O-GlcNAc Transferase Suppresses Inflammation and Necroptosis by Targeting Receptor-Interacting Serine/Threonine-Protein Kinase 3.

Elevated glucose metabolism in immune cells represents a hallmark feature of many inflammatory diseases, such as sepsis. However, the role of individual glucose metabolic pathways during immune cell activation and inflammation remains incompletely understood. Here, we demonstrate a previously unrecognized anti-inflammatory function of the O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling associated with the hexosamine biosynthesis pathway (HBP). Despite elevated activities of glycolysis and the pentose phosphate pathway, activation of macrophages with lipopolysaccharide (LPS) resulted in attenuated HBP activity and protein O-GlcNAcylation. Deletion of O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, led to enhanced innate immune activation and exacerbated septic inflammation. Mechanistically, OGT-mediated O-GlcNAcylation of the serine-threonine kinase RIPK3 on threonine 467 (T467) prevented RIPK3-RIPK1 hetero- and RIPK3-RIPK3 homo-interaction and inhibited downstream innate immunity and necroptosis signaling. Thus, our study identifies an immuno-metabolic crosstalk essential for fine-tuning innate immune cell activation and highlights the importance of glucose metabolism in septic inflammation.

Allosteric inhibitor of SHP2 enhances macrophage endocytosis and bacteria elimination by increasing caveolae activation and protects against bacterial sepsis.

The uncontrolled bacterial infection-induced cytokine storm and sequential immunosuppression are commonly observed in septic patients, which indicates that the activation of phagocytic cells and the efficient and timely elimination of bacteria are crucial for combating bacterial infections. However, the role of dysregulated immune cells and their disrupted function in sepsis remains unclear. Here, we found that macrophages exhibited the impaired endocytosis capabilities in sepsis by Single-cell RNA sequencing and bulk RNA sequencing. Caveolae protein Caveolin-1 (Cav-1) of macrophages was inactivated by SHP2 rapidly during Escherichia coli (E.coli) infection. Allosteric inhibitor of SHP2 effectively maintains Cav-1 phosphorylation to enhance macrophage to endocytose and eliminate bacteria. Additionally, TLR4 endocytosis of macrophage was also enhanced upon E.coli infection by SHP099, inducing an increased and rapidly resolved inflammatory response. In vivo, pretreatment or posttreatment with inhibitor of SHP2 significantly reduced the bacterial burden in organs and mortality of mice subjected E.coli infection or CLP-induced sepsis. The cotreatment of inhibitor of SHP2 with an antibiotic conferred complete protection against mortality in mice. Our findings suggest that Cav-1-mediated endocytosis and bacterial elimination may play a critical role in the pathogenesis of sepsis, highlighting inhibitor of SHP2 as a potential therapeutic agent for sepsis.

Relationship between left ventricular mechanical synchrony and left ventricular systolic function: a CZT-SPECT analysis.

