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NF-κB transcription factors are critical regulators of immunity, stress responses, apoptosis and differentiation. A variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied transcriptional programs. Consequently, NF-κB-dependent transcription is not only tightly controlled by positive and negative regulatory mechanisms but also closely coordinated with other signaling pathways. This intricate crosstalk is crucial to shaping the diverse biological functions of NF-κB into cell type– and context-specific responses.

NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system. Thus, it is not surprising that the clearest biological role of NF-κB is in the development and function of the immune system. Both innate and adaptive immune responses as well as the development and maintenance of the cells and tissues that comprise the immune system are, at multiple steps, under the control of the NF-κB family of transcription factors. Although this is a well-studied area of NF-κB research, new and significant findings continue to accumulate. This review will focus on these areas of recent progress while also providing a broad overview of the roles of NF-κB in mammalian immunobiology.

Key Points Nuclear factor-κB (NF-κB) has a crucial and complex function in orchestrating multiple aspects of inflammation. Increasing knowledge of the complexity within the NF-κB signalling pathways is revealing some of the mechanisms that are used by the NF-κB family to appropriately regulate gene expression during an inflammatory response. IKK (inhibitor of NF-κB (IκB) kinase), which is a key component in the initiation of the NF-κB pathway through the induction of IκB degradation, exerts additional effects on the NF-κB transcriptional programmes. These include negative regulatory effects brought about by targeting of NF-κB proteins for degradation and positive effects brought about by selectively augmenting co-activator recruitment to facilitate the transcription of NF-κB-dependent genes. Certain members of the IκB protein family have now been shown to selectively up-regulate the transcription of specific NF-κB target genes by providing transactivating activity to the otherwise repressive p50 and p52 NF-κB homodimers. IκB proteins can also influence NF-κB transcriptional programmes by affecting the formation, stability and responsiveness of the NF-κB complexes. NF-κB transcriptional specificity can be shaped by crosstalk with other signalling pathways, for example the p38 mitogen-activating protein kinase (MAPK) pathway. The newly described Akirins also function selectively in NF-κB transcriptional responses, although the mechanism of action of these proteins remains unknown. Several new models of the termination of NF-κB transcriptional responses have been proposed. Nuclear degradation of NF-κB subunits, dissociation of co-activators and sub-nuclear relocalization of NF-κB complexes have been implicated in the process of shutting off NF-κB. Components of the NF-κB pathway can both positively and negatively influence gene expression, and NF-κB activation can facilitate and regulate inflammatory processes. Approaches to target NF-κB in inflammatory disease must, therefore, take into account the varied contributions of the NF-κB transcription-factor family in various signalling pathways. Activation of nuclear factor-κB (NF-κB) is crucial for initiating inflammatory responses. In this Review, Sankar Ghosh and Matthew Hayden discuss the roles of several newly identified regulators of the NF-κB pathway, as well as some old factors that have been assigned new functions. Research on the biological function of nuclear factor-κB (NF-κB), a key mediator of inducible transcription in the immune system, has traditionally focused on its role in the initiation of innate and adaptive immune responses. These studies have largely concentrated on the mechanisms of signalling that lead to NF-κB activation and on the positive role of NF-κB in both physiological immunity and pathological inflammation. More recently, there has been growing interest in the mechanisms that directly regulate the NF-κB transcriptional programmes. As a result, several new NF-κB regulatory components have been identified and some of the known components have been assigned new roles. In this Review, we discuss these new insights into the regulation of NF-κB.

The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that are thought to underlie, or are closely associated with human inherited disease. At the time of writing (June 2020), the database contains in excess of 289,000 different gene lesions identified in over 11,100 genes manually curated from 72,987 articles published in over 3100 peer-reviewed journals. There are primarily two main groups of users who utilise HGMD on a regular basis; research scientists and clinical diagnosticians. This review aims to highlight how to make the most out of HGMD data in each setting.

The Human Gene Mutation Database (HGMD ® ) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central unified gene/disease-oriented repository of heritable mutations causing human genetic disease used worldwide by researchers, clinicians, diagnostic laboratories and genetic counsellors, and is an essential tool for the annotation of next-generation sequencing data. The public version of HGMD ( http://www.hgmd.org ) is freely available to registered users from academic institutions and non-profit organisations whilst the subscription version (HGMD Professional) is available to academic, clinical and commercial users under license via QIAGEN Inc.

