PRMT3 methylates HIF-1α to enhance the vascular calcification induced by chronic kidney disease.

BACKGROUND: Medial vascular calcification is commonly identified in chronic kidney disease (CKD) patients and seriously affects the health and life quality of patients. This study aimed to investigate the effects of protein arginine methyltransferase 3 (PRMT3) on vascular calcification induced by CKD. METHODS: A mice model of CKD was established with a two-step diet containing high levels of calcium and phosphorus. Vascular smooth muscle cells (VSMCs) were subjected to ß-glycerophosphate (ß-GP) treatment to induce the osteogenic differentiation as an in vitro CKD model. RESULTS: PRMT3 was upregulated in VSMCs of medial artery of CKD mice and ß-GP-induced VSMCs. The inhibitor of PRMT3 (SGC707) alleviated the vascular calcification and inhibited the glycolysis of CKD mice. Knockdown of PRMT3 alleviated the ß-GP-induced osteogenic transfomation of VSMCs by the repression of glycolysis. Next, PRMT3 interacted with hypoxia-induced factor 1α (HIF-1α), and the knockdown of PRMT3 downregulated the protein expression of HIF-1α by weakening its methylation. Gain of HIF-1α reversed the PRMT3 depletion-induced suppression of osteogenic differentiation and glycolysis of VSMCs. CONCLUSION: The inhibitory role of PRMT3 depletion was at least mediated by the regulation of glycolysis upon repressing the methylation of HIF-1α.

In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators.

Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-ß-caryophyllene (TBC) and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future.

Dexmedetomidine Reduces the Lidocaine-Induced Neurotoxicity by Inhibiting Inflammasome Activation and Reducing Pyroptosis in Rats.

Local anesthetic toxicity is closely related to neuronal death and activation of the inflammatory response. Dexmedetomidine (Dex) is an adrenergic α2 receptor agonist that can reduce the neurotoxicity induced by lidocaine. It also has anti-inflammatory effects. However, the mechanism underlying the neuroprotective effects of Dex against lidocaine-induced toxicity remains to be defined. We hypothesized that Dex exerts its neural protective effect through inhibiting inflammasome activation and through anti-pyroptosis effects against local anesthetic-induced nerve injury. In a rat model of lidocaine-induced spinal cord injury, we studied the protective effect of Dex on lidocaine-induced changes in spinal cord function, inflammasome formation and pyroptosis, pro-inflammatory cytokine expression, and protein kinase C (PKC)-δ phosphorylation. Dex reduced lidocaine-induced neurotoxicity and inhibited PKC-δ phosphorylation in the spinal cord of rats. Furthermore, Dex inhibited pyroptosis and inflammasome formation (caspase-1, NLRP3, and apoptosis-associated speck-like protein (ASC)). Finally, Dex attenuated interleukin (IL)-1ß and IL-18 expression, as well as microglia response. In conclusion, Dex can reduce the severity of lidocaine-induced spinal cord injury in rats by inhibiting priming and inflammasome activation and reducing pyroptosis via PKC-δ phosphorylation.

Anesthesia management in neonatal congenital bronchobiliary fistula: case report and literature review.

BACKGROUND: There is very little published literature and none that discussed care in a neonate regarding anesthetic risk and management of neonate with congenital bronchobiliary fistula during thoracoscopy and thoracotomy. This article analyzes related risk factors and literature review from perioperative ventilation, circulation and other aspects of management. CASE PRESENTATION: A neonate diagnosed as congenital bronchobiliary fistula combined with severe chemical pneumonia, consolidation of the lungs, and infection was facing the risk of anaesthesia under thoracoscopy exploration surgery, who experiened more than 20 days diagnostic period before operation. Many risk factors have led to conversion from minimally invasive surgery to thoracotomy, including persistent hypoxemia, hypercapnia, difficult surgical exposure and extremly difficulty of intraoperative ventilation management. Anesthesia maintenance after conversion to open access remained problematic. Fortunately the patient showed no sign of any adverse CNS effects after 4 months of follow-up. CONCLUSIONS: The most prominent anesthesia challenges are hypoxemia, increased airway resistance, impaired ventilation, and the risk of metabolic acidosis. Close cooperation among the entire neonatal medical team is the key factors in successful management of this rare case.