BACKGROUND: CZT-SPECT has good agreement in the evaluation of mechanical synchronization compared with conventional SPECT. The aim of this study was to evaluate the correlation between left ventricular mechanical contraction synchrony and left ventricular systolic function by gated myocardial perfusion imaging (GMPI) using cadmium-zine-telluride (CZT) single photon emission computed tomography (SPECT). METHODS: This retrospective study involved 371 patients (239 males and 132 females, mean age 61.06 ± 11.78 years old) who underwent GMPI at the Nuclear Medicine Department of Shanxi Cardiovascular Hospital from January 2020 to August 2020. Systolic synchrony parameters and left ventricular systolic function parameters were calculated via Emory Cardiac Toolbox, including PP, PSD, PHB, HS, HK, EDV, ESV, and LVEF. Based on LVEF value, patients were divided into the severe reduction group (group 1, 127 cases, EF < 35%), moderate reduction group (group 2, 47 cases, 35% ≤ EF < 45%), mild reduction group (group 3, 50 cases, 45% ≤ EF < 50%) and normal group (group 4, 147 cases, EF ≥ 50%). Differences in PP, PSD, PHB, HS and HK among the four groups were compared using one-way ANOVA. Differences between two groups were compared using LSD-t test. The correlation among functional and mechanical contraction synchrony factors were analyzed using Pearson test. RESULTS: PP, PSD, PHB, HS and HK were significantly different among the four groups (F = 5.20, 188.72, 202.88, 171.05, 101.36, P < 0.001). Pairwise comparison tests showed significant differences in PSD and PHB in each two groups, and HS and HK in each two groups except for group 2 and 3 (t = 0.28 and 0.39, both P > 0.001). PP was significantly higher in group 1, relative to group 3 (t = 2.43, P < 0.001) and group 4 (t = 3.67, P < 0.001). Pearson correlation analysis revealed that LVEF negatively correlates with PP, PSD, PHB (r = 0.194, - 0.790, - 0.799, all P < 0.001). HS and HK showed positive correlation for LVEF (r = 0.778 and 0.795, P < 0.001), PSD, PHB and ESV were had good positive correlation (r = 0.778, 0.795, P < 0.001), PSD, PHB and EDV had good positive correlation (r = 0.722, 0.732, P < 0.001). However, PP had poor correlation with EDV (r = 0.095, P > 0.001). HS and HK were negatively correlated with EDV and ESV (r = - 0.700 to - 0.594, P < 0.001). CONCLUSION: CZT SPECT GMPI provided left ventricular mechanical contraction synchrony parameters that correlated well with left ventricular systolic function. Worse left ventricular mechanical contraction synchrony lead to decreased LVEF, making the systolic synchrony parameters valuable in the prediction of left ventricular systolic function.

An endosomal LAPF is required for macrophage endocytosis and elimination of bacteria.

Macrophages can internalize the invading pathogens by raft/caveolae and/or clathrin-dependent endocytosis and elicit an immune response against infection. However, the molecular mechanism for macrophage endocytosis remains elusive. Here we report that LAPF (lysosome-associated and apoptosis-inducing protein containing PH and FYVE domains) is required for caveolae-mediated endocytosis. Lapf-deficient macrophages have impaired capacity to endocytose and eliminate bacteria. Macrophage-specific Lapf-deficient mice are more susceptible to Escherichia coli (E. coli) infection with higher bacterial loads. Moreover, Lapf deficiency impairs TLR4 endocytosis, resulting in attenuated production of TLR-triggered proinflammatory cytokines. LAPF is localized to early endosomes and interacts with caveolin-1. Phosphorylation of LAPF by the tyrosine kinase Src is required for LAPF-Src-Caveolin complex formation and endocytosis and elimination of bacteria. Collectively, our work demonstrates that LAPF is critical for endocytosis of bacteria and induction of inflammatory responses, suggesting that LAPF and Src could be potential targets for the control of infectious diseases.

Engineering Oxaliplatin Prodrug Nanoparticles for Second Near-Infrared Fluorescence Imaging-Guided Immunotherapy of Colorectal Cancer.

Colorectal cancer (CRC) ranks as the third common and the fourth lethal cancer type worldwide. Immune checkpoint blockade therapy demonstrates great efficacy in a subset of metastatic CRC patients, but precise activation of the antitumor immune response at the tumor site is still challenging. Here a versatile prodrug nanoparticle for second near-infrared (NIR-II) fluorescence imaging-guided combinatory immunotherapy of CRC is reported. The prodrug nanoparticles are constructed with a polymeric oxaliplatin prodrug (PBOXA) and a donor-spacer-acceptor-spacer-donor type small molecular fluorophore TQTCD. The later displays large Stokes shift (>300 nm), fluorescence emission over 1000 nm, and excellent photothermal conversion performance for NIR-II fluorescence imaging-guided photothermal therapy (PTT). The prodrug nanoparticles show seven times higher intratumoral OXA accumulation than free oxaliplatin. TQTCD-based PTT and PBOXA-induced chemotherapy trigger immunogenic cell death of the tumor cells and elicit antitumor immune response in a spatiotemporally controllable manner. Further combination of the prodrug nanoparticle-based PTT/chemotherapy with programmed death ligand 1 blockade significantly promotes intratumoral infiltration of the cytotoxic T lymphocytes and eradicates the CRC tumors. The NIR-II fluorescence imaging-guided immunotherapy may provide a promising approach for CRC treatment.

Correlation between monocyte to high-density lipoprotein ratio and major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention.