Allopolyploidy greatly expands the range of possible regulatory interactions among functionally redundant homoeologous genes. However, connection between the emerging regulatory complexity and expression and phenotypic diversity in polyploid crops remains elusive. Here, we use diverse wheat accessions to map expression quantitative trait loci (eQTL) and evaluate their effects on the population-scale variation in homoeolog expression dosage. The relative contribution of cis - and trans -eQTL to homoeolog expression variation is strongly affected by both selection and demographic events. Though trans -acting effects play major role in expression regulation, the expression dosage of homoeologs is largely influenced by cis -acting variants, which appear to be subjected to selection. The frequency and expression of homoeologous gene alleles showing strong expression dosage bias are predictive of variation in yield-related traits, and have likely been impacted by breeding for increased productivity. Our study highlights the importance of genomic variants affecting homoeolog expression dosage in shaping agronomic phenotypes and points at their potential utility for improving yield in polyploid crops. The connection between expression variation and phenotypic diversity in the populations of polyploid crops remains elusive. Here, the authors reveal the impact of genetic variants leading to biased expression of homoeologous genes in hexaploid wheat on agronomic traits.

Prolonged exposure to microbial products such as lipopolysaccharide can induce a form of innate immune memory that blunts subsequent responses to unrelated pathogens, known as lipopolysaccharide tolerance. Sepsis is a dysregulated systemic immune response to disseminated infection that has a high mortality rate. In some patients, sepsis results in a period of immunosuppression (known as ‘immunoparalysis’) 1 characterized by reduced inflammatory cytokine output 2 , increased secondary infection 3 and an increased risk of organ failure and mortality 4 . Lipopolysaccharide tolerance recapitulates several key features of sepsis-associated immunosuppression 5 . Although various epigenetic changes have previously been observed in tolerized macrophages 6 – 8 , the molecular basis of tolerance, immunoparalysis and other forms of innate immune memory has remained unclear. Here we perform a screen for tolerance-associated microRNAs and identify miR-221 and miR-222 as regulators of the functional reprogramming of macrophages during lipopolysaccharide tolerization. Prolonged stimulation with lipopolysaccharide in mice leads to increased expression of miR-221 and mir-222, both of which regulate brahma-related gene 1 ( Brg1 , also known as Smarca4 ). This increased expression causes the transcriptional silencing of a subset of inflammatory genes that depend on chromatin remodelling mediated by SWI/SNF (switch/sucrose non-fermentable) and STAT (signal transducer and activator of transcription), which in turn promotes tolerance. In patients with sepsis, increased expression of miR-221 and miR-222 correlates with immunoparalysis and increased organ damage. Our results show that specific microRNAs can regulate macrophage tolerization and may serve as biomarkers of immunoparalysis and poor prognosis in patients with sepsis. The microRNAs miR-221 and miR-222 regulate the reprogramming of macrophages during the development of lipopolysaccharide tolerance, and increased expression of these microRNAs is associated with immunosuppression and poor prognosis in patients with sepsis.

Drought is one of the biggest concerns in agriculture due to the projected reduction of global freshwater supply with a concurrent increase in global food demand. Roots can significantly contribute to improving drought adaptation and productivity. Plants increase water uptake by adjusting root architecture and cooperating with symbiotic soil microbes. Thus, emphasis has been given to root architectural responses and root–microbe relationships in drought-resilient crop development. However, root responses to drought adaptation are continuous and complex processes and involve additional root traits and interactions among themselves. This review comprehensively compiles and discusses several of these root traits such as structural, physiological, molecular, hydraulic, anatomical, and plasticity, which are important to consider together, with architectural changes, when developing drought resilient crop varieties. In addition, it describes the significance of root contribution in improving soil structure and water holding capacity and its implication on long-term resilience to drought. In addition, various drought adaptive root ideotypes of monocot and dicot crops are compared and proposed for given agroclimatic conditions. Overall, this review provides a broader perspective of understanding root structural, physiological, and molecular regulators, and describes the considerations for simultaneously integrating multiple traits for drought tolerance and crop improvement, under specific growing environments.

If global citizenship education (GCE) is to become a pedagogical approach, it must recognize the embedded moral responsibilities contained in its presumptive domains. I propose a theoretical pedagogy that acknowledges the moral dimensions of GCE wherein the process is what matters, not a pre-identification of values that should be accepted as transmitted. This process of public education is grounded in cosmopolitan educational philosophy and articulated through a process called moral agonism, which is employed as a means to engage and create social bonds that allow for the public communication and construction of conceptions of the good, both political and moral. Its theoretical framework is grounded in cosmopolitanism and in Arendt’s conceptions of natality, thinking, and public action as moral action, which lend civic action a moral imperative, and Mouffe’s model for politics as agonism that facilitates the inevitable manifestations of political and moral plurality.