Author Correction: The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming.

CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.

Genomic and structural basis for evolution of tropane alkaloid biosynthesis.

The tropane alkaloids (TAs) cocaine and hyoscyamine have been used medicinally for thousands of years. To understand the evolutionary origins and trajectories of serial biosynthetic enzymes of TAs and especially the characteristic tropane skeletons, we generated the chromosome-level genome assemblies of cocaine-producing Erythroxylum novogranatense (Erythroxylaceae, rosids clade) and hyoscyamine-producing Anisodus acutangulus (Solanaceae, asterids clade). Comparative genomic and phylogenetic analysis suggested that the lack of spermidine synthase/N-methyltransferase (EnSPMT1) in ancestral asterids species contributed to the divergence of polyamine (spermidine or putrescine) methylation in cocaine and hyoscyamine biosynthesis. Molecular docking analysis and key site mutation experiments suggested that ecgonone synthases CYP81AN15 and CYP82M3 adopt different active-site architectures to biosynthesize the same product ecgonone from the same substrate in Erythroxylaceae and Solanaceae. Further synteny analysis showed different evolutionary origins and trajectories of CYP81AN15 and CYP82M3, particularly the emergence of CYP81AN15 through the neofunctionalization of ancient tandem duplication genes. The combination of structural biology and comparative genomic analysis revealed that ecgonone methyltransferase, which is responsible for the biosynthesis of characteristic 2-substituted carboxymethyl group in cocaine, evolved from the tandem copies of salicylic acid methyltransferase by the mutations of critical E216 and S153 residues. Overall, we provided strong evidence for the independent origins of serial TA biosynthetic enzymes on the genomic and structural level, underlying the chemotypic convergence of TAs in phylogenetically distant species.

The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling.

Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell-specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switching by attenuating noncanonical signaling via the transcription factor NF-κB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and identify a unique mechanism that controls IgA production.

Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells.

The maintenance of immune homeostasis requires regulatory T cells (Treg cells). Here we found that Treg cell­specific ablation of Ubc13, a Lys63 (K63)-specific ubiquitin-conjugating enzyme, caused aberrant T cell activation and autoimmunity. Although Ubc13 deficiency did not affect the survival of Treg cells or expression of the transcription factor Foxp3, it impaired the in vivo suppressive function of Treg cells and rendered them sensitive to the acquisition of T helper type 1 (TH1) cell­ and interleukin 17 (IL-17)-producing helper T (TH17) cell­like effector phenotypes. This function of Ubc13 involved its downstream target, the kinase IKK. The Ubc13-IKK signaling axis controlled the expression of specific Treg cell effector molecules, including IL-10 and SOCS1. Collectively, our findings suggest that the Ubc13-IKK signaling axis regulates the molecular program that maintains Treg cell function and prevents Treg cells from acquiring inflammatory phenotypes.

Tyrosine kinase inhibitors for radioiodine refractory differentiated thyroid cancer: A systematic review and meta-analysis.

BACKGROUND: The poor overall prognosis of radioiodine refractory thyroid cancer is an inevitable challenge in managing this disease. A series of trials have demonstrated the antitumor activity of tyrosine kinase inhibitors (TKIs) in radioiodine refractory differentiated thyroid cancer (RAIR-DTC). However, the available evidence cannot determine the optimal choice of TKI in RAIR-DTC. METHODS: This study searched PubMed, EMBASE, Cochrane databases, and the ClinicalTrials website. The Cochrane bias risk tool was used to assess the risk of bias, and to evaluate randomized clinical trials (RCT) of RAIR-DTC patients treated with the TKI system. Outcomes, including progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were reported. RESULTS: Seven studies involving 1310 patients with RAIR-DTC was conducted to compare the PFS and OS of various TKI monotherapies with placebo. The results showed that all TKI monotherapies had a statistically significant benefit in terms of PFS compared with placebo, with lenvatinib demonstrating the greatest benefit (hazard ratio [HR] 0.19, 95% credible interval [CrI] 0.14-0.25). In terms of OS, only apatinib (HR 0.42, 95% CrI 0.18-0.97) and anlotinib (HR 0.36, 95% CrI 0.18-0.73) showed statistically significant benefits compared with placebo. TKIs also had a higher incidence of AEs of grade 3 or higher compared with placebo. The findings suggest that lenvatinib may be the preferred TKI for the treatment of RAIR-DTC, although its high incidence of AEs should be considered. The results also indicate that TKI treatment may be similarly effective in RAIR-DTC patients with BRAF or RAS mutations and in those with papillary or follicular subtypes of the disease, regardless of prior TKI treatment. CONCLUSIONS: The results of this meta-analysis suggest that targeted therapy with TKIs may be beneficial for patients with radioiodine-refractory advanced or metastatic differentiated thyroid cancer. Among the TKIs analyzed, lenvatinib appeared to be the most effective at improving PFS, although it also had the highest incidence of AEs. Further research through direct randomized controlled trials is needed to determine the optimal choice of TKI for treating patients with RAIR-DTC. This study is beneficial for formulating patients' treatment plans and guides clinicians' decision-making.

