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Development of a versatile Method for Removing Effects of Snow and Rainfall from Crustal Deformation Data
Get PDF新潟大学Niigata University博士（理学）新大院博(理)第503
CRISPR/CasRxは新生児期マウスのKRAS変異誘発性脳動静脈奇形の形成を抑制する
Get PDF新潟大学Niigata University博士（医学）Brain arteriovenous malformations (bAVMs) are anomalies forming vascular tangles connecting the arteries and veins, which cause hemorrhagic stroke in young adults. Current surgical approaches are highly invasive, and alternative therapeutic methods are warranted. Recent genetic studies identified KRAS mutations in endothelial cells of bAVMs; however, the underlying process leading to malformation in the postnatal stage remains unknown. Here we established a mouse model of bAVM developing during the early postnatal stage. Among 4 methods tested, mutant KRAS specifically introduced in brain endothelial cells by brain endothelial cell–directed adeno-associated virus (AAV) and endothelial cell–specific Cdh5-CreERT2 mice successfully induced bAVMs in the postnatal period. Mutant KRAS led to the development of multiple vascular tangles and hemorrhage in the brain with increased MAPK/ERK signaling and growth in endothelial cells. Three-dimensional analyses in cleared tissue revealed dilated vascular networks connecting arteries and veins, similar to human bAVMs. Single-cell RNA-Seq revealed dysregulated gene expressions in endothelial cells and multiple cell types involved in the pathological process. Finally, we employed CRISPR/CasRx to knock down mutant KRAS expression, which efficiently suppressed bAVM development. The present model reveals pathological processes that lead to postnatal bAVMs and demonstrates the efficacy of therapeutic strategies with CRISPR/CasRx.Saito S, Nakamura Y, Miyashita S, Sato T, Hoshina K, Okada M, Hasegawa H, Oishi M, Fujii Y, Körbelin J, Kubota Y, Tainaka K, Natsumeda M, Ueno M. CRISPR/CasRx suppresses KRAS-induced brain arteriovenous malformation developed in postnatal brain endothelial cells in mice. JCI Insight. 2024 Nov 22;9(22):e179729. doi: 10.1172/jci.insight.179729.新大院博(医)第1233
6-ハイドロキシドパミンによる両側背側線条体病変を惹起したParkinson病モデルマウスでは認知的アパシー様の行動を呈する
Get PDF新潟大学Niigata University博士（医学）Among the symptoms of Parkinson’s disease (PD), apathy comprises a set of behavioral,affective, and cognitive features that can be classified into several subtypes. However, the
pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 μg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase(TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component.Okitsu, M.; Fujita, M.; Moriya, Y.; Kotajima-Murakami, H.; Ide, S.; Kojima, R.; Sekiyama, K.; Takahashi, K.; Ikeda, K. Mouse Model of Parkinson’s Disease with Bilateral Dorsal Striatum Lesion with 6-Hydroxydopamine Exhibits Cognitive Apathy-like Behavior. Int. J. Mol. Sci. 2024, 25, 7993. https://doi.org/10.3390/ijms25147993新大院博(医)第1247
肺アスペルギルス症診断のための２種類の抗アスペルギルスIgG抗体測定キットの比較
Get PDF新潟大学Niigata University博士（医学）Aspergillus-specific antibodies are diagnostic indicators of allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). Tests for detecting Aspergillus-specific antibodies were not used clinically in Japan,and the production of the Aspergillus precipitin test was discontinued. Thus,alternative tests for diagnosing aspergillosis are urgently needed. We retrospectively evaluated 64 patients with suspected ABPA and CPA who underwent precipitin antibody testing. Serum Aspergillus IgG levels were measured and compared using the Bordier Aspergillus fumigatus ELISA and the Platelia Aspergillus IgG (Bio-Rad) kits. Of the participants,18 