Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.

Role of a novel circRNA-CGNL1 in regulating pancreatic cancer progression via NUDT4-HDAC4-RUNX2-GAMT-mediated apoptosis.

BACKGROUND: Pancreatic cancer (PC) is an extremely malignant tumor with low survival rate. Effective biomarkers and therapeutic targets for PC are lacking. The roles of circular RNAs (circRNAs) in cancers have been explored in various studies, however more work is needed to understand the functional roles of specific circRNAs. In this study, we explore the specific role and mechanism of circ_0035435 (termed circCGNL1) in PC. METHODS: qRT-PCR analysis was performed to detect circCGNL1 expression, indicating circCGNL1 had low expression in PC cells and tissues. The function of circCGNL1 in PC progression was examined both in vitro and in vivo. circCGNL1-interacting proteins were identified by performing RNA pulldown, co-immunoprecipitation, GST-pulldown, and dual-luciferase reporter assays. RESULTS: Overexpressing circCGNL1 inhibited PC proliferation via promoting apoptosis. CircCGNL1 interacted with phosphatase nudix hydrolase 4 (NUDT4) to promote histone deacetylase 4 (HDAC4) dephosphorylation and subsequent HDAC4 nuclear translocation. Intranuclear HDAC4 mediated RUNX Family Transcription Factor 2 (RUNX2) deacetylation and thereby accelerating RUNX2 degradation. The transcription factor, RUNX2, inhibited guanidinoacetate N-methyltransferase (GAMT) expression. GAMT was further verified to induce PC cell apoptosis via AMPK-AKT-Bad signaling pathway. CONCLUSIONS: We discovered that circCGNL1 can interact with NUDT4 to enhance NUDT4-dependent HDAC4 dephosphorylation, subsequently activating HDAC4-RUNX2-GAMT-mediated apoptosis to suppress PC cell growth. These findings suggest new therapeutic targets for PC.

Activation of angiogenin expression in macrophages by lipopolysaccharide via the TLR4/NF-κB pathway in colitis.

Inflammatory bowel disease (IBD) is a debilitating condition that can lead to life-threatening complications. Macrophages are crucial in IBD management because they secrete various cytokines and regulate tissue repair. Macrophage-derived angiogenin (ANG) has been shown to be essential for limiting colonic inflammation, but its upstream regulatory pathway and role in macrophages remain unclear. Here we show that ANG expression is up-regulated in macrophages during colitis treatment or upon lipopolysaccharides (LPS) treatment. Mechanistically, LPS activates Toll-like receptor 4 (TLR4) to initiate NF-κB translocation from the cytoplasm to the nucleus, where it binds to the ANG promoter and enhances its transcriptional activity, leading to increased ANG expression. Interestingly, our data also reveal that the deletion of ANG in macrophages has no adverse effect on key macrophage functions, such as phagocytosis, chemotaxis, and cell survival. Our findings establish a "LPS-TLR4-NF-κB-ANG" regulatory axis in inflammatory disorders and confirm that ANG controls inflammation in a paracrine manner, highlighting the importance of ANG as a key mediator in the complex network of inflammatory processes.

Defect Detection Algorithm for Wing Skin with Stiffener Based on Phased-Array Ultrasonic Imaging.

In response to the real-time imaging detection requirements of structural defects in the R region of rib-stiffened wing skin, a defect detection algorithm based on phased-array ultrasonic imaging for wing skin with stiffener is proposed. We select the full-matrix-full-focusing algorithm with the best imaging quality as the prototype for the required detection algorithm. To address the problem of poor real-time performance of the algorithm, a sparsity-based full-focusing algorithm with symmetry redundancy imaging mode is proposed. To address noise artifacts, an adaptive beamforming method and an equal-acoustic-path echo dynamic removal scheme are proposed to adaptively suppress noise artifacts. Finally, within 0.5 s of imaging time, the algorithm achieves a detection sensitivity of 1 mm and a resolution of 0.5 mm within a single-frame imaging range of 30 mm × 30 mm. The defect detection algorithm proposed in this paper combines phased-array ultrasonic technology and post-processing imaging technology to improve the real-time performance and noise artifact suppression of ultrasound imaging algorithms based on engineering applications. Compared with traditional single-element ultrasonic detection technology, phased-array detection technology based on post-processing algorithms has better defect detection and imaging characterization performance and is suitable for R-region structural detection scenarios.

