Activation of NOTCH signaling impedes cell proliferation and survival in acute megakaryoblastic leukemia.

The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for genetic alterations in AMKL, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines, and detected frequent genetic mutations in NOTCH pathway, besides previously reported alternations in GATA-1 and JAK-STAT pathway. Pharmacological and genetic NOTCH activation, but not inhibition, significantly suppressed AMKL cell proliferation in both in vitro and in vivo assays employing a patient derived xenograft model. These results suggest that NOTCH inactivation underlies AMKL leukemogenesis and NOTCH activation holds a potential of therapeutic application for AMKL.

A Disturbance Compensation Control Strategy for Rotational Speed Standard Device Based on AMB System.

The rotational speed standard device that can carry loads is the key device for calibrating passive rotational speed sensors. The rotor of the passive rotational speed sensor is connected to the rotor of the standard speed device through a coupling, and the standard reference speed is provided by the standard device. Due to the rotor eccentricity, the unbalanced force of the rotor occurs, and it can not only affect the rotational speed accuracy but can also damage the mechanical bearings of the standard speed device. To solve this issue, a method for suppressing the unbalanced force of the speed standard device based on an active magnetic bearing (AMB) force compensation system is proposed. First, the overall structure of the system is briefly introduced. Then, the force feedback control system model with the AMB as the force actuator is established, and a PI controller is designed to achieve the disturbed force control. Finally, a semi-physical simulation experimental platform is built to verify the effectiveness of the proposed method. The experimental results show that the AMB force compensation system can reduce 84.4%, 81.6%, and 79.8% of the unbalanced vibration force at the frequency of 30 Hz, 90 Hz, and 150 Hz, respectively.

Mediating effect of the NLR on the relationship between HbA1c and left atrial stiffness in overweight patients with hypertension.

BACKGROUND: We aimed to investigate the association between hemoglobin A1c (HbA1c) and left atrial (LA) stiffness in patients with hypertension and to explore the mediating effect of the neutrophil/lymphocyte ratio (NLR) on this association. METHODS: Essential hypertensive patients (n=292) aged 18 to 83 years were enrolled and divided into two groups based on the LA stiffness index (LASI): Group I (LASI≤0.32, n=146) and Group II (LASI>0.32, n=146). The LASI was defined as the ratio of early diastolic transmitral flow velocity/lateral mitral annulus myocardial velocity (E/e') to LA reservoir strain. Multivariate linear regression analysis was performed to determine the independent predictors of the LASI. RESULTS: Age, BMI, SBP, HbA1c, CRP and the NLR were significantly greater in Group II than in Group I (P<0.05). Additionally, Group II had a greater LA volume index (LAVI), left ventricular mass index (LVMI), and E/e' and lower LA reservoir, conduit and booster pump strains than Group I (P<0.001). Univariate and multivariate linear regression models revealed that age, SBP, HbA1c, and the NLR were independently associated with the LASI. Further mediation analysis was performed to determine the mediating effect of the NLR on the association between HbA1c and the LASI and revealed that the NLR had a mediating role only in overweight hypertensive patients, and the proportion of the mediating effect was 21.9%. CONCLUSIONS: The NLR was independently correlated with the LASI and played a mediating role in the relationship between HbA1c and the LASI in overweight hypertensive patients.

[Effect of early pulmonary rehabilitation training on the prognosis of patients with acute respiratory distress syndrome after weaning of invasive mechanical ventilation in the intensive care unit].

