MedZIM: Mediation analysis for Zero-Inflated Mediators with applications to microbiome data

The human microbiome can contribute to the pathogenesis of many complex diseases such as cancer and Alzheimer's disease by mediating disease-leading causal pathways. However, standard mediation analysis is not adequate in the context of microbiome data due to the excessive number of zero values in the data. Zero-valued sequencing reads, commonly observed in microbiome studies, arise for technical and/or biological reasons. Mediation analysis approaches for analyzing zero-inflated mediators are still lacking largely because of challenges raised by the zero-inflated data structure: (a) disentangling the mediation effect induced by the point mass at zero; and (b) identifying the observed zero-valued data points that are actually not zero (i.e., false zeros). We develop a novel mediation analysis method under the potential-outcomes framework to fill this gap. We show that the mediation effect of the microbiome can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions. The first component corresponds to the mediation effect attributable to a unit-change over the positive relative abundance and the second component corresponds to the mediation effect attributable to discrete binary change of the mediator from zero to a non-zero state. With probabilistic models to account for observing zeros, we also address the challenge with false zeros. A comprehensive simulation study and the applications in two real microbiome studies demonstrate that our approach outperforms existing mediation analysis approaches.Comment: Corresponding: Zhigang L

Microbiota and host immune responses: a love-hate relationship

A complex relationship between the microbiota and the host emerges early at birth and continues throughout life. The microbiota includes the prokaryotes, viruses and eukaryotes living among us, all of which interact to different extents with various organs and tissues in the body, including the immune system. Although the microbiota is most dense in the lower intestine, its influence on host immunity extends beyond the gastrointestinal tract. These interactions with the immune system operate through the actions of various microbial structures and metabolites, with outcomes ranging from beneficial to deleterious for the host. These differential outcomes are dictated by host factors, environment, and the type of microbes or products present in a specific ecosystem. It is also becoming clear that the microbes are in turn affected and respond to the host immune system. Disruption of this complex dialogue between host and microbiota can lead to immune pathologies such as inflammatory bowel diseases, diabetes and obesity. This review will discuss recent advances regarding the ways in which the host immune system and microbiota interact and communicate with one another

The flavonoid luteolin prevents lipopolysaccharide-induced NF-kappaB signalling and gene expression by blocking IkappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells

The nuclear factor (NF)-κB transcriptional system is a major effector pathway involved in inflammation and innate immune responses. The flavonoid luteolin is found in various herbal extracts and has shown anti-inflammatory properties. However, the mechanism of action and impact of luteolin on innate immunity is still unknown. We report that luteolin significantly blocks lipopolysaccharide (LPS)-induced IκB phosphorylation/degradation, NF-κB transcriptional activity and intercellular adhesion molecule-1 (ICAM-1) gene expression in rat IEC-18 cells. Using chromatin immunoprecipitation, we demonstrate that LPS-induced RelA recruitment to the ICAM-1 gene promoter is significantly reduced in luteolin-treated cells. Moreover, in vitro kinase assays show that luteolin directly inhibits LPS-induced IκB kinase (IKK) activity in IEC-18 cells. Using bone-marrow derived dendritic cells (BMDCs) isolated from interleukin (IL)-10−/− mice or from recently engineered transgenic mice expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-κB cis-elements (cis-NF-κBEGFP), we found that luteolin blocks LPS-induced IκB phosphorylation and IKK activity, and decreases EGFP, IL-12 and tumour necrosis factor-α gene expression. Moreover, intraperitoneal administration of luteolin significantly inhibited LPS-induced EGFP expression in both peripheral blood mononuclear cells and splenocytes isolated from cis-NF-κBEGFP mice. These results indicate that luteolin blocks LPS-induced NF-κB signalling and proinflammatory gene expression in intestinal epithelial cells and dendritic cells. Modulation of innate immunity by natural plant products may represent an attractive strategy to prevent intestinal inflammation associated with dysregulated innate immune responses

Think Small: Zebrafish as a Model System of Human Pathology

Although human pathologies have mostly been modeled using higher mammal systems such as mice, the lower vertebrate zebrafish has gained tremendous attention as a model system. The advantages of zebrafish over classical vertebrate models are multifactorial and include high genetic and organ system homology to humans, high fecundity, external fertilization, ease of genetic manipulation, and transparency through early adulthood that enables powerful imaging modalities. This paper focuses on four areas of human pathology that were developed and/or advanced significantly in zebrafish in the last decade. These areas are (1) wound healing/restitution, (2) gastrointestinal diseases, (3) microbe-host interactions, and (4) genetic diseases and drug screens. Important biological processes and pathologies explored include wound-healing responses, pancreatic cancer, inflammatory bowel diseases, nonalcoholic fatty liver disease, and mycobacterium infection. The utility of zebrafish in screening for novel genes important in various pathologies such as polycystic kidney disease is also discussed

Recovery of the Alpine lynx Lynx lynx metapopulation

We use the case of the Eurasian lynx Lynx lynx in the Alps to discuss how to implement existing directives and recommendations, as well as how to integrate biological concepts, into practical conservation and wildlife management. Since 1995 the occurrence of lynx in the Alpine countries has been monitored and reported by the Status and Conservation of the Alpine Lynx Population expert group. Both the area of occupancy and the estimated number of individuals increased from 1995-1999 to 2000-2004. The estimated number of lynx is 120-150 across the Alps and the area of occupancy 27,800 km2, in six distinct sub-areas. In the highly fragmented Alpine habitat lynx populations expand slowly, even in situations of high local density and when suitable habitat is available. Thus, almost 40 years after the first reintroduction, < 20% of the Alps have been recolonized by lynx. In addition to biological and ecological factors, the persistent disagreements about the return of the lynx between conservationists and other land-users, including livestock breeders and hunters, and the political fragmentation of the Alps (with different regional priorities and large carnivore policies), has prevented the creation of a consensus regarding pan-Alpine conservation goals for the lynx and the implementation of conservation measures such as translocations and reintroductions. We discuss possible approaches in the light of new guidelines for population level management plans for large carnivores recently developed on behalf of the European Commissio

Persuade Oscar, the Grouch: A Design Approach for a Persuasive Gamified Smart Waste App

Littering, for instance caused by awareness lacks on appropriate waste disposal, is one of the pollution causes in cities and can damage water , air , and soil. In the smart city context, smart waste apps (SWAs) can be used to address the change of citizens’ littering behavior by implementing persuasion. This research aims to pro- vide a first step toward a design theory for SWAs that enhances the internal motivation to engage in correct litter disposal. Our research follows a six-step design science approach to identify design requirements, de- rive design principles, and develop design features based on a literature review on SWAs and a series of expert workshops. We investigate which design princi- ples should guide SWAs’ design to select an adequate set of persuasive elements and, thus, better target litter- ing behavior change. The proposed prototypical SWA is expected to motivate citizens\u27 littering behavior change, thereby, improving urban cleanliness

Sorting the Trash: How Smart Waste Management Systems Contribute to Sustainable Development in Smart Cities

Waste management is a relevant challenge for cities around the world to ensure citizens’ life quality, and to significantly contribute to environmental protection. Hence, inefficiencies in waste management thwarts the sustainable development of cities. Smart waste management can help improving the waste management services of cities by pursuing strategic goals, including waste reduction, waste collection and transport optimization, and waste treatment optimization. However, current research insufficiently addresses the contribution of information systems used in the context of smart waste management to sustainable development. Based on a literature review, we show how different systems in the smart waste management context contribute to strategic goals and, thereby, to sustainable development. We call for more research on smart waste management that accounts for the information systems’ contribution to sustainable development