Early expression of serum CCL8 closely correlates to non-relapse mortality after allogeneic hematopoietic stem cell transplantation

To explore the role of Chemokine (C-C motif) ligand 8 (CCL8) as a potential biomarker for acute graft-versus-host disease (aGVHD), we retrospectively analyzed the sera and clinical course of 31 patients with grade II?IV aGVHD. No deaths occurred in the ten patients with serum CCL8 concentrations less than 213 pg/mL, whereas 11 of the 21 patients with more than 213 pg/mL died within 180 days post-transplantation. This landmark analysis revealed a significantly lower urvival rate of patients with a CCL8 serum concentration greater than 213 pg/mL. Thus, elevated serum CCL8 concentration before day 100 post-transplantation may predict aGVHD prognosi

Inositol pyrophosphate profiling reveals regulatory roles of IP6K2-dependent enhanced IP7 metabolism in the enteric nervous system

Inositol pyrophosphates regulate diverse physiological processes; to better understand their functional roles, assessing their tissue-specific distribution is important. Here, we profiled inositol pyrophosphate levels in mammalian organs using an originally designed liquid chromatography-mass spectrometry (LC-MS) protocol and discovered that the gastrointestinal tract (GIT) contained the highest levels of diphosphoinositol pentakisphosphate (IP7) and its precursor inositol hexakisphosphate (IP6). Although their absolute levels in the GIT are diet dependent, elevated IP7 metabolism still exists under dietary regimens devoid of exogenous IP7. Of the major GIT cells, enteric neurons selectively express the IP7-synthesizing enzyme IP6K2. We found that IP6K2-knockout mice exhibited significantly impaired IP7 metabolism in the various organs including the proximal GIT. In addition, our LC-MS analysis displayed that genetic ablation of IP6K2 significantly impaired IP7 metabolism in the gut and duodenal muscularis externa containing myenteric plexus. Whole transcriptome analysis of duodenal muscularis externa further suggested that IP6K2 inhibition significantly altered expression levels of the gene sets associated with mature neurons, neural progenitor/stem cells, and glial cells, as well as of certain genes modulating neuronal differentiation and functioning, implying critical roles of the IP6K2-IP7 axis in developmental and functional regulation of the enteric nervous system. These results collectively reveal an unexpected role of mammalian IP7-a highly active IP6K2-IP7 pathway is conducive to the enteric nervous system

Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy

ObjectivesWe sought to explore the relationship between a Tcap gene (TCAP)abnormality and cardiomyopathy.BackgroundHypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc.MethodsThe TCAPwas analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays—yeast two-hybrid and glutathion S-transferase pull-down competition—were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q.ResultsTwo TCAPmutations, T137I and R153H, were found in patients with HCM, and another TCAPmutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1.ConclusionsThese observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components

Named Entities Extraction by Citizen Participation and Machine Learning for Making Machine-readable Old Records of the Edo Period Remaining in Local Communities

わが国には，江戸時代以前に記された業務記録や証文などの古記録が数多く存在する．これらを有効に活用するためには，少ない工数で機械可読データを構築する必要がある．特に，地域特有の資料の場合には，地域特有の固有表現への対応が必要となる．本研究では，江戸期の業務日誌である「小城藩日記データベース」の目録記事文からLinked Data などの機械可読データを生成することを具体的目標とし，固有表現抽出の効率化を行う．その第1 の手法は，市民参加による人手そのものの有効活用である．第2の手法は，機械学習による固有表現の自動抽出である．これらの手法を組み合わせることで，通常は収集の難しい地域特有の固有表現を記事文から，自動かつ高精度で抽出可能である．There are many ancient documents such as business records and testimonials written before the Edo period in Japan. Machine-readable metadata will be one of effective tools for utilizing those records. In cases of materials related to a very small area, in particular, it is necessary to deal with unique expressionsrestricted in the area. In this study, we set a specific goal to generate machine-readable metadata such as Linked Data from the database of the cataloged articles for the Ogi-han Nikki (business records) from the Edo period. We aim to improve the efficiency in extraction processes of named entities. For this purpose, we employ two methods. The first is effective use of human resources through citizen participation. The secondis automated extraction of named entities by machine learning. We show that the proposed method works well even for materials related to a local area.吉賀, 夏子, 堀, 良彰, 只木, 進一, et al. 郷土に残存する江戸期古記録の機械可読化を目的とした市民参加および機械学習による固有表現抽出 : . 情報処理学会論文誌 63, 310 (2022); https://doi.org/10.20729/00216238

Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats

Background: Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive neurons in the basolateral amygdala and anxiety-like behavior. Results: Three-week-old male rats were divided into two groups: those reared in an enriched environment (EE rats) and those reared in standard cages (SE rats). After 5 weeks of rearing, the EE rats showed decreased anxiety-like behavior in an open field than the SE rats. Under another anxiogenic situation, in a beam walking test, the EE rats more quickly traversed an elevated narrow beam. Anxiety-like behavior in the open field was significantly and negatively correlated with walking time in the beam-walking test. Immunohistochemical tests revealed that the number of parvalbumin-positive neurons significantly increased in the basolateral amygdala of the EE rats than that of the SE rats, while the number of calbindin-D28k-positive neurons did not change. These parvalbumin-positive neurons had small, rounded soma and co-expressed the glutamate decarboxylase (GAD67). Furthermore, the number of parvalbumin-positive small cells in the basolateral amygdala tended to positively correlate with emergence in the center arena of the open field and negatively correlated with walking time in the beam walking test. Conclusion: Rearing in the enriched environment augmented the number of parvalbumin-containing specific inhibitory neuron in the basolateral amygdala, but not that of calbindin-containing neuronal phenotype. Furthermore, the number of parvalbumin-positive small neurons in the basolateral amygdala was negatively correlated with walking time in the beam walking test and tended to be positively correlated with activity in the center arena in the open field test. The results suggest that rearing in the enriched environment augmented parvalbumin-positive specific neurons in the basolateral amygdala, which induced behavioral plasticity that was reflected by a decrease in anxiety-like behavior in anxiogenic situations.This work was supported partly by JSPS (Japan Society for the Promotion of Science) Asian Core Program, and the Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Scientific Research (A) (22240051)

Discovery of Potent Disheveled/Dvl Inhibitors Using Virtual Screening Optimized With NMR-Based Docking Performance Index

Most solid tumors have their own cancer stem cells (CSCs), which are resistant to standard chemo-therapies. Recent reports have described that Wnt pathway plays a key role in self-renewal and tumorigenesis of CSCs. Regarding the Wnt/β-catenin pathway, Dvl (mammalian Disheveled) is an attractive target of drug discovery. After analyzing the PDZ domain of human Dvl1 (Dvl1-PDZ) using NMR, we subjected it to preliminary NMR titration studies with 17 potential PDZ-binding molecules including CalBioChem-322338, a commercially available Dvl PDZ domain inhibitor. Next, we performed virtual screening (VS) using the program GOLD with nine parameter sets. Results were evaluated using the NMR-derived docking performance index (NMR-DPI). One parameter set of GOLD docking showing the best NMR-DPI was selected and used for the second VS against 5,135 compounds. The second docking trial identified more than 1,700 compounds that exhibited higher scores than CalBioChem-322338. Subsequent NMR titration experiments with five new candidate molecules (NPL-4001, 4004, 4011, 4012, and 4013), Dvl1-PDZ revealed larger chemical shift changes than those of CalBioChem-322338. Finally, these compounds showed partial proliferation inhibition activity against BT-20, a triple negative breast cancer (TNBC) cell. These compounds are promising Wnt pathway inhibitors that are potentially useful for anti-TNBC therapy