OBJECTIVE: To investigate the effect of early pulmonary rehabilitation (PR) training on the improvement of respiratory function in patients with acute respiratory distress syndrome (ARDS) after weaning of invasive mechanical ventilation in the intensive care unit (ICU). METHODS: The retrospective cohort research method was used. The clinical information of adult patients with ARDS receiving invasive mechanical ventilation admitted to the ICU of Qingdao Municipal Hospital from January 2019 to March 2023 was collected. The patients were divided into a control group and an observation group according to off-line training program. The control group received traditional training after weaning, and the observation group received the early PR training after weaning. Other treatments and nursing were implemented according to the routine of the ICU. The scores of the short physical performance battery (SPPB) on day 3-day 6 of the weaning training, respiratory muscle strength, level of interleukin-6 (IL-6), number of aspirations of sputum after weaning, length of stay after weaning, rehospitalization rate within 6 months after discharge, and pulmonary function indicators at discharge and 3 months after discharge [peak expiratory flow (PEF), forced expiratory volume in one second/forced vital capacity ratio (FEV1/FVC), and vital capacity (VC)] of the two groups of patients were compared. The Kaplan-Meier survival curve was drawn to analyze the cumulative survival rate of patients 6 months after discharge. RESULTS: A total of 50 of which 25 cases received the traditional training after weaning, 25 cases received the early PR training after weaning. There was no significant difference in gender, age, acute physiology and chronic health evaluation II (APACHE II), oxygenation index upon admission, etiological diagnosis of ARDS upon admission, time of invasive ventilation, mode of invasive mechanical ventilation, pulmonary function indicators at discharge, and other baseline data of the two groups. The SPPB questionnaire scores and respiratory muscle strength in both groups were increased gradually with the extended offline training time, the serum level of IL-6 in both groups were descend gradually with the extended offline training time, especially in the observation group [SPPB questionnaire score in the observation group were 7.81±0.33, 8.72±0.53, 9.44±0.31, 10.57±0.50, while in the control group were 7.74±0.68, 8.73±0.37, 8.72±0.40, 9.33±0.26, effect of time: F = 192.532, P = 0.000, effect of intervention: F = 88.561, P = 0.000, interaction effect between intervention and time: F = 24.724, P = 0.000; respiratory muscle strength (mmHg, 1 mmHg≈0.133 kPa) in the observation group were 123.20±24.84, 137.00±26.47, 149.00±24.70, 155.40±29.37, while in the control group were 129.00±20.34, 126.00±24.01, 132.20±25.15, 138.60±36.67, effect of time: F = 5.926, P = 0.001, effect of intervention: F = 5.248, P = 0.031, interaction effect between intervention and time: F = 3.033, P = 0.043; serum level of IL-6 in the observation group were 80.05±6.81, 74.76±9.33, 63.66±10.19, 56.95±4.72, while in the control group were 80.18±7.21, 77.23±9.78, 71.79±10.40, 66.51±6.49, effect of time: F = 53.485, P = 0.000, effect of intervention: F = 22.942, P = 0.000, interaction effect between intervention and time: F = 3.266, P = 0.026]. Compared with the control group, the number of aspirations of sputum after weaning of patients in the observation group significantly decreased (number: 22.46±1.76 vs. 27.31±0.90), the length of ICU stay after weaning significantly became shorter (days: 6.93±0.95 vs. 8.52±2.21), and the rehospitalization rate within 6 months after discharge significantly decreased [20.00% (5/25) vs. 48.00% (12/25)]. There were significant differences. The pulmonary function indicators 3 months after discharge of two groups of patients significantly increased compared with those at discharge and those of the observation group were significantly higher than those of the control group [PEF (L/min): 430.20±95.18 vs. 370.00±108.44, FEV1/FVC ratio: 0.88±0.04 vs. 0.82±0.05, VC (L): 3.22±0.72 vs. 2.74±0.37, all P < 0.05]. The Kaplan-Meier survival curve showed that the cumulative survival rate of patients 6 months after discharge of patients in the observation group was significantly higher than that of patients in the control group [76.9% vs. 45.5%, hazard ratio (HR) = 0.344, P = 0.017]. CONCLUSIONS: Early PR training can significantly improve the respiratory function of patients with ARDS after weaning of invasive mechanical ventilation. Continuous active respiratory training after discharge can improve the respiratory function of patients and effectively decrease mortality.

A Pre-Leukemic DNA Methylation Signature in Healthy Individuals at Higher Risk for Developing Myeloid Malignancy.

