NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity.

Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8+ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.

NIK signaling axis regulates dendritic cell function in intestinal immunity and homeostasis.

Dendritic cells (DCs) play an integral role in regulating mucosal immunity and homeostasis, but the signaling network mediating this function of DCs is poorly defined. We identified the noncanonical NF-κB-inducing kinase (NIK) as a crucial mediator of mucosal DC function. DC-specific NIK deletion impaired intestinal immunoglobulin A (IgA) secretion and microbiota homeostasis, rendering mice sensitive to an intestinal pathogen, Citrobacter rodentium. DC-specific NIK was required for expression of the IgA transporter polymeric immunoglobulin receptor (pIgR) in intestinal epithelial cells, which in turn relied on the cytokine IL-17 produced by TH17 cells and innate lymphoid cells (ILCs). NIK-activated noncanonical NF-κB induced expression of IL-23 in DCs, contributing to the maintenance of TH17 cells and type 3 ILCs. Consistent with the dual functions of IL-23 and IL-17 in mucosal immunity and inflammation, NIK deficiency also ameliorated colitis induction. Thus, our data suggest a pivotal role for the NIK signaling axis in regulating DC functions in intestinal immunity and homeostasis.

Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid.

The proinflammatory cytokines interleukin 12 (IL-12) and IL-23 connect innate responses and adaptive immune responses and are also involved in autoimmune and inflammatory diseases. Here we describe an epigenetic mechanism for regulation of the genes encoding IL-12 (Il12a and Il12b; collectively called 'Il12' here) and IL-23 (Il23a and Il12b; collectively called 'Il23' here) involving the deubiquitinase Trabid. Deletion of Zranb1 (which encodes Trabid) in dendritic cells inhibited induction of the expression of Il12 and Il23 by Toll-like receptors (TLRs), which impaired the differentiation of inflammatory T cells and protected mice from autoimmune inflammation. Trabid facilitated TLR-induced histone modifications at the promoters of Il12 and Il23, which involved deubiqutination and stabilization of the histone demethylase Jmjd2d. Our findings highlight an epigenetic mechanism for the regulation of Il12 and Il23 and establish Trabid as an innate immunological regulator of inflammatory T cell responses.

The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses.

Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor-infiltrating CD4 and CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wild-type T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as a novel regulator of mTORC1 and downstream mTORC1-mediated actions on T cell metabolism and antitumor immunity.

Myeloid cell TBK1 restricts inflammatory responses.

Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory responses are poorly understood. Here, we show that TANK-binding kinase 1 (TBK1) serves as a vital regulator of proinflammatory macrophage function and protects against tissue inflammation. Myeloid cell-conditional Tbk1 knockout (MKO) mice spontaneously developed adipose hypertrophy and metabolic disorders at old ages, associated with increased adipose tissue M1 macrophage infiltration and proinflammatory cytokine expression. When fed with a high-fat diet, the Tbk1-MKO mice also displayed exacerbated hepatic inflammation and insulin resistance, developing symptoms of nonalcoholic steatohepatitis. Furthermore, myeloid cell-specific TBK1 ablation exacerbates inflammation in experimental colitis. Mechanistically, TBK1 functions in macrophages to suppress the NF-κB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1ß. Ablation of IL-1 receptor 1 (IL-1R1) eliminates the inflammatory symptoms of Tbk1-MKO mice. These results establish TBK1 as a pivotal anti-inflammatory mediator that restricts inflammation in different disease models.

Treponema pallidum lipoprotein Tp0768 promotes the migration and adhesion of THP-1 cells to vascular endothelial cells through stress of the endoplasmic reticulum and the NF-κB/HIF-1α pathway.

Endothelial cell injury is a key factor in the spread of infection and pathogenicity of Treponema pallidum. The migration and adhesion reaction mediated by T. pallidum lipoprotein plays an important role. This study aimed to systematically explore the migration and adhesion effect of T. pallidum lipoprotein Tp0768 and its molecular mechanism. Stimulating vascular endothelial cells with Tp0768 increased the expression of ICAM-1, MCP-1, and IL-8. Moreover, it promoted the migration and adhesion of THP-1 cells to vascular endothelial cells. Our results revealed that Tp0768 promoted the THP-1 cells migrating and adhering to vascular endothelial cells by the PERK and IRE-1α pathways of endoplasmic reticulum (ER) stress. We further demonstrated that the inhibition of the NF-κB pathway and the downregulation of hypoxia-inducible factor 1 alpha (HIF-1α) reduced the mRNA levels of ICAM-1, MCP-1, and IL-8 induced by Tp0768. Also, the adhesion rate of THP-1 cells to endothelial cells decreased. After inhibiting ER stress, NF-κB p65 nuclear translocation was weakened, and the mRNA level of HIF-1α was also significantly downregulated. Our results indicated that T. pallidum lipoprotein Tp0768 promoted the migration and adhesion of THP-1 cells to vascular endothelial cells through ER stress and NF-κB/HIF-1α pathway.

