ABSTRACT
The primary cilium behaves as a platform for sensing and integrating extracellular cues to control a plethora of cellular activities. However, the functional interaction of this sensory organelle with epithelial-mesenchymal transition (EMT) during pulmonary fibrosis remains unclear. Here, we reveal a critical role for cylindromatosis (CYLD) in reciprocally linking the EMT program and ciliary homeostasis during pulmonary fibrosis. A close correlation between the EMT program and primary cilia is observed in bleomycin-induced pulmonary fibrosis as well as TGF-ß-induced EMT model. Mechanistic study reveals that downregulation of CYLD underlies the crosstalk between EMT and ciliary homeostasis by inactivating histone deacetylase 6 (HDAC6) during pulmonary fibrosis. Moreover, manipulation of primary cilia is an effective means to modulate the EMT program. Collectively, these results identify a pivotal role for the CYLD/HDAC6 signaling in regulating the reciprocal interplay between the EMT program and ciliary homeostasis during pulmonary fibrosis.
Subject(s)
Cilia , Deubiquitinating Enzyme CYLD , Epithelial-Mesenchymal Transition , Histone Deacetylase 6 , Homeostasis , Pulmonary Fibrosis , Signal Transduction , Histone Deacetylase 6/metabolism , Histone Deacetylase 6/genetics , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/chemically induced , Animals , Cilia/metabolism , Cilia/pathology , Deubiquitinating Enzyme CYLD/metabolism , Mice , Humans , Bleomycin , Mice, Inbred C57BL , Transforming Growth Factor beta/metabolism , MaleABSTRACT
Chiral multi-resonance thermally activated delayed fluorescence (CP-MR-TADF) materials hold promise for circularly polarized organic light-emitting diodes (CP-OLEDs) and 3D displays. Herein, we present two pairs of tetraborated intrinsically axial CP-MR-TADF materials, R/S-BDBF-BOH and R/S-BDBT-BOH, with conjugation-extended bidibenzo[b,d]furan and bidibenzo[b,d]thiophene as chiral sources, which effectively participate in the distribution of the frontier molecular orbitals. Due to the heavy-atom effect, sulfur atoms are introduced to accelerate the reverse intersystem crossing process and increase the efficiency of molecules. R/S-BDBF-BOH and R/S-BDBT-BOH manifest ultra-pure blue emission with a maximum at 458/459â nm with a full width at half maximum of 27â nm, photoluminescence quantum yields of 90 %/91 %, and dissymmetry factors (|gPL|) of 6.8×10-4/8.5×10-4, respectively. Correspondingly, the CP-OLEDs exhibit good performances with an external quantum efficiency of 30.1 % and |gEL| factors of 1.2×10-3.
ABSTRACT
Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. However, the molecular basis for HSC activation remains poorly understood. Herein, we demonstrate that primary cilia are present on quiescent HSCs but exhibit a significant loss upon HSC activation which correlates with decreased levels of the ciliary protein intraflagellar transport 88 (IFT88). Ift88-knockout mice are more susceptible to chronic carbon tetrachloride-induced liver fibrosis. Mechanistic studies show that the X-linked inhibitor of apoptosis (XIAP) functions as an E3 ubiquitin ligase for IFT88. Transforming growth factor-ß (TGF-ß), a profibrotic factor, enhances XIAP-mediated ubiquitination of IFT88, promoting its proteasomal degradation. Blocking XIAP-mediated IFT88 degradation ablates TGF-ß-induced HSC activation and liver fibrosis. These findings reveal a previously unrecognized role for ciliary homeostasis in regulating HSC activation and identify the XIAP-IFT88 axis as a potential therapeutic target for liver fibrosis.
