Knockdown of KIF23 alleviates the progression of asthma by inhibiting pyroptosis.

BACKGROUND: Asthma is a chronic disease affecting the lower respiratory tract, which can lead to death in severe cases. The cause of asthma is not fully known, so exploring its potential mechanism is necessary for the targeted therapy of asthma. METHOD: Asthma mouse model was established with ovalbumin (OVA). H&E staining, immunohistochemistry and ELISA were used to detect the inflammatory response in asthma. Transcriptome sequencing was performed to screen differentially expressed genes (DEGs). The role of KIF23 silencing in cell viability, proliferation and apoptosis was explored by cell counting kit-8, EdU assay and flow cytometry. Effects of KIF23 knockdown on inflammation, oxidative stress and pyroptosis were detected by ELISA and western blot. After screening KIF23-related signalling pathways, the effect of KIF23 on p53 signalling pathway was explored by western blot. RESULTS: In the asthma model, the levels of caspase-3, IgG in serum and inflammatory factors (interleukin (IL)-1ß, KC and tumour necrosis factor (TNF)-α) in serum and bronchoalveolar lavage fluid were increased. Transcriptome sequencing showed that there were 352 DEGs in the asthma model, and 7 hub genes including KIF23 were identified. Knockdown of KIF23 increased cell proliferation and inhibited apoptosis, inflammation and pyroptosis of BEAS-2B cells induced by IL-13 in vitro. In vivo experiments verified that knockdown of KIF23 inhibited oxidative stress, inflammation and pyroptosis to alleviate OVA-induced asthma mice. In addition, p53 signalling pathway was suppressed by KIF23 knockdown. CONCLUSION: Knockdown of KIF23 alleviated the progression of asthma by suppressing pyroptosis and inhibited p53 signalling pathway.

Isotope Effect-Enabled Crystal Enlargement in Metal-Organic Frameworks.

Synthesizing large metal-organic framework (MOF) single crystals has garnered significant research interest, although it is hindered by the fast nucleation kinetics that gives rise to numerous small nuclei. Given the different chemical origins inherent in various types of MOFs, the development of a general approach to enhancing their crystal sizes presents a formidable challenge. Here, we propose a simple isotopic substitution strategy to promote size growth in MOFs by inhibiting nucleation, resulting in a substantial increase in the crystal volume ranging from 1.7- to 165-fold. Impressively, the crystals prepared under optimized conditions by normal approaches can be further enlarged by the isotope effect, yielding the largest MOF single crystal (2.9 cm × 0.48 cm × 0.23 cm) among the one-pot synthesis method. Detailed in situ characterizations reveal that the isotope effect can retard crystallization kinetics, establish a higher nucleation energy barrier, and consequently generate fewer nuclei that eventually grow larger. Compared with the smaller crystals, the isotope effect-enlarged crystal shows 33% improvement in the X-ray dose rate detection limit. This work enriches the understanding of the isotope effect on regulating the crystallization process and provides inspiration for exploring potential applications of large MOF single crystals.

CRP inhibits the osteoblastic differentiation of OPCs via the up-regulation of primary cilia and repression of the Hedgehog signaling pathway.

Inflammation disrupts bone metabolism and leads to bone damage. C-reactive protein (CRP) is a typical inflammation marker. Although CRP measurement has been conducted for many decades, how osteoblastic differentiation influences molecular mechanisms remains largely unknown. The present study attempted to investigate the effects of CRP on primary cultured osteoblast precursor cells (OPCs) while elucidating the underlying molecular mechanisms. OPCs were isolated from suckling Sprague-Dawleyrats. Fewer OPCs were observed after recombinant C-reactive protein treatment. In a series of experiments, CRP inhibited OPC proliferation, osteoblastic differentiation, and the OPC gene expression of the hedgehog (Hh) signaling pathway. The inhibitory effect of CRP on OPC proliferation occurred via blockade of the G1-S transition of the cell cycle. In addition, the regulation effect of proto cilium on osteoblastic differentiation was analyzed using the bioinformatics p. This revealed the primary cilia activation of recombinant CRP effect on OPCs through in vitro experiments. A specific Sonic Hedgehog signaling agonist (SAG) rescued osteoblastic differentiation inhibited by recombinant CRP. Moreover, chloral hydrate, which removes primary cilia, inhibited the Suppressor of Fused (SUFU) formation and blocked Gli2 degradation. This counteracted osteogenesis inhibition caused by CRP. Therefore, these data depict that CRP can inhibit the proliferation and osteoblastic differentiation of OPCs. The underlying mechanism could be associated with primary cilia activation and Hh pathway repression.

