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Regulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinson’s Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebrospinal fluid (CSF) compared to age-matched healthy controls. However, it is unknown whether peripheral immune cells in the CSF of individuals with PD also exhibit decreased levels of RGS10. Utilizing the Michael J. Fox Foundation Parkinson’s Progression Markers Initiative (PPMI) study we found that RGS10 levels are decreased in the CSF of individuals with PD compared to healthy controls and prodromal individuals. As RGS10 levels are decreased in the CSF and circulating peripheral immune cells of individuals with PD, we hypothesized that RGS10 regulates peripheral immune cell responses to chronic systemic inflammation (CSI) prior to the onset of neurodegeneration. To test this, we induced CSI for 6 weeks in C57BL6/J mice and RGS10 KO mice to assess circulating and CNS-associated immune cell responses. We found that RGS10 deficiency synergizes with CSI to induce a bias for inflammatory and cytotoxic cell populations, a reduction in antigen presentation machinery in peripheral blood immune cells, as well as in and around the brain that is most notable in males. These results highlight RGS10 as an important regulator of the systemic immune response to CSI and implicate RGS10 as a potential contributor to the development of immune dysregulation in PD.

[...]Josephine Lee uses the term \"commodity racism\" (xv) to describe how Gilbert and Sullivan's The Mikado (1885) conflates Japanese people with Japanese export goods, caricaturing them as figures \"On many a vase and jar—/On many a screen and fan\" (Gilbert and Sullivan 1.1.3–4) rather than as individuals with distinct personalities.2 Although this approach offers interesting observations, the consensus among Japanologists is that Saidian criticism ignores many aspects of Japan's relationship with the West.3 Nineteenth- and early twentieth-century observers were just as likely to hold Japan up as an example to the ostensibly decadent, degenerate West as to belittle it, and as it rapidly industrialized and modernized, respect for it grew. Focusing on texts written between 1863 and 1910 by figures influential in forming Western ideas about Japanese design and society, I demonstrate how, besides being a source of inspiration to artists and designers, Japan also became a model of secular civic virtue—a quality that could be instilled by cultivating \"correct\" taste and responsible habits of consumption. Victorian depictions of Japan were never simply studies of a foreign culture; they embodied a particular world view promoted by a social elite that wanted to prove that its own values were universal, incontestable principles shared by civilized individuals of every race, nationality, and religion. In 1625, Shogun Tokugawa Iemitsu, feeling his authority undermined by Jesuit missionaries, had implemented the sakoku edicts, expelling all foreigners from mainland Japan and banning Japanese nationals from travelling abroad. [...]the end of the Edo period (1603–1868), intercourse with foreign nations was minimized, although the Dutch and Chinese had limited trading rights.

Cerebellar Purkinje cells (PCs) show conspicuous damages in many ataxic disorders. Targeted delivery of short nucleic acids, such as antisense oligonucleotides, to PCs may be a potential treatment for ataxic disorders, especially spinocerebellar ataxias (SCAs), which are mostly caused by a gain of toxic function of the mutant RNA or protein. However, oligonucleotides do not cross the blood-brain barrier (BBB), necessitating direct delivery into the central nervous system (CNS) through intra-thecal, intra-cisternal, intra-cerebral ventricular, or stereotactic parenchymal administration. We have developed a novel liposome (100 to 200 nm in diameter) formulation, DCL64, composed of dipalmitoyl-phosphatidylcholine, cholesterol, and poloxamer L64, which incorporates oligonucleotides efficiently (≥ 70%). Confocal microscopy showed that DCL64 was selectively taken up by brain microvascular endothelial cells by interacting with low-density lipoprotein receptor (LDLr) family members on cell surface, but not with other types of lipid receptors such as caveolin or scavenger receptor class B type 1. LDLr family members are implicated in brain microvascular endothelial cell endocytosis/transcytosis, and are abundantly localized on cerebellar PCs. Intravenous administration of DCL64 in normal mice showed distribution of oligonucleotides to the brain, preferentially in PCs. Mice that received DCL64 showed no adverse effect on hematological, hepatic, and renal functions in blood tests, and no histopathological abnormalities in major organs. These studies suggest that DCL64 delivers oligonucleotides to PCs across the BBB via intravenous injection with no detectable adverse effects. This property potentially makes DCL64 particularly attractive as a delivery vehicle in treatments of SCAs.

This practice-led research investigates the artistic practice of documentary filmmaking as a means to explore tensions of place and visuality in landscapes of the South Pennines in the north of England. Created through an iterative process of practice-led and theoretical research, the thesis comprises four films: The North Wind (2013, 6’), Uplands (2014, 11’), Archipelago (2016, 19’), and Crossing (2017, 7’), and a written exegesis. The research addresses the dialectic between landscape’s visual epistemology and dynamic human-centred senses of place. Tensions between the ‘frame’ as a ‘bounded’ world of vision and place as dynamic and mobile engenders, and is developed through, an artistic documentary film practice that is processual and emergent (Hongisto 2015, MacDougall 2014), bringing pictorial and phenomenological concepts of landscape into a new relationship. The research is critically underpinned by Merleau-Ponty’s concept of ‘flesh’ (1968) as a means through which a ‘chiasm’ or ‘crossing over’ between concepts and experiences of place in the research location, and methods of artistic practice which explore and mediate themes of place, is created. An approach to film practice as ‘process’ has engendered a methodology of filmmaking as ‘weaving’ as a generative ontology of ‘making’, in which form ‘unfurls from within’ (Ingold 2005). This concept of weaving analogises the overarching filmmaking process, as well as becoming a means to navigate tensions of place in the landscape as a dynamic ‘play of forces’. Meanings of place in the South Pennines, a region of gritstone moorland straddling the Yorkshire-Lancashire border in the north of England, are central to the research. I argue that distinct tensions of landscape in the South Pennines - a pastoral ‘wilderness’ tied to northern England’s industrial histories - are pivotal to its ‘specific ambience’ (Ingold 1993) as a site of dwelling. Entangled senses of place generating themes of place and landscape in each of the films, interact with a development of practice methods, producing an approach to ‘form’ and ‘content’ that is reciprocal and interdependent. I argue that this triangulation of documentary filmmaking and landscape via theories of embodiment advances a critical understanding of filmic tensions of place and landscape. Valuable insights are also gained into processual and material approaches to documentary film, and film practice as a form of knowledge creation about experiences and senses of place and landscape.