Bending creep behaviour of various polymer films analysed by surface strain measurement.

Understanding the temporal bending deformation of polymer films is key to designing mechanically durable flexible electronic devices. However, such creep behaviour under persistent bending remains unclear due to a lack of precise and accurate bending strain analysis methods. Herein, we quantitatively analysed the bending creep behaviour of various polymeric films using our developed strain measurement method that can precisely measure surface strain from optical diffraction. The surface strain measurement reveals that bending creep deformation differs depending on the polymer structure. The four-element Burgers model was employed to model the temporal strain increase on the bending surface successfully. By fitting the four-element model to the time course of the measured surface strain, we found that each polymer film has a different threshold surface strain for the appearance of bending creep deformation. Such disparity in the bending creep behaviour can be explained by the difference in strain energy density between the polymer films and their elastic model; polymer films with a small strain energy density difference show small bending creep deformation. The results obtained in this study contribute to the elucidation of the bending creep behaviour of polymer films and the development of flexible electronic devices operated under persistent bending.

Comprehensive evaluation of the efficacy and safety of a new multi-component anti-aging topical eye cream.

BACKGROUND: The delicate periorbital region is susceptible to skin dehydration, wrinkles, and loss of elasticity. Thus, targeted and effective anti-aging interventions are necessary for the periorbital area. AIM: To evaluate the efficacy and safety of a new anti-aging eye cream formulated with the active complex (Yeast/rice fermentation filtrate, N-acetylneuraminic acid, palmityl tripeptide-1, and palmitoyl tetrapeptide-7). METHODS: The cell viability and expressions of key extracellular matrix (ECM) components of the active complex were evaluated using a human skin fibroblast model. In the 12-week clinical trial, skin hydration, elasticity, facial photographs, and collagen density following eye cream application were assessed using Corneometer, Cutometer, VISIA, and ultrasound device, respectively. Dermatologists and participants evaluated clinical efficacy and safety at baseline, and after 4, 8, and 12 weeks. RESULTS: PCR and immunofluorescent analyses revealed that the active complex significantly stimulated fibroblast proliferation (p < 0.05) and markedly promote the synthesis of collagen and elastin. Clinical findings exhibited a substantial enhancement in skin hydration (28.12%), elasticity (18.81%), and collagen production (54.99%) following 12 weeks of eye cream application. Dermatological evaluations and participants' assessments reported a significant improvement in skin moisture, roughness, elasticity, as well as fine lines and wrinkles by week 8. CONCLUSION: The new anti-aging eye cream, enriched with the active complex, demonstrates comprehensive rejuvenating effects, effectively addressing aging concerns in the periorbital area, coupled with a high safety profile.

Research on a Critical Link Discovery Method for Network Security Situational Awareness.

