Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.

CDK inhibitor Palbociclib targets STING to alleviate autoinflammation.

Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.

The effects of rTMS on motor recovery after stroke: a systematic review of fMRI studies.

Repetitive transcranial magnetic stimulation (rTMS) has been widely used in motor rehabilitation after stroke, and functional magnetic resonance imaging (fMRI) has been used to investigate the neural mechanisms of motor recovery during stroke therapy. However, there is no review on the mechanism of rTMS intervention for motor recovery after stroke based on fMRI explicitly. We aim to reveal and summarize the neural mechanism of the effects of rTMS on motor function after stroke as measured by fMRI. We carefully performed a literature search using PubMed, EMBASE, Web of Science, and Cochrane Library databases from their respective inceptions to November 2022 to identify any relevant randomized controlled trials. Researchers independently screened the literature, extracted data, and qualitatively described the included studies. Eleven studies with a total of 420 poststroke patients were finally included in this systematic review. A total of 338 of those participants received fMRI examinations before and after rTMS intervention. Five studies reported the effects of rTMS on activation of brain regions, and four studies reported results related to brain functional connectivity (FC). Additionally, five studies analyzed the correlation between fMRI and motor evaluation. The neural mechanism of rTMS in improving motor function after stroke may be the activation and FCs of motor-related brain areas, including enhancement of the activation of motor-related brain areas in the affected hemisphere, inhibition of the activation of motor-related brain areas in the unaffected hemisphere, and changing the FCs of intra-hemispheric and inter-hemispheric motor networks.

Correction: Systemic Delivery of MicroRNA-101 Potently Inhibits Hepatocellular Carcinoma In Vivo by Repressing Multiple Targets.

[This corrects the article DOI: 10.1371/journal.pgen.1004873.].

FF3D: A Rapid and Accurate 3D Fruit Detector for Robotic Harvesting.

This study presents the Fast Fruit 3D Detector (FF3D), a novel framework that contains a 3D neural network for fruit detection and an anisotropic Gaussian-based next-best view estimator. The proposed one-stage 3D detector, which utilizes an end-to-end 3D detection network, shows superior accuracy and robustness compared to traditional 2D methods. The core of the FF3D is a 3D object detection network based on a 3D convolutional neural network (3D CNN) followed by an anisotropic Gaussian-based next-best view estimation module. The innovative architecture combines point cloud feature extraction and object detection tasks, achieving accurate real-time fruit localization. The model is trained on a large-scale 3D fruit dataset and contains data collected from an apple orchard. Additionally, the proposed next-best view estimator improves accuracy and lowers the collision risk for grasping. Thorough assessments on the test set and in a simulated environment validate the efficacy of our FF3D. The experimental results show an AP of 76.3%, an AR of 92.3%, and an average Euclidean distance error of less than 6.2 mm, highlighting the framework's potential to overcome challenges in orchard environments.

An Insulin-Modified pH-Responsive Nanopipette Based on Ion Current Rectification.

The properties of nanopipettes largely rely on the materials introduced onto their inner walls, which allow for a vast extension of their sensing capabilities. The challenge of simultaneously enhancing the sensitivity and selectivity of nanopipettes for pH sensing remains, hindering their practical applications. Herein, we report insulin-modified nanopipettes with excellent pH response performances, which were prepared by introducing insulin onto their inner walls via a two-step reaction involving silanization and amidation. The pH response intensity based on ion current rectification was significantly enhanced by approximately 4.29 times when utilizing insulin-modified nanopipettes compared with bare ones, demonstrating a linear response within the pH range of 2.50 to 7.80. In addition, insulin-modified nanopipettes featured good reversibility and selectivity. The modification processes were monitored using the I-V curves, and the relevant mechanisms were discussed. The effects of solution pH and insulin concentration on the modification results were investigated to achieve optimal insulin introduction. This study showed that the pH response behavior of nanopipettes can be greatly improved by introducing versatile molecules onto the inner walls, thereby contributing to the development and utilization of pH-responsive nanopipettes.

Linking the assessment of ecological engineering construction with zoning management in the typical agro-pastoral area of China: A perspective from quantity, quality and function.

