次世代リージョナルジェット機開発のための多目的設計探査と空力弾性解析

要約のみTohoku University大林茂課

Advance of genomic technology and clinical genomics

In recent years, genome technology has made dramatic progress. Genome analysis technology began with the development of the Sanger method, and the advent of next-generation sequencers has made it possible to obtain vast amounts of genome information very rapidly. We have always explored for the causative genes of genetic diseases by the latest technologies. Identification of causative genes requires a large number of genome samples. To date, we have accumulated a huge number of genome samples, including 900 for amyotrophic lateral sclerosis（ALS）, 4,000 for spinocerebellar degeneration（SCD）, 750 for Parkinsonʼs disease, and 2,000 for dystonia. In order to efficiently identify the causative genes, we have also developed a genetic analysis method using single nucleotide polymorphisms. Utilizing these techniques, we have identified several causative genes as follows : OPTN and LRP12, causing ALS ; CACNA1G and HSD17B4, causing SCD ; and TWNK, causing Perrault syndrome. Furthermore, we have contributed to the elucidation of pathogenesis through functional analysis of these causative genes. Clinical genomics is a medical field that provides services based on genome information. Clinical genomics is expected to be used not only for the diagnosis of rare diseases, but also for the development of new treatment methods, the selection of better therapeutic drugs, and lifestyle advice tailored to the individualʼs constitution. In addition, genomic research is being actively conducted not only on conventional monogenetic diseases, but also on polygenic diseases. The demand for clinical genomics is likely to increase further in the future. Tokushima University Hospital was one of the first hospitals in Japan to engage in clinical genomics, and in December 2022, the Department of Clinical Genetics was renamed the Clinical Genomics Center. We will continue to expand the functions of the Clinical Genomics Center in preparation for the coming era of personal genome

Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient

BACKGROUND: Spinocerebellar ataxias (SCAs) are heterogeneous diseases characterized by progressive cerebellar ataxia associated with dysarthria, oculomotor abnormalities, and mental impairment. To identify the causative gene, we performed exome sequencing on a Japanese patient clinically diagnosed with recessive SCA. METHOD: The patient is a 37-year-old Japanese woman with consanguineous parents. The head magnetic resonance imaging (MRI) showed cerebellar atrophy and T1 low/T2 high intensity at the bilateral inferior olives. Single-nucleotide polymorphism (SNP) genotyping and next-generation sequencing were performed, and the variants obtained were filtered and prioritized. RESULTS: After these manipulations, we identified a homozygous nonsense mutation of the TTC19 gene (p.Q277*). TTC19 has been reported to be a causative gene of a neurodegenerative disease in Italian and Portuguese families and to be involved in the pathogenesis of mitochondrial respiratory chain complex III (cIII) deficiency. This report is the first description of a TTC19 mutation in an Asian population. Clinical symptoms and neuroimaging are consistent with previous reports. The head MRI already showed abnormal features four years before her blood lactate and pyruvate levels were elevated. CONCLUSIONS: We should consider the genetic analysis of TTC19 when we observe such characteristic MRI abnormalities. Genes associated with mitochondrial function cause many types of SCAs; the mutation we identified should help to elucidate the pathology of these disorders

Abeta Is Internalized via Macropinocytosis

Intracellular amyloid β peptide (Aβ) accumulation has drawn attention in relation to the pathophysiology of Alzheimer’s disease in addition to its extracellular deposition as senile plaque. Cellular uptake of extracellular Aβ is one of the possible mechanisms by which intracellular Aβ deposits form. Given the relevance of Aβ inside cells, it is important to understand the mechanism by which it is taken up by them. In this study, we elucidated that Neuro2A and SH-SY5Y cells internalize specifically oligomerized Aβ in a time- and dose-dependent manner. The depletion of plasma membrane cholesterol with methyl-β-cyclodextrin or treatment with trypsin diminished the internalization of oAβ, suggesting that the oAβ uptake might be both a lipid raft-dependent and heparan sulfate proteoglycan-mediated process. Treatment with a macropinocytosis inhibitor (ethylisopropyl amiloride and wortmannin) also drastically reduced the uptake of oligomer-Aβ (oAβ). oAβ-treated cells exhibited an increase in Rac1 activity, indicating that macropinocytosis induced by oAβ is regulated by these small GTPases. These findings suggest that macropinocytosis is a major endocytic route through which oAβ42 enters cells

Screening for OPTN mutations in amyotrophic lateral sclerosis in a mainly Caucasian population

Mutations in the optineurin (OPTN) gene cause amyotrophic lateral sclerosis (ALS). We previously reported 3 types of OPTN mutation in Japanese ALS subjects. Here, to identify the OPTN mutations in individuals of different ethnicity, we screened 563 sporadic ALS (SALS) subjects and 124 familial ALS (FALS) subjects who were mainly Caucasian. We found a c. 964T>C synonymous variation in exon 8. However, we could not find the meaningful OPTN mutations. The results indicate that OPTN mutations causing ALS are rare, especially in mainly Caucasian ALS subjects

Gastrointestinal cancer occurs as extramuscular manifestation in FSHD1 patients

Facioscapulohumeral dystrophy type1 (FSHD1) patients with a shortened D4Z4 repeat containing the DUX4 gene have a broad spectrum of clinical manifestations. In addition, high expression of DUX4 protein with an aberrant C terminus is frequently identified in B cell acute lymphoblastic leukemia. We investigated clinical manifestations in 31 FSHD1 patients and 30 non-affected individuals. Gastrointestinal cancers (gastric and colorectal cancers) increased after the age of 40 years and were more frequently observed in FSHD1 patients (n = 10) than in non-affected individuals (n = 2, p = 0.0217), though the incidence of cancers occurring in non-gastrointestinal tissues of FSHD1 patients was the same as that of non-affected individuals (p > 0.999). These comorbidities of FSHD1 patients were not associated with D4Z4 repeat number. Our results suggest that gastrointestinal cancers are among the extramuscular manifestations of adult FSHD1 patients, and do not depend on D4Z4 repeat number

Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis : a clinical-pathological case report

Background: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. Case presentation: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. Conclusions: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course

ALS clinically presenting with PMA

Amyotrophic lateral sclerosis (ALS) primarily affects upper and lower motor neurons. Phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) inclusion bodies are reportedly a pathological hallmark of sporadic ALS. Here, we present an atypical case of sporadic ALS that progressed very slowly, persisted for 19 years, and clinically appeared to only affect the lower motor neurons; however, upper motor neuron degeneration was detected on autopsy. Furthermore, no inclusion bodies positive for phosphorylated TDP-43, ubiquitin, fused in sarcoma, or SOD1 were detected in the CNS. We performed exome-sequencing data analysis but found no genetic disorders. This was therefore an unusual case of lower motor neuron-predominant ALS without TDP-43 pathology or known gene-disease associations. We also reviewed autopsied ALS cases that progressed slowly and had no phosphorylated TDP-43 or ubiquitin positive inclusions and present the clinicopathological features of such cases. Based on these results, there may be a sporadic ALS subgroup that progresses slowly and shows 76 no accumulation of phosphorylated TDP-43