RESUMEN
AIM: Schizophrenia (SZ) is a severe psychiatric disorder caused by the interaction of genetic and environmental factors. Although somatic mutations that occur in the brain after fertilization may play an important role in the cause of SZ, their frequencies and patterns in the brains of patients and related animal models have not been well studied. This study aimed to find somatic mutations related to the pathophysiology of SZ. METHODS: We performed whole-exome sequencing (WES) of neuronal and nonneuronal nuclei isolated from the postmortem prefrontal cortex of patients with SZ (n = 10) and controls (n = 10). After detecting somatic mutations, we explored the similarities and differences in shared common mutations between two cell types and cell type-specific mutations. We also performed WES of prefrontal cortex samples from an animal model of SZ based on maternal immune activation (MIA) and explored the possible impact of MIA on the patterns of somatic mutations. RESULTS: We did not find quantitative differences in somatic mutations but found higher variant allele fractions of neuron-specific mutations in patients with SZ. In the mouse model, we found a larger variation in the number of somatic mutations in the offspring of MIA mice, with the occurrence of somatic mutations in neurodevelopment-related genes. CONCLUSION: Somatic mutations occurring at an earlier stage of brain cell differentiation toward neurons may be important for the cause of SZ. MIA may affect somatic mutation profiles in the brain.
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Esquizofrenia , Humanos , Ratones , Animales , Esquizofrenia/metabolismo , Encéfalo/metabolismo , Corteza Prefrontal/metabolismo , Neuronas/metabolismo , MutaciónRESUMEN
We quantitatively study the Ibasho project-a unique, innovative community-based project that involves co-creating a building as a social hub. Ibasho's decision-making undertakes a bottom-up approach, differentiating itself from the conventional top-down decision-making process. Using sui generis data, we find that Ibasho projects in the Philippines and Nepal contributed to enhancing social capital among elders in both cases. Yet there are differences between the two communities. In the Philippines, participation in Ibasho increased the number of a participant's friends, or "strong ties," indicating that it is on the intensive margin of human relationships. In contrast, joining Nepal's Ibasho broadened weak ties rather than strong ones. This contrast may stem from the difference in pre-existing social and built infrastructures in the two communities, which were strengthened through the building-human interactions.
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Liderazgo , Capital Social , Humanos , Anciano , Nepal , Filipinas , AmigosRESUMEN
Evidence shows that communal resources, cohesion, and social infrastructure can mitigate shocks and enhance resilience. However, we know less about how specific social capital building interventions facilitate recovery in post-disaster environments. Using a survey of over 1000 residents of Ofunato, Japan after the 2011 Tohoku earthquake and tsunami, this study demonstrates that the individuals who actively participated in a community center-created for and led by neighborhood elders-reported higher levels of family and neighborhood recovery than similar individuals who did not participate. Results from ordinal logistic regression analyses, propensity score matching (PSM) and coarsened exact matching (CEM) show arguably stronger causal links between bottom-up, microlocal programs to boost connections in post-disaster areas and post-disaster outcomes. Community-based programs that strengthen social ties even among elderly residents can measurably improve their recoveries.
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Desastres , Capital Social , Anciano , Humanos , Japón , Autoinforme , TsunamisRESUMEN
SLC6A4, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (N = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL28-A. An in vitro luciferase assay revealed that XL28-A has no transcriptional activity. XL28-A was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL28-A is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.
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Proteínas de Transporte de Serotonina en la Membrana Plasmática , Anciano , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Genotipo , Humanos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genéticaRESUMEN
Working with elders around the world has taught me that those living in grass huts in Africa with children at their feet are often happier than people in assisted-living homes with a chandelier over their heads. My work in design consultancy and in fifteen years of running a nonprofit, Ibasho, that aims to co-create socially integrated and sustainable communities that value their elders has allowed me to learn much about how architects and designers can contribute to helping people live a good life in late life. People often need supportive services or other adaptations as they age, but do they really need-or want-the luxury environment few are accustomed to? The challenge for architects and designers is not to create a built environment whose carefully curated facades hide lives of quiet desperation. It is to help elders access the support they need without upending their lives or severing virtually all ties to their communities.
