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"Smith, H. E."
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Divine machines : Leibniz and the sciences of life
\"Though it did not yet exist as a discrete field of scientific inquiry, biology was at the heart of many of the most important debates in seventeenth-century philosophy. Nowhere is this more apparent than in the work of G. W. Leibniz. In Divine Machines, Justin Smith offers the first in-depth examination of Leibniz's deep and complex engagement with the empirical life sciences of his day, in areas as diverse as medicine, physiology, taxonomy, generation theory, and paleontology. He shows how these wide-ranging pursuits were not only central to Leibniz's philosophical interests, but often provided the insights that led to some of his best-known philosophical doctrines.Presenting the clearest picture yet of the scope of Leibniz's theoretical interest in the life sciences, Divine Machines takes seriously the philosopher's own repeated claims that the world must be understood in fundamentally biological terms. Here Smith reveals a thinker who was immersed in the sciences of life, and looked to the living world for answers to vexing metaphysical problems. He casts Leibniz's philosophy in an entirely new light, demonstrating how it radically departed from the prevailing models of mechanical philosophy and had an enduring influence on the history and development of the life sciences. Along the way, Smith provides a fascinating glimpse into early modern debates about the nature and origins of organic life, and into how philosophers such as Leibniz engaged with the scientific dilemmas of their era\"-- Provided by publisher.
BOOK
Retinopathy of prematurity
The immature retinas of preterm neonates are susceptible to insults that disrupt neurovascular growth, leading to retinopathy of prematurity. Suppression of growth factors due to hyperoxia and loss of the maternal–fetal interaction result in an arrest of retinal vascularisation (phase 1). Subsequently, the increasingly metabolically active, yet poorly vascularised, retina becomes hypoxic, stimulating growth factor-induced vasoproliferation (phase 2), which can cause retinal detachment. In very premature infants, controlled oxygen administration reduces but does not eliminate retinopathy of prematurity. Identification and control of factors that contribute to development of retinopathy of prematurity is essential to prevent progression to severe sight-threatening disease and to limit comorbidities with which the disease shares modifiable risk factors. Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids, as well as curbing of the effects of infection and inflammation to promote normal growth and limit suppression of neurovascular development.
Journal Article
Irrationality : a history of the dark side of reason
\"What every leader needs to know about dignity and how to create a culture in which everyone thrives. This landmark book from an expert in dignity studies explores the essential but under-recognized role of dignity as part of good leadership. Extending the reach of her award-winning book Dignity: Its Essential Role in Resolving Conflict, Donna Hicks now contributes a specific, practical guide to achieving a culture of dignity. Most people know very little about dignity, the author has found, and when leaders fail to respect the dignity of others, conflict and distrust ensue. She highlights three components of leading with dignity: what one must know in order to honor dignity and avoid violating it; what one must do to lead with dignity; and how one can create a culture of dignity in any organization, whether corporate, religious, governmental, healthcare, or beyond. Brimming with key research findings, real-life case studies, and workable recommendations, this book fills an important gap in our understanding of how best to be together in a conflict-ridden world.\"-- Publisher's description.
Book
Müller glial responses compensate for degenerating photoreceptors in retinitis pigmentosa
Photoreceptor degeneration caused by genetic defects leads to retinitis pigmentosa, a rare disease typically diagnosed in adolescents and young adults. In most cases, rod loss occurs first, followed by cone loss as well as altered function in cells connected to photoreceptors directly or indirectly. There remains a gap in our understanding of retinal cellular responses to photoreceptor abnormalities. Here, we utilized single-cell transcriptomics to investigate cellular responses in each major retinal cell type in retinitis pigmentosa model (P23H) mice vs. wild-type littermate mice. We found a significant decrease in the expression of genes associated with phototransduction, the inner/outer segment, photoreceptor cell cilium, and photoreceptor development in both rod and cone clusters, in line with the structural changes seen with immunohistochemistry. Accompanying this loss was a significant decrease in the expression of genes involved in metabolic pathways and energy production in both rods and cones. We found that in the Müller glia/astrocyte cluster, there was a significant increase in gene expression in pathways involving photoreceptor maintenance, while concomitant decreases were observed in rods and cones. Additionally, the expression of genes involved in mitochondrial localization and transport was increased in the Müller glia/astrocyte cluster. The Müller glial compensatory increase in the expression of genes downregulated in photoreceptors suggests that Müller glia adapt their transcriptome to support photoreceptors and could be thought of as general therapeutic targets to protect against retinal degeneration.