OBJECTIVE: To investigate the correlation between monocyte to high-density lipoprotein ratio (MHR) and major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: In this retrospective study, 120 ACS patients who received PCI in our hospital from September 2014 to August 2019 were selected and divided into MACE group and normal discharge (ND) group. Their clinical data were collected, and MHR values were compared. Logistic regression analysis was conducted to analyze the correlations between various factors and ACS. The correlation between MHR and Gensini score was subjected to Pearson's analysis. Receiver operating characteristic (ROC) curve was plotted to analyze the diagnostic value of MHR for MACE. RESULTS: Hypertension degree, white cell count, Gensini score, MHR and the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), apolipoprotein A1 (ApoA1), ApoB, lipoprotein (a) [LP(a)] and uric acid (UA) in MACE group were significantly higher than those in ND group (P<0.05). HDLC, ApoA1, TC, MHR, LDLC and ApoB were independent risk factors for MACE of ACS patients after PCI (P<0.05). There was a positive correlation between MHR and Gensini score (r=0.832, P<0.05), and the optimal cutoff value of MHR for diagnosing MACE was 9.45. CONCLUSION: Serum MHR is positively correlated with Gensini score in ACS patients after PCI, which can be used as an independent predictor for MACE in hospital.

Sensitivity Enhancement of FBG-Based Strain Sensor.

A novel fiber Bragg grating (FBG)-based strain sensor with a high-sensitivity is presented in this paper. The proposed FBG-based strain sensor enhances sensitivity by pasting the FBG on a substrate with a lever structure. This typical mechanical configuration mechanically amplifies the strain of the FBG to enhance overall sensitivity. As this mechanical configuration has a high stiffness, the proposed sensor can achieve a high resonant frequency and a wide dynamic working range. The sensing principle is presented, and the corresponding theoretical model is derived and validated. Experimental results demonstrate that the developed FBG-based strain sensor achieves an enhanced strain sensitivity of 6.2 pm/µÎµ, which is consistent with the theoretical analysis result. The strain sensitivity of the developed sensor is 5.2 times of the strain sensitivity of a bare fiber Bragg grating strain sensor. The dynamic characteristics of this sensor are investigated through the finite element method (FEM) and experimental tests. The developed sensor exhibits an excellent strain-sensitivity-enhancing property in a wide frequency range. The proposed high-sensitivity FBG-based strain sensor can be used for small-amplitude micro-strain measurement in harsh industrial environments.

NAD+ dependent deacetylase Sirtuin 5 rescues the innate inflammatory response of endotoxin tolerant macrophages by promoting acetylation of p65.

The induction and persistence of a hypo-inflammatory and immunosuppressive state in severe sepsis is commonly associated with increased risks of secondary infections and mortality. Toll-like receptor (TLR)-triggered inflammatory response of macrophages/monocytes plays an important role in determining the outcome of hyper-inflammation during the acute phase and the hypo-inflammation during immunosuppressive phase of sepsis. However, the mechanisms for controlling hypo-inflammatory response in endotoxin tolerant macrophages remain to be fully understood. Considering that metabolic control of inflammation is an emerging field and the balance between AMP/ATP and oxidized NAD+/reduced NADH is associated with inflammation and metabolism, we analyzed the level of NAD+ in TLR-triggered innate inflammatory response, and found that the decreased level of NAD+ was significantly related to the increased inflammatory cytokine production both in vivo and in vitro. By screening the expression and function of NAD+ dependent type III deacetylase Sirtuin family members, we found that SIRT5 and SIRT1/2 had opposite expression patterns and functions in macrophages. SIRT5 deficiency decreased TLR-triggered inflammation in both acute and immunosuppressive phases of sepsis. Interestingly, cytoplasmic SIRT5 counteracted the inhibitory effects of SIRT2 and enhanced the innate inflammatory responses in macrophages and even in endotoxin-tolerant macrophages by promoting acetylation of p65 and activation of NF-κB pathway. Mechanistically, SIRT5 competed with SIRT2 to interact with NF-κB p65, in a deacetylase activity-independent way, to block the deacetylation of p65 by SIRT2, which consequently led to increased acetylation of p65 and the activation of NF-κB pathway and its downstream cytokines. Our study discovered the new functions of different Sirtuin members in sepsis, indicating that targeting of Sirtuin family members at different sepsis phases can be helpful to precisely control the progression of sepsis.

