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Critiquing the Rawlsian use of Kant's philosophy of experience, this dissertation draws on Benjamin's and Deleuze's intervention into the Critique of Judgment in order to affirm a \"higher experience\" beyond that through which postwar American citizen-subjectivity is assembled. Specifically, it engages the habits of perception and recollection as they emerged in the period with respect to sight, sound and smell, within the domains of indigeneity, raciality and ethnicity. Instead of a merely pluralist mode of political belonging, it articulates one that is pluralizing, thinking through what it might mean to belong to becoming rather than being.

Metallocyanides have long been studied for their ability to act as ligands to other metals. This property gives rise to the diverse applications of the resulting bridged complexes. Among these applications are the ability to act as geometric building blocks, and as catalysts for the coupling of epoxides and CO2. Unfortunately, double metal cyanides have a propensity towards aggregation, which hinders the characterization of the resulting complexes. It is the purpose of this work to synthesize soluble model complexes of poorly characterized double metal cyanide catalysts from the patent literature, and to further the development of their use in molecular architecture. To this end, a number of soluble double metal cyanide complexes with the core unit comprised of CpFe(CN)2(L) (L = CO or PR3) have been synthesized. This cyanometalate is then bound to Cu(I) or Zn(II) through the cyanide nitrogen. Thus, the products of these reactions take on rhombohedral geometries with the metal centers bridged by cyanide ligands. In cases where the products of the reactions were aggregates, protecting ligands were used to block their formation. Traditionally chelating phosphines have also been used to create a bridged diiron metalocyanide source. This species is a new type of chelate, which has been used to form basket shaped double metal cyanide complexes. The chelate nature of the iron dicyanide serves to further strengthen the already robust metallocyclic core. Furthermore, the length of the bridge may be tailored to control the planarity of the rhombohedral unit. The utility of these complexes as catalysts has also been explored. It was found that they do indeed couple epoxides and CO2 to form polycarbonates. A diminished activity is seen in these model catalysts, as well as an increase in the amount of cyclic carbonate produced. Despite their deficiencies, these model catalysts have paved the way for a better understanding of the industrial heterogeneous systems.

The bone marrow microenvironment has a key role in regulating haematopoiesis, but its molecular complexity and response to stress are incompletely understood. Here we map the transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast cell populations at single-cell resolution, both at homeostasis and under conditions of stress-induced haematopoiesis. This analysis revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-haematopoietic growth factors, chemokines and membrane-bound ligands. Our studies demonstrate a considerable transcriptional remodelling of niche elements under stress conditions, including an adipocytic skewing of perivascular cells. Among the stress-induced changes, we observed that vascular Notch delta-like ligands (encoded by Dll1 and Dll4 ) were downregulated. In the absence of vascular Dll4 , haematopoietic stem cells prematurely induced a myeloid transcriptional program. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress and illustrate the utility of single-cell transcriptomic data in evaluating the regulation of haematopoiesis by discrete niche populations. The transcriptional landscape of cell populations of the mouse bone marrow microenvironment, mapped at single-cell resolution, reveals cellular heterogeneity in this niche as well as substantial transcriptional remodelling under stress conditions.

Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols. Bone marrow endothelial cells have dual roles in the regulation of haematopoietic stem cell maintenance and in the trafficking of blood cells between the bone marrow and the blood circulatory system; this study shows that these different functions are regulated by distinct types of endothelial blood vessels with different permeability properties, affecting the metabolic state of their neighbouring stem cells. Bone marrow blood vessel specialization Endothelial cells of the bone marrow modulate both haematopoietic stem cell (HSC) maintenance and the trafficking of blood cells out of the bone marrow. Tsvee Lapidot and colleagues find that these two aspects are controlled by two distinct types of blood vessels in the bone marrow, with different permeability properties and reactive oxygen species (ROS) levels. Less permeable arteries surrounded by pericytes maintain HSCs in a low reactive oxygen species (ROS) state, whereas the more permeable smaller sinusoids promote HSC activation and allow trafficking of immature and mature leukocytes. The authors also show that in conditions that allow for expansion of HSCs, endothelial integrity is increased, with fewer blood cells moving in and out. Disruption of the endothelial barrier has the reverse effects. Elsewhere in this issue ( page 380 ), Anjali Kusumbe et al . demonstrate that Notch signalling in endothelial cells of bone marrow induces change in the capillaries and mesenchymal stem cells of the environment to support HSC amplification.

Background Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. Results We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1 df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. Conclusions This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors are engineered cell-surface receptors that sense a target antigen and respond by activating T cell receptor signaling or a customized gene program, respectively. Here, to expand the targeting capabilities of these receptors, we develop “universal” receptor systems for which receptor specificity can be directed post-translationally via covalent attachment of a co-administered antibody bearing a benzylguanine (BG) motif. A SNAPtag self-labeling enzyme is genetically fused to the receptor and reacts with BG-conjugated antibodies for covalent assembly, programming antigen recognition. We demonstrate that activation of SNAP-CAR and SNAP-synNotch receptors can be successfully targeted by clinically relevant BG-conjugated antibodies, including anti-tumor activity of SNAP-CAR T cells in vivo in a human tumor xenograft mouse model. Finally, we develop a mathematical model to better define the parameters affecting universal receptor signaling. SNAP receptors provide a powerful strategy to post-translationally reprogram the targeting specificity of engineered cells. Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors are promising platforms for cell-based immunotherapies. Here, the authors develop highly programmable versions of these receptors that can be universally targeted to antigens of interest through covalent enzyme chemistry.

Agriculture is a major contributor to air pollution, the largest environmental risk factor for mortality in the United States and worldwide. It is largely unknown, however, how individual foods or entire diets affect human health via poor air quality. We show how food production negatively impacts human health by increasing atmospheric fine particulate matter (PM2.5), and we identify ways to reduce these negative impacts of agriculture. We quantify the air quality–related health damages attributable to 95 agricultural commodities and 67 final food products, which encompass >99% of agricultural production in the United States. Agricultural production in the United States results in 17,900 annual air quality–related deaths, 15,900 of which are from food production. Of those, 80% are attributable to animal-based foods, both directly from animal production and indirectly from growing animal feed. On-farm interventions can reduce PM2.5-related mortality by 50%, including improved livestock waste management and fertilizer application practices that reduce emissions of ammonia, a secondary PM2.5 precursor, and improved crop and animal production practices that reduce primary PM2.5 emissions from tillage, field burning, livestock dust, and machinery. Dietary shifts toward more plant-based foods that maintain protein intake and other nutritional needs could reduce agricultural air quality–related mortality by 68 to 83%. In sum, improved livestock and fertilization practices, and dietary shifts could greatly decrease the health impacts of agriculture caused by its contribution to reduced air quality.

New animal models of Zika virus (ZIKV) infection are imperative to accelerating efforts to treat or prevent disease in humans. Adams Waldorf et al . now report that ZIKV infection of a pregnant female pigtailed macaque caused brain lesions in the developing fetus, suggesting that this model may be useful for understanding ZIKV-associated congenital abnormalities in humans. We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital–parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.