[...] a central concern for human rights activists over the past two hundred years has been to ensure, through employment and other legislation, that children are entitled to leisure time. According to Paul Harris, autistic children practice \"stereotyped\" or repetitive symbolic play \"without regard to suggestions from other children,\" and \"almost never produce more advanced forms of make-believe such as object-substitutions, the activation of a doll as an agent, or the creation of imaginary entities\" (236).\\n The nineteenth century seems not to have had a total consensus on imagination.

Often elites from radically different cultures have many interests in common; they share the desire to maintain the status quo at home and they cooperate together across ethnic boundaries when challenged from within by different \"other\"--for example, the disenfranchised lower orders or the young. Middle- and upper-class British, American, and Japanese writers combined forces during the late nineteenth and early twentieth centuries to promote the idea that civic harmony could only be achieved under the authority of an organically evolved \"samurai\" class. Here, Holt discusses how writers used ideas and images of Japanese filial piety and social consensus to promote an essentially conservative, antidemocratic social agenda to certain supposedly unruly elements in British and American society. He also explains how writers of juvenile literature used idealized images of Japanese children and family life to promote these ideas among the young.

Targeted AAV vectors are needed for safe and efficient delivery to and transduction of specific tissue target(s) in patients. Effective intravitreal delivery for retina gene therapy is not feasible with wildtype AAV. We employed directed evolution in nonhuman primates (NHP) to discover an AAV variant (R100) for intravitreal treatment of multiple target cells in the primate retina. R100 demonstrated superior transduction of human retinal cells compared to wildtype AAV. Furthermore, three R100-based gene therapeutics demonstrated safety, delivery, and durable pan-retinal expression of intracellular or secreted transgenes throughout the NHP retina following intravitreal administration. Finally, efficacy of R100 mediated delivery of therapeutic transgenes was demonstrated in patient-derived retinal cells (monogenic diseases) and in an NHP model of pathogenic retinal angiogenesis. Competing Interest Statement The authors declare the following competing interests: All authors are or were full-time employees of or consultants to 4D Molecular Therapeutics, Inc. while engaged in the research project. M.K., D.S., and D.K. are co-founders and owners of shares in 4D Molecular Therapeutics, Inc. M.K., P.S., D.S., P.F., and D.K. are inventors on patents and/or pending patent applications related to AAV capsid variants and AAV gene delivery. Specifically, 4D Molecular Therapeutics patent application number PCT/US17/032542 and associated national phase patents and applications relate to the composition of matter and methods of use of the R100 capsid described in this manuscript and 4D Molecular Therapeutics patent application number PCT/US18/062478 and associated national phase patents and applications relate to the composition of matter and methods of use of the anti-VEGF product described in this manuscript.

This essay discusses power struggles in Gerard Manley Hopkins' poetry and life. Topics include anxiety, negativity, and language.

Regulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinson's Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebral spinal fluid (CSF) compared to age-matched healthy controls. However, it is unknown whether CSF-resident peripheral immune cells in individuals with PD also exhibit decreased levels of RGS10. Therefore, we performed an analysis of RGS10 levels in the proteomic database of the CSF from the Michael J. Fox Foundation Parkinson's Progression Markers Initiative (PPMI) study. We found that RGS10 levels are decreased in the CSF of individuals with PD compared to healthy controls and prodromal individuals. Moreover, we find that RGS10 levels decrease with age but not PD progression and that males have less RGS10 than females in PD. Importantly, studies have established an association between chronic systemic inflammation (CSI) and neurodegenerative diseases, such as PD, and known sources of CSI have been identified as risk factors for developing PD; however, the role of peripheral immune cell dysregulation in this process has been underexplored. As RGS10 levels are decreased in the CSF and circulating peripheral immune cells of individuals with PD, we hypothesized that RGS10 regulates peripheral immune cell responses to CSI prior to the onset of neurodegeneration. To test this, we induced CSI for 6 weeks in C57BL6/J mice and RGS10 KO mice to assess circulating and CNS-associated peripheral immune cell responses. We found that RGS10 deficiency synergizes with CSI to induce a bias for inflammatory and cytotoxic cell populations, a reduction in antigen presentation in peripheral blood immune cells, as well as in and around the brain that is most notable in males. These results highlight RGS10 as an important regulator of the systemic immune response to CSI and implicate RGS10 as a potential contributor to the development of immune dysregulation in PD.