PURPOSE: DNA methylation alterations are widespread in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), some of which appear to have evolved independently of somatic mutations in epigenetic regulators. Although the presence of somatic mutations in peripheral blood can predict the risk of development of AML and MDS, its accuracy remains unsatisfactory. EXPERIMENTAL DESIGN: We performed global DNA methylation profiling in a case control study nested within the Singapore Chinese Health Study to evaluate whether DNA methylation alterations were associated with AML/MDS development. Targeted deep sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-seq) were performed on peripheral blood collected a median of 9.9 years before diagnosis of AML or MDS, together with age-matched still-healthy individuals as controls. RESULTS: Sixty-six individuals who developed AML or MDS displayed significant DNA methylation changes in the peripheral blood compared with 167 age- and gender-matched controls who did not develop AML/MDS during the follow-up period. Alterations in methylation in the differentially methylation regions were associated with increased odds of developing AML/MDS. CONCLUSIONS: The epigenetic changes may be acquired independently and before somatic mutations that are relevant for AML/MDS development. The association between methylation changes and the risk of pre-AML/MDS in these individuals was considerably stronger than somatic mutations, suggesting that methylation changes could be used as biomarkers for pre-AML/MDS screening.

Direct C-H Sulfuration: Synthesis of Disulfides, Dithiocarbamates, Xanthates, Thiocarbamates and Thiocarbonates.

In light of the important biological activities and widespread applications of organic disulfides, dithiocarbamates, xanthates, thiocarbamates and thiocarbonates, the continual persuit of efficient methods for their synthesis remains crucial. Traditionally, the preparation of such compounds heavily relied on intricate multi-step syntheses and the use of highly prefunctionalized starting materials. Over the past two decades, the direct sulfuration of C-H bonds has evolved into a straightforward, atom- and step-economical method for the preparation of organosulfur compounds. This review aims to provide an up-to-date discussion on direct C-H disulfuration, dithiocarbamation, xanthylation, thiocarbamation and thiocarbonation, with a special focus on describing scopes and mechanistic aspects. Moreover, the synthetic limitations and applications of some of these methodologies, along with the key unsolved challenges to be addressed in the future are also discussed. The majority of examples covered in this review are accomplished via metal-free, photochemical or electrochemical approaches, which are in alignment with the overraching objectives of green and sustainable chemistry. This comprehensive review aims to consolidate recent advancements, providing valuable insights into the dynamic landscape of efficient and sustainable synthetic strategies for these crucial classes of organosulfur compounds.

Recent advances in selective mono-/dichalcogenation and exclusive dichalcogenation of C(sp2)-H and C(sp3)-H bonds.

Organochalcogen compounds are prevalent in numerous natural products, pharmaceuticals, agrochemicals, polymers, biological molecules and synthetic intermediates. Direct chalcogenation of C-H bonds has evolved as a step- and atom-economical method for the synthesis of chalcogen-bearing compounds. Nevertheless, direct C-H chalcogenation severely lags behind C-C, C-N and C-O bond formations. Moreover, compared with the C-H monochalcogenation, reports of selective mono-/dichalcogenation and exclusive dichalcogenation of C-H bonds are relatively scarce. The past decade has witnessed significant advancements in selective mono-/dichalcogenation and exclusive dichalcogenation of various C(sp2)-H and C(sp3)-H bonds via transition-metal-catalyzed/mediated, photocatalytic, electrochemical or metal-free approaches. In light of the significance of both mono- and dichalcogen-containing compounds in various fields of chemical science and the critical issue of chemoselectivity in organic synthesis, the present review systematically summarizes the advances in these research fields, with a special focus on elucidating scopes and mechanistic aspects. Moreover, the synthetic limitations, applications of some of these processes, the current challenges and our own perspectives on these highly active research fields are also discussed. Based on the substrate types and C-H bonds being chalcogenated, the present review is organized into four sections: (1) transition-metal-catalyzed/mediated chelation-assisted selective C-H mono-/dichalcogenation or exclusive dichalcogenation of (hetero)arenes; (2) directing group-free selective C-H mono-/dichalcogenation or exclusive dichalcogenation of electron-rich (hetero)arenes; (3) C(sp3)-H dichalcogenation; (4) dichalcogenation of both C(sp2)-H and C(sp3)-H bonds. We believe the present review will serve as an invaluable resource for future innovations and drug discovery.