Iron deficiency affects oxygen transport and activates HIF1 signaling pathway to regulate phenotypic transformation of VSMC in aortic dissection.

BACKGROUND: Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration.This experiment aims to explore how iron deficiency (ID) affects the function of vascular smooth muscle cell (VSMC) and participates in the occurrence and development of AD by regulating gene expression. METHODS: The relationship between iron and AD was proved by Western-blot (WB) and immunostaining experiments in human and animals. Transcriptomic sequencing explored the transcription factors that were altered downstream. WB, flow cytometry and immunofluorescence were used to demonstrate whether ID affected HIF1 expression through oxygen transport. HIF1 signaling pathway and phenotypic transformation indexes were detected in cell experiments. The use of the specific HIF1 inhibitor PX478 further demonstrated that ID worked by regulating HIF1. RESULTS: The survival period of ID mice was significantly shortened and the pathological staining results were the worst. Transcriptomic sequencing indicated that HIF1 was closely related to ID and the experimental results indicated that ID might regulate HIF1 expression by affecting oxygen balance. HIF1 activation regulates the phenotypic transformation of VSMC and participates in the occurrence and development of AD in vivo and in vitro.PX478, the inhibition of HIF1, can improve ID-induced AD exacerbation.

Mitochondrion-targeted carboxymethyl chitosan hybrid nanoparticles loaded with Coenzyme Q10 protect cardiac grafts against cold ischaemia‒reperfusion injury in heart transplantation.

BACKGROUND: Heart transplantation (HT) has been approved as an optimal therapeutic regimen for patients with terminal-stage cardiac failure. However, cold ischaemia‒reperfusion (I/R) injury remains an unavoidable and outstanding challenge, which is a major factor in early graft dysfunction and an obstacle to long-term survival in HT. Cold I/R injury induces cardiac graft injury by promoting mitochondrial dysfunction and augmenting free radical production and inflammatory responses. We therefore designed a mitochondrion-targeted nanocarrier loaded with Coenzyme Q10 (CoQ10) (CoQ10@TNPs) for treatment of cold I/R injury after cardiac graft in a murine heterotopic cardiac transplantation model. METHODS: Hybrid nanoparticles composed of CaCO3/CaP/biotinylated-carboxymethylchitosan (CaCO3/CaP/BCMC) were synthesized using the coprecipitation method, and the mitochondria-targeting tetrapeptide SS31 was incorporated onto the surface of the hybrid nanoparticles through biotin-avidin interactions. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis were used for characterisation. In vitro, the hypoxia-reoxygenation model of H9c2 cells was employed to replicate in vivo cold I/R injury and treated with CoQ10@TNPs. The impact of CoQ10@TNPs on H9c2 cell injury was assessed by analysis of oxidative damage and apoptosis. In vivo, donor hearts (DHs) were perfused with preservation solution containing CoQ10@TNPs and stored in vitro at 4 °C for 12 h. The DHs were heterotopically transplanted and analysed for graft function, oxidative damage, apoptosis, and inflammatory markers 1 day post-transplantation. RESULTS: CoQ10@TNPs were successfully synthesized and delivered CoQ10 to the mitochondria of the cold ischaemic myocardium. In vitro experiments demonstrated that CoQ10@TNPs was taken up by H9c2 cells at 4 °C and localized within the mitochondria, thus ameliorating oxidative stress damage and mitochondrial injury in cold I/R injury. In vivo experiments showed that CoQ10@TNPs accumulated in DH tissue at 4 °C, localized within the mitochondria during cold storage and improved cardiac graft function by attenuating mitochondrial oxidative injury and inflammation. CONCLUSIONS: CoQ10@TNPs can precisely deliver CoQ10 to the mitochondria of cold I/R-injured cardiomyocytes to effectively eliminate mitochondrial reactive oxygen species (mtROS), thus reducing oxidative injury and inflammatory reactions in cold I/R-injured graft tissues and finally improving heart graft function. Thus, CoQ10@TNPs offer an effective approach for safeguarding cardiac grafts against extended periods of cold ischaemia, emphasizing the therapeutic potential in mitigating cold I/R injury during HT. These findings present an opportunity to enhance existing results following HT and broaden the range of viable grafts for transplantation.