Retinitis pigmentosa: Focus on genes suggests possible treatments
Insights into the genetic and metabolic changes in retinitis pigmentosa, a rare genetic disorder that leads to increasingly worse vision, suggest a new approach for treating degenerative diseases of the retina. Researchers in the US led by Zhongiie Fu at Boston Children’s Hospital/Harvard Medical School, Boston, analyzed the activity of genes in the retinal cells of mice used to model retinitis pigmentosa in humans. They detected a significant decrease in the activity of several genes involved in light reception, subsequent reduced nerve signalling activities and metabolism in the rod and cone cells of the retina. These cells facilitate vision at low and high light levels, respectively. Increased gene activity in retinal cells called the Müller glial cluster partially compensated for these defects. The results suggest possible gene and protein targets for new treatments.
Journal Article
الفيلسوف : تاريخ من ستة أنماط
يسعى هذا الكتاب، وهو مقال بالمعنى المونتيني [نسبة إلى ميشيل دي مونتين، رائد المقالة الحديثة في أوروبا]، إلى الإجابة عن أهم الأسئلة الفلسفية : ما الفلسفة ؟، لكنه يجيب عن السؤال بطريقة غير عادية، وذلك من خلال الامتناع عن التصريح عما يجب أن تكون عليه الفلسفة، من الناحية المثالية، ومن خلال السؤال بدلا من ذلك عن الفلسفة بحد ذاتها، وما الذي فعله الناس تحت راية الفلسفة في أوقات وأماكن مختلفة. كما يستعرض تاريخ المفاهيم الذاتية المختلفة للفلاسفة عبر العصور والسياقات التاريخية المختلفة.
Book
Vitreous metabolomics profiling of proliferative diabetic retinopathy
Aims/hypothesisProliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR.MethodsWe analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27–80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration.ResultsWe identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024).Conclusions/interpretationThese results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR.
Journal Article
Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice
The mouse model of laser-induced choroidal neovascularization (CNV) has been used in studies of the exudative form of age-related macular degeneration using both the conventional slit lamp and a new image-guided laser system. A standardized protocol is needed for consistent results using this model, which has been lacking. We optimized details of laser-induced CNV using the image-guided laser photocoagulation system. Four lesions with similar size were consistently applied per eye at approximately double the disc diameter away from the optic nerve, using different laser power levels, and mice of various ages and genders. After 7 days, the mice were sacrificed and retinal pigment epithelium/choroid/sclera was flat-mounted, stained with Isolectin B4, and imaged. Quantification of the area of the laser-induced lesions was performed using an established and constant threshold. Exclusion criteria are described that were necessary for reliable data analysis of the laser-induced CNV lesions. The CNV lesion area was proportional to the laser power levels. Mice at 12-16 weeks of age developed more severe CNV than those at 6-8 weeks of age, and the gender difference was only significant in mice at 12-16 weeks of age, but not in those at 6-8 weeks of age. Dietary intake of omega-3 long-chain polyunsaturated fatty acid reduced laser-induced CNV in mice. Taken together, laser-induced CNV lesions can be easily and consistently applied using the image-guided laser platform. Mice at 6-8 weeks of age are ideal for the laser-induced CNV model.
Journal Article
Retinopathy of prematurity: Metabolic risk factors
At preterm birth, the retina is incompletely vascularized. Retinopathy of prematurity (ROP) is initiated by the postnatal suppression of physiological retinal vascular development that would normally occur in utero. As the neural retina slowly matures, increasing metabolic demand including in the peripheral avascular retina, leads to signals for compensatory but pathological neovascularization. Currently, only late neovascular ROP is treated. ROP could be prevented by promoting normal vascular growth. Early perinatal metabolic dysregulation is a strong but understudied risk factor for ROP and other long-term sequelae of preterm birth. We will discuss the metabolic and oxygen needs of retina, current treatments, and potential interventions to promote normal vessel growth including control of postnatal hyperglycemia, dyslipidemia and hyperoxia-induced retinal metabolic alterations. Early supplementation of missing nutrients and growth factors and control of supplemental oxygen promotes physiological retinal development. We will discuss the current knowledge gap in retinal metabolism after preterm birth.
Journal Article