Subject(s)
Cilia , Liver Cirrhosis , Animals , Mice , Cilia/metabolism , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Liver/metabolism , Liver Cirrhosis/chemically induced , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Transforming Growth Factor beta/metabolismABSTRACT
Primary cilia are distributed extensively within the corneal epithelium and endothelium. However, the presence of cilia in the corneal stroma and the dynamic changes and roles of endothelial and stromal cilia in corneal homeostasis remain largely unknown. Here, we present compelling evidence for the presence of primary cilia in the corneal stroma, both in vivo and in vitro. We also demonstrate dynamic changes of both endothelial and stromal cilia during corneal development. In addition, our data show that cryoinjury triggers dramatic cilium formation in the corneal endothelium and stroma. Furthermore, depletion of cilia in mutant mice lacking intraflagellar transport protein 88 compromises the corneal endothelial capacity to establish the effective tissue barrier, leading to an upregulation of α-smooth muscle actin within the corneal stroma in response to cryoinjury. These observations underscore the essential involvement of corneal endothelial and stromal cilia in maintaining corneal homeostasis and provide an innovative strategy for the treatment of corneal injuries and diseases.
Subject(s)
Cilia , Corneal Stroma , Endothelium, Corneal , Homeostasis , Animals , Mice , Actins/metabolism , Cilia/metabolism , Corneal Injuries/metabolism , Corneal Injuries/pathology , Corneal Injuries/therapy , Corneal Stroma/cytology , Corneal Stroma/growth & development , Corneal Stroma/metabolism , Endothelium, Corneal/cytology , Endothelium, Corneal/growth & development , Endothelium, Corneal/metabolism , Homeostasis/physiology , Mice, Inbred C57BL , Mice, Knockout , Tumor Suppressor Proteins/genetics , Ciliopathies/metabolism , Ciliopathies/pathology , Ciliopathies/therapyABSTRACT
In ruminants, establishment and maintenance of pregnancy depends upon a well-coordinated interaction between the conceptus and the maternal endometrium. Epidermal growth factor (EGF) is important for embryo implantation and pregnancy establishment. However, the regulatory mechanisms of EGF expression remain unclear. FOXO1, a member of the Forkhead box O (FOXO) subfamily of transcription factors, is currently accepted as a novel endometrial receptivity marker for humans and mice owing to its timely and specific expression at the window of implantation. In this study, we examined the spatiotemporal expression profile of EGF in goat uterus during early pregnancy (Day 0 to Day 50 of pregnancy) and verified that EGF expression was regulated by FOXO1 and interferon tau (IFNT). Our results showed that EGF was highly expressed in the luminal epithelium (LE) and the glandular epithelium (GE) during conceptus adhesion (Day 16 to Day 25 of pregnancy). After implantation, EGF protein signals were continuously detected in the endometrial epithelia and appeared in the conceptus trophectoderm. Furthermore, EGF expression could be up-regulated by IFNT in goat uterus and primary endometrial epithelium cells (EECs). The luciferase assay results showed that FOXO1 could promote EGF transcription by binding to its promoter. And FOXO1 positively regulates EGF expression in goat EECs. These findings contribute to better understanding the role and regulation mechanisms of EGF during ruminant early pregnancy.
Subject(s)
Endometrium , Epidermal Growth Factor , Interferon Type I , Pregnancy Proteins , Pregnancy , Humans , Female , Animals , Mice , Epidermal Growth Factor/genetics , Epidermal Growth Factor/pharmacology , Epidermal Growth Factor/metabolism , Endometrium/metabolism , Embryo Implantation/physiology , Uterus/metabolism , Ruminants , Goats , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/metabolismABSTRACT