Network security situational awareness (NSSA) aims to capture, understand, and display security elements in large-scale network environments in order to predict security trends in the relevant network environment. With the internet's increasingly large scale, increasingly complex structure, and gradual diversification of components, the traditional single-layer network topology model can no longer meet the needs of network security analysis. Therefore, we conduct research based on a multi-layer network model for network security situational awareness, which is characterized by the three-layer network structure of a physical device network, a business application network, and a user role network. Its network characteristics require new assessment methods, so we propose a multi-layer network link importance assessment metric: the multi-layer-dependent link entropy (MDLE). On the one hand, the MDLE comprehensively evaluates the connectivity importance of links by fitting the link-local betweenness centrality and mapping entropy. On the other hand, it relies on the link-dependent mechanism to better aggregate the link importance contributions in each network layer. The experimental results show that the MDLE has better ordering monotonicity during critical link discovery and a higher destruction efficacy in destruction simulations compared to classical link importance metrics, thus better adapting to the critical link discovery requirements of a multi-layer network topology.

The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity.

T cell activation is subject to tight regulation to avoid inappropriate responses to self antigens. Here we show that genetic deficiency in the ubiquitin ligase Peli1 caused hyperactivation of T cells and rendered T cells refractory to suppression by regulatory T cells and transforming growth factor-ß (TGF-ß). As a result, Peli1-deficient mice spontaneously developed autoimmunity characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency resulted in the nuclear accumulation of c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T cell activation. Peli1 negatively regulated c-Rel by mediating its Lys48 (K48) ubiquitination. Our results identify Peli1 as a critical factor in the maintenance of peripheral T cell tolerance and demonstrate a previously unknown mechanism of c-Rel regulation.

Second-order statistics of a Hermite-Gaussian correlated Schell-model beam carrying twisted phase propagation in turbulent atmosphere.

We investigate the second-order statistics of a twisted Hermite-Gaussian correlated Schell-model (THGCSM) beam propagation in turbulent atmosphere, including the spectral density, degree of coherence (DOC), root mean square (r.m.s.) beam wander and orbital angular momentum (OAM) flux density. Our results reveal that the atmospheric turbulence and the twist phase play a role in preventing the beam splitting during beam propagation. However, the two factors have opposite effects on the evolution of the DOC. The twist phase preserves the DOC profile invariant on propagation, whereas the turbulence degenerates the DOC. In addition, the influences of the beam parameters and the turbulence on the beam wander are also studied through numerical examples, which show that the beam wander can be reduced by modulating the initial parameters of the beam. Further, the behavior of the z-component OAM flux density in free space and in atmosphere is thoroughly examined. We show that the direction of the OAM flux density without the twist phase will be suddenly inversed at each point across the beam section in the turbulence. This inversion only depends on the initial beam width and the turbulence strength, and in turn, it offers an effective protocol to determine the turbulence strength by measuring the propagation distance where the direction of OAM flux density is inversed.

Enhancing fiber-coupling efficiency of beam-to-fiber links in turbulence by spatial non-uniform coherence engineering.

We present a general formula for the fiber-coupling efficiency of various types of non-uniformly correlated beams propagating in a turbulent atmosphere. With it, we calculate the fiber-coupling efficiency of a specific type of non-uniformly correlated beams, Laguerre non-uniformly correlated (LNUC) beams, to investigate how the non-uniform correlation structure plays a role in enhancing the fiber-coupling efficiency. Compared with conventional Gaussian Schell-model beams, the LNUC beams possess better coupling behavior, and the initial coherence length and beam order of such beams can be adjusted to further improve the fiber-coupling efficiency in turbulence. Our results demonstrate how non-uniformly correlated beams can be used for fiber-coupling applications, and demonstrate their intriguing potential for free-space optical communications.

Synthesis of partially coherent beams with a prescribed conjugate-model correlation structure.

Using the sum of two mutually complex conjugate functions as the integral kernel of the necessary and sufficient condition derived by Gori et al., the conjugate-model correlation structure can be constructed. Here, we introduced a general strategy for the synthesis of partially coherent beams with such correlation structures. With it, we described a specific family of such beams, called Hermite conjugate-model beams. Their focusing properties were investigated numerically and experimentally. The experimental results are consistent with the theoretical predictions, and show that the proposed beams possess novel physical features compared with well-known Schell-model beams, such as controllable intensity distributions both at the source and focal plane, which may prove useful in free-space optical communications and optical trapping.

Generating multi-focus beams with a spatial non-uniform coherence structure.