The inter-link of ageing, cancer and immunity: findings from real-world retrospective study.

BACKGROUND: Although the concept of declined immune function associated with cancer has been accepted extensively, real-world clinical studies focusing on analysis of the peripheral blood immune changes underlying ageing, immunity and cancer are scarce. METHODS: In this case-control study, we retrospectively analysed 1375 cancer patients and enrolled 275 age and gender matched healthy individuals. Flow cytometry was conducted to assess the immune changes. Further analysis was examined by SPSS 17.0 and GraphPad Prism 9 software. RESULTS: Cancer patients showed obviously decreased CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B, CD16+CD56+ NK cell counts and lower percentage of PD-1 (programmed cell death protein-1, PD-1) positive cells than healthy control (P < 0.0001). For cancer patients, the reference range of circulating percentage of PD-1+CD45+ cells, PD-1+CD3+ T cells, PD-1+CD3+CD4+ Th cells and PD-1+CD3+CD8+ CTL (Cytotoxic T Lymphocyte, CTL) were 11.2% (95% CI 10.8%-11.6%), 15.5% (95% CI 14.7%-16.0%), 15.4% (95% CI 14.9%-16.0%) and 14.5% (95% CI 14.0%-15.5%), respectively. Moreover, the reduction of CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B cell counts accompanied with age and stage advancing (P < 0.05). CD16+CD56+ NK cells decreased with stage, but elevated in aged and male cancer patients (P < 0.05). Additionally, the percentage of PD-1 positive cells varied across cancer types, raised with age and stage. Head and neck, pancreatic, gynaecological and lung demonstrated a higher level of the percentage of PD-1 positive cells than melanoma, prostate, and breast cancer (P < 0.05). CONCLUSIONS: This study provides the reference range of the percentage of PD-1 positive cells on peripheral blood, confirms the decreased immune cells and a series of immune changes accompanying with cancer, expands our real world evidence to better understand the interactions of ageing, cancer and immunity. Moreover, the circulating percentage of PD-1 positive cells shows similar tumor type distribution with tumor mutational burden (TMB), supports that it maybe a potential predictive biomarker for immune checkpoint inhibitor therapy.

[A comparative study of the effects of citrate and heparin anticoagulation on coagulation function and efficacy in children with septic shock undergoing continuous blood purification].