Diaphragm Based Fiber Bragg Grating Acceleration Sensor with Temperature Compensation.

A novel fiber Bragg grating (FBG) sensing-based acceleration sensor has been proposed to simultaneously decouple and measure temperature and acceleration in real-time. This design applied a diaphragm structure and utilized the axial property of a tightly suspended optical fiber, enabling improvement in its sensitivity and resonant frequency and achieve a low cross-sensitivity. The theoretical vibrational model of the sensor has been built, and its design parameters and sensing properties have been analyzed through the numerical analysis. A decoupling method has been presented with consideration of the thermal expansion of the sensor structure to realize temperature compensation. Experimental results show that the temperature sensitivity is 8.66 pm/°C within the range of 30-90 °C. The acceleration sensitivity is 20.189 pm/g with a linearity of 0.764% within the range of 5~65 m/s². The corresponding working bandwidth is 10~200 Hz and its resonant frequency is 600 Hz. This sensor possesses an excellent impact resistance for the cross direction, and the cross-axis sensitivity is below 3.31%. This implementation can avoid the FBG-pasting procedure and overcome its associated shortcomings. The performance of the proposed acceleration sensor can be easily adjusted by modifying their corresponding physical parameters to satisfy requirements from different vibration measurements.

DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells.

TNFRSF10A and TNFRSF10B are cell surface receptors that bind to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mediate the extrinsic pathway of apoptosis. However, the mechanisms of transcriptional regulation of TNFRSF10A and TNFRSF10B remain largely uncharacterized. In this study, two putative DDIT3 binding sites (-1636/-1625; -374/-364) and a putative AP-1 binding site (-304/-298) were identified in the TNFRSF10A promoter region. We found that DDIT3 interacts with phospho-JUN, and the DDIT3·phospho-JUN complex binds to the AP-1 binding site (-304/-298) within the TNFRSF10A promoter region. In addition, we confirmed that KAT2A physically interacts with the N-terminal region (amino acids 1-26) of DDIT3. Importantly, knockdown of KAT2A down-regulated TNFRSF10A and TNFRSF10B and dramatically decreased promoter activity of cells transfected with luciferase reporter plasmid containing the AP-1 binding site (-304/-298) of the TNFRSF10A promoter, as well as cells transfected with luciferase reporter plasmid containing DDIT3 binding site (-276/-264) of the TNFRSF10B promoter. ChIP results suggest that KAT2A may participate in a KAT2A·DDIT3·phospho-JUN complex, or may participate in a KAT2A·DDIT3 complex and acetylate H3K9/K14, respectively. Moreover, we verified that TNFRSF10A mediates apoptosis triggered by endoplasmic reticulum stress in human lung cancer cells. Collectively, we demonstrate that DDIT3 and KAT2A cooperatively up-regulate TNFRSF10A and TNFRSF10B. Our findings highlight novel mechanisms underlying endoplasmic reticulum stress-induced TNFRSF10A and TNFRSF10B expressions and apoptosis. These findings will be helpful for elucidating mechanisms related to anticancer drugs in mediating apoptosis.

A Fiber Bragg Grating Sensing-Based Micro-Vibration Sensor and Its Application.

This paper proposes a fiber Bragg grating sensing-based micro-vibration sensor. The optical fiber has been directly treated as an elastomer to design the micro-vibration sensor, which possesses two FBGs. The mass is fixed on the middle of the fiber, and the vertical vibration of the mass has been converted into the axial tension/compression of the fiber. The principle of the sensor has been introduced, and the experiment conclusions show that the sensor sensitivity is 2362 pm/g within the range of 200-1200 mm/s², which is consistent with theoretical analysis sensitivity of 2532.6 pm/g, and it shows an excellent linearity of 1.376%, while the resonant frequency of the sensor is 34 Hz, and the flat frequency range resides in the 0-22 Hz range. When used to measure micro-vibrations, its measured frequency relative error is less than 1.69% compared with the values acquired with a MEMS accelerometer, and the amplitude values of its measured vibration signal are consistent with the MEMS accelerometer under different excitation conditions too, so it can effectively realize the micro-vibration measurements.

