Genome-wide search for strabismus susceptibility loci.

The purpose of this study was to search for chromosomal susceptibility loci for comitant strabismus. Genomic DNA was isolated from 10mL blood taken from each member of 30 nuclear families in which 2 or more siblings are affected by either esotropia or exotropia. A genome-wide search was performed with amplification by polymerase chain reaction of 400 markers in microsatellite regions with approximately 10 cM resolution. For each locus, non-parametric affected sib-pair analysis and non-parametric linkage analysis for multiple pedigrees (Genehunter software, http://linkage.rockefeller.edu/soft/) were used to calculate multipoint lod scores and non-parametric linkage (NPL) scores, respectively. In sib-pair analysis, lod scores showed basically flat lines with several peaks of 0.25 on all chromosomes. In non-parametric linkage analysis for multiple pedigrees, NPL scores showed one peak as high as 1.34 on chromosomes 1, 2, 4, 7, 10, 15, and 16, while 2 such peaks were found on chromosomes 3, 9, 11, 12, 18, and 20. Non-parametric linkage analysis for multiple pedigrees of 30 families with comitant strabismus suggested a number of chromosomal susceptibility loci. Our ongoing study involving a larger number of families will refine the accuracy of statistical analysis to pinpoint susceptibility loci for comitant strabismus.&#60;/P&#62;</p

Growth ability in various macaque cell lines of HIV-1 with simian cell-tropism

We have recently constructed a series of novel human immunodeficiency viruses (HIV-1s) that are tropic for a macaque cell line (mt ; macaque cell-tropic) to generate and establish a primate experimental system for HIV-1/AIDS study. In order to determine biological properties of these viruses effectively, several other macaque cell lines with distinct characteristics that can be routinely and easily used, instead of primary cells, for infection experiments are required. In this study, we have examined four macaque cell lines for their surface expression of virus receptor molecules and for their genotype of a major anti-viral capsid gene. Furthermore, we monitored the susceptibility of the cell lines to a standard simian immunodeficiency virus (SIV) clone and three representative basic mt HIV-1 clones. Results obtained here have clearly indicated that these cell lines are exquisitely useful to characterize various SIVs and more importantly, mt HIV-1s

Suppressive effects of transforming growth factor-beta1 produced by hepatocellular carcinoma cell lines on interferon-gamma production by peripheral blood mononuclear cells.

Transforming growth factor-beta1 (TGF-beta1) exerts potent immunosuppressive effects. In this study, we investigated the potential role of TGF-beta1 produced by hepatocellular carcinoma (HCC) cell lines in immunosuppression mechanisms. Using the Mv1Lu cell-growth inhibition assay and an enzyme-linked immunosorbent assay (ELISA), we detected optimal levels of TGF-beta1 in the culture supernatants conditioned by the HCC cell lines PLC/PRF/5, Hep3B, and HepG2. To determine the biological activity of TGF-beta1 in the supernatants, we examined the effects of the culture supernatants on the production of interferon (IFN)-gamma induced during the culture of peripheral blood mononuclear cells (PBMCs) stimulated with interleukin (IL)-12. IFN-gamma production of IL-12-stimulated PBMCs in the 1:1 dilution of the acid-activated conditioned medium of PLC/PRF/5, Hep3B, and HepG2 reduced to 14.7 +/- 0.8, 17.3 +/- 9.0, and 35.9 +/- 14.6%, respectively, compared with the value in the culture with control medium (complete culture medium). These results suggest that HCC cells producing TGF-beta1 may reduce the generation or activation of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, and thus could enhance their ability to escape immune-mediated surveillance.</p

Semaphorin 3F and Netrin-1: The Novel Function as a Regulator of Tumor Microenvironment

Axon guidance molecules play an important role in regulating proper neuronal networking during neuronal development. They also have non-neuronal properties, which include angiogenesis, inflammation, and tumor development. Semaphorin 3F (SEMA3F), a member of the class 3 semaphorins, was initially identified as an axon guidance factor, that repels axons and collapses growth cones. However, SEMA3F has similar effects on endothelial cells (ECs) and tumor cells. In this review, we discuss the novel molecular mechanisms underlying SEMA3F activity in vascular and tumor biology. Recent evidence suggests that SEMA3F functions as a PI3K-Akt-mTOR inhibitor in mammalian cells, including T cells, ECs, and tumor cells. Therefore, SEMA3F may have broad therapeutic implications. We also discuss the key role of axon guidance molecules as regulators of the tumor microenvironment. Netrin-1, a chemoattractant factor in the neuronal system, promotes tumor progression by enhancing angiogenesis and metastasis. Moreover, our recent studies demonstrate that netrin-1/neogenin interactions augment CD4+ T cell chemokinesis and elicit pro-inflammatory responses, suggesting that netrin-1 plays a key role in modulating the function of a tumor and its surrounding cells in the tumor microenvironment. Overall, this review focuses on SEMA3F and netrin-1 signaling mechanisms to understand the diverse biological functions of axon guidance molecules