Research on Photoacoustic Synthetic Aperture Focusing Technology Imaging Method of Internal Defects in Cylindrical Components.

Cylindrical components are parts with curved surfaces, and their high-precision defect testing is of great significance to industrial production. This paper proposes a noncontact internal defect imaging method for cylindrical components, and an automatic photoacoustic testing platform is built. A synthetic aperture focusing technology in the polar coordinate system based on laser ultrasonic (LU-pSAFT) is established, and the relationship between the imaging quality and position of discrete points is analyzed. In order to verify the validity of this method, small holes of Φ0.5 mm in the aluminum alloy rod are tested. During the imaging process, since a variety of waveforms can be excited by the pulsed laser synchronously, the masked longitudinal waves reflected by small holes need to be filtered and windowed to achieve high-quality imaging. In addition, the influence of ultrasonic beam angle and signal array spacing on imaging quality is analyzed. The results show that the method can accurately present the outline of the small hole, the circumferential resolution of the small hole is less than 1° and the dimensional accuracy and position error are less than 0.1 mm.

OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.

Myddosome is an oligomeric complex required for the transmission of inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for the self-assemble of Myddosome proteins and regulation of intracellular signaling remains poorly understood. Here, we identify OTUD5 acts as an essential regulator for MyD88 oligomerization and Myddosome formation. OTUD5 directly interacts with MyD88 and cleaves its K11-linked polyubiquitin chains at Lys95, Lys231 and Lys250. This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-κB and MAPK signaling and production of inflammatory cytokines. Consistently, Otud5-deficient mice are less susceptible to LPS- and CLP-induced sepsis. Taken together, our findings reveal a positive regulatory role of OTUD5 in MyD88 oligomerization and Myddosome formation, which provides new sights into the treatment of inflammatory diseases.

An accurate and ultrasensitive ratiometric electrochemical aptasensor for determination of Ochratoxin A based on catalytic hairpin assembly.

Ochratoxin A (OTA) pollution in agricultural products has raised the pressing to develop sensitive, accurate and convenient detection methods. Herein, an accurate and ultrasensitive ratiometric electrochemical aptasensor was proposed based on catalytic hairpin assembly (CHA) for OTA detection. In this strategy, the target recognition and CHA reaction were both accomplished in the same system, which avoided tedious multi-steps operation and extra reagents, providing the advantage of convenience with only a one-step reaction and without enzyme. The labeled Fc and MB were used as the signal-switching molecules, avoiding various interferences and greatly improving the reproducibility (RSD: 3.197%). This aptasensor achieved trace-level detection for OTA with LOD of 81 fg/mL in the linear range of lower concentration (100 fg/mL-50 ng/mL). Moreover, this strategy was successfully applied to OTA detection in cereals with comparable results of HPLC-MS. This aptasensor provided a viable platform for accurate, ultrasensitive, and one-step detection of OTA in food.

Effects of irrigation on the fate of microplastics in typical agricultural soil and freshwater environments in the upper irrigation area of the Yellow River.

