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Pathogen-derived nucleic acids are crucial signals for innate immunity. Despite the structural similarity between those and host nucleic acids, mammalian cells have been able to evolve powerful innate immune signaling pathways that originate from the detection of cytosolic nucleic acid species, one of the most prominent being the cGAS–STING pathway for DNA and the RLR–MAVS pathway for RNA, respectively. Recent advances have revealed a plethora of regulatory mechanisms that are crucial for balancing the activity of nucleic acid sensors for the maintenance of overall cellular homeostasis. Elucidation of the various mechanisms that enable cells to maintain control over the activity of cytosolic nucleic acid sensors has provided new insight into the pathology of human diseases and, at the same time, offers a rich and largely unexplored source for new therapeutic targets. This Review addresses the emerging literature on regulation of the sensing of cytosolic DNA and RNA via cGAS and RLRs. Ablasser and Hur review the emerging literature on regulation of the sensing of cytosolic DNA and RNA via cGAS and RLRs.

RIG-I protein recognizes viral duplex RNA with a 5′-triphosphate group, activating innate immune responses; a crystal structure of its tetrameric CARD signalling domain reveals that non-covalently linked ubiquitin chains stabilize the tetramer in a ‘lock-washer’ structure that serves as a signalling platform for the recruitment and activation of MAVS. Mechanism of RIG-I protein virus recognition The protein RIG-I recognizes viral RNA sequences, activating innate immune responses. This protein is known to make both covalent and non-covalent interactions with K63-linked ubiquitin chains. It has remained unclear, however, how these ubiquitin modifications regulate the activity of 2CARD, the signalling domain of RIG-I, to allow its release in response to viral RNA and subsequent interaction with the downstream signalling molecule MAVS. Sun Hur and colleagues now present the crystal structure of 2CARD tetramer bound by three K63-ubiquitin chains. They find that the non-covalently linked ubiquitin chains bridge adjacent subunits of 2CARD and the covalently linked chains further stabilize this tetramer, which resembles a 'lock-washer' with its surface serving as a signalling platform for recruitment and activation of MAVS. Ubiquitin (Ub) has important roles in a wide range of intracellular signalling pathways. In the conventional view, ubiquitin alters the signalling activity of the target protein through covalent modification, but accumulating evidence points to the emerging role of non-covalent interaction between ubiquitin and the target. In the innate immune signalling pathway of a viral RNA sensor, RIG-I, both covalent and non-covalent interactions with K63-linked ubiquitin chains (K63-Ub n ) were shown to occur in its signalling domain, a tandem caspase activation and recruitment domain (hereafter referred to as 2CARD) 1 , 2 . Non-covalent binding of K63-Ub n to 2CARD induces its tetramer formation, a requirement for downstream signal activation 3 . Here we report the crystal structure of the tetramer of human RIG-I 2CARD bound by three chains of K63-Ub 2 . 2CARD assembles into a helical tetramer resembling a ‘lock-washer’, in which the tetrameric surface serves as a signalling platform for recruitment and activation of the downstream signalling molecule, MAVS. Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses reveals that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub–2CARD interaction and thus the 2CARD tetramer. Our work provides unique insights into the novel types of ubiquitin-mediated signal-activation mechanism, and previously unexpected synergism between the covalent and non-covalent ubiquitin interaction modes.

This study was conducted to determine the muscular arrangement of the human pyloric sphincter using a comprehensive approach that involved microdissection, histology, and microcomputed tomography (micro‐CT). The stomachs of 80 embalmed Korean adult cadavers were obtained. In all specimens, loose muscular tissue of the innermost aspect of the sphincter wall ran aborally, forming the newly found inner longitudinal muscle bundles, entered the duodenum, and connected with the nearby circular bundles. In all specimens, approximately one-third of the outer longitudinal layer of the sphincter entered its inner circular layer, divided the circular layer into several parts, and finally connected with the circular bundles. Anatomical findings around the sphincter were confirmed in micro-CT images. The sphincter wall comprised three layers: an inner layer of longitudinal bundles, a middle layer of major circular and minor longitudinal bundles, and an outer layer of longitudinal bundles. The stomach outer longitudinal bundles were connected to the sphincter circular bundles. The inner longitudinal bundles of the sphincter were connected to the adjacent circular bundles of the duodenum.