Combatting land damage has become a global priority, and China has adopted a series of ecological engineering measures, especially in the agro-pastoral area with fragile ecological environment. The effectiveness of ecological engineering construction (EEC), from a comprehensive recognition encompassing its quality, quantity, and function, has remained largely unknown. To this end, Zhangbei County, a typical agro-pastoral ecotone of northern China, was chosen as our focal area. After summarizing the timelines, aims and results of the EEC during various periods in Zhangbei, the linear spectral mixture analysis was employed to process Landsat 5 TM images in 2000 and 2010, as well as Landsat 8 OLI images in 2020. Then, a comprehensive evaluation framework of EEC was established from the perspective of "quantity-quality-function", and the ecological effectiveness of EEC was evaluated from 2000 to 2020 in Zhangbei. Results revealed that EEC played a critical role in enhancing quantity, quality and function, in spite of that, there were still numerous regions showing varying degrees of degradation in terms of these aspects. Then, by extending the three-dimensional cube as the theoretical basis for the zoning management of EEC, we merged four zones according to the space matching relationship among quantity, quality and function of EEC, namely, Ecological conservation area, Ecological improvement area, Ecological restoration area and Ecological remodeling zone. More targeted ecological measures were required for specific matching relationship among quantity, quality and function of EEC. This study is expected to present an empirical case for assessing the ecological effectiveness of EEC in areas or countries with similar restoration demand and support regional management.

Glutathione disrupts galectin-10 Charcot-Leyden crystal formation to possibly ameliorate eosinophil-based diseases such as asthma.

Charcot-Leyden crystals (CLCs) are the hallmark of many eosinophilic-based diseases, such as asthma. Here, we report that reduced glutathione (GSH) disrupts CLCs and inhibits crystallization of human galectin-10 (Gal-10). GSH has no effect on CLCs from monkeys ( Macaca fascicularis or M. mulatta), even though monkey Gal-10s contain Cys29 and Cys32. Interestingly, human Gal-10 contains another cysteine residue (Cys57). Because GSH cannot disrupt CLCs formed by the human Gal-10 variant C57A or inhibit its crystallization, the effects of GSH on human Gal-10 or CLCs most likely occur by chemical modification of Cys57. We further report the crystal structures of Gal-10 from M. fascicularis and M. mulatta, along with their ability to bind to lactose and inhibit erythrocyte agglutination. Structural comparison with human Gal-10 shows that Cys57 and Gln75 within the ligand binding site are responsible for the loss of lactose binding. Pull-down experiments and mass spectrometry show that human Gal-10 interacts with tubulin α-1B, with GSH, GTP and Mg 2+ stabilizing this interaction and colchicine inhibiting it. Overall, this study enhances our understanding of Gal-10 function and CLC formation and suggests that GSH may be used as a pharmaceutical agent to ameliorate CLC-induced diseases.

Influence of Different Pt Functionalization Modes on the Properties of CuO Gas-Sensing Materials.

The functionalization of noble metals is an effective approach to lowering the sensing temperature and improving the sensitivity of metal oxide semiconductor (MOS)-based gas sensors. However, there is a dearth of comparative analyses regarding the differences in sensitization mechanisms between the two functionalization modes of noble metal loading and doping. In this investigation, we synthesized Pt-doped CuO gas-sensing materials using a one-pot hydrothermal method. And for Pt-loaded CuO, Pt was deposited on the synthesized pristine CuO surface by using a dipping method. We found that both functionalization methods can considerably enhance the response and selectivity of CuO toward NO2 at low temperatures. However, we observed that CuO with Pt loading had superior sensing performance at 25 °C, while CuO with Pt doping showed more substantial response changes with an increase in the operating temperature. This is mainly due to the different dominant roles of electron sensitization and chemical sensitization resulting from the different forms of Pt present in different functionalization modes. For Pt doping, electron sensitization is stronger, and for Pt loading, chemical sensitization is stronger. The results of this study present innovative ideas for understanding the optimization of noble metal functionalization for the gas-sensing performance of metal oxide semiconductors.

Structural basis for glucosylsucrose synthesis by a member of the α-1,2-glucosyltransferase family.