Characterization of the structure of rabbit anterior cruciate ligament and its stem/progenitor cells.

BACKGROUND: It is known that anterior cruciate ligament (ACL) of the knee joint is prone to injuries with poor healing potential. The healing capacity of a tissue-like ACL is dependent on its structural components and the properties of the stem cells (SCs). Therefore, this study aimed to characterize the structure of ACL tissue and the properties of the SCs derived from the tissue components. METHODS: The tissue structure of rabbit ACL was determined using a scanning electron microscope, hematoxylin and eosin, and immunohistochemical staining. The biological properties of SCs derived from the structural components of ACL were studied by colony formation, cell proliferation assay, SC marker expression and collagen exhibition, and multidifferentiation potential. RESULTS: The two distinct components of ACL are classified as sheath and core, which possess differential properties in terms of collagen type, organization, and presence of blood vessels. The sheath tissue contains vascular SCs and the core tissue contains ligamentous SCs, respectively. The two types of SCs differ in clonogenicity, proliferation, and multidifferentiation potential. CONCLUSION: This study shows that ACL consists of sheath and core tissues, which contain sheath and core SCs with distinctive biological properties. These findings highlight the need for use of both sheath and core SCs to promote the repair of the complex structure of injured ACL.

Efficacy and Safety of Computed Tomography-Guided Pulsed Radiofrequency Modulation of Thoracic Dorsal Root Ganglion on Herpes Zoster Neuralgia.

OBJECTIVE: Pulsed radiofrequency (PRF) can relieve postherpetic neuralgia (PHN) caused by herpes zoster (HZ) infection. Nevertheless, its curative effect can vary and may be related to the duration of treatment period. The following study investigates the efficacy and safety of CT-guided PRF modulation on HZ neuralgia over different periods and different time points. MATERIALS AND METHODS: A total of 150 patients with HZ/PHN were enrolled at the Pain Department, Shengjing Hospital of China Medical University between January 2013 and December 2016. According to the course of disease, the patients were randomly divided into group A, which included patients with acute stage (n = 50; course <1 m); group B, which included patients with subacute stage (n = 50; 1 m 3 m). The PRF therapy was performed in all patients by targeting thoracic dorsal root ganglion (DRG). The visual analogue scale (VAS), SF-36, total effective rate of treatment, and dosage of antiepileptic analgesic drugs were observed at different time points, before and after the surgery. RESULTS: Compared to preoperative time, decreased VAS, improved SF-36, and the decreased dosage of antiepileptic analgesic drugs were observed at all time points, and in all groups after surgery (p < 0.05). In group A, pain relief lasted longer, and it further decreased over time. In addition, significantly lower VAS, higher SF-36, and lower dosage of antiepileptic analgesic drugs were found in group A compared to group B, and in group B compared to group C (all p < 0.05). Furthermore, the total effective rates in groups A, B, and C were 88, 72, and 52%, respectively. CONCLUSIONS: CT-guided PRF targeting thoracic DRG for modulation of HZ neuralgia in different periods is safe and effective. It is recommended to perform early intervention therapy at the acute phase of HZ.

Influence of isoflurane exposure in pregnant rats on the learning and memory of offsprings.

BACKGROUND: About 2% of pregnant women receive non-obstetric surgery under general anesthesia each year. During pregnancy, general anesthetics may affect brain development of the fetus. This study aimed to investigate safe dosage range of isoflurane. METHODS: Forty-eight SpragueDawley (SD) pregnant rats were randomly divided into 3 groups and inhaled 1.3% isoflurane (the Iso1 group), 2.0% isoflurane (the Iso2 group) and 50% O2 alone (the control group) for 3 h, respectively. Their offsprings were subjected to Morris water maze at day 28 and day 90 after birth to evaluate learning and memory. The expression of cAMP-response element binding protein (CREB) and phosphorylated cAMP-response element binding protein (p-CREB) was detected in the hippocampus dentate gyrus. RESULTS: Less offsprings of Iso2 group were able to cross the platform than that of the control group (P < 0.05). Accordingly, the Iso2 offsprings expressed p-CREB mainly in the subgranular zone in contrast to the whole granular cell layer of hippocampus dentate gyrus as detected in the Iso1 and control offsprings; the expression level of pCREB was also lower in the Iso2 than Iso1 or control offsprings (P < 0.05). CONCLUSION: Inhalation of isoflurane at 1.3% during pregnancy has no significant influence on learning and memory of the offspring; exposure to isoflurane at 2.0% causes damage to spatial memory associated with inhibition of CREB phosphorylation in the granular cell layer of hippocampus dentate gyrus.