OBJECTIVE: To compare the effects of citrate and heparin anticoagulation on coagulation function and efficacy in children with septic shock undergoing continuous blood purification (CBP), and to provide guidance for CBP anticoagulation in children with septic shock. METHODS: A case control study was conducted. Thirty-seven children with septic shock admitted to the pediatric intensive care unit (PICU) of the First Affiliated Hospital of Gannan Medical University from July 2019 to September 2022 were enrolled as the research subjects. The patients were divided into citrate local anticoagulation group and heparin systemic anticoagulation group according to different anticoagulation methods. The baseline data, the level of coagulation indicators [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fib), D-dimer] before treatment and 1 day after weaning from CBP, serum inflammatory mediators [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), hypersensitivity C-reactive protein (hs-CRP), procalcitonin (PCT)], bleeding complications during CBP and 7-day mortality were collected. RESULTS: A total of 37 cases were enrolled finally, including 17 cases with citric acid local anticoagulation and 20 cases with heparin systemic anticoagulation. There was no statistically significant difference in general data such as gender, age, and body weight of children between the two groups. There were no statistically significant differences in baseline levels of coagulation indicators and inflammatory mediators before treatment of children between the two groups. One day after weaning from CBP, both groups showed varying degrees of improvement in coagulation indicators compared with those before treatment. Compared with before treatment, the PT of the heparin systemic anticoagulation group was significantly shortened after 1 day of weaning (s: 11.82±2.05 vs. 13.64±2.54), APTT and TT were significantly prolonged [APTT (s): 51.54±12.69 vs. 35.53±10.79, TT (s): 21.95±4.74 vs. 19.30±3.33], D-dimer level was significantly reduced (mg/L: 1.92±1.58 vs. 4.94±3.94), with statistically significant differences (all P < 0.05). While in the citrate local anticoagulation group, only APTT was significantly prolonged after treatment compared with that before treatment (s: 49.28±10.32 vs. 34.34±10.32, P < 0.05). There were no statistically significant differences in other coagulation indicators compared with before treatment. Compared with the citric acid local anticoagulation group, the PT of the heparin systemic anticoagulation group was significantly shortened after treatment (s: 11.82±2.05 vs. 13.61±3.05, P < 0.05), and the D-dimer level was significantly reduced (mg/L: 1.92±1.58 vs. 3.77±2.38, P < 0.01). The levels of inflammatory mediators in both groups were significantly reduced 1 day after CBP weaning compared with those before treatment [citric acid local anticoagulation group: hs-CRP (mg/L) was 12.53±5.44 vs. 22.65±7.27, PCT (µg/L) was 1.86±1.20 vs. 3.30±2.34, IL-6 (ng/L) was 148.48±34.83 vs. 202.32±48.62, TNF-α (ng/L) was 21.38±7.71 vs. 55.14±15.07; heparin systemic anticoagulation group: hs-CRP (mg/L) was 11.82±4.93 vs. 21.62±8.35, PCT (µg/L) was 1.90±1.08 vs. 3.18±1.97, IL-6 (ng/L) was 143.81±33.41 vs. 194.02±46.89, TNF-α (ng/L) was 22.44±8.17 vs. 56.17±16.92, all P < 0.05]. However, there was no statistically significant difference between the two groups (all P > 0.05). There was no statistically significant difference in bleeding complication during CBP and 7-day mortality in children between the citrate local anticoagulation group and the heparin systemic anticoagulation group (5.9% vs. 30.0%, 17.6% vs. 20.0%, both P > 0.05). CONCLUSIONS: Heparin for systemic anticoagulation and regional citrate anticoagulation can significantly reduce the levels of IL-6, TNF-α, hs-CRP and PCT in children with septic shock, and relieve inflammatory storm. Compared with citric acid local anticoagulation, heparin systemic anticoagulation can shorten the PT and reduce the level of D-dimer in children with septic shock, which may benefit in the prevention and treatment of disseminated intravascular coagulation (DIC).

Corrigendum: The critical role of PARPs in regulating innate immune responses.

[This corrects the article DOI: 10.3389/fimmu.2021.712556.].

NLRC4 promotes the cGAS-STING signaling pathway by facilitating CBL-mediated K63-linked polyubiquitination of TBK1.

TANK-binding kinase 1 (TBK1) is crucial in producing type Ⅰ interferons (IFN-Ⅰ) that play critical functions in antiviral innate immunity. The tight regulation of TBK1, especially its activation, is very important. Here we identify NLRC4 as a positive regulator of TBK1. Ectopic expression of NLRC4 facilitates the activation of the IFN-ß promoter, the mRNA levels of IFN-ß, ISG54, and ISG56, and the nuclear translocation of interferon regulatory factor 3 induced by cGAS and STING. Consistently, under herpes simplex virus-1 (HSV-1) infection, knockdown or knockout of NLRC4 in BJ cells and primary peritoneal macrophages from Nlrc4-deficient (Nlrc4-/- ) mice show attenuated Ifn-ß, Isg54, and Isg56 mRNA transcription, TBK1 phosphorylation, and augmented viral replications. Moreover, Nlrc4-/- mice show higher mortality upon HSV-1 infection. Mechanistically, NLRC4 facilitates the interaction between TBK1 and the E3 ubiquitin ligase CBL to enhance the K63-linked polyubiquitination of TBK1. Our study elucidates a previously uncharacterized function for NLRC4 in upregulating the cGAS-STING signaling pathway and antiviral innate immunity.

K235 acetylation couples with PSPC1 to regulate the m6A demethylation activity of ALKBH5 and tumorigenesis.