Glucosylsucroses are potentially useful as additives in cosmetic and pharmaceutical formulations. Although enzymatic synthesis of glucosylsucroses is the most efficient method for their production, the key enzyme that produces them has remained unknown. Here, we report that glucosylsucrose synthase from (TeGSS) catalyzes the synthesis of glucosylsucrose using sucrose and UDP-glucose as substrates. These saccharides are homologous to glucosylsucroses produced by sp. PCC 7120 (referred to as protein alr1000). When the ratio of UDP-glucose to sucrose is relatively high, TeGSS from cyanobacteria can hydrolyze excess UDP-glucose to UDP and glucose, indicating that sucrose provides a feedback mechanism for the control of glucosylsucrose synthesis. In the present study, we solved the crystal structure of TeGSS bound to UDP and sucrose. Our structure shows that the catalytic site contains a circular region that may allow glucosylsucroses with a right-hand helical structure to enter the catalytic site. Because active site residues Tyr18 and Arg179 are proximal to UDP and sucrose, we mutate these residues (., Y18F and R179A) and show that they exhibit very low activity, supporting their role as catalytic groups. Overall, our study provides insight into the catalytic mechanism of TeGSS.

Actin binding to galectin-13/placental protein-13 occurs independently of the galectin canonical ligand-binding site.

The gene for galectin-13 (Gal-13, placental protein 13) is only present in primates, and its low expression level in maternal serum may promote preeclampsia. In the present study, we used pull-down experiments and biolayer interferometry to assess the interaction between Gal-13 and actin. These studies uncovered that human Gal-13 (hGal-13) and Saimiri boliviensis boliviensis (sGal-13) strongly bind to α- and ß-/γ-actin, with Ca2+ and adenosine triphosphate, significantly enhancing the interactions. This in turn suggests that h/sGal-13 may inhibit myosin-induced contraction when vascular smooth muscle cells undergo polarization. Here, we solved the crystal structure of sGal-13 bound to lactose and found that it exists as a monomer in contrast to hGal-13 which is a dimer. The distribution of sGal-13 in HeLa cells is similar to that of hGal-13, indicating that monomeric Gal-13 is the primary form in cells. Even though sGal-13 binds to actin, hGal-13 ligand-binding site mutants do not influence hGal-13/actin binding, whereas the monomeric mutant C136S/C138S binds to actin more strongly than the wild-type hGal-13. Overall, our study demonstrates that monomeric Gal-13 binds to actin, an interaction that is independent of the galectin canonical ligand-binding site.

miR-1283 Contributes to Endoplasmic Reticulum Stress in the Development of Hypertension Through the Activating Transcription Factor-4 (ATF4)/C/EBP-Homologous Protein (CHOP) Signaling Pathway.

BACKGROUND Hypertension-related microRNA(miR)-1283 and its target gene, activating transcription factor-4 (ATF4), can regulate vascular endothelial dysfunction. This study aimed to explore whether miR-1283 prevents hypertension through targeting ATF4. MATERIAL AND METHODS Transcriptome sequencing was performed after overexpression or inhibition of miR-1283 in human amniotic epithelial cells (HAECs). After miR-1283 was overexpressed or inhibited in HAECs, ATF4+/- and wild-type mice were induced with a high-salt diet. We detected the expression of ATF4, C/EBP-homologous protein (CHOP), BH3-interacting domain death agonist (BID), Bcl-2, Bcl-2-like protein 11 (BIM), Bcl-2-like protein 1 (BCL-X), and caspase-3 by PCR and western blotting. We detected the changes of vasoactive substances including nitric oxide (NO), endothelin 1 (ET-1), endothelial protein C receptor (EPCR), thrombin (TM), and von Willebrand factor (vWF) by ELISA. RESULTS Compared with that of the miR-1283- inhibited group, NO was higher in the miR-1283 overexpression group, while the expression of ET-1, EPCR, TM, and vWF were lower. Similarly, compared with that of the miR-1283 inhibited group, the expression of ATF4, CHOP, BID, BIM, and caspase-3 in the miR-1283 overexpression group was downregulated, while the expression of BCL-2 and BCL-X was upregulated (P<0.05). In vivo experiments showed the lack of ATF4 gene could prevent hypertension in mice induced by high-salt diet and protect endothelial function. CONCLUSIONS The mechanism of regulating blood pressure and endothelial function of the miR-1283/ATF4 axis was related to inhibiting endoplasmic reticulum stress and cell apoptosis through the ATF4/CHOP signaling pathway. Therefore, the miR-1283/ATF4 axis may be a target for the prevention and treatment of hypertension.