Real-Time Monitoring of Platelet Activation Using Quartz Thickness-Shear Mode Resonator Sensors.

In this study, quartz thickness-shear mode (TSM) resonator sensors were adopted to monitor the process of platelet activation. Resting platelets adhering to fibrinogen-coated electrodes were activated by different concentrations of thrombin (1, 10, and 100 U/mL), and the corresponding electrical admittance spectra of TSM resonators during this process were recorded. Based on a bilayer-loading transmission line model of TSM resonators, the complex shear modulus (G' + jG″) and the average thickness (hPL) of the platelet monolayer at a series of time points were obtained. Decrease in thrombin concentration from 100 to 1 U/mL shifted all peaks and plateaus in G', G″, and hPL to higher time points, which could be attributed to the partial activation of platelets by low concentrations of thrombin. The peak value of hPL was acquired when platelets presented their typical spherical shape as the first transformation in activation process. The G' peak appeared 10 ∼ 20 min after hPL peak, when some filopods were observed along the periphery of platelets but without obvious cell spreading. As platelet spreading began and continued, G', G″, and hPL decreased, leading to a steady rise of resonance frequency shift of TSM resonator sensors. The results show high reliability and stability of TSM resonator sensors in monitoring the process of platelet activation, revealing an effective method to measure platelet activities in real-time under multiple experimental conditions. The G', G″, and hPL values could provide useful quantitative measures on platelet structure variations in activation process, indicating potential of TSM resonators in characterization of cells during their transformation.

Deletion of Calponin 2 in Mouse Fibroblasts Increases Myosin II-Dependent Cell Traction Force.

Cell traction force (CTF) plays a critical role in controlling cell shape, permitting cell motility, and maintaining cellular homeostasis in many biological processes such as angiogenesis, development, wound healing, and cancer metastasis. Calponin is an actin filament-associated cytoskeletal protein in smooth muscles and multiple types of non-muscle cells. An established biochemical function of calponin is the inhibition of myosin ATPase in smooth muscle cells. Vertebrates have three calponin isoforms. Among them, calponin 2 is expressed in epithelial cells, endothelial cells, macrophages, myoblasts, and fibroblasts and plays a role in regulating cytoskeleton activities such as cell adhesion, migration, and cytokinesis. Knockout (KO) of the gene encoding calponin 2 (Cnn2) in mice increased cell motility, suggesting a function of calponin 2 in modulating CTF. In this study, we examined fibroblasts isolated from Cnn2 KO and wild-type (WT) mice using CTF microscopy. Primary mouse fibroblasts were cultured on polyacrylamide gel substrates embedded with fluorescent beads to measure root-mean-square traction, total strain energy, and net contractile movement. The results showed that calponin 2-null fibroblasts exhibit traction force greater than that of WT cells. Adherent calponin 2-null fibroblasts de-adhered faster than the WT control during mild trypsin treatment, consistent with an increased CTF. Blebbistatin, an inhibitor of myosin II ATPase, is more effective upon an alteration in cell morphology when calponin 2 is present in WT fibroblasts than that on Cnn2 KO cells, indicating their additive effects in inhibiting myosin motor activity. The novel finding that calponin 2 regulates myosin-dependent CTF in non-muscle cells demonstrates a mechanism for controlling cell motility-based functions.

Dexmedetomidine preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest.