We introduce a class of structured light beams, named multi-focus beams, which exhibit self-focusing at multiple propagation distances. We show that the proposed beams not only have the ability to produce multiple longitudinal focal spots, but also that the number, intensity, and position of the foci can be controlled by adjusting the initial beam parameters. Furthermore, we demonstrate that these beams still exhibit self-focusing in the shadow of an obstacle. We have experimentally generated such beams and the results are consistent with the theoretical predictions. Our studies may find application where fine control of the longitudinal spectral density is needed, such as longitudinal optical trapping and manipulation of multiple particles, and transparent material cutting.

On z-coherence of Schell-model sources carrying a prescribed astigmatic phase.

A simple expression for the correlations of beams radiated by Schell-model sources carrying a prescribed astigmatic phase (cross phase) in 3D space is derived. The z-coherence of such sources upon free-space propagation is investigated in detail. It is demonstrated that the z-coherence does not decrease to zero with an increasing separation of two axial points. Our results show that the initial cross phase, coherence, and correlation state of such sources affect the distribution of the z-coherence. Furthermore, the cross phase plays a role in maintaining z-coherence, which will be useful in applications where high z-coherence is required.

Noncanonical NF-κB pathway controls the production of type I interferons in antiviral innate immunity.

Production of type I interferons (IFN-I) is a crucial innate immune mechanism against viral infections. IFN-I induction is subject to negative regulation by both viral and cellular factors, but the underlying mechanism remains unclear. We report that the noncanonical NF-κB pathway was stimulated along with innate immune cell differentiation and viral infections and had a vital role in negatively regulating IFN-I induction. Genetic deficiencies in major components of the noncanonical NF-κB pathway caused IFN-I hyperinduction and rendered cells and mice substantially more resistant to viral infection. Noncanonical NF-κB suppressed signal-induced histone modifications at the Ifnb promoter, an action that involved attenuated recruitment of the transcription factor RelA and a histone demethylase, JMJD2A. These findings reveal an unexpected function of the noncanonical NF-κB pathway and highlight an important mechanism regulating antiviral innate immunity.

Development of a CT radiomics nomogram for preoperative prediction of Ki-67 index in pancreatic ductal adenocarcinoma: a two-center retrospective study.

OBJECTIVES: To develop and validate a contrast-enhanced computed tomography (CECT)-based radiomics nomogram for the preoperative evaluation of Ki-67 proliferation status in pancreatic ductal adenocarcinoma (PDAC). METHODS: In this two-center retrospective study, a total of 181 patients (95 in the training cohort; 42 in the testing cohort, and 44 in the external validation cohort) with PDAC who underwent CECT examination were included. Radiomic features were extracted from portal venous phase images. The radiomics signatures were built by using two feature-selecting methods (relief and recursive feature elimination) and four classifiers (support vector machine, naive Bayes, linear discriminant analysis (LDA), and logistic regression (LR)). Multivariate LR was used to build a clinical model and radiomics-clinical nomogram. The predictive performances of the models were evaluated using area under receiver operating characteristic curve (AUC) and decision curve analysis (DCA). RESULTS: The relief selector and LDA classifier using twelve features built the optimal radiomics signature, with AUCs of 0.948, 0.927, and 0.824 in the training, testing, and external validation cohorts, respectively. The radiomics-clinical nomogram incorporating the optimal radiomics signature, CT-reported lymph node status, and CA19-9 showed better predictive performance with AUCs of 0.976, 0.955, and 0.882 in the training, testing, and external validation cohorts, respectively. The calibration curve and DCA demonstrated goodness-of-fit and improved benefits in clinical practice of the nomogram. CONCLUSIONS: The radiomics-clinical nomogram is an effective and non-invasive computer-aided tool to predict the Ki-67 expression status in patients with PDAC. CLINICAL RELEVANCE STATEMENT: The radiomics-clinical nomogram is an effective and non-invasive computer-aided tool to predict the Ki-67 expression status in patients with pancreatic ductal adenocarcinoma. KEY POINTS: The radiomics analysis could be helpful to predict Ki-67 expression status in patients with pancreatic ductal adenocarcinoma (PDAC). The radiomics-clinical nomogram integrated with the radiomics signature, clinical data, and CT radiological features could significantly improve the differential diagnosis of Ki-67 expression status. The radiomics-clinical nomogram showed satisfactory calibration and net benefit for discriminating high and low Ki-67 expression status in PDAC.