Association between Type 1 Diabetes Mellitus and Parkinson's Disease: A Mendelian Randomization Study.

While much evidence suggests that type 2 diabetes mellitus increases the risk of Parkinson's disease (PD), the relationship between type 1 diabetes mellitus (T1DM) and PD is unclear. To study their association, we performed a two-sample Mendelian randomization (MR) using the following statistical methods: inverse variance weighting (IVW), MR-Egger, weight median, and weighted mode. Independent datasets with no sample overlap were retrieved from the IEU GWAS platform. All the MR methods found a lower risk of PD in T1DM (IVW-OR 0.93, 95% CI 0.91-0.96, p = 3.12 × 10-5; MR-Egger-OR 0.93, 95% CI 0.88-0.98, p = 1.45 × 10-2; weighted median-OR 0.93, 95% CI 0.89-0.98, p = 2.76 × 10-3; and weighted mode-OR 0.94, 95% CI 0.9-0.98, p = 1.58 × 10-2). The findings were then replicated with another independent GWAS dataset on T1DM (IVW-OR 0.97, 95% CI 0.95-0.99, p = 3.10 × 10-3; MR-Egger-OR 0.96, 95% CI 0.93-0.99, p = 1.08 × 10-2; weighted median-OR 0.97, 95% CI 0.94-0.99, p = 1.88 × 10-2; weighted mode-OR 0.97, 95% CI 0.94-0.99, p = 1.43 × 10-2). Thus, our study provides evidence that T1DM may have a protective effect on PD risk, though further studies are needed to clarify the underlying mechanisms.

How loan descriptions affect the likelihood that borrowers obtain loans in P2P networks? -An empirical analysis based on the "Renrendai" platform.

Information asymmetry is widespread in the P2P online lending market, creating an imbalance in the position of lenders and borrowers. This paper aims to expand the process of information exchange between lenders and borrowers by analyzing the link between soft information such as borrowers' loan descriptions and lending outcomes. Based on the transaction data of the 'Renrendai' platform, this paper analyzed the linguistic features and extracted the content of loan descriptions using a latent Dirichlet allocation (LDA) theme model. To further explore the value of loan descriptions in predicting lending success, this paper conducts a prediction study based on a support vector machine model. It is found that: lenders focus on effective information in the loan descriptions, the linguistic complexity affects the transaction, with simple and direct statements being more favorable; the content for building a good personal image of the borrower will significantly contribute to the lending success. In the prediction study section, it is demonstrated that loan descriptions' language feature indicators can improve prediction accuracy. This paper uncovers the importance of loan descriptions in online lending transactions, which has implications in assisting lenders' investment judgments, as well as in platform information system improvements.

SYVN1 Promotes STAT3 Protein Ubiquitination and Exerts Antiangiogenesis Effects in Retinopathy of Prematurity Development.

Purpose: SYVN1, a gene involved in endoplasmic reticulum-associated degradation, has been found to exert a protective effect by inhibiting inflammation in retinopathy. This study aimed to clarify whether SYVN1 is involved in the pathogenesis of retinopathy of prematurity (ROP) and its potential as a candidate for target therapy. Methods: Human retinal microvascular endothelial cells (hRMECs) and a mouse model of oxygen-induced retinopathy (OIR) were used to reveal the retinopathy development-associated protein expression and molecular mechanism. An adenovirus overexpressing SYVN1 or vehicle control was injected intravitreally at postnatal day 12 (P12), and the neovascular lesions were evaluated in retinal flatmounts with immunofluorescence staining, and hematoxylin and eosin staining at P17. Visual function was assessed by using electroretinogram (ERG). Results: Endogenous SYVN1 expression dramatically decreased in hRMECs under hypoxia and in ROP mouse retinas. SYVN1 regulated the signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor (VEGF) axis. SYVN1 overexpression promoted ubiquitination and degradation of STAT3, decreased the levels of phospho-STAT3, secretion of VEGF, and formation of neovascularization in hRMECs, which could be rescued by STAT3 activator treatment. In addition, SYVN1 overexpression prevented neovascularization and extended physiologic retinal vascular development in the retinal tissues of OIR mice without affecting retinal function. Conclusions: SYVN1 has a protective effect against OIR, and the molecular mechanisms are partly through SYVN1-mediated ubiquitination of STAT3 and the subsequent downregulation of VEGF. These findings strongly support our assumption that SYVN1 confers ROP resistance and may be a potentially novel pharmaceutical target against proliferative retinopathy.