Network Pharmacology Identifies the Mechanisms of Action of TaohongSiwu Decoction Against Essential Hypertension.

BACKGROUND TaohongSiwu decoction (THSWT), a traditional herbal formula, has been used to treat cardiovascular and cerebrovascular diseases such as essential hypertension (EH) in China. However, the pharmacological mechanism is not clear. To investigate the mechanisms of THSWT in the treatment of EH, we performed compounds, targets prediction and network analysis using a network pharmacology method. MATERIAL AND METHODS We selected chemical constituents and targets of THSWT according to TCMSP and UniProtKB databases and collected therapeutic targets on EH from Online Mendelian Inheritance in Man (OMIM), Drugbank and DisGeNET databases. The protein-protein interaction (PPI) was analyzed by using String database. Then network was constructed by using Cytoscape_v3.7.1, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was performed by using Database for Annotation, Visualization and Integrated Discovery (DAVID) software. RESULTS The results of our network pharmacology research showed that the THSWT, composed of 6 Chinese herbs, contained 15 compounds, and 23 genes regulated the main signaling pathways related to EH. Moreover, the PPI network based on targets of THSWT on EH revealed the interaction relationship between targets. These core compounds were 6 of the 15 disease-related compounds in the network, kaempferol, quercetin, luteolin, Myricanone, beta-sitosterol, baicalein, and the core genes contained ADRB2, CALM1, HMOX1, JUN, PPARG, and VEGFA, which were regulated by more than 3 compounds and significantly associated with Calcium signaling pathway, cGMP-PKG signaling pathway, cAMP signaling pathway, PI3K-Akt signaling pathway, Rap1 signaling pathway, and Ras signaling pathway. CONCLUSIONS This network pharmacological study can reveal potential mechanisms of multi-target and multi-component THSWT in the treatment of EH, provide a scientific basis for studying the mechanism.

Construction and Analysis of lncRNA-Mediated ceRNA Network in Cervical Squamous Cell Carcinoma by Weighted Gene Co-Expression Network Analysis.

BACKGROUND More and more recent studies have clearly shown that long non-coding RNA (lncRNA) should be considered as a fundamental part of the ceRNA network, mainly because lncRNA can act as miRNA sponges to regulate the protein-coding gene expression. Nevertheless, it is still not clear how lncRNA-mediated ceRNAs function in cervical squamous cell carcinoma (CESC). Moreover, information about the ceRNA regulatory mechanism is also remarkably limited; thus, prediction of CESC prognosis using ceRNA-related information remains challenging. MATERIAL AND METHODS We collected 306 RNA (lncRNA, miRNA, and mRNA) expression profile datasets obtained from cervical squamous cancer tissues plus 3 more from adjacent cervical tissues via the TCGA database. Subsequently, we constructed a lncRNAs-miRNAs-mRNAs CESC ceRNA network, and Gene Ontology (GO) analysis was carried out. RESULTS We identified a total of 30 DElncRNAs, 70 DEmiRNAs, and 1089 DEmRNAs in CESC. Subsequently, to reveal the expression patterns of dysregulated genes, weighted gene co-expression network analysis was carried out, resulting in 3 co-expression modules with significantly related clinical properties. The constructed aberrant lncRNAs-miRNAs-mRNAs CESC ceRNA network was composed of 17 DEmiRNAs, 5 DElncRNAs, and 7 DEmRNAs. Moreover, the survival analysis was performed for DElncRNAs, DEmiRNAs, and DEmRNAs. CONCLUSIONS The present study shows the involvement of the lncRNA-related ceRNA network in the pathogenesis of CESC. We believe the newly generated ceRNA network will provide more insights into the lncRNA-mediated ceRNA regulatory mechanisms.

Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.

Targeted therapy based on adjustment of microRNA (miRNA)s activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC) remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05). In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT) and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.

Fluorescence Enhancement of Terminal Amine Assembled on Gold Nanoclusters and Its Application to Ratiometric Lysine Detection.