were diagnosed with CPA, and 8 were diagnosed with ABPA. Both the Bordier and Bio-Rad kits showed high sensitivity and specificity for CPA and ABPA. The area under the receiver operating characteristic curves for the Bordier and Bio-Rad kits were 0.97 and 0.95,respectively,for CPA,and 0.89 and 0.91,respectively, for ABPA. In contrast to the Bordier kit,the Bio-Rad kit showed relatively low anti-Aspergillus IgG levels and lower sensitivity to non-fumigatus Aspergillus infections. The Aspergillus-specific IgG ELISA tests showed sufficient diagnostic accuracy. Therefore,these assays are recommended as alternatives to the precipitin kit for diagnosing aspergillosis in clinical settings in Japan.Ikumi Yamagishi, Yuuki Bamba, Hiroshi Moro, Naoto Kanno, Hayato Tsuruma, Mariko Hakamata, Hideyuki Ogata, Satoshi Shibata, Nobumasa Aoki, Yasuyoshi Ohshima, Satoshi Watanabe, Toshiyuki Koya, Toshiaki Kikuchi, Retrospective Comparison of Two Aspergillus IgG Enzyme Immunoassays for Diagnosing Pulmonary Aspergillosis, Medical Mycology Journal, 2024, 65 巻, 3 号, p. 41-47, 公開日 2024/08/31, Online ISSN 2186-165X, Print ISSN 2185-6486, https://doi.org/10.3314/mmj.24.00004, https://www.jstage.jst.go.jp/article/mmj/65/3/65_41/_article/-char/ja新大院博(医)第1263
BRAF non-V600E変異大腸癌の粘液形質と遺伝子変異の特徴
Get PDF新潟大学博士（医学）Colorectal cancer (CRC) is a heterogeneous disease that develops through stepwise accumulation of genetic alterations and progresses via several distinct pathways. However, the tumorigenesis of CRCs with BRAF non-V600E mutations remains unclear. Here, we aimed to elucidate the tumorigenesis of CRCs with BRAF non-V600E mutations, focusing on differences in mucin phenotype and genetic alterations between CRCs with non-V600E and V600E mutations. We investigated 201 patients with CRC and performed panel testing of 415 genes to identify BRAF mutations. Patients were classified into five mucin phenotypes – large-intestinal, small-intestinal, gastric, mixed, and unclassified – using immunohistochemistry for CD10, MUC2, MUC5AC, and MUC6. BRAF mutations were identified in 24 of 201 patients’ samples, of which 13 (6.5%) had a V600E mutation (V600E-mutant) and 11 (5.5%) had non-V600E mutations (non-V600E-mutant). MUC5AC expression was significantly associated with V600E mutations (P = 0.040), while CD10 expression was significantly associated with non-V600E mutations (P = 0.010). The small-intestinal mucin phenotype was significantly associated with non-V600E mutations (P = 0.031), while the mixed mucin phenotype was significantly associated with V600E mutations (P = 0.027). Regarding genetic alterations, focusing on the WNT signaling pathway, APC mutation was significantly associated with non-V600E mutations (P < 0.001), while RNF43 mutation was significantly associated with V600E mutations (P = 0.020). Considering the differences in mucin phenotype and genetic alterations, different modes of tumorigenesis are assumed for CRC with BRAF V600E mutation and non-V600E mutations. These findings are important in understanding the biology and treatment strategies for BRAF-mutant CRC.Hikaru Ozeki, Yoshifumi Shimada, Mae Nakano, Shuhei Kondo, Riuko Ohashi, Yamato Miwa, Daisuke Yamai, Akio Matsumoto, Kaoru Abe, Yosuke Tajima, Hiroshi Ichikawa, Jun Sakata, Yasumasa Takii, Mika Sugai, Takahiro Nagai, Yiwei Ling, Shujiro Okuda, Toshifumi Wakai,
Mucin phenotype and genetic alterations in non-V600E BRAF-mutated colorectal cancer,
Human Pathology,
Volume 145,
2024,
Pages 71-79,
ISSN 0046-8177,
https://doi.org/10.1016/j.humpath.2024.02.009.
(https://www.sciencedirect.com/science/article/pii/S0046817724000327)新大院博（医）第1272