IL-38 suppresses macrophage M1 polarization to ameliorate synovial inflammation in the TMJ via GLUT-1 inhibition.

OBJECTIVES: Interleukin (IL)-38 was discovered as an anti-inflammatory factor. However, IL-38's role in M1 macrophage polarization in the temporomandibular joint (TMJ) and the related mechanism are still unclear. We aimed to explore the effect and the mechanism of IL-38 on synovial inflammation in the TMJ in this study. METHODS: The expression of IL-38 in the TMJ synovium and macrophages was determined using immunohistochemistry (IHC) and Western blotting (WB). M1 macrophage polarization was induced by LPS, the macrophages were pre-treated with IL-38, and the levels of inflammatory markers associated with M1 macrophages were measured. To assess the mechanism of IL-38, small-interfering RNA (siRNA)-GLUT-1 and STF31 were administered to macrophages, and the affected pathways were identified by WB. The effect of macrophage-conditioned medium (CM) on chondrocyte function was also determined. Finally, a mouse model of CFA-induced TMJ inflammation was established. Histological staining and IHC were used to determine the effect of IL-38. RESULTS: IL-38 was detected at high levels in macrophages after lipopolysaccharide (LPS)challenge, and IL-38 downregulated M1 macrophage-related proinflammatory markers (iNOS, IL-6, TNF-α, and COX-2) in vitro. IL-38 suppressed M1 polarization by inhibiting GLUT-1 expression, NF-κB signaling, and MAPK signaling. Intriguingly, CM from macrophages that were pretreated with IL-38 and STF31 decreased inflammatory protein expression in chondrocytes. In addition, intra-articular injection of recombinant IL-38 ameliorated synovial inflammation in the TMJ by inhibiting M1 macrophage polarization and suppressing cartilage inflammation in vivo. CONCLUSIONS: IL-38 is a novel anti-inflammatory factor that contributes to alleviating TMJ inflammation by inhibiting macrophage M1 polarization, thereby ameliorating chondrocyte inflammation and restoring TMJ homeostasis.

Nicotine exposure disrupts placental development via the Notch signaling pathway.

In brief: Normal gene expression during early embryonic development and in the placenta is crucial for a successful pregnancy. Nicotine can disrupt normal gene expression during development, leading to abnormal embryonic and placental development. Abstract: Nicotine is a common indoor air pollutant that is present in cigarette fumes. Due to its lipophilic nature, nicotine can rapidly transport through membrane barriers and spread throughout the body, which can lead to the development of diseases. However, the impact of nicotine exposure during early embryonic development on subsequent development remains elusive. In this study, we found that nicotine significantly elevated reactive oxygen species, DNA damage and cell apoptosis levels with the decrease of blastocyst formation during early embryonic development. More importantly, nicotine exposure during early embryonic development increased placental weight and disrupted placental structure. In molecular level, we also observed that nicotine exposure could specifically cause the hypermethylation of Phlda2 promoter (a maternally expressed imprinted gene associated with placental development) and reduce the mRNA expression of Phlda2. By RNA sequencing analysis, we demonstrated that nicotine exposure affected the gene expression and excessive activation of the Notch signaling pathway thereby affecting placental development. Blocking the Notch signaling pathway by DAPT treatment could recover abnormal placental weight and structure induced by nicotine exposure. Taken together, this study indicates that nicotine causes the declining quality of early embryos and leads to placental abnormalities related to over-activation of the Notch signaling pathway.