BACKGROUND/AIMS: To investigate the protection effect of dexmedetomidine preconditioning on global cerebral ischemic injury following asphyxial cardiac arrest (CA) in rats. METHODS: Seventy-two rats were randomly assigned into three groups, sham group (no asphyxia), control group (asphyxia only), and dexmedetomidine preconditioned group (asphyxia + dexmedetomidine). Dexmedetomidine was administered 5 minutes before an 8 min of asphyxia. Rats were resuscitated by a standardized method. Blood O(2) and CO(2) partial pressures were, pH, base excess (BE), and blood glucose concentration measured before asphyxial CA and 1 h after resuscitation. Neurological deficit score (NDS) was measured at 12, 24, 48, and 72 h after CA. Histopathologic changes in the hippocampal region were observed by H&E staining and histopathologic damage score. Ultrastructural morphology was observed by transmission electron microscopy. HIF-1 and VEGF expression were measured by immunostaining of serial sections obtained from brain tissue. RESULTS: Asphyxial CA -induced global cerebral ischemic decreased PaO(2), pH, BE and increased PaCO(2), blood glucose. Dexmedetomidine preconditioning improved neurologic outcome, which was associated with reduction in histopathologic injury measured by H&E staining, the histopathologic damage score and electron microscopy. Dexmedetomidine preconditioning also elevated HIF-1α and VEGF expression after global cerebral ischemia following asphyxial CA. CONCLUSION: Dexmedetomidine preconditioning protected against cerebral ischemic injury and was associated with upregulation of HIF-1α and VEGF expression.

Comparison of hemodynamics after combined spinal-epidural anesthesia between decubitus and sitting positions in aged patients undergoing total hip replacement.

OBJECTIVE: To compare the hemodynamics after combined spinal-epidural anesthesia (CSEA) between decubitus and sitting positions in aged patients undergoing total hip replacement. METHODS: A total of 80 aged patients who underwent CSEA for elective total hip replacement were randomly divided into a decubitus position group (group D) and a sitting position group (group S; each group with 40 patients). In group D, 10 mg of 0.5% bupivacaine were given into the subarachnoid space in decubitus position. In group S, 10 mg of 0.5% bupivacaine were given into the subarachnoid space in the sitting position, which was maintained for 1 min, after which the patients were in decubitus position. In both groups, the sensory block levels and changes in hemodynamics were assessed. RESULTS: The mean arterial blood pressure was significantly higher in group S than in group D at each time point within 30 min after anesthesia. There were no significant differences in heart rate between the two groups at each time point. There was also no significant difference in the level of sensory block between the two groups 20 min after the administration of CSEA. CONCLUSION: For aged patients undergoing total hip replacement, CSEA is safer and more effective in the sitting position than in decubitus position.

Interactions between genetic variants and environmental risk factors are associated with the severity of pelvic organ prolapse.

OBJECTIVE: Both environmental and genetic risk factors contribute to pelvic organ prolapse (POP). No genome-wide study has investigated the gene-environment (G × E) interactions. In this study, we aim to identify single nucleotide polymorphisms (SNPs) that may interact with the potential environmental factors, maximum birth weight, and age in Chinese women. METHODS: We recruited 576 women for phase 1 and 264 women for phase 2 with stages III and IV prolapse from six geographic regions of China. Genomic DNAs from blood samples were genotyped using Affymetrix Axiom Genome-Wide CHB1 Array of 640,674 SNPs for phase 1 and Illumina Infinium Asian Screening Array of 743,722 SNPs for phase 2. Meta-analysis was used to combine the two results. Interactions of genetic variants with maximum birth weight and age on POP severity were identified. RESULTS: In phase 1, 502,283 SNPs in 523 women passed quality control and 450 women had complete POP-quantification measurements. In phase 2, 463,351 SNPs in 257 women passed quality control with complete POP-quantification measurements. Three SNPs rs76662748 ( WDR59 , Pmeta = 2.146 × 10 -8 ), rs149541061 ( 3p26.1 , Pmeta = 9.273 × 10 -9 ), and rs34503674 ( DOCK9 , Pmeta = 1.778 × 10 -9 ) respectively interacted with maximum birth weight, and two SNPs rs74065743 ( LINC01343 , Pmeta = 4.386 × 10 -8 ) and rs322376 ( NEURL1B - DUSP1 , Pmeta = 2.263 × 10 -8 ), respectively, interacted with age. The magnitude of disease severity associated with maximum birth weight and age differed according to genetic variants. CONCLUSIONS: This study provided preliminary evidence that interactions between genetic variants and environmental risk factors are associated with POP severity, suggesting the potential use of combining epidemiologic exposure data with selected genotyping for risk assessment and patient stratification.

mTOR inhibition suppresses Myc-driven polyposis by inducing immunogenic cell death.