Amino acid alterations in Gag that confer the ability to grow in simian cells on HIV-1 are located at a narrow CA region

We previously generated a prototype monkey-tropic human immunodeficiency virus type 1 (HIV-1) designated NL-DT5R. This viral clone has a small region of simian immunodeficiency virus (SIV) within Gag capsid (CA) protein and also SIV Vif protein, but displays a poor growth phenotype in simian cells. To improve the growth potential of NL-DT5R, we have constructed a series of its gag variant viruses. Out of fourteen viral clones generated, five were infectious for simian HSC-F cells, and two of the infectious variants grew similarly with NL-DT5R. Taking their genome structures into consideration, our data here clearly show that a narrow CA region within the Gag protein, i.e., the domain around cyclophilin A (CypA)-binding loop, is critical for the growth ability of HIV-1 in simian cells

ERRγ agonist under mechanical stretching manifests hypertrophic cardiomyopathy phenotypes of engineered cardiac tissue through maturation

iPS細胞から成熟した人工心筋組織の作製方法の開発 肥大型心筋症の治療法開発への利用に期待. 京都大学プレスリリース. 2023-10-06.Stretching and stimulating engineered heart tissues to accurately portray hypertrophic cardiomyopathy. 京都大学プレスリリース. 2023-10-17.Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115∗) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations

Neoadjuvant Chemotherapy with or without Concurrent Hormone Therapy in Estrogen Receptor-Positive Breast Cancer:NACED-Randomized Multicenter Phase II Trial

Although in the neoadjuvant setting for estrogen receptor (ER)-positive breast cancers, chemotherapy or hormone therapy alone does not result in satisfactory tumor response, it is unknown whether concurrent chemo-endocrine therapy is superior to chemotherapy alone in clinical outcomes. We conducted a randomized phase II trial to test the responses of ER-positive patients to concurrent administration of chemo-endocrine therapy in the neoadjuvant setting. Women with stage II-III, ER-positive, invasive breast cancer (n=28) received paclitaxel followed by fluorouracil, epirubicin, cyclophosphamide (T-FEC) and were randomized to receive concurrent chemo-endocrine therapy consisting of goserelin administered subcutaneously for premenopausal women or an aromatase inhibitor for postmenopausal women. The primary endpoint was the pathological complete response (pCR) rate after neoadjuvant therapy. Twenty-eight patients were randomized. There were no significant differences in pCR rate between the concurrent group (12.5%;2/16) and the chemotherapy alone group (8.3%;1/12). Tumor size after therapy was significantly reduced in the concurrent therapy group (p=0.035), but not in the chemotherapy-alone group (p=0.622). Neoadjuvant chemotherapy with concurrent hormone therapy provided no significant improvement in pCR rate in ER-positive breast cancers. These preliminary results should be followed up by further studies

Therapeutic effects of azathioprine in combination with low-dose prednisolone in patients with intractable autoimmune hepatitis type 1.

This study evaluated the effects of azathioprine in combination with low-dose prednisolone in the management of patients with intractable autoimmune hepatitis. Thirteen patients with intractable autoimmune hepatitis who had an incomplete or arrested response to conventional prednisolone therapy, or who relapsed during prednisolone maintenance therapy were additionally administered 50 or 100 mg/day of azathioprine in combination with prednisolone. This regimen reliably induced complete remission in 12 of 13 patients, and these 12 remained in remission during the follow-up period with maintenance therapy of 50 mg/day of azathioprine in combination with 5 mg/day of prednisolone. The findings of the current study indicate that the azathioprine and low-dose prednisolone combined therapy may offer a satisfactory alternative therapy for patients with intractable autoimmune hepatitis who have an incomplete or arrested response to conventional prednisolone therapy, or who relapse during prednisolone maintenance therapy.</p

Trends and Practical Issues in Collaboration between Communities and Schools: Focusing on School Management Councils and Community Schools

This paper aimed to summarize trends in educational policies, pedagogical research, and educational practices concerning communities and schools, and to clarify the practical matters of school-based community development, especially practical development and issues concerning collaboration between communities and schools, with a focus on school management councils and community schools. To this end, we examined trends in educational policies in terms of collaboration between communities and schools. Next, we explored trends in pedagogical research and educational practices from three perspectives (educational methods, educational administration, and social education), and their regional development and issues. Then, from the perspective of collaboration between different types of schools and between schools and local communities, we investigated discuss two local practices (Waki-Cho in Yamaguchi Prefecture and Niseko-Cho in Hokkaido) that promote advanced practices through the establishment of school management councils. Finally, based on the field research, we examined the significance of these practices and future topics