Agricultural activities are among the most significant sources of microplastics (MPs) in water. However, few studies have explored the effect of irrigation on the fate of MPs in agricultural systems. This study investigated the distribution of MPs in agricultural soil, surface water, and sediment of adjacent rivers, as well as the "MP communities" in various environments before and after irrigation in a typical agricultural irrigation area of the Yellow River. MPs were detected in all of the examined sites. The number of MPs in surface water and sediment increased after irrigation, whereas those in the surface soil of croplands decreased. In the vertical direction, irrigation accelerated the migration of MPs (< 100 µm) deep into the soil. The vertical mobility of fibers in soil was faster than that of other types of MPs. Moreover, irrigation decreased the correlation between soil properties and MPs in soils. MP community analysis indicated that irrigation enhanced the differences between MP communities among adjacent environments. Collectively, our findings confirmed that river water irrigation caused secondary MP pollution in the soil environment and accelerated MP pollution in deep soil. Therefore, this study provides a theoretical basis for the development of strategies for MP pollution control in agricultural soil.

Linc-UROD stabilizes ENO1 and PKM to strengthen glycolysis, proliferation and migration of pancreatic cancer cells.

Pancreatic cancer (PC) is a fatal malignancy, threatening human health in worldwide. Long non-coding RNAs (lncRNAs) have been acknowledged to be essential regulators in various biological processes of human cancers. However, the role of some novel lncRNAs in PC remain to be explored. In this study, we focused on the function and molecular mechanism of a novel lncRNA linc-UROD (also named TCONS_00002016 or XLOC_000166) in PC. The expression of linc-UROD was found to be upregulated in PC cells. The results of loss-of-function assays demonstrated that linc-UROD knockdown suppressed cell proliferation and migration, induced cell cycle G0/G1 arrest, and accelerated apoptosis of PC cells. Through mechanistic experiments, we found that IGF2BP3 stabilized linc-UROD through METTL3-mediated m6A modification. In addition, linc-UROD enhances the stability of ENO1 and PKM through interacting with them to inhibit ubiquitination. Detection on glucose consumption, pyruvate kinase activity and lactate production indicated that linc-UROD accelerated glycolysis of PC cells through PKM/ENO1-mediated pathway. To summarize, linc-UROD stabilized by IGF2BP3/METTL3 contributes to glycolysis and malignant phenotype of PC cells by stabilizing ENO1 and PKM. The findings suggest that linc-UROD may be a novel therapeutic target for PC patients.

Adsorption of chitosan combined with nicotinamide-modified eupatorium adenophorum biochar to Sb3+: Application of DFT calculation.

The pollution and harm of Sb3+ to aquatic systems is a global problem, so Sb3+ removal from the water environment to make sure environment safety and human beings wellbeing is of urgency. This study explored the effect of chitosan combined with nicotinamide-modified eupatorium adenophorum biochar (CEBC) on adsorbing Sb3+ through batch adsorption experiments. The experiments indicated CEBC's maximum adsorption capacity to Sb3+ is 170.15 mg·g-1. Meanwhile, the capacity of the original biochar (EBC) is only 9.97 mg·g-1. Compared with EBC, CEBC contains more functional groups, such as CO, -OH and -NH2. In addition, the pseudo-second-order kinetic model and the Langmuir model are fit to describe the kinetics and isotherms of adsorption of CEBC to Sb3+, which suggests that the adsorption of CEBC to Sb3+ is dominated by monolayer chemisorption. Density functional theory (DFT) calculations confirmed that the chelation between -NH2 and Sb3+ is of significance in the adsorption process of CEBC. DFT calculations also found that the newly added -OH and CO in EBC have a synergistic enhancement effect on the absorption of Sb3+. The mechanism of CEBC absorbing Sb3+ includes electrostatic interactions, pore filling, Л-Л interactions, hydrogen bonding, functional group complexation, chelation, and oxidation. CEBC has an excellent anti-interference ability for inorganic anions (NO3-, SO42- and Cl-) and can also use the coexisting HA to improve its adsorption performance. In addition, CEBC has better mitigation of Sb3+ on the performance of Sb3+ about its secondary release and good reproducibility, which indicates that CEBC is a viable Sb3+ adsorbent.

Spatiotemporal variations and impact factors of nutrients in the Sanya Bay, northern South China Sea.