INTRODUCTION: Before tracheal intubation, it is essential to provide sufficient oxygen reserve for emergency patients with full stomachs. Recent studies have demonstrated that high-flow nasal oxygen (HFNO) effectively pre-oxygenates and prolongs apneic oxygenation during tracheal intubation. Despite its effectiveness, the use of HFNO remains controversial due to concerns regarding carbon dioxide clearance. The air leakage and unknown upper airway obstruction during HFNO therapy cause reduced oxygen flow above the vocal cords, possibly weaken the carbon dioxide clearance. METHODS: Patients requiring emergency surgery who had fasted < 8 h and not drunk < 2 h were randomly assigned to the high-flow group, who received 100% oxygen at 30-60 L/min through nasopharyngeal airway (NPA), or the mask group, who received 100% oxygen at 8 L/min. PaO2 and PaCO2 were measured immediately before pre-oxygenation (T0), anesthesia induction (T1), tracheal intubation (T2), and mechanical ventilation (T3). The gastric antrum's cross-sectional area (CSA) was measured using ultrasound technology at T0, T1, and T3. Details of complications, including hypoxemia, reflux, nasopharyngeal bleeding, postoperative pulmonary infection, postoperative nausea and vomiting (PONV), and postoperative nasopharyngeal pain, were recorded. The primary outcomes were PaCO2 measured at T1, T2, and T3. The secondary outcomes included PaO2 at T1, T2, and T3, CSA at T1 and T3, and complications happened during this trial. RESULTS: Pre-oxygenation was administered by high-flow oxygen through NPA (n = 58) or facemask (n = 57) to 115 patients. The mean (SD) PaCO2 was 32.3 (6.7) mmHg in the high-flow group and 34.6 (5.2) mmHg in the mask group (P = 0.045) at T1, 45.0 (5.5) mmHg and 49.4 (4.6) mmHg (P < 0.001) at T2, and 47.9 (5.1) mmHg and 52.9 (4.6) mmHg (P < 0.001) at T3, respectively. The median ([IQR] [range]) PaO2 in the high-flow and mask groups was 404.5 (329.1-458.1 [159.8-552.9]) mmHg and 358.9 (274.0-413.3 [129.0-539.1]) mmHg (P = 0.007) at T1, 343.0 (251.6-428.7 [73.9-522.1]) mmHg and 258.3 (162.5-347.5 [56.0-481.0]) mmHg (P < 0.001) at T2, and 333.5 (229.9-411.4 [60.5-492.4]) mmHg and 149.8 (87.0-246.6 [51.2-447.5]) mmHg (P < 0.001) at T3, respectively. The CSA in the high-flow and mask groups was 371.9 (287.4-557.9 [129.0-991.2]) mm2 and 386.8 (292.0-537.3 [88.3-1651.7]) mm2 at T1 (P = 0.920) and 452.6 (343.7-618.4 [161.6-988.1]) mm2 and 385.6 (306.3-562.0 [105.5-922.9]) mm2 at T3 (P = 0.173), respectively. The number (proportion) of complications in the high-flow and mask groups is shown below: hypoxemia: 1 (1.7%) vs. 9 (15.8%, P = 0.019); reflux: 0 (0%) vs. 0 (0%); nasopharyngeal bleeding: 1 (1.7%) vs. 0 (0%, P = 1.000); pulmonary infection: 4 (6.9%) vs. 3 (5.3%, P = 1.000); PONV: 4 (6.9%) vs. 4 (7.0%, P = 1.000), and nasopharyngeal pain: 0 (0%) vs. 0 (0%). CONCLUSIONS: Compared to facemasks, pre-oxygenation with high-flow oxygen through NPA offers improved carbon dioxide clearance and enhanced oxygenation prior to tracheal intubation in patients undergoing emergency surgery, while the risk of gastric inflation had not been ruled out. TRIAL REGISTRATION: This trial was registered prospectively at the Chinese Clinical Research Registry on 26/4/2022 (Registration number: ChiCTR2200059192).
Subject(s)
Carbon Dioxide , Intubation, Intratracheal , Masks , Oxygen Inhalation Therapy , Humans , Male , Female , Prospective Studies , Middle Aged , Oxygen Inhalation Therapy/methods , Adult , Oxygen/metabolism , Nasopharynx , Respiration, Artificial , AgedABSTRACT
Carbohydrate metabolism disorders (CMDs), such as diabetes, galactosemia, and mannosidosis, cause ciliopathy-like multiorgan defects. However, the mechanistic link of cilia to CMD complications is still poorly understood. Herein, we describe a significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols. Moreover, environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups. Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane, which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly. In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella. These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.