N6-methyladenosine (m6A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m6A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m6A demethylation activity of ALKBH5 by increasing its recognition of m6A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m6A mRNA by ALKBH5, thereby promoting m6A erasure. Mitogenic signals promote ALKBH5 K235 acetylation. K235 acetylation of ALKBH5 is upregulated in cancers and promotes tumorigenesis. Thus, our findings reveal that the m6A demethylation activity of ALKBH5 is orchestrated by its K235 acetylation and regulatory subunit PSPC1 and that K235 acetylation is necessary for the m6A demethylase activity and oncogenic roles of ALKBH5.

Ciclopirox olamine sensitizes leukemia cells to natural killer cell-mediated cytolysis by upregulating NKG2DLs via the Akt signaling pathway.

The activating receptor natural killer group 2D (NKG2D) expressed by Natural killer (NK) cells functions as a "master-switch" in governing the awakening status of NK cells. The NKG2D-mediated cytotoxicity has been declared to be related with the expression levels of NKG2D ligands (NKG2DLs) expressed on tumor cells. Therefore, selective induction of NKG2DLs could be a reliable approach to enhance the efficacy of NK cell-mediated immunotherapy. Our existing study demonstrated that Ciclopirox Olamine (CPX), an off-patent antifungal agent, effectively elevated the expression of NKG2DLs on leukemia cells and sensitized leukemia cells to NK-cell mediated cytolysis. Induction of ROS production and AKT phosphorylation by CPX is essential for the up-regulation of NKG2DLs expressions. Inhibition of AKT by using AKT inhibitor MK2206 decreased both NKG2DLs expressions and NK cell cytotoxicity. These data indicated that increased sensitivity of CPX-treated leukemia cells to NK cell cytolysis was attributed to higher NKG2DLs expressions, resulting from activated AKT signaling pathway. Our findings support the ongoing development of CPX as an anti-tumor agent and suggest its promising immunotherapeutic value in the medication of leukemia.

Effect of low skeletal muscle mass on long-term mortality after abdominal aortic aneurysm repair: A meta-analysis.

Objective: This meta-analysis was designed to assess if pre-operative low skeletal muscle mass impacts mortality rates of patients undergoing abdominal aortic aneurysm (AAA) repair. Methods: Datasets of PubMed, CENTRAL, ScienceDirect, Embase, and Google Scholar were searched from 1st January 1980 to 15th December 2021 for studies assessing the role of low skeletal muscle mass on mortality rates of AAA repair. Studies measuring skeletal muscle mass on computed tomography scans and reporting long-term mortality (>1 year) were included. Multivariable adjusted ratios were combined in a random-effects model. Results: Fifteen studies with 3776 patients were included. Meta-analysis showed a statistically significant increased risk of all-cause mortality in patients with low skeletal muscle mass (HR: 2.07 95% CI: 1.56, 2.74 I2=65% p<0.00001) as compared to normal muscle mass patients. Pooled data indicated that low skeletal muscle mass was associated with statistically significant increased risk of mortality in studies on endovascular repair (HR: 2.86 95% CI: 1.95, 4.20 I2=58% p<0.00001) as well as those including a mixed group of patients (HR: 1.39 95% CI: 1.06, 1.82 I2=31% p=0.02). Conclusion: Low skeletal muscle mass in AAA patients undergoing surgical repair is associated with increased risk of long-term mortality. Current evidence is limited by the retrospective nature of data and variability in defining and measuring low skeletal muscle mass. There is a need for future prospective studies defining the optimal cut-off of low skeletal muscle mass in different populations.

Integrated proteomic and phosphoproteomic analysis for characterization of colorectal cancer.

