cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that ...specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus, inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1−/− BMDM cells and in Trex1−/− mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.
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•Astin C impairs cGAS-STING signaling and the inflammatory responses•Astin C attenuates autoinflammatory responses in Trex1−/− cells and disease model•Astin C specifically binds to STING•Astin C prevents the recruitment of IRF3 onto STING signalosome
Li et al. have characterized a small-molecule cyclopeptide, astin C, which specifically inhibits cGAS-STING signaling as well as the innate inflammatory responses. This finding provides a way to potentially manipulate STING-mediated clinical diseases.
Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase ...CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates. Mechanistically, STING translocated from the ER to the Golgi upon HSV-1 stimulation; CYLD partially accumulated with STING and interacted selectively with K48-linked polyubiquitin chains on STING, specifically removing the K48-linked polyubiquitin chains from STING and ultimately boosting the innate antiviral response. Our study reveals that CYLD is a novel checkpoint in the cGAS-STING signaling pathway and sheds new light on the dynamic regulation of STING activity by ubiquitination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Activation-induced cytidine deaminase (AID) initiates both antibody class switch recombination (CSR) and somatic hypermutation (SHM) in antibody diversification. DNA double-strand break response ...(DSBR) factors promote rearrangement in CSR, while translesion synthesis (TLS) polymerases generate mutations in SHM. REV7, a component of TLS polymerase zeta, is also a downstream effector of 53BP1-RIF1 DSBR pathway. Here, we study the multi-functions of REV7 and find that REV7 is required for the B cell survival upon AID-deamination, which is independent of its roles in DSBR, G2/M transition or REV1-mediated TLS. The cell death in REV7-deficient activated B cells can be fully rescued by AID-deficiency in vivo. We further identify that REV7-depedent TLS across UNG-processed apurinic/apyrimidinic sites is required for cell survival upon AID/APOBEC deamination. This study dissects the multiple roles of Rev7 in antibody diversification, and discovers that TLS is not only required for sequence diversification but also B cell survival upon AID-initiated lesions.
Flatfoot is a condition commonly seen in children; however, there is general disagreement over its incidence, characterization and correction. Painful flatfoot accompanied with musculoskeletal and ...soft tissue problems requires surgery to avoid arthritis in adulthood, the most common surgical approach being two osteotomies to the calcaneus and medial cuneiform bones of the foot.
This study focuses on the parametrization of these two bones to understand their bone morphology differences in a population sample among 23 normal subjects. Population differences could help in understanding whether bone shape may be an important factor in aiding surgical planning and outcomes.
A total of 45 sets of CT scans of these subjects were used to generate surface meshes of the two bones and converted to be iso-topological meshes, simplifying the application of Generalized Procrustes Analysis and Principal Component Analysis, allowing the main sources of variation between the subjects to be quantified.
For the calcaneus, 16 Principal Components (PCs) and, for the medial cuneiform, 12 PCs were sufficient to describe 90% of the dataset variability. The quantitative and qualitative analyses confirm that for the calcaneus PC1 describes the Achilles attachment location and PC2 largely describes the anterior part of the bone. For the medial cuneiform, PC1 describes the medial part of the bone, while PC2 mainly describes the superior part.
Most importantly, the PCs did not seem to describe the osteotomy sites for both bones, suggesting low population variability at the bone cutting points. Further studies are needed to evaluate how shape variability impacts surgical outcomes. Future implications could include better surgical planning and may pave the way for complex robotic surgeries to become a reality.
We compared neuromechanical adjustments between traditional and eccentric load reduction weighted jump squats (WJSs). On separate visits, sixteen strength‐trained men performed three sets of six ...consecutive WJS with 0% (traditional WJS) or 50% eccentric loading reduction with a mechanical braking unit, while concentric load was set at 30% of 1 RM in all trials. A force platform and a motion capture system were used to assess neuromechanical parameters during eccentric and concentric phases of WJS. Peak power output (+4.5 ± 4.1%; p < 0.001), maximal concentric velocity (+3.2 ± 3.6%; p = 0.004), jump height (+19.6 ± 17.4%; p < 0.001), and reactive strength index (+28.2 ± 20.0%; p < 0.001) were higher when eccentric load was reduced by 50% versus 0%. Compared with traditional jump squat, eccentric phase duration (−6.7 ± 9.9%; p = 0.014), contact time (−6.3 ± 7.2%; p = 0.004), and time to reach peak power output (−7.8 ± 7.6%; p < 0.001) were shorter, while peak vertical force (−15.2 ± 17.5%; p = 0.005) and eccentric mechanical work (−23.9 ± 6.6%; p < 0.001) were lower with eccentric load reduction. Eccentric depth (p = 0.613), eccentric velocity (p = 0.070), amortization time (p = 0.060), maximal concentric force (p = 0.727), and concentric mechanical work (p = 0.396) did not differ significantly between conditions. Compared with traditional isoinertial loading, eccentric load reduction promoted more favorable neuromechanical adjustments during landing and propulsion phases in turn maximizing WJS performance.
Highlights
Eccentric load reduction weighted jump squat is a form of plyometric exercise during which a rapid, eccentrically braked downward movement is immediately followed by a maximal effort jump.
In strength‐trained men, we found this approach advantageous compared with no braking for potentiating weighted jump squat performance due to more favorable eccentric‐ and concentric‐phase metrics.
It is possible that smaller training volumes could be completed in each exercise session without compromising on concentric outputs. Under such circumstances, employing eccentric load reduction weighted jump squat might be a more suitable approach when attempting to execute greater workloads while minimizing fatigue.
Base editors (BEs) introduce base substitutions without double-strand DNA cleavage. Besides precise substitutions, BEs generate low-frequency 'stochastic' byproducts through unclear mechanisms. Here, ...we performed in-depth outcome profiling and genetic dissection, revealing that C-to-G BEs (CGBEs) generate substantial amounts of intermediate double-strand breaks (DSBs), which are at the centre of several byproducts. Imperfect DSB end-joining leads to small deletions via end-resection, templated insertions or aberrant transversions during end fill-in. Chromosomal translocations were detected between the editing target and off-targets of Cas9/deaminase origin. Genetic screenings of DNA repair factors disclosed a central role of abasic site processing in DSB formation. Shielding of abasic sites by the suicide enzyme HMCES reduced CGBE-initiated DSBs, providing an effective way to minimize DSB-triggered events without affecting substitutions. This work demonstrates that CGBEs can initiate deleterious intermediate DSBs and therefore require careful consideration for therapeutic applications, and that HMCES-aided CGBEs hold promise as safer tools.
Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations ...intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma.
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•AID activity on single-strand DNA per se shapes the CDR-preferential SHM profile•Non-coding function of DNA at the mesoscale level directs AID deamination in vivo•Flexibility of single-strand DNA substrate contributes to AID substrate preference•DNA alteration can make a cold FR hot
Somatic hypermutation in antibody-coding sequences preferentially occurs within specific regions; this study uncovers that the intrinsic single-stranded DNA flexibility within the regions confers the specificity.
Developing highly accurate critical dimension standards is a significant task for nanoscale metrology. In this paper, we put forward an alternative approach to fabricate amorphous Si critical ...dimension structures with direct Si lattice calibration in the same frame scanning transmission electron microscopy image. Based on the traceable measurement analysis, the optimized method can provide the same calibration accuracy and increase the fabrication throughput and lower the cost simultaneously, which benefits the application needs in atomic force microscopy (AFM) tip geometry characterization, benchmarking measurement tools, and conducting comparison measurements between different approaches.
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