Nutrients play a fundamental role in maintaining coastal ecosystem stability. Based on two cruise observations in the winter of 2020 and the summer of 2021, the spatiotemporal variations of dissolved inorganic nitrogen (DIN) and orthophosphate (PO43-) and their influencing factors in Sanya Bay were analyzed. Results show that the mean DIN concentrations in the bay are 2.36 µmol/L in winter and 1.73 µmol/L in summer, and the mean PO43- concentrations are 0.08 µmol/L in winter and 0.04 µmol/L in summer. The nutrient concentrations and composition are significantly affected by the Sanya River. The surface DIN concentrations at the Sanya River estuary are 15.80 and 5.25 times than those inside the bay in winter and summer, respectively. Meanwhile, a high proportion of NO3- (74%) and a low proportion of NH4+ (20%) in DIN appear near the river estuary, while a low proportion of NO3- (37%) and a high proportion of NH4+ (53%) occur away from the estuary. In addition, the thermocline promotes the accumulation of NH4+ at the bottom layer in summer. The high proportion of NO3- is likely not favorable for the survival of coral reefs in eastern bay. Compared with the previous nutrient concentrations, the DIN concentration in the bay has a decrease after 2014, which might benefit from the implementation of the environmental protection policy by government.

Using Electronic Health Records to understand the population of local children captured in a large health system in Durham County, NC, USA, and implications for population health research.

Although local policies aimed at reducing childhood health inequities can benefit from local data, sample size constraints in population representative health surveys often prevent rigorous evaluations of child health disparities and health care patterns at local levels. Electronic Health Records (EHRs) offer a possible solution as they contain large amounts of information on pediatric patients within a health system. In this paper, we consider the suitability of using EHRs from a large health system to study local children's health by evaluating the extent to which the EHRs capture the county's child population. First, we compare the demographic characteristics of Duke University Health System pediatric patients who live in Durham County, NC (USA) to the child population estimates in the 2015-2019 American Community Survey. We then examine geographic variation in census tract rates of children captured in the EHR data and estimate negative binomial models to assess how tract characteristics are associated with these rates. We also perform these analyses for the subset of pediatric patients who have a well-child encounter. We find that the demographic characteristics of pediatric patients captured by the EHRs are similar to those of the county's child population. Although the county rate of children captured in the EHRs is high, there is variation across census tracts. On average, census tracts with higher concentrations of non-Hispanic Black residents have lower capture rates and tracts with higher concentrations of poverty have higher capture rates, with the poorest tracts showing the largest racial gap in rates of children captured by EHRs. Our findings suggest that EHRs from a large health system can be used to assess children's population health, but that EHR-based evaluations of children's health disparities and health care patterns should account for differences in who is captured by the EHRs based on census tract characteristics.

Univ-flu: A structure-based model of influenza A virus hemagglutinin for universal antigenic prediction.

The rapid mutations on hemagglutinin (HA) of influenza A virus (IAV) can lead to significant antigenic variance and consequent immune mismatch of vaccine strains. Thus, rapid antigenicity evaluation is highly desired. The subtype-specific antigenicity models have been widely used for common subtypes such as H1 and H3. However, the continuous emerging of new IAV subtypes requires the construction of universal antigenic prediction model which could be applied on multiple IAV subtypes, including the emerging or re-emerging ones. In this study, we presented Univ-Flu, series structure-based universal models for HA antigenicity prediction. Initially, the universal antigenic regions were derived on multiple subtypes. Then, a radial shell structure combined with amino acid indexes were introduced to generate the new three-dimensional structure based descriptors, which could characterize the comprehensive physical-chemical property changes between two HA variants within or across different subtypes. Further, by combining with Random Forest classifier and different training datasets, Univ-Flu could achieve high prediction performances on intra-subtype (average AUC of 0.939), inter-subtype (average AUC of 0.771), and universal-subtype (AUC of 0.978) prediction, through independent test. Results illustrated that the designed descriptor could provide accurate universal antigenic description. Finally, the application on high-throughput antigenic coverage prediction for circulating strains showed that the Univ-Flu could screen out virus strains with high cross-protective spectrum, which could provide in-silico reference for vaccine recommendation.