Myc is a key driver of colorectal cancer initiation and progression, but remains a difficult drug target. In this study, we show that mTOR inhibition potently suppresses intestinal polyp formation, regresses established polyps, and prolongs lifespan of APCMin/+ mice. Everolimus in diet strongly reduces p-4EBP1, p-S6, and Myc levels, and induces apoptosis of cells with activated ß-catenin (p-S552) in the polyps on day 3. The cell death is accompanied by ER stress, activation of the extrinsic apoptotic pathway, innate immune cell recruitment, and followed by T-cell infiltration on day 14 persisting for months thereafter. These effects are absent in normal intestinal crypts with physiologic levels of Myc and a high rate of proliferation. Using normal human colonic epithelial cells, EIF4E S209A knockin and BID knockout mice, we found that local inflammation and antitumor efficacy of Everolimus requires Myc-dependent induction of ER stress and apoptosis. These findings demonstrate mTOR and deregulated Myc as a selective vulnerability of mutant APC-driven intestinal tumorigenesis, whose inhibition disrupts metabolic and immune adaptation and reactivates immune surveillance necessary for long-term tumor control.

Precise preparation of biomass-based porous carbon with pore structure-dependent VOCs adsorption/desorption performance by bacterial pretreatment and its forming process.

Pore distribution characteristic is one of the most crucial factors for porous adsorption materials, and the variety of volatile organic compounds (VOCs) approaches about how to simply and accurately tailor practical porous carbons for VOCs adsorption has gradually attracted attention. Here, precursors with different lignocellulose mass ratios have been used to produce porous carbon for model experiments to investigate the influence of the precursor lignocellulose contents on the pore structure and distribution characteristics of porous carbon, and the applicability of these mechanisms to real biomass materials has been further verified through bacteria-targeted bagasse decomposition: the microvolumes of ultra-micropores have decreased with decrease in cellulose contents, while mesopores have followed the reverse trend. The dynamic toluene adsorption/desorption performances of the obtained samples have been tested. The BACs-36 exhibits high toluene adsorption performance in low concentration with 635 mg/g while the BACs-48 shows excellent reusability in 10 times cycles. Based on this the balance between the adsorptive and regenerative capacities has been observed which indicates that carbon materials with abundant micropores and narrow mesopores have much better adsorption performance than porous carbon with a hierarchical pore structure, while the latter show better regeneration abilities than the former, which resulting in less desorption as a counter-acting force at the pore wall. Furthermore, the porous carbon has been shaped by one-step co-pyrolysis method using phenolic resin, which can not only maintain the hardness but also can avoid pore plugging phenomenon.

Mitotic CDK1 and 4E-BP1 I: Loss of 4E-BP1 serine 82 phosphorylation promotes proliferative polycystic disease and lymphoma in aged or sublethally irradiated mice.

4E-BP1 is a tumor suppressor regulating cap-dependent translation that is in turn controlled by mechanistic target of rapamycin (mTOR) or cyclin-dependent kinase 1 (CDK1) phosphorylation. 4E-BP1 serine 82 (S82) is phosphorylated by CDK1, but not mTOR, and the consequences of this mitosis-specific phosphorylation are unknown. Knock-in mice were generated with a single 4E-BP1 S82 alanine (S82A) substitution leaving other phosphorylation sites intact. S82A mice were fertile and exhibited no gross developmental or behavioral abnormalities, but the homozygotes developed diffuse and severe polycystic liver and kidney disease with aging, and lymphoid malignancies after irradiation. Sublethal irradiation caused immature T-cell lymphoma only in S82A mice while S82A homozygous mice have normal T-cell hematopoiesis before irradiation. Whole genome sequencing identified PTEN mutations in S82A lymphoma and impaired PTEN expression was verified in S82A lymphomas derived cell lines. Our study suggests that the absence of 4E-BP1S82 phosphorylation, a subtle change in 4E-BP1 phosphorylation, might predispose to polycystic proliferative disease and lymphoma under certain stressful circumstances, such as aging and irradiation.