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Envejecimiento/psicología , Planificación Ambiental , Poder Psicológico , Envejecimiento Saludable , HumanosRESUMEN
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is one of the scavenger receptors that recognizes oxidized low-density lipoprotein as a major ligand. The placenta is a major source of prooxidant during pregnancy, and the level of placental oxidative stress increases rapidly at the end of the first trimester and tapers off later in gestation. In our study, we evaluated placental expression of LOX-1 during different gestational stages in mice and humans. We used immunohistochemistry and ISH to identify LOX-1-expressing cells in murine and human placentas. In both species, higher expression of LOX-1 mRNA during early to midgestational stages compared with late gestation-corresponding to the increased oxidative stress in early pregnancy-was shown by real-time RT-PCR. In murine placenta, we showed that LOX-1-expressing cells were fibroblast-like stromal cells in metrial glands and decidua basalis and that they were glycogen trophoblast cells in the junctional and labyrinth zones. In the human, LOX-1 expression was detected in villous cytotrophoblasts in both first trimester and term placentas. These localization patterns of LOX-1 in murine and human placentas suggest the possible involvement of LOX-1 in high oxidative stress conditions of pregnancy.
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Placenta/metabolismo , Receptores Depuradores de Clase E/metabolismo , Animales , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Estrés Oxidativo , Reacción en Cadena de la Polimerasa , Embarazo , ARN Mensajero/biosíntesis , Receptores Depuradores de Clase E/biosíntesis , Especificidad de la EspecieRESUMEN
A new monoclonal antibody, PM-1K, was raised against 24-h cultured human peritoneal macrophages. In immunohistochemical assays, PM-1K recognized freshly isolated blood monocytes and most tissue macrophages as well as myeloid dendritic cells such as Langerhans cells and interdigitating cells. The molecular size of the antigen recognized by PM-1K was determined to be 110 kD by means of immunoaffinity purification. Because this affinity-purified antigen recognized by PM-1K was also recognized by anti-CD68 antibodies, it is believed to be one of the heterogeneous molecules of the CD68 antigen. Analysis showed interspecies reactivity of PM-1K with macrophages from guinea pigs, pigs, bovine species, and monkeys. Among these macrophages, those of the guinea pig reacted strongly with PM-1K. Patterns of PM-1K immunostaining in guinea pig tissues were similar to those found in human tissues. Studies with the immunoelectron microscope revealed reaction products of PM-1K in the cytoplasm, especially around endosomes. Since only a few antibodies are available to label guinea pig macrophages, PM-1K is considered to be one of the most suitable antibodies to examine macrophages in experimental guinea pig models.
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Anticuerpos Monoclonales/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Macrófagos/metabolismo , Animales , Antígenos CD/análisis , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/análisis , Antígenos de Diferenciación Mielomonocítica/inmunología , Biomarcadores/análisis , Biomarcadores/metabolismo , Western Blotting , Células Dendríticas/química , Células Dendríticas/metabolismo , Endosomas/química , Endosomas/metabolismo , Endosomas/ultraestructura , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Cobayas , Humanos , Técnicas para Inmunoenzimas , Macrófagos/química , Macrófagos/citología , Macrófagos Peritoneales/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Microscopía Confocal , Microscopía Inmunoelectrónica , Especificidad de la EspecieRESUMEN
CD163 is a member of the scavenger receptor cysteine-rich superfamily restricted to the monocyte/macrophage lineage and is thought to be a useful marker for anti-inflammatory or alternatively activated macrophages. In this study we used mass spectrometric analysis to determine that the antigen recognized by the antibody AM-3K, which we previously generated as a tissue macrophage-specific monoclonal antibody, was CD163. An anti-inflammatory subtype of macrophages stimulated by dexamethasone or interleukin-10 showed strong reactivity for AM-3K and increased expression of CD163 mRNA. Immunohistochemical staining of routinely processed pathological specimens revealed that AM-3K recognized a specialized subpopulation of macrophages. In granulomatous diseases such as tuberculosis, sarcoidosis, or foreign body reactions, tissue macrophages around granulomas, but not component cells of the granulomas such as epithelioid cells and multinucleated giant cells, showed positive staining for AM-3K. In atherosclerotic lesions, scattered macrophages in diffuse intimal lesions were strongly positive for AM-3K, whereas foamy macrophages in atheromatous plaques demonstrated only weak staining. We therefore suggest that, in routine pathological specimens, AM-3K is a useful marker for anti-inflammatory macrophages because these cells can be distinguished from inflammatory or classically activated macrophages. Because AM-3K cross-reacts with macrophage subpopulations in different animal species including rats, guinea pigs, rabbits, cats, dogs, goats, pigs, bovine species, horses, monkeys, and cetaceans, it will have wide application for detection of CD163 in various animals.
