Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordThere is another record in ORE for this publication: http://hdl.handle.net/10871/33419The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.We thank D.R. Alessi (Dundee) and R.P. Lifton (Rockefeller) for their support. K.T.K. is supported by the March of Dimes Basil O'Connor Award, a Simons Foundation SFARI Grant, the Hydrocephalus Association Innovator Award, and the NIH (4K12NS080223-05). J.M.S. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (NS060801; NS061808) and the US Department of Veterans Affairs (1BX002889); R.M. is supported by the Howard Hughes Medical Institute

The Role of Scale and Technology Maturity in Life Cycle Assessment of Emerging Technologies: A Case Study on Carbon Nanotubes

Summary: Life cycle assessment (LCA) has been applied for assessing emerging technologies, where large-scale production data are generally lacking. This study introduces a standardized scheme for technology and manufacturing readiness levels to contextualize a technology's development stage. We applied the scheme to a carbon nanotube (CNT) LCA and found that, regardless of synthesis technique, CNT manufacturing will become less energy intensive with increased levels of readiness. We examined the influence of production volume on LCA results using primary data from a commercial CNT manufacturer with approximately 100 grams per day production volume and engineering design of a scaled-up process with 1 tonne per day production capacity. The results show that scaling up could reduce 84% to 94% of its cradle-to-gate impacts, mainly as a result of the recycling of feedstock that becomes economically viable only beyond certain minimum production volume. This study shows that LCAs on emerging technologies based on immature data should be interpreted in conjunction with their technology and manufacturing readiness levels and reinforces the need of standardizing and communicating information on these readiness levels and scale of production in life cycle inventory practices

Critical Components of Uncertainty Communication in Life Cycle Assessments of Emerging Technologies: Nanotechnology as a Case Study

Because of their recognition as a comprehensive tool of environmental assessments and their increasing use by governments and industries, life cycle assessments (LCAs) are positioned to be prominent sources of mass media information on new products and technologies. The LCA studies underlying media reports are often viewed by nonexperts after the initial reporting. However, uncertainty is rife in early assessments of emerging technologies, and LCA's ability to inform environmental opinions and decisions is limited without the accompanying communication on uncertainty. Though approaches to the technical aspects of uncertainty analysis in LCA are available in the literature, those on communicating that uncertainty, in ways that are cognitively accessible to the nonexperts, are still lacking despite their highlighted importance across various disciplines. With the focus on communication, this article uses the existing literature to derive five criteria for making uncertainty communication accessible to a nonexpert audience. Then, LCAs on engineered nanomaterial (ENM) and ENM-enabled products, as a case study of emerging technologies where uncertainties abound, are reviewed for whether they meet these five criteria. The study concludes with recommendations for communicating uncertainty in LCAs in order to enhance their role as decision- and public opinion-informing assessments

Extraction of high quality genomic DNA from Madhuca longifolia (J. Koenig ex l.) J.F. macbr.

Madhuca longifolia commonly known as the Mahua tree is a medium to large sized deciduous tree distributed in India, Nepal and Sri Lanka. It is found growing wild and cultivated. The tree is considered as a kalpavriksha by the tribal who are forest dwellers and keenly conserve this tree. The flowers and fruits are edible and the flowers are fermented to prepare mahua drink which is an integral part of their cultural heritage. The seeds are good source of edible fats and used to extract oil. Several pharmacological activities are reported using various parts of the tree. Very little information exists on the molecular aspects of Madhuca longifolia which requires high quality DNA. Optimization of DNA extraction using CTAB and SDS buffer system was standardized. A protocol for extraction of high quality DNA from tree species which are rich in polyphenols is hereby discussed.</jats:p