Verification of combustion rate of recovery and counting efficiency in the analysis of organically bound tritium in biota samples.

The analysis procedure of five biota samples's organically bound tritium (OBT) based on oxidation combustion and liquid scintillation counter (LSC) measurement was established. The combustion experiment under one atmospheric pressure in the presence of Pt-Al2O3 catalyst were carried out. The experiment results shown that the combustion recovery of five samples ranged from 86.4 % to 91.1 %, the combustion recovery of glucose monohydrate is about 93.7 %, which indicate that combustion recovery of biota samples differed from one species to another. Meanwhile, The counting efficiency of quenching agents CH3NO2 and CCl4 decreases from 20.3 % to 0 and from 19.3 % to 0 respectively as the quench agent mass increases from 10 µL to 500 µL. The counting efficiency of quenching agent HNO3 decreases from 22.4 % to 14.6 % as the quench agent mass increases from 10 µL to 500 µL. The SQP (E) value of CH3NO2 and CCl4 decreases as the mass of quenching agents increases, while the SQP (E) value of HNO3 increases as the quench agent mass increases. The SQP(E) of three tested quench agents ranges from 401.8 to 738.4, which covers the SQP(E) range of all the monitored biota samples in recent years. Therefore, the mapped curves and fixed equations are applicable. In addition, comparison experiment of four biota samples between two laboratories shown a relative deviation from 1.2 % to 12.8 %.

The main effect and gene-environment interaction effect of the ADCYAP1R1 polymorphism rs2267735 on the course of posttraumatic stress disorder symptoms-A longitudinal analysis.

Background: Many studies have been performed to investigate the association between the ADCYAP1R1 polymorphism rs2267735 and posttraumatic stress disorder (PTSD), but the results have been inconsistent, and the way in which this gene affects the course of PTSD has not been widely investigated. Thus, a longitudinal study of the course (development trajectory) of PTSD is needed. Methods: In this study, we performed a longitudinal analysis of rs2267735 in 1017 young, trauma-exposed Chinese people (549 females and 468 males, ranging from 7 to 11 years old). At four time points after trauma exposure (2.5, 3.5, 4.5, and 5.5 years), we measured PTSD symptoms with the University of California, Los Angeles PTSD Reaction Index (PTSD-RI) for DSM-IV (Child Version). We employed a latent growth model (LGM) for the longitudinal data to test the association between rs2267735 (main and gene-environment interaction effects) and the course of PTSD symptoms. Results: The results of LGM showed that the gene-environment interaction (rs2267735 × trauma exposure) effects were associated with PTSD symptoms in girls at 2.5 years (ß = -0.291 and P = 0.013 for LGM intercept). The gene-environment interaction (rs2267735 × trauma exposure) effect was also correlated with PTSD symptoms in girls at 3.5 and 4.5 years (ß = -0.264 and P = 0.005; ß = -0.217 and P = 0.013). Conclusion: Our study revealed that the gene-environment interaction of the ADCYAP1R1 polymorphism rs2267735 is associated with PTSD symptoms in girls at 2.5 years and that the effects may be stable over time and not related to the PTSD symptom recovery rate. This is the first study to detect the how the ADCYAP1R1 gene affects the course of PTSD after trauma exposure in a longitudinal view.

Interferon b drives intestinal regeneration after radiation.

The cGAS-STING cytosolic DNA sensing pathway is critical for host defense. Here, we report that cGAS-STING­dependent type 1 interferon (IFN) response drives intestinal regeneration and animal recovery from radiation injury. STING deficiency has no effect on radiation-induced DNA damage or crypt apoptosis but abrogates epithelial IFN-ß production, local inflammation, innate transcriptional response, and subsequent crypt regeneration. cGAS KO, IFNAR1 KO, or CCR2 KO also abrogates radiation-induced acute crypt inflammation and regeneration. Impaired intestinal regeneration and survival in STING-deficient mice are fully rescued by a single IFN-ß treatment given 48 hours after irradiation but not by wild-type (WT) bone marrow. IFN-ß treatment remarkably improves the survival of WT mice and Lgr5+ stem cell regeneration through elevated compensatory proliferation and more rapid DNA damage removal. Our findings support that inducible IFN-ß production in the niche couples ISC injury and regeneration and its potential use to treat acute radiation injury.