The current study examined the incisivus labii superioris muscle (ILS) and its morphologic and spatial relationships with the surrounding structures, especially focusing on the upper mucolabial fold, labial glands, and modiolar area. ILSs were investigated in 52 specimens obtained from formalin-fixed Korean adult cadavers (26 left sides, 26 right sides of the face; 15 men, 11 women; mean age, 70.8 years). ILSs were observed in all specimens (100%). The ILS has an oblique and linear origin from the incisive fossa of the maxilla to the point just medial to the origin of the levator anguli oris muscle (LAO). The arising fibers of the ILS arched and covered the prominent labial glands at the superior margin of the orbicularis oris muscle (OOr). After the ILS coursed laterally along the anterior part of the upper mucolabial fold, it divided into superficial and deep inserting fibers in 48 specimens (92.3%) and it did not divide in 4 specimens (7.7%). The superficial inserting ILS fibers and the ILS fibers that did not divide blended with the medial fibers of the LAO to converge toward the modiolus. The deep inserting fibers of the ILS blended with the lateral deep fibers of the OOr in the 48 specimens (92.3%), and the deep inserting fibers continued to descend to converge toward the modiolus in 20 of those specimens (38.5%). These observations indicate that the ILS may assist to compress the labial glands and the upper oral vestibule, controlling modiolar movements and thereby integrating the movements of the mouth and lips.

Brassinosteroid-Insensitive 1-Associated Receptor Kinase 1 (BAK1) is a versatile kinase involved in many different plant developmental responses. Previously, we showed that BAK1 interacts with open stomata 1 (OST1), a cytoplasmic kinase, to promote abscisic acid (ABA)-induced stomatal closure. ABA is a plant hormone that primarily regulates stress responses and is recognized by the PYRABACTIN RESISTANCE1 (PYR1)/PYR1-LIKE (PYL)/REGULATORY COMPONENT OF ABA RECEPTORS (RCAR), which activates ABA signaling. Here, we demonstrated that BAK1 interacts with PYR1 and phosphorylates PYR1 in response to ABA in plants. We identified T137 and S142 of PYR1 as the phosphosites targeted by BAK1. Using phosphomimetic (PYR1DD) and phospho-dead (PYR1AA) PYR1 compared with wild-type PYR1, we showed that transgenic plants overexpressing a phosphomimetic PYR1 exhibited hypersensitivity to the inhibition of ABA-induced root growth and seed germination and increased ABA-induced stomatal closure and ABA-inducible gene expression. As underlying reasons for these phenomena, we further demonstrated that phosphorylated PYR1 existed in a monomeric form, in which ABA binding was increased, and the degree of complex formation with ABI1 was also increased. These results suggest that BAK1 positively modulates ABA signaling through interaction with PYR1, in addition to OST1.

Arabidopsis thaliana homeobox 12 (ATHB12), a homeodomain‐leucine zipper class I (HD‐Zip I) gene, is highly expressed in leaves and stems, and induced by abiotic stresses, but its role in development remains obscure. To understand its function during plant development, we studied the effects of loss and gain of function. Expression of ATHB12 fused to the EAR‐motif repression domain (SRDX) – P₃₅S::ATHB12SRDX (A12SRDX) and PATHB₁₂::ATHB12SRDX – slowed both leaf and root growth, while the growth of ATHB12‐overexpressing seedlings (A12OX) was accelerated. Microscopic examination revealed changes in the size and number of leaf cells. Ploidy was reduced in A12SRDX plants, accompanied by decreased cell expansion and increased cell numbers. By contrast, cell size was increased in A12OX plants, along with increased ploidy and elevated expression of cell cycle switch 52s (CCS52s), which are positive regulators of endoreduplication, indicating that ATHB12 promotes leaf cell expansion and endoreduplication. Overexpression of ATHB12 led to decreased phosphorylation of Arabidopsis thaliana ribosomal protein S6 (AtRPS6), a regulator of cell growth. In addition, induction of ATHB12 in the presence of cycloheximide increased the expression of several genes related to cell expansion, such as EXPANSIN A10 (EXPA10) and DWARF4 (DWF4). Our findings strongly suggest that ATHB12 acts as a positive regulator of endoreduplication and cell growth during leaf development.

The aim of this study was to clarify the heights and spatial relationships of the facial muscles acting on the nasolabial fold (NLF) by dissection and three-dimensional microcomputed tomography for use in aesthetic treatments. This study used 56 specimens from 34 embalmed adult Korean. A reference line (RF) was set to imitate the NLF after removing the skin, from the superior point of the alar facial crease to the lateral point of the orbicularis oris muscle at the level of the corner of the mouth. The heights and spatial relationships of the facial muscles along the RF could be categorized into five main patterns. The dominant pattern was that the levator labii superioris alaeque nasi muscle (LLSAN), levator labii superioris muscle (LLS), zygomaticus minor muscle (Zmi), and zygomaticus major muscle (Zmj) were on the medial third, medial half, middle third, and lateral third of the RF, respectively. In micro-CT imaging, beneath the skin of the medial half of the NLF, the LLSAN and Zmi fibers inserted into the dermis of the NLF and adjacent to the NLF. Beneath the skin of the middle third of the NLF, the Zmi fibers were found before the muscle inserted into the dermis of the NLF and adjacent to the NLF. Beneath the skin of the lateral third of the NLF, the lateral margin of the orbicularis oris muscle and some Zmj fibers were found at the location of the NLF. The present study utilized dissections and micro-CT to reveal the general pattern and variations of heights and spatial relationships of the facial muscles passing beneath the NLF. These findings will be useful for understanding which muscles affect specific parts of NLFs with various contours, for reducing the NLF in aesthetic treatments, and for reconstructing the NLF in cases of facial paralysis.