Association between neutrophil-to-albumin ratio and long-term mortality of aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The prognosis of aneurysmal subarachnoid hemorrhage (aSAH) survivors is concerning. The goal of this study was to investigate and demonstrate the relationship between the neutrophil-to-albumin ratio (NAR) and long-term mortality of aSAH survivors. METHODS: A retrospective observational cohort study was conducted at Sichuan University West China Hospital between January 2009 and June 2019. The investigation of relationship between NAR and long-term mortality was conducted using univariable and multivariable Cox regression models. To demonstrate the predictive performance of different biomarkers over time, time-dependent receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA) were created. RESULTS: In total, 3173 aSAH patients were included in this study. There was a strong and continuous relationship between NAR levels and long-term mortality (HR 3.23 95% CI 2.75-3.79, p < 0.001). After adjustment, the result was still significant (adjusted HR 1.78 95% CI 1.49-2.12). Compared with patients with the lowest quartile (< 0.15) of NAR levels, the risk of long-term mortality in the other groups was higher (0.15-0.20: adjusted HR 1.30 95% CI 0.97-1.73; 0.20-0.28: adjusted HR 1.37 95% CI 1.03-1.82; >0.28: adjusted HR 1.74 95% CI 1.30-2.32). Results in survivors were found to be still robust. Moreover, out of all the inflammatory markers studied, NAR demonstrated the highest correlation with long-term mortality. CONCLUSIONS: A high level of NAR was associated with increased long-term mortality among patients with aSAH. NAR was a promising inflammatory marker for long-term mortality of aSAH.

COMPARISON OF THREE INTERNAL LIMITING MEMBRANE PEELING TECHNIQUES FOR MYOPIC TRACTION MACULOPATHY WITH HIGH RISK OF POSTOPERATIVE MACULAR HOLE DEVELOPMENT.

PURPOSE: To compare three different internal limiting membrane (ILM) peeling techniques, including standard ILM peeling, fovea-sparing ILM peeling, and inverted ILM flap (ILMF), in the treatment of myopic traction maculopathy with high risk of postoperative macular hole development. METHOD: This retrospective cohort study enrolled 101 eyes suffering from lamellar macular hole combined with myopic traction maculopathy in 98 consecutive patients who underwent vitrectomy with either standard ILM peeling, fovea-sparing ILM peeling, or ILMF from July 2017 to August 2020. All patients were followed up for at least 12 months after surgery. Best-corrected visual acuity, macular anatomical outcomes, and postoperative full-thickness macular hole (FTMH) formation were evaluated. RESULTS: No significant differences were found among the three surgical groups in baseline characteristics. 12 months after surgery, the mean best-corrected visual acuity was significantly improved ( P < 0.001) and showed no significant differences among groups ( P = 0.452). None of the eyes in the ILMF group, five eyes (15.6%) in the standard ILM peeling group, and six eyes (17.1%) in the fovea-sparing ILM peeling group developed a postoperative FTMH ( P = 0.026). Logistic regression showed that the ILM peeling technique was an independent influencing factor for FTMH formation (OR = 0.209, P = 0.014). CONCLUSION: Compared with the standard ILM peeling or fovea-sparing ILM peeling technique, the ILMF technique resulted in similar visual outcomes but a relatively low incidence of postoperative FTMH in the treatment of lamellar macular hole combined with myopic traction maculopathy. Inverted ILM flap is an effective technique for treating myopic traction maculopathy with high risk of postoperative FTMH development.

Vitamin C Deficiency Causes Cell Type-Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model.

BACKGROUND: Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown. METHODS: We showed that vitamin C deficiency leads to acute tubular necrosis (ATN) using a vitamin C-deficient mouse model (Gulo knock-out). DNA/RNA epigenetic modifications and injured S3 proximal tubule cells were identified in the vitamin C-deficient kidneys using whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing. RESULTS: Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C-deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C-induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN. CONCLUSIONS: Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.