DYRK1a mediates BAFF-induced noncanonical NF-κB activation to promote autoimmunity and B-cell leukemogenesis.

B-cell-activating factor (BAFF) mediates B-cell survival and, when deregulated, contributes to autoimmune diseases and B-cell malignancies. The mechanism connecting BAFF receptor (BAFFR) signal to downstream pathways and pathophysiological functions is not well understood. Here we identified DYRK1a as a kinase that responds to BAFF stimulation and mediates BAFF-induced B-cell survival. B-cell-specific DYRK1a deficiency causes peripheral B-cell reduction and ameliorates autoimmunity in a mouse model of lupus. An unbiased screen identified DYRK1a as a protein that interacts with TRAF3, a ubiquitin ligase component mediating degradation of the noncanonical nuclear factor (NF)-κB-inducing kinase (NIK). DYRK1a phosphorylates TRAF3 at serine-29 to interfere with its function in mediating NIK degradation, thereby facilitating BAFF-induced NIK accumulation and noncanonical NF-κB activation. Interestingly, B-cell acute lymphoblastic leukemia (B-ALL) cells express high levels of BAFFR and respond to BAFF for noncanonical NF-κB activation and survival in a DYRK1a-dependent manner. Furthermore, DYRK1a promotes a mouse model of B-ALL through activation of the noncanonical NF-κB pathway. These results establish DYRK1a as a critical BAFFR signaling mediator and provide novel insight into B-ALL pathogenesis.

Artificial intelligence-based diagnosis of abnormalities in small-bowel capsule endoscopy.

BACKGROUND : Further development of deep learning-based artificial intelligence (AI) technology to automatically diagnose multiple abnormalities in small-bowel capsule endoscopy (SBCE) videos is necessary. We aimed to develop an AI model, to compare its diagnostic performance with doctors of different experience levels, and to further evaluate its auxiliary role for doctors in diagnosing multiple abnormalities in SBCE videos. METHODS : The AI model was trained using 280 426 images from 2565 patients, and the diagnostic performance was validated in 240 videos. RESULTS : The sensitivity of the AI model for red spots, inflammation, blood content, vascular lesions, protruding lesions, parasites, diverticulum, and normal variants was 97.8 %, 96.1 %, 96.1 %, 94.7 %, 95.6 %, 100 %, 100 %, and 96.4 %, respectively. The specificity was 86.0 %, 75.3 %, 87.3 %, 77.8 %, 67.7 %, 97.5 %, 91.2 %, and 81.3 %, respectively. The accuracy was 95.0 %, 88.8 %, 89.2 %, 79.2 %, 80.8 %, 97.5 %, 91.3 %, and 93.3 %, respectively. For junior doctors, the assistance of the AI model increased the overall accuracy from 85.5 % to 97.9 % (P  < 0.001, Bonferroni corrected), comparable to that of experts (96.6 %, P > 0.0125, Bonferroni corrected). CONCLUSIONS : This well-trained AI diagnostic model automatically diagnosed multiple small-bowel abnormalities simultaneously based on video-level recognition, with potential as an excellent auxiliary system for less-experienced endoscopists.

Investigation of the immune escape mechanism of Treponema pallidum.

BACKGROUND: Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subspecies pallidum (T. pallidum), which is a public health problem that seriously affects human health worldwide. T. pallidum is characterized by early transmission and immune escape and is therefore termed an "invisible pathogen". METHODS: This review systematically summarizes the host's innate and adaptive immune responses to T. pallidum infection as well as the escape mechanisms of T. pallidum. PURPOSE: To lay the foundation for assessing the pathogenic mechanism and the systematic prevention and treatment of syphilis. CONCLUSION: The immune escape mechanism of T. pallidum plays an important role in its survival. Exploring the occurrence and development of these mechanisms has laid the foundation for the development of syphilis vaccine.

Near-noiseless and small-footprint phase sensitive optical parametric amplifier using AlGaAs-on-insulator waveguides.