ABSTRACT
O-GlcNAcylation functions as a cellular nutrient and stress sensor and participates in almost all cellular processes. However, it remains unclear whether O-GlcNAcylation plays a role in the establishment and maintenance of cell polarity, because mice lacking O-GlcNAc transferase (OGT) are embryonically lethal. Here, a mild Ogt knockout mouse model is constructed and the important role of O-GlcNAcylation in establishing and maintaining cell polarity is demonstrated. Ogt knockout leads to severe pulmonary fibrosis and dramatically promotes epithelial-to-mesenchymal transition. Mechanistic studies reveal that OGT interacts with pericentriolar material 1 (PCM1) and centrosomal protein 131 (CEP131), components of centriolar satellites required for anchoring microtubules to the centrosome. These data further show that O-GlcNAcylation of PCM1 and CEP131 promotes their centrosomal localization through phase separation. Decrease in O-GlcNAcylation prevents PCM1 and CEP131 from localizing to the centrosome, instead dispersing these proteins throughout the cell and impairing the microtubule-centrosome interaction to disrupt centrosome positioning and cell polarity. These findings identify a previously unrecognized role for protein O-GlcNAcylation in establishing and maintaining cell polarity with important implications for the pathogenesis of pulmonary fibrosis.
Subject(s)
Pulmonary Fibrosis , Mice , Animals , Pulmonary Fibrosis/metabolism , Cell Polarity , Centrosome/metabolism , PhenotypeABSTRACT
Systemic capillary leak syndrome (SCLS) is a rare and complex adverse effect of immune checkpoint inhibitors (ICIs). The diagnosis of drug-induced SCLS is based on diffuse infusions of exudative fluid into the interstitial areas and the exclusion of other causes. The best management of ICIs-induced SCLS is not settled, though proper supportive care and corticosteroids were commonly applied as the first-line treatment. In our patient with advanced gastroesophageal junction squamous cell carcinoma, although ICIs-induced SCLS was successfully controlled with corticosteroids, the patient soon experienced cancer progress and died of pulmonary infections. Based on our experience and the reported cases by other hospitals, different stages of SCLS might respond differently to the same treatment. Therefore, a grading of ICIs-induced SCLS might help to stratify the patient for different treatment strategies. Besides, corticosteroids-sensitive patients, though waived from deadly SCLS, might be at higher risk of cancer progress and subsequent infections due to the application of corticosteroids. Considering that the inflammatory factors should be closely involved in the development of ICIs-induced SCLS, targeted therapy against the driver inflammatory cytokine might offer treatment regimens that are more effective and safer.
Subject(s)
Capillary Leak Syndrome , Carcinoma, Squamous Cell , Humans , Capillary Leak Syndrome/chemically induced , Capillary Leak Syndrome/diagnosis , Capillary Leak Syndrome/drug therapy , Antibodies, Monoclonal, Humanized/adverse effects , Carcinoma, Squamous Cell/complications , Adrenal Cortex Hormones/therapeutic useABSTRACT
The primary cilium is increasingly recognized as a crucial player in the physiology of biliary epithelial cells (BECs). However, the precise role of primary cilia in the development of age-related biliary fibrosis remains unclear. Herein, using cilium-deficient mice, we demonstrate that disruption of ciliary homeostasis in BECs in aged mice leads to significant bile duct proliferation, augmented biliary fibrosis, and heightened indicators of liver injury. Our RNA-sequencing data revealed a dysregulation in genes associated with various biological processes such as bile secretion, fatty acid metabolism, and inflammation. Loss of primary cilia also significantly enhanced signaling pathways driving the development of biliary fibrosis. Our findings collectively suggest that loss of primary cilia in the BECs of aged mice initiates a cascade of signaling events that contribute to biliary fibrosis, highlighting the primary cilium as a potential therapeutic target in the treatment of fibrosing cholangiopathies.