Fibrin Glue-Kartogenin Complex Promotes the Regeneration of the Tendon-Bone Interface in Rotator Cuff Injury.

OBJECTIVE: Rotator cuff injury healing is problematic because the tendon-bone junction often forms cicatricial tissues, rather than fibrocartilage, which leads to mechanical impairment and is prone to redamage. Kartogenin (KGN) is a newly discovered small molecule compound which can induce cartilage formation through chondrogenesis of endogenous mesenchymal stem cells. METHODS: In this study, we used KGN with fibrin glue (FG) to repair the rotator cuff injury by promoting the formation of fibrocartilage at the tendon to bone interface. Firstly, we assessed the release rate of KGN from the FG-KGN complex and then created a rabbit rotator cuff tendon graft-bone tunnel model. The rabbits received saline, FG-KGN, or FG injections onto the tendon to bone interface after injury. Shoulder tissues were harvested at 6 and 12 weeks, and the sections were stained with HE and Safranin O/Fast green. The samples were assessed by histologic evaluation and biomechanical testing. Synovial mesenchymal stem cells derived from the synovial tissue around the rotator cuff were harvested for western blotting and qRT-PCR analysis. RESULTS: KGN was released rapidly from the FG-KGN complex during first 4 hrs and followed by a slow release until 7 days. The tendon graft-bone interface in the control (saline) group and the FG group was filled with scar tissue, rather than cartilage-like tissue, and only a small number of chondrocytes were found at the adjacent bone surface. In the FG-KGN group, the tendon to bone interface was fully integrated and populated by chondrocytes with proteoglycan deposition, indicating the formation of fibrocartilage-like tissues. At 12 weeks, the maximum tensile strength of the FG-KGN group was significantly higher than that of the FG and control groups (P < 0.01). The RNA expression levels of tendinous genes such as Tenascin C and the chondrogenic gene Sox-9 were substantially elevated in SMSCs treated with the FG-KGN complex compared to the other two groups. CONCLUSION: These results indicated that fibrin glue is an effective carrier for KGN, allowing for the sustained release of KGN. The FG-KGN complex could effectively promote the regeneration and formation of fibrocartilage tissue of the tendon-bone interface in the rabbit rotator cuff tendon graft-bone tunnel model.

The ADCYAP1R1 Gene Is Correlated With Posttraumatic Stress Disorder Symptoms Through Diverse Epistases in a Traumatized Chinese Population.

The adenylate cyclase activating polypeptide 1 (pituitary) receptor (ADCYAP1R1) gene is associated with the hypothalamic-pituitary-adrenal (HPA) axis, which controls stress responses. The single-nucleotide polymorphism of ADCYAP1R1, rs2267735, has been investigated in many studies to test its association with posttraumatic stress disorder (PTSD), but the results have not been consistent. It is worth systematically exploring the role of rs2267735 in PTSD development. In this study, we analyzed rs2267735 in 1,132 trauma-exposed Chinese individuals (772 females and 360 males). We utilized the PTSD checklist for DSM-5 (PCL-5) to measure the PTSD symptoms. Then, we analyzed the main, G × E (rs2267735 × trauma exposure), and G × G (with other HPA axis gene polymorphisms) effects of rs2267735 on PTSD severity (total symptoms). There were no significant main or G × E effects (P > 0.05). The G × G ADCYAP1R1-FKBP5 interaction (rs2267735 × rs1360780) was associated with PTSD severity (beta = -1.31 and P = 0.049) based on all subjects, and the G × G ADCYAP1R1-CRHR1 interaction (rs2267735 × rs242924) was correlated with PTSD severity in men (beta = -4.72 and P = 0.023). Our study indicated that the ADCYAP1R1 polymorphism rs2267735 may affect PTSD development through diverse gene-gene interactions.