The aim of this study was to determine how the depressor supercilii (DS) connects to the levator labii superioris alaeque nasi (LLSAN) and inferior fibers of the orbicularis oculi (OOc INF) in the human midface. While grimacing, contraction of the DS with fibers connecting to the LLSAN and OOc INF can assist in pulling the medial eyebrow downward more than when these connecting fibers are not present. Contraction of these distinct connecting fibers between the DS and the LLSAN can also slightly elevate the nasal ala and upper lip. The DS was examined in 44 specimens of embalmed adult Korean cadavers. We found that the DS connected to the LLSAN or the OOc INF by muscle fibers or thin aponeuroses in 33 (75.0%) of the 44 specimens. The DS was connected to both the LLSAN and OOc INF by muscle fibers or aponeuroses and had no connection to either in 5 (11.4%) and 11 (25.0%) specimens, respectively. The DS was connected to the LLSAN by the muscle fibers and thin aponeuroses in 6 (13.6%) and 4 (9.1%) specimens, respectively. The DS was connected to the OOc INF by the muscle fibers and thin aponeuroses in 5 (11.4%) and 23 (52.3%) specimens, respectively. Our findings regarding the anatomical connections of the glabellar region DS to the midface LLSAN and OOc INF provide insights on the dynamic balance between the brow depressors such as the DS and brow-elevating muscle and contribute to understanding the anatomical origins of individual variation in facial expressions. These results can also improve the safety, predictability, and aesthetics of treatments for the glabellar region with botulinum toxin type A and can be helpful when performing electromyography.

The parotid duct (Stensen’s duct) runs superficially across the midface and is often encountered during aesthetic or surgical procedures. Accurate knowledge of its spatial orientation is essential to avoid iatrogenic injury. This study aimed to define the spatial course of the parotid duct relative to facial surface landmarks to demonstrate the feasibility of ultrasonographic identification of these relationships in vivo. Thirty-two hemifaces from sixteen adult cadavers (15 Korean, 1 Caucasian; 9 males, 7 females; mean age 82 years) were dissected to trace the parotid duct from the gland to its penetration through the buccinator. The position of the duct was analyzed relative to (1) the tragus–mouth corner line, (2) the philtrum level (midpoint, upper one-third, or lower one-third), and (3) vertical lines through the canthi. High-resolution ultrasonography was performed in a single healthy volunteer to provide an in vivo feasibility demonstration of the cadaveric findings. At the anterior border of the masseter, the duct was located slightly superior to the tragus–mouth corner line in 84.4% of specimens, on the line in 3.1%, and below it in 12.5%, most of which possessed an accessory parotid gland. Horizontally, the duct aligned with the philtrum midpoint in 65.6%, with the upper one-third in 25.0%, and with the lower one-third in 9.4%. The buccinator penetration point was medial to the vertical line through the lateral canthus in 87.5%. Ultrasonography in a single healthy volunteer visually demonstrated the feasibility of identifying these anatomical relationships in vivo. The parotid duct follows a relatively reproducible course that may be estimated using established facial landmarks.

The aim of this study was to elucidate the positional relationship between the courses of the angular veins and the facial muscles, and the possible roles of the latter as alternative venous valves. The angular veins of 44 specimens of embalmed Korean adult cadavers were examined. Facial muscles were studied to establish their relationships with the angular vein, including the orbicularis oculi (OOc), depressor supercilii (DS), zygomaticus minor (Zmi), zygomaticus major (Zmj), and levator labii superioris (LLS). In the upper face of all specimens, the angular vein passed through the DS and descended to the medial palpebral ligament. In the midface, it passed between the origin of the levator labii superioris alaeque nasi (LLSAN) and the inferior OOc fibers. The vein coursed along the deep surface of the inferior margin of the OOc in all specimens. At the level of the nasal ala, the course of the angular vein was classified into three types: in type I it passed between the LLS and Zmi (38.6%), in type II it passed between the superficial and deep fibers of the Zmi (47.7%), and in type III it passed between the Zmi and Zmj (13.6%). In the lower face of all specimens, the angular or facial vein passed through the anterior lobe of the buccal fat pad. This study found that the angular vein coursed along the sites where facial muscle contractions are assumed to efficiently compress the veins, likely controlling venous flow as valves. The observations made and analysis performed in this study will improve the understanding of the physiological function of the facial muscles as alternative venous valves.