Explore the vast range of titles available.

Toll-like receptors (TLRs) are innate immune receptors that sense a variety of pathogen-associated molecular patterns (PAMPs) by interacting with them and subsequently initiating signal transduction cascades that elicit immune responses. TLR11 has been shown to interact with two known protein PAMPs: Salmonella and E. coli flagellin FliC and Toxoplasma gondii profilin-like protein. Given the highly divergent biology of these pathogens recognized by TLR11, it is unclear whether common mechanisms are used to recognize these distinct protein PAMPs. Here we show that TLR11 interacts with these two PAMPs using different receptor domains. Furthermore, TLR11 binding to flagellin and profilin exhibits differential dependency on pH and receptor ectodomain cleavage.

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.

The discovery of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system has revolutionized gene editing research. Through the repurposing of programmable RNA-guided CRISPR-associated (Cas) nucleases, CRISPR-based genome editing systems allow for the precise modification of specific sites in the human genome and inspire novel approaches for the study and treatment of inherited and acquired human diseases. Here, we review how CRISPR technologies have stimulated key advances in dermatologic research. We discuss the role of CRISPR in genome editing for cutaneous disease and highlight studies on the use of CRISPR-Cas technologies for genodermatoses, cutaneous viruses and bacteria, and melanoma. Additionally, we examine key limitations of current CRISPR technologies, including the challenges these limitations pose for the widespread therapeutic application of CRISPR-based therapeutics.

Mechanistic target of rapamycin complex 1 (mTORC1), defined by the presence of Raptor, is an evolutionarily conserved and nutrient-sensitive regulator of cellular growth and other metabolic processes. To date, all known functions of Raptor involve its scaffolding mTOR kinase with substrate. Here we report that mTORC1-independent (‘free’) Raptor negatively regulates hepatic Akt activity and lipogenesis. Free Raptor levels in liver decline with age and in obesity; restoration of free Raptor levels reduces liver triglyceride content, through reduced β-TrCP-mediated degradation of the Akt phosphatase, PHLPP2. Commensurately, forced PHLPP2 expression ameliorates hepatic steatosis in diet-induced obese mice. These data suggest that the balance of free and mTORC1-associated Raptor governs hepatic lipid accumulation, and uncover the potentially therapeutic role of PHLPP2 activators in non-alcoholic fatty liver disease. The protein raptor is a subunit of the mTORC signalling complex. Here the authors show that Raptor also exists in a free form, unbound to mTORC, and that this free Raptor negatively regulates hepatic Akt activity and lipid metabolism in mice via a mechanism involving the Akt phosphatase PHLPP2.

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.

Mammalian Toll-like receptors (TLRs) play an important role in the innate recognition of pathogens by dendritic cells (DCs). Although TLRs are clearly involved in the detection of bacteria and viruses, relatively little is known about their function in the innate response to eukaryotic microorganisms. Here we identify a profilin-like molecule from the protozoan parasite Toxoplasma gondii that generates a potent interleukin-12 (IL-12) response in murine DCs that is dependent on myeloid differentiation factor 88. T. gondii profilin activates DCs through TLR11 and is the first chemically defined ligand for this TLR. Moreover, TLR11 is required in vivo for parasite-induced IL-12 production and optimal resistance to infection, thereby establishing a role for the receptor in host recognition of protozoan pathogens.

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.

Successful treatment of solid cancers relies on complete surgical excision of the tumor either for definitive treatment or before adjuvant therapy. Intraoperative and postoperative radial sectioning, the most common form of margin assessment, can lead to incomplete excision and increase the risk of recurrence and repeat procedures. Mohs Micrographic Surgery is associated with complete removal of basal cell and squamous cell carcinoma through real-time margin assessment of 100% of the peripheral and deep margins. Real-time assessment in many tumor types is constrained by tissue size, complexity, and specimen processing / assessment time during general anesthesia. We developed an artificial intelligence platform to reduce the tissue preprocessing and histological assessment time through automated grossing recommendations, mapping and orientation of tumor to the surgical specimen. Using basal cell carcinoma as a model system, results demonstrate that this approach can address surgical laboratory efficiency bottlenecks for rapid and complete intraoperative margin assessment.

The discovery of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system has revolutionized gene editing research. Through the repurposing of programmable RNA-guided CRISPR-associated (Cas) nucleases, CRISPR-based genome editing systems allow for the precise modification of specific sites in the human genome and inspire novel approaches for the study and treatment of inherited and acquired human diseases. Here, we review how CRISPR technologies have stimulated key advances in dermatologic research.  We discuss the role of CRISPR in genome editing for cutaneous disease and highlight studies on the use of CRISPR-Cas technologies for genodermatoses, cutaneous viruses and bacteria, and melanoma. Additionally, we examine key limitations of current CRISPR technologies, including the challenges these limitations pose for the widespread therapeutic application of CRISPR-based therapeutics.