Subject(s)
Cilia , Liver Diseases , Animals , Mice , Cilia/metabolism , Liver Diseases/metabolism , Epithelial Cells/metabolism , FibrosisABSTRACT
Purpose: Dexmedetomidine exerts a neuroprotective effect, however, the mechanism underlying this effect remains unclear. This study aimed to explore whether dexmedetomidine can reduce the increase in neurofilament light chain (NfL) protein concentration to play a neuroprotective role during thoracoscopic surgery. Patients and Methods: Patients aged ≥60 years undergoing general anesthesia for thoracoscopic surgery were randomly assigned to receive dexmedetomidine (group D) or not receive dexmedetomidine (group C). Patients in group D received a loading dose of dexmedetomidine 0.5 µg/kg before anesthesia induction and a continuous infusion at 0.5 µg·kg-1·h-1 until the end of the surgery. Dexmedetomidine was not administered in group C. The primary outcome was the NfL concentration on postoperative day 1. The concentrations of procalcitonin (PCT), serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP) were detected preoperatively and on postoperative day 1. In addition, the numerical rating scale (NRS) and quality of recovery-40 (QoR-40) scores were evaluated. Results: A total of 38 patients in group D and 37 in group C were included in the analysis. No differences were observed between the groups in terms of the plasma concentration of NfL preoperatively and on postoperative day 1 (11.17 [8.86, 13.93] vs 13.15 [10.76, 15.56] pg/mL, P > 0.05; 16.70 [12.23, 21.15] vs 19.48 [15.25, 22.85] pg/mL, P > 0.05, respectively). However, the postoperative plasma NfL concentration was significantly higher than the preoperative value in both groups (both P < 0.001). The groups exhibited no differences in PCT, SAA, hs-CRP, NRS, and QoR-40 (all P > 0.05). Conclusion: Intraoperative administration of dexmedetomidine at a conventional dose does not appear to significantly reduce the increase in postoperative plasma NfL concentration in elderly patients undergoing thoracoscopic surgery. This finding suggests that the neuroprotective effect of dexmedetomidine at a conventional dose was not obvious during general anesthesia.
Subject(s)
C-Reactive Protein , Neuroprotective Agents , Aged , Humans , Intermediate Filaments , Prospective Studies , Anesthesia, GeneralABSTRACT
Hematopoietic stem and progenitor cells (HSPCs) are cells mainly present in the bone marrow and capable of forming mature blood cells. However, the epigenetic mechanisms governing the homeostasis of HSPCs remain elusive. Here, we demonstrate an important role for histone deacetylase 6 (HDAC6) in regulating this process. Our data show that the percentage of HSPCs in Hdac6 knockout mice is lower than in wild-type mice due to decreased HSPC proliferation. HDAC6 interacts with isocitrate dehydrogenase 1 (IDH1) and deacetylates IDH1 at lysine 233. The deacetylation of IDH1 inhibits its catalytic activity and thereby decreases the 5-hydroxymethylcytosine level of ten-eleven translocation 2 (TET2) target genes, changing gene expression patterns to promote the proliferation of HSPCs. These findings uncover a role for HDAC6 and IDH1 in regulating the homeostasis of HSPCs and may have implications for the treatment of hematological diseases.
Subject(s)
Bone Marrow , Hematopoietic Stem Cells , Animals , Mice , Histone Deacetylase 6/genetics , Histone Deacetylase 6/metabolism , Hematopoietic Stem Cells/metabolism , Bone Marrow Cells/metabolism , HomeostasisABSTRACT
In ruminants, IFN-tau (IFNT) regulates the production of prostaglandins (PG) in the endometrium, which is crucial for conceptus adhesion. However, the related molecular regulatory mechanisms remain unclear. Forkhead box O1 (FOXO1), a member of the FOXO subfamily of transcription factors, is known to be important for mouse implantation and decidualization. In this study, we determined the spatiotemporal expression profile of FOXO1 in goat endometrium during early pregnancy. FOXO1 was highly expressed in the glandular epithelium since the onset of conceptus adhesion (d 16 of pregnancy). Then, we validated that FOXO1 could bind to the promoter of prostaglandin-endoperoxide synthase 2 (PTGS2) and increase its transcription. And the expression profile of PTGS2 was similar to that of FOXO1 in the peri-implantation uterus. Moreover, IFNT could upregulate the levels of FOXO1 and PTGS2 in goat uterus and primary endometrial epithelium cells (EEC). In EEC, the intracellular content of PGF2α was positively correlated with the levels of IFNT and FOXO1. Altogether, we found an IFNT/FOXO1/PTGS2 axis that controls the synthesis of PGF2α but not prostaglandin E2 in goat uterine glands. These findings contribute to better understanding the function of FOXO1 in the reproductive physiology of goats and provide more insights into the implantation of small ruminants.