Ratiometric fluorescent sensors have emerged as an attractive tool for analytical sensing and optical imaging due to their providing a built-in self-calibration for environmental effects. However, cumbersome processes of nanoparticles modified with fluorophores for constructing traditional ratiometric sensors limit their further application. Herein, we report a facile and label-free strategy for constructing a ratiometric sensor based on an aggregation-induced-emission (AIE)-active amine-terminated small molecule on the surface of gold nanoclusters (AuNCs). Intrinsic fluorescence of the terminal primary amine of the small molecule lysine resulting from AIE was first observed in the presence of glutathione-stabilized gold nanoclusters (GSH-AuNCs). Using lysine as both the fluorophore and the analyte, the synthesized GSH-AuNCs showed a good lysine-responsive ratiometric property. The AIE-active dual-emitting fluorescence property of the GSH-AuNCs/lysine complex made it feasible to achieve ratiometrically detection of the analyte without conjugated fluorogen. This AIE-active GSH-AuNC-based biosensor possesses high selectivity, rapid response, and excellent photostability. Moreover, the strategy opens a new pathway for the construction of a label-free ratiometric fluorescent sensor with various applications.

"Back to the future" projections for COVID-19 surges.

We argue that information from countries who had earlier COVID-19 surges can be used to inform another country's current model, then generating what we call back-to-the-future (BTF) projections. We show that these projections can be used to accurately predict future COVID-19 surges prior to an inflection point of the daily infection curve. We show, across 12 different countries from all populated continents around the world, that our method can often predict future surges in scenarios where the traditional approaches would always predict no future surges. However, as expected, BTF projections cannot accurately predict a surge due to the emergence of a new variant. To generate BTF projections, we make use of a matching scheme for asynchronous time series combined with a response coaching SIR model.

Dynamic analysis and optimal control of stochastic information cross-dissemination and variation model with random parametric perturbations.

Information dissemination has a significant impact on social development. This paper considers that there are many stochastic factors in the social system, which will result in the phenomena of information cross-dissemination and variation. The dual-system stochastic susceptible-infectious-mutant-recovered model of information cross-dissemination and variation is derived from this problem. Afterward, the existence of the global positive solution is demonstrated, sufficient conditions for the disappearance of information and its stationary distribution are calculated, and the optimal control strategy for the stochastic model is proposed. The numerical simulation supports the results of the theoretical analysis and is compared to the parameter variation of the deterministic model. The results demonstrate that cross-dissemination of information can result in information variation and diffusion. Meanwhile, white noise has a positive effect on information dissemination, which can be improved by adjusting the perturbation parameters.

Temperature fluctuation in soil alters the nanoplastic sensitivity in wheat.

Despite the wide acknowledgment that plastic pollution and global warming have become serious agricultural concerns, their combined impact on crop growth remains poorly understood. Given the unabated megatrend, a simulated soil warming (SWT, +4 °C) microcosm experiment was carried out to provide a better understanding of the effects of temperature fluctuations on wheat seedlings exposed to nanoplastics (NPs, 1 g L-1 61.71 ± 0.31 nm polystyrene). It was documented that SWT induced oxidative stress in wheat seedlings grown in NPs-contaminated soil, with an 85.56 % increase in root activity, while decreasing plant height, fresh weight, and leaf area by 8.72 %, 47.68 %, and 15.04 % respectively. The SWT also resulted in reduced photosynthetic electron-transfer reaction and Calvin-Benson cycle in NPs-treated plants. Under NPs, SWT stimulated the tricarboxylic acid (TCA) metabolism and bio-oxidation process. The decrease in photosynthesis and the increase in respiration resulted in an 11.94 % decrease in net photosynthetic rate (Pn). These results indicated the complicated interplay between climate change and nanoplastic pollution in crop growth and underscored the potential risk of nanoplastic pollution on crop production in the future climate.

cGAS: action in the nucleus.

As a canonical cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) plays a key role in innate immunity. In recent years, a growing number of studies have shown that cGAS can also be located in the nucleus and plays new functions such as regulating DNA damage repair, nuclear membrane repair, chromosome fusion, DNA replication, angiogenesis and other non-canonical functions. Meanwhile, the mechanisms underlying the nucleo-cytoplasmic transport and the regulation of cGAS activation have been revealed in recent years. Based on the current understanding of the structure, subcellular localization and canonical functions of cGAS, this review focuses on summarizing the mechanisms underlying nucleo-cytoplasmic transport, activity regulation and non-canonical functions of cGAS in the nucleus. We aim to provide insights into exploring the new functions of cGAS in the nucleus and advance its clinical translation.