Identification of prohibitin 1 as a potential prognostic biomarker in human pancreatic carcinoma using modified aqueous two-phase partition system combined with 2D-MALDI-TOF-TOF-MS/MS.

Membrane proteins are an important source of potential targets for anticancer drugs or biomarkers for early diagnosis. In this study, we used a modified aqueous two-phase partition system combined with two-dimensional (2D) matrix-assisted laser desorption ionization (MALDI) time of flight (TOF) mass spectrometry (MS, 2D-MALDI-TOF-TOF-MS/MS) analysis to isolate and identify membrane proteins in PANC-1 pancreatic cancer cells. Using this method, we identified 55 proteins, of which 31 (56.4 %) were membrane proteins, which, according to gene ontology annotation, are associated with various cellular processes including cell signal transduction, differentiation, and apoptosis. Immunohistochemical analysis showed that the expression level of one of the identified mitochondria membrane proteins, prohibitin 1 (PHB1), is correlated with pancreatic carcinoma differentiation; PHB1 is expressed at a higher level in normal pancreatic tissue than in well-differentiated carcinoma tissue. Further studies showed that PHB1 plays a proapoptotic role in human pancreatic cancer cells, which suggests that PHB1 has antitumorigenic properties. In conclusion, we have provided a modified method for isolating and identifying membrane proteins and demonstrated that PHB1 may be a promising biomarker for early diagnosis and therapy of pancreatic (and potentially other) cancers.

A Fiber Bragg Grating Sensing Based Triaxial Vibration Sensor.

A fiber Bragg grating (FBG) sensing based triaxial vibration sensor has been presented in this paper. The optical fiber is directly employed as elastomer, and the triaxial vibration of a measured body can be obtained by two pairs of FBGs. A model of a triaxial vibration sensor as well as decoupling principles of triaxial vibration and experimental analyses are proposed. Experimental results show that: sensitivities of 86.9 pm/g, 971.8 pm/g and 154.7 pm/g for each orthogonal sensitive direction with linearity are separately 3.64%, 1.50% and 3.01%. The flat frequency ranges reside in 20-200 Hz, 3-20 Hz and 4-50 Hz, respectively; in addition, the resonant frequencies are separately 700 Hz, 40 Hz and 110 Hz in the x/y/z direction. When the sensor is excited in a single direction vibration, the outputs of sensor in the other two directions are consistent with the outputs in the non-working state. Therefore, it is effectively demonstrated that it can be used for three-dimensional vibration measurement.

Machine-Learning-Driven G-Quartet-Based Circularly Polarized Luminescence Materials.

Circularly polarized luminescence (CPL) materials have garnered significant interest due to their potential applications in chiral functional devices. Synthesizing CPL materials with a high dissymmetry factor (glum ) remains a significant challenge. Inspired by efficient machine learning (ML) applications in scientific research, this work demonstrates ML-based techniques for the first time to guide the synthesis of G-quartet-based CPL gels with high glum values and multiple chiral regulation strategies. Employing an "experiment-prediction-verification" approach, this work devises a ML classification and regression model for the solvothermal synthesis of G-quartet gels in deep eutectic solvents. This process illustrates the relationship between various synthesis parameters and the glum value. The decision tree algorithm demonstrates superior performance across six ML models, with model accuracy and determination coefficients amounting to 0.97 and 0.96, respectively. The screened CPL gels exhibiting a glum value up to 0.15 are obtained through combined ML guidance and experimental verification, among the highest ones reported till now for biomolecule-based CPL systems. These findings indicate that ML can streamline the rational design of chiral nanomaterials, thereby expediting their further development.

Metabolism/Immunity Dual-Regulation Thermogels Potentiating Immunotherapy of Glioblastoma Through Lactate-Excretion Inhibition and PD-1/PD-L1 Blockade.