ABSTRACT
N6-methyladenosine (m6A), an epigenetic modification on RNAs, plays an important role in many physiological and pathological processes. However, the involvement of m6A in goat uterus during early pregnancy remains largely unknown. In this study, we found that the total m6A level was increasing in goat uterus as early pregnancy progressed. Methyltransferase-like 3 (METTL3) is a core catalytic subunit of the m6A methyltransferase. We thus determined the expression and regulation of METTL3 in goat uterus. METTL3 was highly expressed in the luminal and glandular epithelia from day 16 (D16) to D25 of pregnancy, and it could be up-regulated by estrogen and progesterone in goat uterus and primary endometrial epithelial cells (EECs). In EECs, knockdown or overexpression of METTL3 resulted in a significant decrease or increase of cell proliferation, respectively. METTL3 knockdown reduced the m6A level of not only total RNA but also connective tissue growth factor (CTGF) mRNA. Luciferase assay suggested that METTL3 might target the potential m6A sites in the 3'untranslated region (3'UTR) of CTGF mRNA. Moreover, METTL3 positively regulated CTGF expression, and CTGF knockdown significantly counteracted the promoting effect of METTL3 overexpression on EEC proliferation. Collectively, METTL3 is dynamically expressed in goat uterus and can affect EEC proliferation by regulating CTGF in an m6A-dependent manner. Our results will lay a foundation for further studying the crucial mechanism of METTL3-mediated m6A modification in goat uterus during early pregnancy.
Subject(s)
Connective Tissue Growth Factor , Goats , Animals , Female , Connective Tissue Growth Factor/genetics , Goats/genetics , Methyltransferases/genetics , Methyltransferases/metabolism , Epithelial Cells/metabolism , RNA, Messenger/metabolism , Cell Proliferation/geneticsABSTRACT
The non-receptor tyrosine kinase Src plays a key role in cell division, migration, adhesion, and survival. Src is overactivated in several cancers, where it transmits signals that promote cell survival, mitosis, and other important cancer hallmarks. Src is therefore a promising target in cancer therapy, but the underlying mechanisms are still uncertain. Here we show that Src is highly conserved across different species. Src expression increases during mitosis and is localized to the chromosomal passenger complex. Knockdown or inhibition of Src induces multipolar spindle formation, resulting in abnormal expression of the Aurora B and INCENP components of the chromosomal passenger complex. Molecular mechanism studies have found that Src interacts with and phosphorylates INCENP. This then leads to incorrect chromosome arrangement and segregation, resulting in cell division failure. Herein, Src and chromosomal passenger complex co-localize and Src inhibition impedes mitotic progression by inducing multipolar spindle formation. These findings provide novel insights into the molecular basis for using Src inhibitors to treat cancer.
Subject(s)
Antineoplastic Agents , Genes, src , Mitosis , Proto-Oncogene Proteins pp60(c-src) , Humans , Chromosomal Proteins, Non-Histone/metabolism , Chromosomes/metabolism , Cytoskeleton/metabolism , Genes, src/drug effects , Mitosis/drug effects , Spindle Apparatus/genetics , Spindle Apparatus/metabolism , Proto-Oncogene Proteins pp60(c-src)/antagonists & inhibitors , Antineoplastic Agents/pharmacologyABSTRACT
By inserting a tricoordinate B atom into an indolo[3,2,1-jk]carbazole precursor, an efficient fused multiple resonance-induced thermally activated delayed fluorescence emitter was prepared, which exhibits a narrowband emission and a considerable reverse intersystem crossing rate. The corresponding organic light-emitting diode displays an external quantum efficiency of 27.2% with a suppressed efficiency roll-off.