USP5 attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3.

ABBREVIATIONS: 3-MA: 3-methyladenine; AIM2: absent in melanoma 2; ATG5: autophagy related 5; BafA1: bafilomycin A1; CASP1: caspase 1; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; DUBs: deubiquitinases; IL1B/IL-1ß: interleukin 1 beta; LAMP1: lysosomal associated membrane protein 1; LPS: lipopolysaccharide; MARCHF7/MARCH7: membrane associated RING-CH-type finger 7; NFKB/NF-κB: nuclear factor kappa B; Nig.: nigericin; NLRC4: NLR family CARD domain containing 4; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PMN: polymorphonuclear; PMs: peritoneal macrophages; PYCARD/ASC: PYD and CARD domain containing; TLRs: toll like receptors; TNF/TNF-α: tumor necrosis factor; Ub: ubiquitin; USP5: ubiquitin specific peptidase 5; WT: wild type.

Self-driven microstructural evolution of Au@Pd core-shell nanoparticles for greatly enhanced catalytic performance during methanol electrooxidation.

The lack of direct insight into the microstructural evolution of catalytic materials under electrochemical polarization has inhibited the development of heterogeneous catalysts. By investigating a typical Au@Pd core-shell nanostructure, the present study discloses the microstructural evolution of heterogeneous catalytic materials during the methanol electrooxidation reaction (MOR). The electrocatalytic activity of the as-prepared Au@Pd_core-shell nanoparticles continuously increased during the first 100 successive voltammetry cycles of the MOR. Microstructural characterization studies revealed that during the MOR, an Au/Pd mixed bimetallic shell was formed by the self-driven microstructural evolution of the Au@Pd_core-shell nanoparticles. Both the experimental and calculation results indicated that the Au/Pd mixed bimetallic shell reduced the binding strength of OH- and CO on the catalyst surface. The exposed Au atoms in the shell region also produced large-scale reactive ˙OH radicals that facilitated the oxidative removal of the adsorbed carbonaceous species from the adjacent Pd active sites.

Intramolecular vibrational energy redistribution in aromatic molecules of type C6H5X (X = H, D, F, Cl, CH3, CF3).

Femtosecond IR pump UV probe spectroscopy was employed in the gas phase to study intramolecular vibrational energy redistribution (IVR) in benzene and five monosubstituted derivatives thereof. After selective excitation of the first overtone of the ring CH-stretch vibration, all molecules showed the same two-step redistribution dynamics characteristic for nonstatistical IVR. The nature of the substituent influences mainly the second, slower IVR component. The presence of an internal rotor does not alter the redistribution rate or pathway compared to that of a monatomic substituent of equal mass. Coupling order model calculations reflect the experimental trends well if the polyatomic substituents are regarded as decoupled from the intra-ring dynamics and modeled as point masses.

Dynamical consequences of symmetry breaking in benzene and difluorobenzene.

The systems benzene/benzene-d(1) and o-/m-/p-difluorobenzene were studied in the dense gas phase with ultrafast transient absorption spectroscopy to investigate the effect of symmetry reduction through monodeuteration and constitutional isomerism on the timescales of intramolecular vibrational energy redistribution (IVR). In both systems IVR proceeds faster in the molecules of lower symmetry. In addition the dynamics were simulated in vibrational quantum number space using a simple model based on scaling state-to-state interactions by coupling order and the energy gap law. These simulations (semi-) quantitatively reproduce the experimental data for benzene and benzene-d(1) without incorporating further molecular symmetry restrictions. The relative impact of molecular symmetry and vibrational state space structure on IVR is discussed.

Development of an electronic health records datamart to support clinical and population health research.

INTRODUCTION: Electronic health record (EHR) data have emerged as an important resource for population health and clinical research. There have been significant efforts to leverage EHR data for research; however, given data security concerns and the complexity of the data, EHR data are frequently difficult to access and use for clinical studies. We describe the development of a Clinical Research Datamart (CRDM) that was developed to provide well-curated and easily accessible EHR data to Duke University investigators. METHODS: The CRDM was designed to (1) contain most of the patient-level data elements needed for research studies; (2) be directly accessible by individuals conducting statistical analyses (including Biostatistics, Epidemiology, and Research Design (BERD) core members); (3) be queried via a code-based system to promote reproducibility and consistency across studies; and (4) utilize a secure protected analytic workspace in which sensitive EHR data can be stored and analyzed. The CRDM utilizes data transformed for the PCORnet data network, and was augmented with additional data tables containing site-specific data elements to provide additional contextual information. RESULTS: We provide descriptions of ideal use cases and discuss dissemination and evaluation methods, including future work to expand the user base and track the use and impact of this data resource. CONCLUSIONS: The CRDM utilizes resources developed as part of the Clinical and Translational Science Awards (CTSAs) program and could be replicated by other institutions with CTSAs.

Plasmonic-enhanced catalytic activity of methanol oxidation on Au-graphene-Cu nanosandwiches.

The plasmonic-enhanced catalytic activity of methanol oxidation on Au-based catalysts provides a promising strategy for direct methanol fuel cells (DMFCs) to avoid the CO poisoning of traditional Pt-based catalysts. However, the effect of surface plasmon resonance on the light-enhanced methanol oxidation activity of Au or Au-based catalysts has not been fully understood. The mechanism by which hot plasmonic carriers participate in the methanol oxidation reaction (MOR) has not been elucidated. Herein, Au nanoparticles (Au NPs) are loaded on a support of single-layer graphene-Cu contacts (SG/Cu) to construct a nanosandwich structure of a Au-graphene-Cu catalytic electrode (Au-n/SG/Cu). The Au-6T/SG/Cu catalytic electrode exhibits an MOR catalytic activity of approximately 288 µA µg-1 under simulated solar light irradiation, which is approximately 1.7 times higher than that without irradiation. The chemisorption capacity of OH- anions is enhanced on the Au-6T/SG/Cu catalytic electrode compared with the pure Au NP surface. The adsorbed OH- anions are oxidised into ˙OH radicals by the trapped positive holes on the Au NP surface. These OH radicals possessed a high oxidation capacity for the direct oxidation of HCOO- intermediates and promoted the complete methanol oxidation on Au NPs, which is beneficial for improving the fuel efficiency of DMFCs.

Bifunctional Electrocatalysts for Oxygen Reduction and Borohydride Oxidation Reactions Using Ag3Sn Nanointermetallic for the Ensemble Effect.

Incorporating an oxophilic metal into a noble metal to produce a cost-effective Ag3Sn nanointermetallic catalyst is an emerging approach to enhance the catalytic activity of monometallic Ag in fuel cells, which is different from previous notions that consider a transition metal to increase the catalytic activity of Pt. The Ag3Sn electrocatalyst is prepared by a facile electrodeposition method and exhibits high catalytic performance for the oxygen reduction reaction (ORR) and borohydride oxidation reaction (BOR). The Ag3Sn electrocatalyst has an ORR specific activity of 0.246 mA cm-2, 1.3 times greater than the value of commercial Pt/C (0.187 mA cm-2) and a long-term stability with an 11 mV decrement in the half-wave potential and 7.01% loss of the diffusion-limiting current density after 2000 cycles, superior to that of Pt/C. Moreover, the Ag3Sn electrocatalyst delivers a surprisingly higher BOR current density of 11.332 mA cm-2 than most bimetallic Ag alloys. The better ORR catalytic activities of Ag-based alloys may arise from the ensemble effect, in which Sn atoms may promote the oxygen adsorption and Ag atoms may contribute to the removal of reaction products.