We further provide formulas for predicting the clinical benefits attributable to containment strategies in a wide range of scenarios and compare the outcomes of theoretically optimal treatments with those of more practical protocols. Our results strengthen the rationale for clinical trials of evolutionarily informed cancer therapy, while also clarifying conditions under which containment might fail to outperform standard of care.There has been a steep increase in allergic and autoimmune diseases, reaching epidemic proportions and now affecting more than one billion people worldwide. These diseases are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel to urbanization and industrialization. Intact skin and mucosal barriers are crucial for the maintenance of tissue homeostasis as they protect host tissues from infections, environmental toxins, pollutants and allergens. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, coeliac disease and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and autoimmune hepatitis. Finally, distant inflammatory responses due to a 'leaky gut' and microbiome changes are suspected in Alzheimer disease, Parkinson disease, chronic depression and autism spectrum disorders. This article introduces an extended 'epithelial barrier hypothesis', which proposes that the increase in epithelial barrier-damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. Furthermore, it discusses how the immune responses to dysbiotic microbiota that cross the damaged barrier may be involved in the development of these diseases.Bacteria acquire novel DNA through horizontal gene transfer (HGT), a process that enables an organism to rapidly adapt to changing environmental conditions, provides a competitive edge and potentially alters its relationship with its host. Although the HGT process is routinely exploited in laboratories, there is a surprising disconnect between what we know from laboratory experiments and what we know from natural environments, such as the human gut microbiome. Owing to a suite of newly available computational algorithms and experimental approaches, we have a broader understanding of the genes that are being transferred and are starting to understand the ecology of HGT in natural microbial communities. This Review focuses on these new technologies, the questions they can address and their limitations. As these methods are applied more broadly, we are beginning to recognize the full extent of HGT possible within a microbiome and the punctuated dynamics of HGT, specifically in response to external stimuli. Furthermore, we are better characterizing the complex selective pressures on mobile genetic elements and the mechanisms by which they interact with the bacterial host genome.Gene regulation is a dynamic process in which transcription factors (TFs) play an important role in controlling spatiotemporal gene expression. selleck kinase inhibitor To enhance our global understanding of regulatory interactions in Arabidopsis thaliana, different regulatory input networks capturing complementary information about DNA motifs, open chromatin, TF-binding and expression-based regulatory interactions were combined using a supervised learning approach, resulting in an integrated gene regulatory network (iGRN) covering 1,491 TFs and 31,393 target genes (1.7 million interactions). This iGRN outperforms the different input networks to predict known regulatory interactions and has a similar performance to recover functional interactions compared to state-of-the-art experimental methods. The iGRN correctly inferred known functions for 681 TFs and predicted new gene functions for hundreds of unknown TFs. For regulators predicted to be involved in reactive oxygen species (ROS) stress regulation, we confirmed in total 75% of TFs with a function in ROS and/or physiological stress responses. This includes 13 ROS regulators, previously not connected to any ROS or stress function, that were experimentally validated in our ROS-specific phenotypic assays of loss- or gain-of-function lines. In conclusion, the presented iGRN offers a high-quality starting point to enhance our understanding of gene regulation in plants by integrating different experimental data types.Cis-regulatory mutations underlie important crop domestication and improvement traits1,2. However, limited allelic diversity has hindered functional dissection of the large number of cis-regulatory elements and their potential interactions, thereby precluding a deeper understanding of how cis-regulatory variation impacts traits quantitatively. Here, we engineered over 60 promoter alleles in two tomato fruit size genes3,4 to characterize cis-regulatory sequences and study their functional relationships. We found that targeted mutations in conserved promoter sequences of SlCLV3, a repressor of stem cell proliferation5,6, have a weak impact on fruit locule number. Pairwise combinations of these mutations mildly enhance this phenotype, revealing additive and synergistic relationships between conserved regions and further suggesting even higher-order cis-regulatory interactions within the SlCLV3 promoter. In contrast, SlWUS, a positive regulator of stem cell proliferation repressed by SlCLV3 (refs. 5,6), is more tolerant to promoter perturbations. Our results show that complex interplay among cis-regulatory variants can shape quantitative variation, and suggest that empirical dissections of this hidden complexity can guide promoter engineering to predictably modify crop traits.Despite the crucial importance of flower-visiting insects in modern ecosystems, there is little fossil evidence on the origins of angiosperm pollination. Most reports of pollination in the Mesozoic fossil record have been based on the co-occurrence of the purported pollinators with pollen grains and assumed morphological adaptations for vectoring pollen. Here, we describe an exceptionally preserved short-winged flower beetle (Cucujoidea Kateretidae) from mid-Cretaceous amber, Pelretes vivificus gen. et sp. nov., associated with pollen aggregations and coprolites consisting mainly of pollen, providing direct evidence of pollen-feeding in a Cretaceous beetle and confirming that diverse beetle lineages visited early angiosperms in the Cretaceous. The exquisite preservation of our fossil permits the identification of the pollen grains as Tricolpopollenites (Asteridae or Rosidae), representing a record of flower beetle pollination of a group of derived angiosperms in the Mesozoic and suggesting that potentially diverse beetle lineages visited early angiosperms by the mid-Cretaceous.