Critical Role Played by Interface Engineering in Weakening Thickness Dependence of Superconducting and Structural Properties of FeSe0.5Te0.5-Coated Conductors.

Increasing the thickness of a superconducting layer and simultaneously reducing the thickness effect in iron-based superconducting coated conductors are particularly essential for improving the critical current Ic. Here, for the first time, we have deposited high-performance FeSe0.5Te0.5 (FST) superconducting films up to 2 µm on LaMnO3-buffered metal tapes by pulsed laser deposition. An interface engineering strategy, alternating growth of a 10 nm-thick nonsuperconducting FST seed layer and a 400 nm-thick FST superconducting layer, was employed to guarantee the crystalline quality of the films with thicknesses of the order of micrometers, resulting in a highly biaxial texture with grain boundary misorientation angle less than the critical value θc ∼ 9°. Moreover, the thickness effect, that the critical current density (Jc) shows a clear dependence on thickness as in cuprates, is reduced by the interface engineering. Also, the maximum Jc was found for a 400 nm-thick film with 1.3 MA/cm2 in self-field at 4.2 K and 0.71 MA/cm2 (H∥ab) and 0.50 MA/cm2 (H∥c) at 9 T. Anisotropic Ginzburg-Landau scaling indicates that the major pinning centers vary from correlated to uncorrelated as the film thickness increases, while the thickness effect is most likely related to the weakening of flux pinning by the fluctuation of charge-carrier mean free path (δl) and strengthening of flux pinning caused by the variation of superconducting transition temperature (δTc) due to off-stoichiometry with thickness.

The important role of surface charge on a new mechanism of nitrogen reduction.

The electrocatalytic nitrogen reduction reaction (NRR) is a green and sustainable approach for producing ammonia. Low-cost carbon-based materials are promising catalysts for the electrochemical NRR. Among them, Cu-N4-graphene is a unique catalytic substrate. Its catalytic performance for the NRR has remained unclear as N2 can only be physisorbed on such a substrate. In this work, we focus on the influence of an electronic environment on the electrocatalytic NRR. DFT computations reveal that the NN bond can be effectively activated at a surface charge density of -1.88 × 1014 e cm-2 on Cu-N4-graphene and further the NRR proceeds via an alternating hydrogenation pathway. This work offers a new insight into the mechanism of the electrocatalytic NRR and emphasizes the importance of environmental charges in the electrocatalytic process of the NRR.

Effect of total glycosides of Cistanche deserticola on the energy metabolism of human HepG2 cells.

To study the anti-tumor effect of Cistanche deserticola Y. Ma, HepG2 cells were treated with 0, 3.5, 10.5, 21, 31.5, and 42 µg/ml of total glycosides (TG) from Cistanche deserticola. The HepG2 cell survival rate and 50% inhibition concentration (IC50) were detected using the CCK-8 method, and the level of reactive oxygen species (ROS) was detected by using a DCFH-DA fluorescence probe. Finally, a Seahorse XFe24 energy analyzer (Agilent, United States) was used to detect cell mitochondrial pressure and glycolytic pressure. The results showed that TG could reduce the survival rate of HepG2 cells and that the IC50 level was 35.28 µg/ml. With increasing TG concentration, the level of ROS showed a concentration-dependent upward trend. Energy metabolism showed that each dose group of TG could significantly decline the mitochondrial respiratory and glycolytic functions of HepG2 cells. In conclusion, TG could significantly inhibit the mitochondrial respiration and glycolysis functions of HepG2 cells, increase the level of ROS, and inhibit cell proliferation. Thus, this experiment pointed out that Cistanche deserticola can be used as a source of anti-cancer foods or drugs in the future. However, further studies on its mechanisms and clinical applications are needed.

Targeting RNA Exonuclease XRN1 Potentiates Efficacy of Cancer Immunotherapy.

