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"Robert, P."
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Trace metals in aquatic systems
This book provides a detailed examination of the concentration, form and cycling of trace metals and metalloids through the aquatic biosphere, and has sections dealing with the atmosphere, the ocean, lakes and rivers.
eBook
The role of microbial amyloid in neurodegeneration
It has become apparent that the intestinal microbiota orchestrates important aspects of our metabolism, immunity, and development. Recent work has demonstrated that the microbiota also influences brain function in healthy and diseased individuals. Of great interest are reports that intestinal bacteria play a role in the pathogenic cascade of both Parkinson and Alzheimer diseases. These neurodegenerative disorders both involve misfolding of endogenous proteins that spreads from one region of the body to another in a manner analogous to prions. The mechanisms of how the microbiota influences or is correlated with disease require elaboration. Microbial proteins or metabolites may influence neurodegeneration through the promotion of amyloid formation by human proteins or by enhancing inflammatory responses to endogenous neuronal amyloids. We review the current knowledge concerning bacterial amyloids and their potential to influence cerebral amyloid aggregation and neuroinflammation. We propose the term \"mapranosis\" to describe the process of microbiota-associated proteopathy and neuroinflammation. The study of amyloid proteins made by the microbiota and their influence on health and disease is in its infancy. This is a promising area for therapeutic intervention because there are many ways to alter our microbial partners and their products, including amyloid proteins.
Journal Article
Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles
The backbone of ovarian cancer treatment is platinum-based chemotherapy and aggressive surgical debulking. New therapeutic approaches using immunotherapy via immune checkpoint blockade, which have demonstrated clinical efficacy in other tumor types, have been less promising in ovarian cancer. To increase their clinical efficacy, checkpoint inhibitors are now being tested in clinical trials in combination with chemotherapy. Here, we evaluated the impact of cisplatin on tumor immunogenicity and its in vivo roles when used alone or in combination with anti-PD-L1, in two novel murine ovarian cancer cell models. The 2F8 and its platinum-resistant derivative 2F8cis model, display distinct inflammatory profiles and chemotherapy sensitivities, and mirror the primary and recurrent human disease, respectively. Acute and chronic exposure to cisplatin enhances tumor immunogenicity by increasing calreticulin, MHC class I, antigen presentation and T-cell infiltration. Cisplatin also upregulates PD-L1 expression in vitro and in vivo, demonstrating a dual, paradoxical immune modulatory effect and supporting the rationale for combination with immune checkpoint blockade. One of the pathways activated by cisplatin treatment is the cGAS/STING pathway. Chronic cisplatin treatment led to upregulation of cGAS and STING proteins in 2F8cis compared to parental 2F8 cells, while acute exposure to cisplatin further increases cGAS and STING levels in both 2F8 and 2F8cis cells. Overexpression of cGAS/STING modifies tumor immunogenicity by upregulating PD-L1, MHC I and calreticulin in tumor cells. Anti-PD-L1 alone in a platinum-sensitive model or with cisplatin in a platinum-resistant model increases survival. These studies have high translational potential in ovarian cancer.
Journal Article
When and how should biotic interactions be considered in models of species niches and distributions?
Biotic interactions can influence the ranges and abundances of species, but no clear guidelines exist for integrating them into correlative models of niches and distributions. Niche/distributional models characterize environmental/habitat suitability or species presence using predictor variables unaffected by (= unlinked to) the population of the focal species. Such variables (termed 'scenopoetic') typically have been considered to include only abiotic factors. In contrast, population—demographic approaches model the abundance of the focal species by including linked predictor variables, which frequently are biotic interactors. Nevertheless, a focal species might hold no, or negligible, population-level effects on its biotic interactors. Hence, contrary to current theory, such interactors would represent unlinked variables valid and potentially very useful for niche/distributional models. Consideration of population-level effects indicates that facilitators and affecting amensals (species that negatively affect another species but are not affected by it) constitute unlinked variables, but commensals and affected amensals do not. For competitors, mutualists, predators/prey, consumers/resources, and parasites/hosts, additional information is necessary. Specifically, available ecological/natural history information for the particular species involved (e.g. regarding specificity) and theory regarding ecological networks can allow identification of interactors that are likely to be unlinked or nearly so. Including an unlinked biotic interactor as a predictor variable in a niche/distributional model should improve predictions when the effects of the biotic interactor vary across the study region, or in another place or time period. Other relevant interactors must be taken into account by post-processing a niche/distributional model, or via population—demographic models that require abundance data over time. This framework should improve current correlative models and highlights areas requiring progress.
Journal Article
Quantitative CRISPR interference screens in yeast identify chemical-genetic interactions and new rules for guide RNA design
Background
Genome-scale CRISPR interference (CRISPRi) has been used in human cell lines; however, the features of effective guide RNAs (gRNAs) in different organisms have not been well characterized. Here, we define rules that determine gRNA effectiveness for transcriptional repression in
Saccharomyces cerevisiae
.
Results
We create an inducible single plasmid CRISPRi system for gene repression in yeast, and use it to analyze fitness effects of gRNAs under 18 small molecule treatments. Our approach correctly identifies previously described chemical-genetic interactions, as well as a new mechanism of suppressing fluconazole toxicity by repression of the ERG25 gene. Assessment of multiple target loci across treatments using gRNA libraries allows us to determine generalizable features associated with gRNA efficacy. Guides that target regions with low nucleosome occupancy and high chromatin accessibility are clearly more effective. We also find that the best region to target gRNAs is between the transcription start site (TSS) and 200 bp upstream of the TSS. Finally, unlike nuclease-proficient Cas9 in human cells, the specificity of truncated gRNAs (18 nt of complementarity to the target) is not clearly superior to full-length gRNAs (20 nt of complementarity), as truncated gRNAs are generally less potent against both mismatched and perfectly matched targets.
Conclusions
Our results establish a powerful functional and chemical genomics screening method and provide guidelines for designing effective gRNAs, which consider chromatin state and position relative to the target gene TSS. These findings will enable effective library design and genome-wide programmable gene repression in many genetic backgrounds.
Journal Article