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Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Macrófagos/citología , Receptores de Superficie Celular/metabolismo , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Antígenos de Diferenciación Mielomonocítica/inmunología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Neoplasias Óseas/inmunología , Neoplasias Óseas/metabolismo , Diferenciación Celular , Electroforesis en Gel de Poliacrilamida , Reacción a Cuerpo Extraño/inmunología , Reacción a Cuerpo Extraño/metabolismo , Enfermedad de Gaucher/inmunología , Enfermedad de Gaucher/metabolismo , Tumores de Células Gigantes/inmunología , Tumores de Células Gigantes/metabolismo , Histiocitosis de Células no Langerhans/inmunología , Histiocitosis de Células no Langerhans/metabolismo , Histiocitosis Sinusal/inmunología , Histiocitosis Sinusal/metabolismo , Humanos , Inmunohistoquímica , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Espectrometría de Masas , Adhesión en Parafina , Fenotipo , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/inmunología , Sarcoidosis/inmunología , Sarcoidosis/metabolismo , Neoplasias de los Tejidos Blandos/inmunología , Neoplasias de los Tejidos Blandos/metabolismo , Membrana Sinovial/patología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/metabolismoRESUMEN
Nonalcoholic steatohepatitis (NASH) is one of the life-threatening hepatic diseases; however, its pathogenesis is still unknown. To evaluate the causative role of hyperlipidaemia and high-fat diet, we compared C57BL/6 mice with inherited hyperlipidaemic model mice (LDLR(-/-)mice and ApoE(-/-) mice) fed a normal or a high-fat diet. LDLR(-/-) and ApoE(-/-) mice fed the normal diet showed significantly higher serum cholesterol level than that of C57BL/6 mice fed the high-fat diet. These mice, however, have shown neither significant elevation of serum alanine transaminase (ALT) level nor histopathologic features of steatohepatitis. High-fat diet groups of all three strains showed histopathological characteristics of steatohepatitis with elevated serum ALT levels and high expression of macrophage scavenger receptor MARCO mRNA in the liver. Semiquantitative endotoxin analysis showed an elevated serum endotoxin level in the portal vein but not in the vena cava in ApoE(-/-) mice fed the high-fat diet. These results indicate that long-term feeding of a high-fat diet induces NASH, whereas hyperlipidaemia alone is not enough to induce NASH. Liver-restricted induction of MARCO in mice with high-fat diet and portal endotoxaemia in ApoE(-/-) mice fed the high-fat diet suggest the possible involvement of endotoxin in the pathogenesis of NASH.
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Endotoxinas/metabolismo , Hígado Graso/metabolismo , Hepatitis/metabolismo , Receptores Inmunológicos/metabolismo , Alanina Transaminasa/sangre , Animales , Apolipoproteínas E/metabolismo , Colesterol/sangre , Grasas de la Dieta/administración & dosificación , Endotoxinas/análisis , Hígado Graso/complicaciones , Hígado Graso/patología , Femenino , Hepatitis/complicaciones , Hepatitis/patología , Hiperlipidemias/complicaciones , Hiperlipidemias/metabolismo , Inmunohistoquímica/métodos , Hígado/patología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/análisis , Receptores Depuradores , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
To test the possibility that acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) may be expressed in human macrophages under pathologic conditions, we employed specific anti-ACAT2 antibodies and found clear ACAT2 signals in lipid-laden as well as lipid-free macrophages under various disease conditions, including atherosclerosis. However, no ACAT2 signal was detectable in macrophages under normal physiologic conditions. Using cultured human macrophages derived from blood-borne monocytes, immunoblot and RT-PCR analyses demonstrated that immature macrophages expressed only ACAT1, but the fully differentiated macrophages expressed both ACAT1 and ACAT2. Furthermore, RT-PCR clearly revealed the presence of both ACAT1 and ACAT2 mRNAs in human atherosclerotic aorta. Double immunohistochemical staining indicated that in human atherosclerotic aorta, all macrophages expressed ACAT1, while approximately 70% to 80% of macrophages also expressed ACAT2. In congenital hyperlipidemic mice, immunohistochemistry and RT-PCR demonstrated that ACAT2 was also present in lipid-laden cells of the atheromatous plaques. Our results suggest that in atherosclerotic plaque, the ability of macrophage foam cell transformation may be augmented by the dual expressions of ACAT1 and ACAT2. Additional immunoblot and RT-PCR experiments showed that the ACAT2 signal was clearly detectable in thioglycollate-elicited exudate mouse macrophages but not in peritoneal resident macrophages. We conclude that under various pathologic conditions, fully differentiated macrophages express ACAT2 in addition to ACAT1.