Despite the remarkable clinical responses achieved with immune checkpoint blockade therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. Aberrant RNA accumulation can mediate IFN signaling and stimulate an immune response, suggesting that targeting RNA decay machinery might sensitize tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1, as a potential therapeutic target to suppress RNA decay and stimulate antitumor immunity. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy efficacy, while silencing of XRN1 alone did not affect tumor growth in immunodeficient mice. Mechanistically, XRN1 depletion activated IFN signaling and the viral defense pathway; both pathways play determinant roles in regulating immune evasion. Aberrant RNA-sensing signaling proteins (RIG-I/MAVS) mediated the expression of IFN genes, as depletion of each of them blunted the elevation of antiviral/IFN signaling in XRN1-silenced cells. Analysis of pan-cancer CRISPR-screening data indicated that IFN signaling triggered by XRN1 silencing is a common phenomenon, suggesting that the effect of XRN1 silencing may be extended to multiple types of cancers. Overall, XRN1 depletion triggers aberrant RNA-mediated IFN signaling, highlighting the importance of the aberrant RNA-sensing pathway in regulating immune responses. These findings provide the molecular rationale for developing XRN1 inhibitors and exploring their potential clinical application in combination with cancer immunotherapy. SIGNIFICANCE: Targeting XRN1 activates an intracellular innate immune response mediated by RNA-sensing signaling and potentiates cancer immunotherapy efficacy, suggesting inhibition of RNA decay machinery as a novel strategy for cancer treatment.

Optic Nerve Sheath Fenestration for Progressive Visual Loss in Cerebral Venous Sinus Thrombosis: A Long-Term Retrospective Observational Study.

INTRODUCTION: Progressive cerebral venous sinus thrombosis (CVST)-induced visual loss remains problematic, despite decreasing overall mortality owing to early diagnosis and aggressive treatment. Optic nerve sheath fenestration (ONSF) improves or stabilizes visual function in patients with idiopathic intracranial hypertension; however, its role in CVST awaits elucidation. We evaluated the efficacy and safety of ONSF in resolving CVST-induced visual impairment based on long-term observation. METHODS: This observational study included 18 patients with progressive CVST-induced visual loss, who had undergone ONSF between 2012 and 2021. Patients received maximum medical therapy, including anticoagulants and intracranial pressure (ICP)-lowering medications. The best-corrected visual acuity (BCVA), visual fields (VFs), and optic nerve head were assessed at baseline, at 1 week after ONSF, and over 6 months after ONSF. Activities of daily living (ADL) and National Eye Institute Visual Function Questionnaire-25 (VFQ-25) scores were assessed at final follow-up. RESULTS: Thirty-one ONSF-treated eyes of 18 patients were included. The mean follow-up duration was 35.6 months (range 1 week-8 years). Two patients were lost to follow-up. Before ONSF, all patients were still experiencing progressive visual loss despite receiving adequate anticoagulation and ICP-lowering therapy. Postoperative BCVA remained stable or improved in 25/31 eyes (80.6%) 1 week postoperatively and 17/28 eyes (60.7%) upon final follow-up. All papilledema resolved postoperatively. No complications were reported except for one transient postoperative diplopia. The median ADL score was 100 (range 25-100), and the mean total VFQ-25 score was 40.6 (range 9.5-87.3). CONCLUSION: This was the largest study to describe ONSF's role in CVST based on a long-term follow-up. Considering its efficacy and favorable safety, ONSF can be considered an important adjunctive approach to resolving progressive visual loss of CVST patients, on the basis of anticoagulation and ICP-lowering therapy.