ABSTRACT
O-GlcNAcylation is a post-translational modification that serves as a cellular nutrient sensor and participates in multiple physiological and pathological processes. However, it remains uncertain whether O-GlcNAcylation is involved in the regulation of phagocytosis. Here, we demonstrate a rapid increase in protein O-GlcNAcylation in response to phagocytotic stimuli. Knockout of the O-GlcNAc transferase or pharmacological inhibition of O-GlcNAcylation dramatically blocks phagocytosis, resulting in the disruption of retinal structure and function. Mechanistic studies reveal that the O-GlcNAc transferase interacts with Ezrin, a membrane-cytoskeleton linker protein, to catalyze its O-GlcNAcylation. Our data further show that Ezrin O-GlcNAcylation promotes its localization to the cell cortex, thereby stimulating the membrane-cytoskeleton interaction needed for efficient phagocytosis. These findings identify a previously unrecognized role for protein O-GlcNAcylation in phagocytosis with important implications in both health and diseases.
Subject(s)
Phagocytosis , Protein Processing, Post-Translational , Acetylglucosamine/metabolism , Cytoplasm/metabolism , N-Acetylglucosaminyltransferases/genetics , N-Acetylglucosaminyltransferases/metabolism , Animals , MiceABSTRACT
PURPOSE: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). EXPERIMENTAL DESIGN: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. RESULTS: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures. CONCLUSIONS: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.
Subject(s)
Breast Neoplasms , Paclitaxel , Humans , Female , Paclitaxel/therapeutic use , Trastuzumab/therapeutic use , Neoadjuvant Therapy , Biomarkers, Tumor/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Receptor, ErbB-2/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , RNAABSTRACT
BACKGROUND: The aim of this study is to evaluate analgesic efficacy of pericapsular nerve group (PENG) block in patients with intertrochanteric femur fracture (IFF). METHODS: This double-blinded randomized controlled trial in patients with IFF scheduled for proximal femoral nail antirotation (PFNA) between December 2020 and November 2021. The primary outcome was VAS scores during exercising at 6 h after surgery; secondary outcomes were pain during exercising and rest, intraoperative dose of remifentanil, cumulative dose of postoperative fentanyl, postoperative analgesia satisfaction scores, and ratio of quadriceps weakness. RESULTS: A total of 50 patients were randomly divided into PENG block group (n = 25) or fascia iliaca compartment block (FICB) group (n = 25). Exercising VAS scores at 6 h after surgery were significantly lower in PENG block group than that in FICB group (2 (2, 4) vs. 6 (4, 7), P < 0.001). The intraoperative dose of remifentanil and cumulative dose of postoperative fentanyl by patient-controlled intravenous analgesia within 24 h after surgery in PENG block group were significantly lower than in FICB group (both P < 0.001). Postoperative analgesia satisfaction scores in PENG block group were significantly higher than those in FICB group (P = 0.016). The ratio of quadriceps weakness at 6 h after surgery was significantly higher in FICB group than PENG block group (48% vs. 0%, P < 0.001). CONCLUSIONS: Compared to FICB, ultrasound-guided PENG block may provide better postoperative pain relief in patients with IFF, with less pronounced quadriceps weakness.
Subject(s)
Femoral Nerve , Hip Fractures , Analgesics , Femur , Fentanyl , Hip Fractures/surgery , Humans , Pain, Postoperative/drug therapy , RemifentanilABSTRACT
Herein, we report two multiple-resonance thermally activated delayed fluorescence emitters (VTCzBN and TCz-VTCzBN) based on indolo[3,2,1-jk]carbazole unit and boron-nitrogen skeletons, whose emissions peaking at 496 and 521â nm with full width at half maximum of 34 and 29â nm, respectively. Meanwhile, fast rate constants of reverse intersystem crossing of above 106 â s-1 are obtained due to small singlet-triplet energy gaps and large spin-orbital coupling values. Notably, planar molecular structures along the transition dipole moment direction endow them with high horizontal emitting dipole ratios of up to 94 %. Consequently, the corresponding organic light-emitting diodes (OLEDs) show the maximum external quantum efficiencies of 31.7 % and 32.2 %, respectively. Particularly, OLED with TCz-VTCzBN display ultra-pure green emission with Commission Internationale de l'Eclairage coordinates of (0.22, 0.71), consistent with the green display standard of the National Television System Committee.