Intrinsic immunosuppressive tumor microenvironment (ITM) and insufficient tumor infiltration of T cells severely impede the progress of glioblastoma (GBM) immunotherapy. In this study, it is identify that inhibiting the expression of glucose transporter 1 (GLUT1) can facilitate the prevention of lactate excretion from tumor glycolysis, which significantly alleviates the lactate-driven ITM by reducing immunosuppressive tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). Simultaneously, the findings show that the generated inflammatory cytokine IFN-γ during immune activation aggravates the immune escape by upregulating immune checkpoint programmed death-ligand 1 (PD-L1) in tumor cells and TAMs. Therefore, an injectable thermogel loaded with a GLUT1 inhibitor BAY-876 and a PD-1/PD-L1 blocker BMS-1 (Gel@B-B) for dual-regulation of metabolism and immunity of GBM is developed. Consequently, in situ injection of Gel@B-B significantly delays tumor growth and prolongs the survival of the orthotopic GBM mouse model. By actively exposing tumor antigens to antigen-presenting cells, the GBM vaccine combined with Gel@B-B is found to significantly increase the fraction of effector T cells (Th1/CTLs) in the tumor microenvironment, thereby remarkably mitigating tumor recurrence long-term. This study may provide a promising strategy for GBM immunotherapy.

Plant volatiles mediated the orientation preference of slugs to different plant species.

BACKGROUND: Slugs mechanically damage plant leaves, resulting in significant economic losses. However, there are limited cost-efficient strategies available in slug management. By studying how slugs utilize plant volatiles to locate host plants, we can gain insights into the design of attractants and repellents. RESULTS: Bioassay results suggest slugs (Agriolimax agrestis) prefer to orientate to lettuce (Lactuca sativa), cabbage (Brassica oleracea L.), and young tobacco seedlings, compared with old tobacco seedlings. We analyzed the volatomics of lettuce, cabbage, young and old tobacco seedlings. 2-(2-butoxyethoxy)-ethanol acetate (2EA) had high abundance while nonanal, decanal, and ß-cylocitral had relatively low content in volatiles. Old tobacco seedlings released significantly more hexanal but fewer 1,4-dihydro-4-oxopyridazine (DO). In olfactory tests, hexanal, nonanal, decanal, and ß-cylocitral showed strong repellency to slugs, while DO at a dose of 500 ng/µL and 2EA at a dose of 1% were attractive to slugs. The two alkanes, hexadecane and heptadecane, had no effect on slug orientating to host plants. DO and 2EA can thus alleviate the repellency of hexanal, nonanal, decanal and ß-cylocitral. CONCLUSION: The high emission of hexanal in old tobacco seedlings helps repel slugs, while 2EA and DO attract slugs to lettuce and cabbage. These findings suggest that these chemicals can be utilized in the design of repellents and attractants, and contribute to constructing a push-pull system for slug control. © 2023 Society of Chemical Industry.

Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt -/- ) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene (Apc min ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt -/- cancer cells restored tumor growth, and this correlated with impaired CD8+ T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.

Targeted protein degradation in drug development: Recent advances and future challenges.

Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.

CRISPR/Cas9-Mediated Mutagenesis of Antennapedia in Spodoptera frugiperda.

The homeotic gene Antennapedia (Antp) has been identified as playing a pivotal role in the morphogenesis of the thorax and wings across various insect species. Leveraging insights from previous studies, the functional characterization of Antp in S. frugiperda was undertaken using RT-qPCR and the CRISPR/Cas9 genome-editing system. Phylogenetic analyses indicate that Antp shares a high degree of sequence homology among Lepidoptera species. The expression profile of SfAntp was detected by RT-qPCR. The results showed that SfAntp was expressed in the whole growth cycle of S. frugiperda, the expression level was the highest in the egg stage, and the expression level was higher from 12 h to 48 h. Tissue-specific expression profiling demonstrated that SfAntp was most abundantly expressed in the thoracic segments and legs. To functionally disrupt SfAntp, two sgRNA sites were designed at the first exon of SfAntp and the gene was knocked out by CRISPR/Cas9 via microinjection. The results showed that the deletion of SfAntp produced a mutant phenotype of thoracic fusion, thoracic leg defect, leg-like protrusions between the head and thoracic segments and pupation deformity. In addition, deletion of SfAntp resulted in high embryo mortality. Through DNA sequencing, it was found that the target site of the SfAntp mutant had different degrees of frameshift mutations, indicating that the mutant phenotype was indeed caused by the knockout of SfAntp.