Cerebral venous sinus thrombosis (CVST) is a cerebrovascular disease that generally affects young patients. Medical treatments include anticoagulants, intracranial pressure (ICP)-lowering medications, and repeated lumbar punctures, effectively reducing CVST's mortality rate. However, CVST still carries a potential risk of progressive vision loss. Optic nerve sheath fenestration (ONSF) has been reported to be effective and safe in protecting visual function of patients with idiopathic intracranial hypertension. However, its efficacy and safety have not been evaluated in visual loss caused by CVST. We were the first to evaluate the efficacy and safety of ONSF in CVST-induced progressive visual loss based on long-term follow-ups. Before ONSF, all patients were still experiencing progressive visual loss despite receiving adequate anticoagulation and ICP-lowering therapy. We found ONSF to be 80.6% (1 week postoperatively) and 60.7% (after long-term follow-up of over 6 months) effective in stabilizing and/or improving visual function as well as 100% effective in papilledema resolution. Moreover, ONSF exhibited a favorable safety profile, with an extremely low complication rate of 5.6% despite under perioperative anticoagulation. Although visual impairment in CVST was reported to be uncommon, it often significantly affects quality of life and social value of patients. Thus, visual loss in CVST deserves more attention from neurologists, neurosurgeons, and ophthalmologists. Considering its efficacy and favorable safety, ONSF could be regarded a potentially important adjunctive approach to resolving progressive visual loss in CVST patients, on the basis of anticoagulation and ICP-lowering therapy.Procedural videos available for this article.

Resource Utilization of Bovine Neck Ligament: Enzymatic Preparation of Elastin Peptide and Its Antioxidant Activity.

Elastin is considered an excellent resource for obtaining antioxidant peptides due to unique amino acid composition. However, it is hardly soluble in water or in dilute acid or alkali; most of the elastases have low yields for preparing elastin peptides, making it difficult to meet industrial applications. To address above problems, enzymes capable of hydrolyzing elastin into soluble peptides were preferred from typical commercial protease preparations. The optimal enzymatic hydrolysis process conditions for elastin peptides were obtained by response surface optimization design. The molecular weight, amino acid composition, and antioxidant activity of the enzymatic hydrolysis products were determined. The results show that the alkaline protease NUE has a strong hydrolysis effect. The optimized enzymatic hydrolysis conditions are as follows: substrate concentration is 5%, enzyme concentration is 650 U/mL, pH is 10.0, temperature is 60 °C, time is 6 h. The degree of hydrolysis of elastic protein peptides obtained through this method is 14.42%. The distribution of molecular weight is 200-6500 Da, more than 85% of the component molecular amount is greater than 800 Da; the amino acid content related to antioxidant activity has reached 68 mg/100 mg, so it has extremely high free radical clearance. Compared with acid and alkali methods, the anti-oxidation capacity of enzyme-based peptide is better, the reaction conditions are milder, the yield is higher, and by-products and pollutants are fewer. It provides an effective way to industrialized production of elastin peptides with high antioxidant activity and a basis for its widespread application in the food and pharmaceutical industries.

m6 A demethylase Fto regulates the TNF-α-induced inflammatory response in cementoblasts.

OBJECTIVE: Apical periodontitis is the most frequently occurring pathological lesion. Fat mass and obesity-associated protein (Fto) is the first identified RNA N6-methyladenosine demethylase. However, whether Fto regulates apical periodontitis remains unclear. This study aimed to explore the mechanisms of Fto in the tumor necrosis factor-α (TNF-α)-induced inflammatory response. MATERIALS AND METHODS: We established an apical periodontitis model. An immortalized cementoblast cell line (OCCM-30) cells were exposed to TNF-α. Fto, Il6, Mcp1, and Mmp9 expressions were assessed by qRT-PCR. We knocked down Fto using lentiviruses and detected TNF-α-induced inflammation-related gene expressions and mRNA stability. RESULTS: Mice with apical periodontitis showed downregulation of Fto expression. OCCM-30 cells exposed to TNF-α showed an upregulation of inflammation-related genes with a decrease in Fto. Furthermore, knockdown of Fto promoted the expressions of Il6, Mcp1, and Mmp9 in TNF-α-treated OCCM-30 cells as compared with negative control cells, whereas it did not affect the mRNA stability. Interestingly, Fto knockdown activated the p65, p38, and ERK1/2 pathways, and it slightly activated the JNK signaling pathway after TNF-α administration in OCCM-30 cells. CONCLUSION: A TNF-α-induced decrease in the expression of Fto might play a critical role in the inflammatory response in cementoblasts, and knockdown of Fto might upregulate the inflammatory response.