Proteins and translationally modified proteins like phosphoproteins have essential regulatory roles in tumorigenesis. This study attempts to elucidate the dysregulated proteins driving colorectal cancer (CRC). To explore the differential proteins, we performed iTRAQ labeling proteomics and TMT labeling phosphoproteomics analysis of CRC tissues and adjacent non-cancerous tissues. The functions of quantified proteins were analyzed using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Subcellular localization analysis. Depending on the results, we identified 330 differential proteins and 82 phosphoproteins in CRC. GO and KEGG analyses demonstrated that protein changes were primarily associated with regulating biological and metabolic processes through binding to other molecules. Co-expression relationships between proteomic and phosphoproteomic analysis revealed that TMC5, SMC4, SLBP, VSIG2, and NDRG2 were significantly dysregulated differential proteins. Additionally, based on the predicted co-expression proteins, we identified that the stem-loop binding protein (SLBP) was up-regulated in CRC cells and promoted the proliferation and migration of CRC. This study reports an integrated proteomic and phosphoproteomic analysis of CRC to discern the functional impact of protein alterations and provides a candidate diagnostic biomarker or therapeutic target for CRC. SIGNIFICANCE: Combining one or more high-throughput omics technologies with bioinformatics to analyze biological samples and explore the links between biomolecules and their functions can provide more comprehensive and multi-level insights for disease mechanism research. Proteomics, phosphoproteomics, metabolomics and their combined analysis play an important role in the auxiliary diagnosis, the discovery of biomarkers and novel therapeutic targets for colorectal cancer. In this integrated proteomic and phosphoproteomic analysis, we identified proteins and phosphoproteins in colorectal cancer tissue and analyzed potential mechanisms contributing to progression in colorectal cancer. The results of this study provide a foundation to focus future experiments on the contribution of altered protein and phosphorylation patterns to prevention and treatment of colorectal cancer.

Formin-like 2 promotes angiogenesis and metastasis of colorectal cancer by regulating the EGFL6/CKAP4/ERK axis.

Increasing evidence indicates that angiogenesis plays a pivotal role in tumor progression. Formin-like 2 (FMNL2) is well-known for promoting metastasis; however, the molecular mechanisms by which FMNL2 promotes angiogenesis in colorectal cancer (CRC) remain unclear. Here, we found that FMNL2 promotes angiogenesis and metastasis of CRC in vitro and in vivo. The GDB/FH3 domain of FMNL2 directly interacts with epidermal growth factor-like protein 6 (EGFL6). Formin-like 2 promotes EGFL6 paracrine signaling by exosomes to regulate angiogenesis in CRC. Cytoskeleton associated protein 4 (CKAP4) is a downstream target of EGFL6 and is involved in CRC angiogenesis. Epidermal growth factor-like protein 6 binds to the N-terminus of CKAP4 to promote the migration of HUVECs by activating the ERK/MMP pathway. These findings suggest that FMNL2 promotes the migration of HUVECs and enhances angiogenesis and tumorigenesis in CRC by regulating the EGFL6/CKAP4/ERK axis. Therefore, the EGFL6/CKAP4/ERK axis could be a candidate therapeutic target for CRC treatment.

Hsa_Circ_0000826 inhibits the proliferation of colorectal cancer by targeting AUF1.

Many circular RNAs (circRNAs) are reported to be abnormally expressed during the progression of various tumors, and these circRNAs can be used as anti-tumor targets. Therefore, it is important to identify circRNAs that can be used effectively for the clinical diagnosis and treatment of colorectal cancer (CRC). Here, we report that hsa_Circ_0000826 (Circ_0000826), a circRNA with significantly reduced expression level in CRC tissues, is associated with a poor prognosis in patients. The silencing of Circ_0000826 promotes the proliferation of CRC cells. Conversely, the overexpression of Circ_0000826 restricted CRC cell proliferation both in vitro and in vivo. Furthermore, Circ_0000826 could target AU-rich element RNA-binding protein 1 (AUF1). AUF1, known as heterogeneous nuclear ribonucleoprotein D (hnRNP D), could bind to the c-MYC 3'-UTR and promote c-MYC expression. When Circ_0000826 binds to AUF1, it competitively inhibits the binding of AUF1 to the c-MYC 3'-UTR, which inhibits the c-MYC expression and cell proliferation. These results provide novel insights into the functional mechanism of Circ_0000826 action in CRC progression and indicate its potential use as a therapeutic target in CRC.

Icariin Treatment Rescues Diabetes Induced Bone Loss via Scavenging ROS and Activating Primary Cilia/Gli2/Osteocalcin Signaling Pathway.