Phase sensitive amplifiers (PSAs) based on optical parametric amplification feature near noiseless amplification, which is of considerable benefit for improving the performance of optical communication systems. Currently, the majority of research on PSAs is carried out on the basis of highly nonlinear fibers or periodically poled lithium niobite waveguides, with the impediments of being susceptible to environmental interference and requiring complex temperature control systems to maintain quasi-phase matching conditions, respectively. Here, a near-noiseless and small-footprint PSA based on dispersion-engineered AlGaAs-on-insulator (AlGaAsOI) waveguides is proposed and demonstrated theoretically. The phase-dependent gain and the phase-to-phase transfer function of the PSA are calculated to analyze its characteristics. Furthermore, we investigate in detail the effects of linear loss, nonlinear coefficient, and pump power on the PSA gain and noise figure (NF) in AlGaAsOI waveguides. The results show that a PSA based on an AlGaAsOI waveguide is feasible with a maximum phase sensitive gain of 33 dB, achieving an NF of less than 1 dB over a gain bandwidth of 245 nm with a gain of >15d B, which completely covers the S + C + L band. This investigation is worthwhile for noiseless PSAs on photonic integrated chips, which are promising for low-noise optical amplification, multifunctional photonic integrated chips, quantum communication, and spectroscopy, and as a reference for low-noise PSAs depending on the third-order nonlinearity, χ (3), of the waveguide material.

On-orbit demonstration of inter-satellite free-space optical stable communication enabled by integrated optical amplification of HPA and LNA.

Satellite free-space optical (FSO) communication is very promising in improving the bandwidth and capacity of space information networks in the future. However, the inter-satellite transmission distance of over 1000 km leads to unstable optical beam pointing, acquisition, and tracking and then generates optical power jitter by a large margin before detection-demodulation. Therefore, it is difficult to realize high-stability and long-time FSO communication between satellites due to the generated bit error rate (BER) by jitter. In this paper, we report an autonomously self-designed and high-integration laser communication payload (LCP) and on-orbit-demonstrated inter-satellite 145 min, zero-BER FSO stable communication with a line rate of 2.8 Gbps. Moreover, based on the inter-satellite laser communication link, a video phone was clearly implemented for more than 10 min, and authentic user data transmitted 459,149 packets, achieving results of zero-packet loss. Summarily, this on-orbit experiment demonstrated an excellent performance of the LCP owing to the distinctive design of integrating a high-power amplifier and low-noise amplifier optical amplification function. Our space mission was successfully completed, and the on-orbit demonstration results may offer a significant reference for the field of satellite laser communication and space information networks.

Research and practice of the BOPPPS teaching model based on the OBE concept in clinical basic laboratory experiment teaching.

"Clinical basic inspection technology" is one of the essential courses in the medical laboratory profession. Combining the characteristics of the discipline itself, the research and practice of the BOPPPS model based on the OBE concept in clinical basic laboratory experiment teaching are discussed, and the reform of in teaching objectives, teaching contents, and teaching design path is implemented. The "student-centered" teaching process is divided into six stages: before, during, and after class, and the teaching process is continuously improved to achieve the desired teaching effect. Results of the experiment teaching show that the model has improved students' active participation and developed their clinical thinking skills, and more than 95% of students are satisfied with this teaching model.

Features of capsule endoscopy in COVID-19 patients with a six-month follow-up: A prospective observational study.

Recently, the coronavirus disease 2019 (COVID-19) has caused a global pandemic. Several studies indicate that the digestive system can also be affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, patients with digestive symptoms should have a capsule endoscopy (CE). COVID-19 patients with gastrointestinal (GI) symptoms who underwent CE were recruited from March 2020 to April 2020. We collected patients' data and performed a prospective follow-up study for 6 months. All 11 COVID-19 cases with GI symptoms who underwent CE presented gastritis. Eight cases (72.7%) had intestinal mucosa inflammation. Among them, two cases showed intestinal ulcers or erosions. Moreover, two cases displayed colonic mucositis. One case was lost during follow-up. At 3-6 months after hospital discharge, five patients underwent CE again, presenting gastrointestinal lesions. Five of the 10 cases had GI symptoms, such as abdominal pain, diarrhea, constipation, and others. Among these five cases, the GI symptoms of three patients disappeared at the last follow-up and two patients still presented diarrhea symptoms. Overall, we observed damaged digestive tract mucosa that could be caused by SARS-CoV-2. Moreover, after discharge, some patients still presented intestinal lesions and GI symptoms.

Multi-modulation compatible miniaturization system for FSO communication assisted by chirp-managed laser.

