Science of Thought and the Culture of Democracy in Postwar Japan, 1946-1962

This dissertation examines efforts to foster a culture of democracy in postwar Japan, focusing on Science of Thought, one of the most influential associations engaged in publicly rethinking democracy in the years after fascism and defeat. The group was founded in 1946 by seven young intellectuals whose wartime experiences had convinced them of the urgent need to bridge the gap between the world of intellectuals and that of "ordinary people." My dissertation shows how the group's many attempts to realize that goal embodied a vision of democratic experimentation that had to be re-articulated again and again in response to challenges that arose in connection with geopolitical events and also with the social changes that accompanied economic recovery and growth. For Science of Thought, democracy was not something that could be decreed by occupation authorities or conjured into existence by the media. Its seeds had to be sought in the "thought" (shisô) of the "man on the street." Contributors to the group's journal espoused a "science of thought" capable of enabling researchers to discover the mental worlds and implicit philosophies of ordinary people. Drawing methodological insight from American pragmatist philosophy and social science, the group conducted statistical surveys and interviews, and produced content analyses of popular movies, novels, and comic books in an unusual experiment to probe the mind of the "common man." In the charged political context of the early fifties, members of the group searched for new ways to nurture democracy from the grassroots. Inspired by the apparent success of the ongoing social revolution in China, members began promoting and facilitating educational and cultural movements underway in the Japanese countryside. In the process, Science of Thought became an anchor for a nation-wide network of factory workers, engineers, students, and housewives linked together by reading groups and writing circles. As economic growth began to transform Japanese society in the late fifties and early sixties, the group's earlier faith in the inherent democratic pragmatism of ordinary people gave way to promoting a more oppositional stance, embodied in the classless ideal of the citizen-activist confronting the pressures of conformism in mass society and white-collar life. On the basis of this ideal, the group became an enthusiastic supporter of the large-scale protests against the US-Japan Security Treaty in 1960, which marked the beginning of citizen movements that influenced Japanese civil society in the subsequent decades. The evolution of the group from a small research circle into a standard-bearer for citizen's activism in the sixties can be seen as a metonym for the experience of postwar progressives, an experience that included moments of pro-Enlightenment optimism and anti-American nationalism. Rather than through developing a specific theory of democracy or citizenship, the significance of Science of Thought lay in the way it exemplified democracy in practice. The accumulated practical experience of the intellectuals and citizens associated with the group remains relevant to those who continue to grapple with the dilemmas of democracy today

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Genomic discovery and functional validation of MRP1 as a novel fetal hemoglobin modulator and potential therapeutic target in sickle cell disease

ABSTRACT Sickle cell disease (SCD) remains a major health burden with limited treatment options. Despite promising gene-editing clinical trials, there is an unmet need for cost-effective therapies. As induction of fetal hemoglobin (HbF) is an established therapeutic strategy for SCD, we conducted a genome-wide association study of circulating HbF levels in ~11,000 participants to identify further HbF modulators. We identified associations in 11 genomic regions, including eight novel loci such as ABCC1 (encoding multidrug resistance-associated protein 1, MRP1). Using gene-editing and pharmacological approaches, we showed that inhibition of MRP1 increases HbF, intracellular glutathione levels, and reduces sickling in erythroid cells from SCD patients. Overall, our findings identify several novel genetically-validated potential therapeutic targets for SCD, including promising proof-of-principle results from small molecule inhibition of MRP1

Quotations on Contextual Art

Swidzinski reformulates his Contextual Art theory of the ’70s from the perspective of the ’80s, and situates it within the history of ideas. Responding to Conceptual Art and its failure to address the rapid changes of modernity, Swidzinski defines art as a social act which changes reality perpetually, destroying old meanings and constructing new ones. In a transcript from a 1976 conference in Toronto, Canadian and international artists and others debate Swidzinski’s theory and discuss the questions then facing artists, such as how they should make a living, engage with a wider audience, or be more politically effective

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

10.1038/s41467-020-20851-4Nature Communications121125

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids