Hepatitis B virus RNAs co-opt ELAVL1 for stabilization and CRM1-dependent nuclear export.

Hepatitis B virus (HBV) chronically infects 296 million people worldwide, posing a major global health threat. Export of HBV RNAs from the nucleus to the cytoplasm is indispensable for viral protein translation and genome replication, however the mechanisms regulating this critical process remain largely elusive. Here, we identify a key host factor embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) that binds HBV RNAs and controls their nuclear export. Using an unbiased quantitative proteomics screen, we demonstrate direct binding of ELAVL1 to the HBV pregenomic RNA (pgRNA). ELAVL1 knockdown inhibits HBV RNAs posttranscriptional regulation and suppresses viral replication. Further mechanistic studies reveal ELAVL1 recruits the nuclear export receptor CRM1 through ANP32A and ANP32B to transport HBV RNAs to the cytoplasm via specific AU-rich elements, which can be targeted by a compound CMLD-2. Moreover, ELAVL1 protects HBV RNAs from DIS3+RRP6+ RNA exosome mediated nuclear RNA degradation. Notably, we find HBV core protein is dispensable for HBV RNA-CRM1 interaction and nuclear export. Our results unveil ELAVL1 as a crucial host factor that regulates HBV RNAs stability and trafficking. By orchestrating viral RNA nuclear export, ELAVL1 is indispensable for the HBV life cycle. Our study highlights a virus-host interaction that may be exploited as a new therapeutic target against chronic hepatitis B.

Hepatitis B virus hijacks TSG101 to facilitate egress via multiple vesicle bodies.

Hepatitis B virus (HBV) chronically infects 296 million individuals and there is no cure. As an important step of viral life cycle, the mechanisms of HBV egress remain poorly elucidated. With proteomic approach to identify capsid protein (HBc) associated host factors and siRNA screen, we uncovered tumor susceptibility gene 101 (TSG101). Knockdown of TSG101 in HBV-producing cells, HBV-infected cells and HBV transgenic mice suppressed HBV release. Co-immunoprecipitation and site mutagenesis revealed that VFND motif in TSG101 and Lys-96 ubiquitination in HBc were essential for TSG101-HBc interaction. In vitro ubiquitination experiment demonstrated that UbcH6 and NEDD4 were potential E2 ubiquitin-conjugating enzyme and E3 ligase that catalyzed HBc ubiquitination, respectively. PPAY motif in HBc and Cys-867 in NEDD4 were required for HBc ubiquitination, TSG101-HBc interaction and HBV egress. Transmission electron microscopy confirmed that TSG101 or NEDD4 knockdown reduces HBV particles count in multivesicular bodies (MVBs). Our work indicates that TSG101 recognition for NEDD4 ubiquitylated HBc is critical for MVBs mediated HBV egress.

Frank-Kasper phases in charge transfer complexes enable tunable photoelectronic properties.

Understanding how particles pack in space and the mechanisms underlying symmetry selection across soft matter is challenging. The Frank-Kasper (F-K) phase of complex spherical packing is amongst the most fascinating phases; however, it has not been observed in discotic liquid crystals until now. Herein, we report the first observation of F-K phases of charge transfer complexes (CTCs) obtained from triphenylene derivatives as donors and 2,4,7-trinitro-9-fluorenone as the acceptor. The CTCs were characterized using experimental and theoretical calculations, indicating that the F-K A15 cubic lattice possesses a unit cell containing 8 sphere-like supramolecules, each of which was self-assembled from 3 CTC complexes. The lattice constant was only 3.2 nm, which is by far the smallest for the A15 phase. Interestingly, the supramolecular assembly can be regarded as the molecular column splitting into isolated spherical fragments, impeding charge transfer and turning it into one insulator. This provides a simple and effective method for preparing asymmetric complex compounds for the design of unconventional self-assembled nanostructures.

Guest-Responsive Near-Infrared-Luminescent Metal-Organic Cage Organized by Porphyrin Dyes and Yb(III) Complexes.

Metal-organic cages (MOCs) with luminophores have significant advantages for the facile detection of specific molecules based on turn-on or turn-off luminescence changes induced by host-guest complexation. One important challenge is the development of turn-on-type near-infrared (NIR)-luminescent MOCs. In this study, we synthesized a novel MOC consisting of two porphyrin dyes linked by four Yb(III) complexes, which exhibit bimodal red and NIR fluorescence signals upon photoexcitation of the porphyrin π system. Single-crystal X-ray structural analysis and computational molecular modeling revealed that planar aromatic perfluorocarbons were intercalated into the MOC. The tight packing between the MOC and guests enhanced the NIR fluorescence of Yb(III) by suppressing energy transfer from the photoexcited porphyrin to oxygen molecules. Guest-responsive turn-on NIR fluorescence changes in an MOC were successfully demonstrated.

Research on Intelligent Vehicle Trajectory Tracking Control Based on Improved Adaptive MPC.

Intelligent vehicle trajectory tracking exhibits problems such as low adaptability, low tracking accuracy, and poor robustness in complex driving environments with uncertain road conditions. Therefore, an improved method of adaptive model predictive control (AMPC) for trajectory tracking was designed in this study to increase the corresponding tracking accuracy and driving stability of intelligent vehicles under uncertain and complex working conditions. First, based on the unscented Kalman filter, longitudinal speed, yaw speed, and lateral acceleration were considered as the observed variables of the measurement equation to estimate the lateral force of the front and rear tires accurately in real time. Subsequently, an adaptive correction estimation strategy for tire cornering stiffness was designed, an AMPC method was established, and a dynamic prediction time-domain adaptive model was constructed for optimization according to vehicle speed and road adhesion conditions. The improved AMPC method for trajectory tracking was then realized. Finally, the control effectiveness and trajectory tracking accuracy of the proposed AMPC technique were verified via co-simulation using CarSim and MATLAB/Simulink. From the results, a low lateral position error and heading angle error in trajectory tracking were obtained under different vehicle driving conditions and road adhesion conditions, producing high trajectory-tracking control accuracy. Thus, this work provides an important reference for improving the adaptability, robustness, and optimization of intelligent vehicle tracking control systems.

[Effect of Huanglian Jiedu Decoction on TREM2/Akt/GSK3ß pathway in cerebral cortex of APP/PS1 transgenic mice].

The Chinese medical mechanism of Huanglian Jieduo Decoction on treating Alzheimer's disease(AD) characterized by "toxin damaging brain collateral" is still unclear. This study aims to explore the mechanism of Huanglian Jieduo Decoction on regulating triggering receptor expressed on myeloid cells 2(TREM2)/protein kinase B(Akt)/glycogen synthase kinase 3ß(GSK3ß) pathway to improve the cognitive deficit in APP/PS1 transgenic mice. APP/PS1 mice of approximately nine months old were randomly divided into the model group, the low, medium, and high(2.5, 5, and 10 g·kg~(-1)) groups of Huanglian Jiedu Decoction, and 0.75 mg·kg~(-1) donepezil hydrochloride group, and the C57BL/6J mice with the same age were taken as the normal group. After one month of continuous oral administration, a Morris water maze was performed to detect the learning and memory ability of mice. Hematoxylin-eosin(HE) staining was applied to observe the morphology of neuronal cells in the cortical area of mice. Immunofluorescence was used to detect the protein expressions of ß-amyloid(Aß_(1-42)), CD86, and arginase 1(Arg1). The mRNA levels of interleukin(IL)-1ß, IL-6, and IL-10 in the cortex of mice were detected by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR). The protein expressions of TREM2, phosphoinositide-3 kinase(PI3K), Akt, GSK3ß, and beta-catenin(ß-catenin) in mouse cortex were determined by Western blot. The results indicated that the escape latency of the model group was significantly prolonged, and the residence time in the target quadrant and the number of crossing the platform were significantly reduced compared with the normal group. Mice in the model group had a significantly lower number of neurons in the cortex and showed nuclear pyknosis and a significant increase in the expressions of Aß_(1-42) and CD86. The mRNA levels of IL-1ß and IL-6 in tissue were significantly increased, IL-10 were increased, while Arg1 were significantly decreased. The expression of TREM2, p-PI3K(Y607), p-Akt(T308), p-GSK3ß(Ser9), and ß-catenin in the cortex were significantly down-regulated. Compared with the model group, the escape latency of the mice in the administration group was significantly shortened, and the number of crossing the platform and the residence time in the target quadrant were significantly increased. Furthermore, the number of neurons in the cortex of mice was increased, and nuclear pyknosis was improved. Aß_(1-42) deposition was decreased significantly. The mRNA levels of IL-1ß, IL-6 and CD86 were significantly decreased, while IL-10 and Arg1 levels were significantly increased. The expression of TREM2, p-PI3K(Y607), p-Akt(T308), p-GSK3ß(Ser9), and ß-catenin protein in the cortex of each administration group was significantly up-regulated compared with the model group. In conclusion, Huanglian Jiedu Decoction reduced the expression of Aß_(1-42) and neuroinflammation to a neuro-protective effect, thereby improving the learning and memory ability in APP/PS1 mice, which may be related to the TREM2/Akt/GSK3ß signaling pathway.

[Ischemic stroke infarct segmentation model based on depthwise separable convolution for multimodal magnetic resonance imaging].

Magnetic resonance imaging (MRI) plays a crucial role in the diagnosis of ischemic stroke. Accurate segmentation of the infarct is of great significance for selecting intervention treatment methods and evaluating the prognosis of patients. To address the issue of poor segmentation accuracy of existing methods for multiscale stroke lesions, a novel encoder-decoder architecture network based on depthwise separable convolution is proposed. Firstly, this network replaces the convolutional layer modules of the U-Net with redesigned depthwise separable convolution modules. Secondly, an modified Atrous spatial pyramid pooling (MASPP) is introduced to enlarge the receptive field and enhance the extraction of multiscale features. Thirdly, an attention gate (AG) structure is incorporated at the skip connections of the network to further enhance the segmentation accuracy of multiscale targets. Finally, Experimental evaluations are conducted using the ischemic stroke lesion segmentation 2022 challenge (ISLES2022) dataset. The proposed algorithm in this paper achieves Dice similarity coefficient (DSC), Hausdorff distance (HD), sensitivity (SEN), and precision (PRE) scores of 0.816 5, 3.668 1, 0.889 2, and 0.894 6, respectively, outperforming other mainstream segmentation algorithms. The experimental results demonstrate that the method in this paper effectively improves the segmentation of infarct lesions, and is expected to provide a reliable support for clinical diagnosis and treatment.

Chiral Tetrakis Eu(III) Complexes with Ammonium Cations for Improved Circularly Polarized Luminescence.

Large dissymmetry factor of the circularly polarized luminescence (gCPL) was observed in ligand and coordination tuned chiral tetrakis europium (Eu(III)) complexes with ammonium cations. The gCPL value was estimated to be -1.54, which is the largest among chiral luminescent molecules. Through photophysical measurements, single crystal X-ray structural analyses and quantum chemical calculations, changes in the geometric and electronic structures were observed for a series of chiral tetrakis Eu(III) complexes which enhanced the gCPL value. The emission quantum yield and photosensitized energy transfer efficiencies of chiral Eu(III) complexes with ammonium cations were also larger than that with previous Cs+. Based on the systematic modifications and analyses for chiral tetrakis Eu(III) complex, effect of the ammonium cation on enhanced CPL brightness is reported.

[Recent research on the role of oxidative stress in the pathogenesis of attention deficit hyperactivity disorder]. / æ°§åŒ–åº”æ¿€åœ¨æ³¨æ„ç¼ºé™·å¤šåŠ¨éšœç¢å‘ç— æœºåˆ¶ä¸­çš„ç ”ç©¶è¿›å±•.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents, and its etiology and pathogenesis are still unclear. Brain is the organ with the largest oxygen consumption in human body and is easily affected by oxidative imbalance. Oxidative stress has become the key research direction for the pathogenesis of ADHD, but there is still a lack of relevant studies in China. Based on the latest research findings in China and overseas, this article reviews the clinical and experimental studies on oxidative stress in ADHD and explores the association of oxidative stress with neurotransmitter imbalance, neuroinflammation, and cell apoptosis in the pathogenesis of ADHD, so as to provide new research ideas for exploring the pathogenesis of ADHD.

Synergism of Fe/Ti Enabled Regioselective Arene Difunctionalization.

Regioselective difunctionalization of arenes remains a long-standing challenge in organic chemistry. We report a novel and general Fe/Ti synergistic methodology for regioselective synthesis of various polysubstituted arenes through either E/E' or Nu/E ortho difunctionalizations of arenes. Preliminary results showed that an unprecedented 1,2-Fe/Ti heterobimetallic arylene intermediate bearing two distinct C-M bonds is essential to the regioselective difunctionalization.

Impacts of Non-alcoholic Fatty Liver Disease on Acute Coronary Syndrome: Evidence and Controversies.

PURPOSE OF REVIEW: Acute coronary syndrome (ACS) and non-alcoholic fatty liver disease (NAFLD) are two clinically common disease entities that share numerous risk factors. This review aimed to discuss the impacts of NAFLD on ACS. RECENT FINDINGS: In an era of improved control of traditional risk factors, the substantial burden of cardiometabolic abnormalities has caused widespread concern. NAFLD is considered the hepatic component of metabolic syndrome, which can exert an impact on human health beyond the liver. Accumulating studies have demonstrated that NAFLD is closely related to cardiovascular disease, especially coronary artery disease. Interestingly, although recent data have suggested an association between NAFLD and the incidence and outcomes of ACS, the results are not consistent. In this review, we comprehensively summarized evidence and controversies regarding whether NAFLD is a contributor to either the development of ACS or worse outcomes in patients with ACS. The potential pathophysiological and molecular mechanisms involved in the impacts of NAFLD on ACS were also elucidated.

Sandglass-Typed Single Chameleon Luminophore for Water Mapping Measurements: Intramolecular Energy Migrations in the Hydrophilic Tb(III)/Sm(III) Cluster.

Novel hydrophilic and color-changeable single chameleon luminophores composed of Tb(III)/Sm(III) nona-nuclear clusters [TbxSm9-x(Sal-PEG-n)16(µ-OH)10]+(NO3)- (x = 1, 2, 3, and 9; Sal-PEG-n: salicylate polyethylene glycolmethylester, n = 2 and 4) are reported for water mapping measurements. Their characteristic sandglass structures and aggregates were analyzed using X-ray single crystal analysis and dynamic light scattering (DLS) measurements. The green- and yellow-luminescence of [Tb3Sm6(Sal-PEG-4)16(µ-OH)]+(NO3)- in water were observed at 20 and 50 °C, respectively. The ratio-metric luminescence analysis using green Tb(III) and orange Sm(III) emission bands is a promising candidate for exact temperature distribution measurements in fluid dynamics. The effective temperature-sensing property based on the competitive intramolecular energy transfer processes between Tb(III)-to-ligand and Tb(III)-to-Sm(III) in a non-a-nuclear cluster is explained using temperature-dependent kinetic analyses in the excited state.

Artemannuols A-C, novel sesquiterpenoid-flavonol hybrids with antihepatoma activity from Artemisia annua.

Artemisia annua, also known as "Qinghao" in Chinese, is a famous traditional Chinese medicine and has been used for the treatment of malaria and various tumors. In this study, three novel sesquiterpenoid-flavonol hybrids, artemannuols A-C (1-3), were isolated and elucidated by extensive spectral data and ECD calculations. Structurally, artemannuols A-C (1-3) are the first examples of sesquiterpenoid-flavonol hybrids fused by an ether bond, among which artemannuols A and B (1 and 2) are composed of bisabolane-type sesquiterpenoid and flavonol moieties, and artemannuol C (3) is composed of humulane-type sesquiterpenoid and flavonol moieties. The antihepatoma assay suggested that compounds 1-3 showed inhibitory effects against HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values in the range of 32.7 to 70.4 µM.

Defective zirconium/titanium bimetallic metal-organic framework as a highly selective and sensitive electrochemical aptasensor for deoxynivalenol determination in foodstuffs.

An electrochemical aptsensor for deoxynivalenol determination was successfully designed and constructed based on a defective bimetallic organic framework (denoted as ZrTi-MOF). The high porosity, large specific surface area, several structural defects, mixed metal clusters, and rich functionality of ZrTi-MOF markedly enhanced its electrochemical activity and facilitated the aptamer immobilization. As a result, the ZrTi-MOF-based aptasensor shows high sensitivity to detect deoxynivalenol via specific recognition between aptamer and deoxynivalenol, as well as the formation of aptamer-deoxynivalenol complex. On this basis, the developed ZrTi-MOF-based impedimetric aptasensor showed a low detection limit of 0.24 fg mL-1 for deoxynivalenol determination in the deoxynivalenol concentration range 1 fg mL-1- 1 ng mL-1 under optimized conditions, which also exhibited satisfactory selectivity, stability, reproducibility, and regenerability. Furthermore, determination of deoxynivalenol was achieved in bread and wheat flour samples via the developed ZrTi-MOF-based deoxynivalenol aptasensor. The result from this study showed that the ZrTi-MOF-based electrochemical aptasensor could become a promising strategy for detecting deoxynivalenol in foodstuffs in the future.

A Red-Light-Driven CO-Releasing Complex: Photoreactivities and Excited-State Dynamics of Highly Distorted Tricarbonyl Rhenium Phthalocyanines.

A complex comprising one [Re(CO)3 ]+ unit and a phthalocyanine (Pc) ligand (Re1 Pc) is shown to function as a photo-induced CO-releasing molecule (photoCORM) in the presence of O2 and a coordinative solvent under irradiation with red light, which can deeply penetrate living tissues. Transient absorption spectroscopic measurements indicate very short excited-state lifetimes and ultrafast intersystem crossing for Re1 Pc and Re2 Pc, which contains two [Re(CO)3 ]+ units. The excited-state properties are ascribed to efficient spin-orbit coupling and large Franck-Condon factors originating from the complexes' distorted structures, that is, unsymmetric coordination of [Re(CO)3 ]+ unit(s), one of which was confirmed by single-crystal X-ray analysis of a symmetrically substituted Pc with two [Re(CO)3 ]+ units. Re1 Pc represents a promising red-light-driven photoCORM that can be applied in biological environments or therapeutic applications.

Novel Advances in the Study of IgG4-Related Disease in the Eye and Ocular Adnexa.

Immunoglobin G4 (IgG4)-related disease in the eye and ocular adnexa (IgG4-ROD) is a newly discovered autoimmune disease that histologically exhibits extensive lymphocyte and plasma cell infiltration, occlusive phlebitis, and mat or whorled fibrosis. The disease can affect multiple ocular tissues and organs, such as the lacrimal gland, extraocular muscles, orbital fat, and trigeminal nerve. The main clinical manifestations are chronic, painless swelling of the orbit or unilateral orbit and proptosis, which may be accompanied by peripheral lymphadenopathy. Usually, visual impairment is not apparent, but in severe cases, it can cause a loss of function of the tissues and organs involved and affect the daily lives of patients. The pathogenesis of IgG4-ROD is not clear. Based on existing literature, it is speculated that it may be related to factors such as autoantibody production, microbial infection, and genetic inheritance. For the treatment of IgG4-ROD, glucocorticoids, immunosuppressive agents, biological agents, and surgery are mainly used in clinical practice. Although these treatment methods can achieve a particular effect, they have limitations, such as high recurrence rates, serious side effects, and postoperative complications. With the increase in IgG4-ROD-related reports, some progress has been made in the current understanding and research of the disease.

Optimizing Multiple Entropy Thresholding by the Chaotic Combination Strategy Sparrow Search Algorithm for Aggregate Image Segmentation.

Aggregate measurement and analysis are critical for civil engineering. Multiple entropy thresholding (MET) is inefficient, and the accuracy of related optimization strategies is unsatisfactory, which results in the segmented aggregate images lacking many surface roughness and aggregate edge features. Thus, this research proposes an autonomous segmentation model (i.e., PERSSA-MET) that optimizes MET based on the chaotic combination strategy sparrow search algorithm (SSA). First, aiming at the characteristics of the many extreme values of an aggregate image, a novel expansion parameter and range-control elite mutation strategies were studied and combined with piecewise mapping, named PERSSA, to improve the SSA's accuracy. This was compared with seven optimization algorithms using benchmark function experiments and a Wilcoxon rank-sum test, and the PERSSA's superiority was proved with the tests. Then, PERSSA was utilized to swiftly determine MET thresholds, and the METs were the Renyi entropy, symmetric cross entropy, and Kapur entropy. In the segmentation experiments of the aggregate images, it was proven that PERSSA-MET effectively segmented more details. Compared with SSA-MET, it achieved 28.90%, 12.55%, and 6.00% improvements in the peak signal-to-noise ratio (PSNR), the structural similarity (SSIM), and the feature similarity (FSIM). Finally, a new parameter, overall merit weight proportion (OMWP), is suggested to calculate this segmentation method's superiority over all other algorithms. The results show that PERSSA-Renyi entropy outperforms well, and it can effectively keep the aggregate surface texture features and attain a balance between accuracy and speed.

A Yeast-Based Drug Discovery Platform To Identify Plasmodium falciparum Type II NADH Dehydrogenase Inhibitors.

Conventional methods utilizing in vitro protein activity assay or in vivo parasite survival to screen for malaria inhibitors suffer from high experimental background and/or inconvenience. Here, we introduce a yeast-based system to facilitate chemical screening for specific protein or pathway inhibitors. The platform comprises several isogeneic Pichia strains that differ only in the target of interest, so that a compound which inhibits one strain but not the other is implicated in working specifically against the target. We used Plasmodium falciparum NDH2 (PfNDH2), a type II NADH dehydrogenase, as a proof of principle to show how well this works. Three isogenic Pichia strains harboring, respectively, exogeneously introduced PfNDH2, its own complex I (a type I NADH dehydrogenase), and PfNDH2 with its own complex I, were constructed. In a pilot screen of more than 2,000 compounds, we identified a highly specific inhibitor that acts on PfNDH2. This compound poorly inhibits the parasites at the asexual blood stage; however, is highly effective in repressing oocyst maturation in the mosquito stage. Our results demonstrate that the yeast cell-based screen platform is feasible, efficient, economical, and has very low background noise. Similar strategies could be extended to the functional screen for interacting molecules of other targets.

Distorted Porphyrins with High Stability: Synthesis and Characteristic Electronic Properties of Mono- and Di-Nuclear Tricarbonyl Rhenium Tetraazaporphyrin Complexes.

Mono- and di-nuclear tricarbonyl Re(I) tetraazaporphyrin complexes (Re1 TAP and Re2 TAP) are investigated and compared with Re(I) phthalocyanine complexes (Re1 Pc and Re2 Pc). Although Re2 Pc is unstable in polar solvents, and easily undergoes demetallation reaction, the coordination of the TAP ligand significantly improves the tolerance toward polar solvents, affording more stability to Re2 TAP. Additionally, the incorporation of [Re(CO)3 ]+ unit(s) and the TAP ligand results in remarkable positive shifts in both oxidation and reduction potentials. Consequently, the more positive oxidation potentials of the ReTAP complexes significantly increase the tolerance toward oxidation, while the reduction potential indicates that Re2 TAP is suitable for a soluble electron acceptor. In contrast to Re1 Pc and Re2 Pc, Re1 TAP and Re2 TAP show unique broad Q bands, which can be attributed to the admixture of the π-π* and metal-to-ligand charge transfer characters, owing to the lowered π orbital energy in the TAP complexes. This study is useful for controlling electronic properties and realizing high stability in Pc analogues.

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer resistant to traditional treatments, although a limited number of early-stage patients can undergo radical resection. Immunotherapies for the treatment of haematological malignancies as well as solid tumours have been substantially improved over the past decades, and impressive results have been obtained in recent preclinical and clinical trials. However, PDAC is likely the exception because of its unique tumour microenvironment (TME). In this review, we summarize the characteristics of the PDAC TME and focus on the network of various tumour-infiltrating immune cells, outlining the current advances in PDAC immunotherapy and addressing the effect of the PDAC TME on immunotherapy. This review further explores the combinations of different therapies used to enhance antitumour efficacy or reverse immunodeficiencies and describes optimizable immunotherapeutic strategies for PDAC. The concordant combination of various treatments, such as targeting cancer cells and the stroma, reversing suppressive immune reactions and enhancing antitumour reactivity, may be the most promising approach for the treatment of PDAC. Traditional treatments, especially chemotherapy, may also be optimized for individual patients to remodel the immunosuppressive microenvironment for enhanced therapy.