In recent years, the thriving satellite laser communication industry has been severely hindered by the limitations of incompatible modulation formats and restricted Size Weight and Power (SWaP). A multi-modulation compatible method serving for free-space optical (FSO) communication has been proposed assisted by chirp-managed laser (CML). The corresponding demonstration system has been established for realizing free-switching between intensity (OOK) and phase modulation (RZ-DPSK). The feasibility and performance of system have been evaluated sufficiently when loading with 2.5 and 5 Gbps data streams, respectively. Additionally, a control-group system has been operated utilizing Mach-Zehnder modulator (MZM) for comparison between CML-based and MZM-based compatibility solutions. The OOK receiving sensitivities of CML-based system are -47.02 dBm@2.5 Gbps and -46.12 dBm@5 Gbps at BER of 1×10-3 which are 0.62 dB and 1.11 dB higher than that of MZM; the receiving sensitivities of RZ-DPSK are -50.12 dBm@2.5 Gbps and -47.03 dBm@5 Gbps which are 0.79 dB and 0.47 dB higher than that of MZM respectively. Meanwhile, CML-based transmitter abandoned the traditional modulator and its complicated supporting devices which can effectively contribute to the reduction of SWaP. The CML-based system has been proven to have the compatibility between intensity and phase modulation while also possesses a miniaturized design. It may provide fresh thinking to achieve a practical miniaturization system for satisfying the requirements of space optical network in future.

150 Gbit/s 1 km high-sensitivity FSO communication outfield demonstration based on a soliton microcomb.

A high-sensitivity and large-capacity free space optical (FSO) communication scheme based on the soliton microcomb (SMC) is proposed. Using ultra-large bandwidth stabilized SMC with a frequency interval of 48.97 GHz as the laser source, 60 optical wavelengths modulated by 2.5 Gbit/s 16-Pulse position modulation (PPM) are transmitted in parallel. A corresponding outfield high-sensitivity 150 Gbit/s FSO communication experiment based on the SMC was carried out with 1 km space distance. Our experimental results show that the best sensitivity of the single comb wavelength which has higher OSNR can reach -52.62 dBm, and the difference is only 1.38 dB from the theoretical limit under the BER of 1 × 10-3 without forward error correction (FEC). In addition, at BER of 1 × 10-3, 16-PPM has a higher received sensitivity of 6.73dB and 3.72dB compared to on-off keying (OOK) and differential phase shift keying (DPSK) respectively. Meanwhile, taking the advantage of multi-channel SMC, 60 × 2.5 Gbit/s can achieve 150 Gbit/s large-capacity free-space transmission. For comparison, commercially available single-wavelength laser based FSO communication system have also been performed in the outfield. The outfield experimental results demonstrated the feasibility of high-sensitivity, large-capacity PPM FSO communication based on SMCs and provided a new perspective for the future development of large-capacity, long-haul FSO communication.

Fracture risks in patients with atrial fibrillation treated with different oral anticoagulants: a meta-analysis and systematic review.

AIMS: evidence on the difference in fracture risks for patients with atrial fibrillation (AF) receiving direct oral anticoagulants (DOACs) versus warfarin remains controversial. We aim to compare the fracture risks between the DOAC and warfarin prescriptions among the AF patients. METHODS AND RESULTS: we systematically searched PubMed, EMBASE, the Cochrane Library and Web of Science up to 19 April 2021 for relevant studies. And the observational studies regarding the relationship between the DAOC versus warfarin prescriptions and fracture risks among the patients with AF were included in this meta-analysis. Two investigators independently screened the articles and extracted the relevant data. A random- or fixed-effect model was applied to calculate the pooled hazard ratio/relative ratios with 95% confidence intervals of fracture risks associated with the DOAC and warfarin prescriptions. Six studies comprising 351,208 patients and 9,424 fractures were included in this meta-analysis. Overall, the AF patients treated with DOACs tend to present a lower risk of any fracture compared with those treated with warfarin (relative ratio: 0.82, 95% confidence interval (CI): 0.74-0.91). Sub-analyses for each individual DOAC indicate that apixaban and rivaroxan are associated with lower risk of any fracture compared with warfarin (HR: 0.75, 95% CI: 0.60-0.92, and HR: 0.79, 95% CI: 0.71-0.88, respectively). CONCLUSION: this meta-analysis suggests that DOAC users have a lower risk of fractures than the warfarin users. The results of this study may provide optimal anticoagulation opportunities for AF patients with high fracture risk factors.

Changes of Migration, Immunoregulation and Osteogenic Differentiation of Mesenchymal Stem Cells in Different Stages of Inflammation.

Bone infection has always been the focus of orthopedic research. Mesenchymal stem cells (MSCs) are the natural progenitors of osteoblasts, and the process of osteogenesis is triggered in response to different signals from the extracellular matrix. MSCs exert important functions including secretion and immune regulation and also play a key role in bone regeneration. The biological behavior of MSCs in acute and chronic inflammation, especially the transformation between acute inflammation and chronic inflammation, has aroused great interest among researchers. This paper reviews the recent literature and summarizes the behavior and biological characteristics of MSCs in acute and chronic inflammation to stimulate further research on MSCs and treatment of bone diseases.