-time mCOP-PCR Screening for SMA.

Background: Spinal Muscular Atrophy (SMA) is a common autosomal recessive disorder caused by SMN1 gene deletion. SMA has been considered an incurable disease. However, a newly-developed antisense oligonucleotide drug, nusinersen, brings about a good outcome to SMA patients in the clinical trials.