Diabetes-associated bone complications lead to fragile bone mechanical strength and osteoporosis, aggravating the disease burden of patients. Advanced evidence shows that chronic hyperglycemia and metabolic intermediates, such as inflammatory factor, reactive oxygen species (ROS), and advanced glycation end products (AGEs), are regarded as dominant hazardous factors of bone complications, whereas the pathophysiological mechanisms are complex and controversial. By establishing a diabetic Sprague-Dawley (SD) rat model and diabetic bone loss cell model in vitro, we confirmed that diabetes impaired primary cilia and led to bone loss, while adding Icariin (ICA) could relieve the inhibitions. Mechanistically, ICA could scavenge ROS to maintain the mitochondrial and primary cilia homeostasis of osteoblasts. Intact primary cilia acted as anchoring and modifying sites of Gli2, thereby activating the primary cilia/Gli2/osteocalcin signaling pathway to promote osteoblast differentiation. All results suggest that ICA has potential as a therapeutic drug targeting bone loss induced by diabetes.

TIGIT-expressing zoledronate-specific γδ T cells display enhanced antitumor activity.

Human γδ T cells hold a pivotal role in tumor immunosurveillance through their prompt activation and cytokine secretion and have received much attention in adoptive immunotherapy of clear cell renal cell carcinoma (ccRCC). However, the therapeutic effects are limited in ccRCC. Therefore, it is now critical to improve therapeutic strategies based on γδ T cells, especially identification of functional γδ T cell subsets. In this study, we aimed to identify γδ T cells that might have enhanced responses against ccRCC. Bioinformatic analysis showed that ccRCC patients with high T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression had higher levels of effector molecules. Then, we examined the changes in the TIGIT+ γδ T cell percentages of 6 ccRCC patients and 14 healthy subjects through zoledronate (ZOL) stimulation. Results indicated that percentages of TIGIT+ γδ T cells were positively correlated with activated γδ T cells in early activation stage. Further study demonstrated that TIGIT+ γδ T cells exhibited enhanced activation, contained more terminally differentiated effector γδ T cells and produced higher cytokine compared with TIGIT- γδ T cells. Finally, we investigated the functions and found that TIGIT+ γδ T cells exhibited stronger tumor reactivities and higher cytotoxicity when challenged by tumor cells. Above results imply that TIGIT+ γδ T cells are the main effectors in ZOL recognition and tumor cells challenging. The results of the present study serve as basis for future functional studies on TIGIT+ γδ T cells and provide a promising approach of immunotherapy in ccRCC.

Diagnostic and prognostic predictive values of triggering receptor expressed on myeloid cell-1 expression in neonatal sepsis: A meta-analysis and systematic review.

Objective: The purpose of this systematic review was to explore the value of the expression level of the triggering receptor expressed on myeloid cell-1 (TREM-1) in the diagnosis and prognosis of neonatal sepsis. Methods: A comprehensive search was performed to identify the diagnostic and prognostic predictive values of the TREM-1 expression level in neonatal sepsis. Based on the retrieval strategy, Cochrane Library, Embase, Ovid, ProQuest, PubMed, Scopus, and Web of Science databases were searched from inception to February 2022. Studies were included if they assessed the accuracy of TREM-1 expression in the diagnosis of neonatal sepsis and distinguished survival and death in neonatal sepsis. Two authors independently evaluated the study and extracted the data, including the first author of the literature, country, total study population, basic population characteristics of the study group and the control group, study design (observational studies), type of sample, sepsis onset, type of biomarker, assay method, cut-off, sensitivity, specificity, true positives (TP), false positives (FP), false negatives (FN), and true negatives (TN). A third party will be consulted if disputed. The accuracy of TREM-1 expression in the diagnosis and prognostic prediction of neonatal sepsis was evaluated by a bivariate mixed-effects model. The source of heterogeneity was explored through meta-regression analysis. Results: Thirteen articles that met the research criteria were included in qualitative analysis, and 11 of them were included in quantitative analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operator characteristic (SROC) curve of soluble TREM-1 (sTREM-1) were 0.94 (95% CI: 0.82, 0.98), 0.87 (95% CI: 0.70, 0.95), 7.36 (95% CI: 2.75, 19.74), 0.07 (95% CI: 0.02, 0.24), 111.71 (95% CI: 13.24, 942.92), and 0.96 (95% CI: 0.94, 0.98), respectively. Meta-regression and subgroup analysis were used to investigate the heterogeneity, owing to non-threshold effects caused by types of test sample and research design. sTREM-1 as a biomarker for distinguishing survival and death in neonates with sepsis had pooled sensitivity, specificity, area under the SROC curve, PLR, NLR, and DOR of 0.95 (95% CI: 0.83, 0.99), 0.98 (95% CI: 0.68, 1.00), 0.99 (95% CI: 0.97, 0.99), 39.28 (95% CI: 2.13, 723.99), 0.05 (95% CI: 0.01, 0.19), and 789.61 (95% CI: 17.53, 35,560.72), respectively. Conclusion: The study showed that TREM-1 was a potential biomarker for the diagnosis and prognosis of neonatal sepsis. The biggest advantage of this study is that it is the first to comprehensively explore the role of TREM-1 expression in the diagnosis and prognosis of neonatal sepsis. However, there are some limitations in this study, such as the reduced number of clinical studies on TREM-1 expression as a biomarker of neonatal sepsis, regional bias, and differences in detection methods. Hence, more large-scale and high-quality studies are needed to improve diagnostic accuracy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022338041.

UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation.

Stimulator of interferon genes (STING) is a pivotal innate immune adaptor, and its functions during DNA virus infections have been extensively documented. However, its homeostatic regulation is not well understood. Our study demonstrates that Unc-93 homolog B1 (UNC93B1) is a crucial checker for STING to prevent hyperactivation. Ectopic expression of UNC93B1 attenuates IFN-ß promoter activity and the transcriptions of IFN-ß, ISG54, and ISG56 genes. Moreover, UNC93B1 also blocks the IRF3 nuclear translocation induced by ectopic expression of both cyclic GMP-AMP synthase (cGAS) and STING and reduces the stability of STING by facilitating its autophagy-lysosome degradation, which can be reversed by lysosome inhibitors. Mechanistically, UNC93B1 interacts with STING and suppresses STING-activated downstream signaling by delivering STING to the lysosomes for degradation, depending on its trafficking capability. UNC93B1 knockout in human embryonic kidney 293T cells facilitates IFN-ß promoter activity, IFN-ß, ISG54, and ISG56 transcriptions, and IRF3 nuclear translocation induced by ectopic expression of cGAS and STING. Infected with herpes simplex virus-1 (HSV-1), UNC93B1 knockdown BJ cells or primary peritoneal macrophages from Unc93b1-deficient (Unc93b1-/- ) mice show enhanced IFN-ß, ISG54, and ISG56 transcriptions, TBK1 phosphorylation, and reduced STING degradation and viral replication. In addition, Unc93b1-/-  mice exhibit higher IFN-ß, ISG54, and ISG56 transcriptions and lower mortality upon HSV-1 infection in vivo. Collectively, these findings demonstrate that UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation and provide novel insights into the function of UNC93B1 in antiviral innate immunity.

Innate Immune Evasion by Human Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is the leading cause of severe respiratory infection in young children. Nearly all individuals become infected in their early childhood, and reinfections with RSV are common throughout life. Primary infection with RSV is usually involved in the symptom of bronchiolitis and pneumonia in the lower respiratory tract, which accounts for over 3 million hospitalizations and approximately 66,000 deaths annually worldwide. Despite the widespread prevalence and high morbidity and lethality rates of diseases caused by RSV infection, there is currently no licensed RSV vaccine. During RSV infection, innate immunity plays the first line of defense to suppress RSV infection and replication. However, RSV has evolved multiple mechanisms to evade the host's innate immune responses to gain a window of opportunity for efficient viral replication. This review discusses the comprehensive interaction between RSV infection and the host antiviral innate immunity and updates recent findings on how RSV modulates the host innate immune response for survival, which may provide novel insights to find potent drug targets and vaccines against RSV.

The remodeling roles of lipid metabolism in colorectal cancer cells and immune microenvironment.

Lipid is a key component of plasma membrane, which plays an important role in the regulation of various cell biological behaviors, including cell proliferation, growth, differentiation and intracellular signal transduction. Studies have shown that abnormal lipid metabolism is involved in many malignant processes, including colorectal cancer (CRC). Lipid metabolism in CRC cells can be regulated not only by intracellular signals, but also by various components in the tumor microenvironment, including various cells, cytokines, DNA, RNA, and nutrients including lipids. In contrast, abnormal lipid metabolism provides energy and nutrition support for abnormal malignant growth and distal metastasis of CRC cells. In this review, we highlight the remodeling roles of lipid metabolism crosstalk between the CRC cells and the components of tumor microenvironment.