A small peptide inhibits siRNA amplification in plants by mediating autophagic degradation of SGS3/RDR6 bodies.

Selective autophagy mediates specific degradation of unwanted cytoplasmic components to maintain cellular homeostasis. The suppressor of gene silencing 3 (SGS3) and RNA-dependent RNA polymerase 6 (RDR6)-formed bodies (SGS3/RDR6 bodies) are essential for siRNA amplification in planta. However, whether autophagy receptors regulate selective turnover of SGS3/RDR6 bodies is unknown. By analyzing the transcriptomic response to virus infection in Arabidopsis, we identified a virus-induced small peptide 1 (VISP1) composed of 71 amino acids, which harbor a ubiquitin-interacting motif that mediates interaction with autophagy-related protein 8. Overexpression of VISP1 induced selective autophagy and compromised antiviral immunity by inhibiting SGS3/RDR6-dependent viral siRNA amplification, whereas visp1 mutants exhibited opposite effects. Biochemistry assays demonstrate that VISP1 interacted with SGS3 and mediated autophagic degradation of SGS3/RDR6 bodies. Further analyses revealed that overexpression of VISP1, mimicking the sgs3 mutant, impaired biogenesis of endogenous trans-acting siRNAs and up-regulated their targets. Collectively, we propose that VISP1 is a small peptide receptor functioning in the crosstalk between selective autophagy and RNA silencing.

The Plasma Concentration of Ticagrelor and Aspirin as a Predictor of Bleeding Complications in Chinese Acute Coronary Syndrome Patients With Dual Antiplatelet Therapy: A Prospective Observational Study.

PURPOSE: This study evaluated the association among the plasma concentration of ticagrelor, ARC124910XX, aspirin, and salicylic acid with the risk of recent bleeding in patients with the acute coronary syndrome. To this end, we developed an accurate model to predict bleeding. METHODS: A total of 84 patients included in this study cohort between May 2021 and November 2021. The risk factors were identified by univariate and multivariate analyses, and statistically significant risk factors identified in the multivariate analysis were included in the nomogram. We used the calibration curve and the receiver operating characteristic curve to verify the accuracy of the prediction model. RESULTS: Multivariable logistic analysis showed that ticagrelor concentration (odds ratio [OR]: 2.47, 95% confidence interval [CI], 1.51-4.75, P = 0.002), ST-segment elevation acute myocardial infarction (OR: 32.2, 95% CI, 2.37-780, P = 0.016), and lipid-lowering drugs (OR: 11.52, 95% CI, 1.91-110, P = 0.015) were positively correlated with bleeding. However, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (OR: 0.04, 95% CI, 0.004-0.213, P < 0.001) was negatively correlated with bleeding. The receiver operating characteristic curve analysis showed that ticagrelor concentration and these factors together predict the occurrence of bleeding (area under receiver operating characteristic curve = 0.945, 95% CI, 0.896-0.994) and that ticagrelor concentration >694.90 ng/mL is the threshold of bleeding concentration (area under receiver operating characteristic curve = 0.696, 95% CI, 0.558-0.834). CONCLUSION: In patients with acute coronary syndrome treated with dual antiplatelet therapy, ticagrelor concentration >694.90 ng/mL was an independent risk factor for bleeding (OR: 2.47, 95% CI, 1.51-4.75, P = 0.002), but ARC124910XX and salicylic acid concentration did not affect bleeding risk ( P > 0.05).

1D Chiral Enantiomer Lead-Free Perovskites Induced Chiralopical Activity and Photoelectric Response.

Chirality is a fascinating geometrical concept with widespread applications in biology, chemistry, and materials. Incorporating chirality into hybrid perovskite materials can induce novel physical properties (chiral optical activity, nonlinear optics, etc.). Hybrid lead-free or lead-substituted perovskite materials, as representatives of perovskites, have been widely used in fields such as photovoltaics, sensors, catalysis, and detectors. However, the successful introduction of chirality into hybrid lead-free perovskites, which can enable their potential applications in areas such as circularly polarized light photodetectors, memories, and spin transistors, remains a challenging research topic. Here, we synthesized two new chiral lead-free perovskites, [(R)-2-methylpiperazine][BiI5] and [(S)-2-methylpiperazine][BiI5]. The material possesses a perovskite structure with a one-dimensional (1D) arrangement, denoted as ABX5. This structure is composed of chiral cations, specifically methylpiperazine, and endless chains of [BiI3] along the a-axis. These chains are assembled from distorted coplanar [BiI5]2- octahedra. The testing results revealed that (R)-1 and (S)-1 have narrow band gaps (Eg-R = 2.016 eV, Eg-S = 1.964 eV), high photoelectric response, and long carrier lifetime [R = 4.94 µs (τ), S = 7.85 µs (τ)]. It is worth noting that 1D chiral lead-free perovskites (R)-1 and (S)-1, which are synthesized in this study with narrow band gaps, high photoelectric response, and long carrier lifetime, have the potential to serve as alternative materials for the perovskite layer in future iterations of lead-free perovskite solar cells. Moreover, this research will inspire the preparation of multifunctional, lead-free perovskites.

Deficiency of astrocyte CysLT1R ameliorates depression-like behaviors in mice by modulating glutamate synaptic transmission.

Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT1R) could be involved in depression. Herein we hypothesize that CysLT1R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT1R in the astrocytes that participate in occurrence of depression. We found that CysLT1R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT1R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT1R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT1R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT1R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT1R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by ß-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT1R of DG. Our study demonstrated that astrocyte CysLT1R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT1R could be a potential target for developing novel drugs of anti-depression.

Enantioselective Reductive Homocoupling of Allylic Acetates Enabled by Dual Photoredox/Palladium Catalysis: Access to C2-Symmetrical 1,5-Dienes.

Transition-metal-catalyzed reductive coupling reactions have emerged as powerful protocols to construct C-C bonds. However, the development of enantioselective C(sp3)-C(sp3) reductive coupling remains challenging. Herein, we report a highly regio-, diastereo-, and enantioselective reductive homocoupling of allylic acetates through cooperative palladium and photoredox catalysis using diisopropylethylamine or Hantzsch ester as a homogeneous organic reductant. This straightforward protocol enables the stereoselective construction of C(sp3)-C(sp3) bonds under mild reaction conditions. A series of C2-symmetrical chiral 1,5-dienes were easily prepared with excellent enantioselectivities (up to >99% ee), diastereoselectivities (up to >95:5 dr), and regioselectivities (up to >95:5 rr). The resultant chiral 1,5-dienes can be directly used as chiral ligands in asymmetric synthesis, and they can be also transformed into other valuable chiral ligands.

Comparison of three treatment methods for simple bone cyst in children.

BACKGROUND: The unicameral bone cyst (UBC) is a kind of benign tumor whose clinical treatments and efficacy are controversial. The purpose of this study was to evaluate the efficacy of the elastic stable intramedullary nail (ESIN), the injection of autologous bone marrow (ABM), and the combination of ESIN and ABM in the treatment of bone cyst in children. METHODS: Eighty-three cases with simple bone cyst were analyzed retrospectively. Twenty-eight cases were treated with ABM. Twenty-eight cases were treated with ESIN. Twenty-seven cases were treated with ABM and ESIN. All cases were diagnosed through X-ray, CT, or MRI scans. For the suspicious ones, the pathological biopsy was performed for an accurate diagnosis. X-ray examinations were carried out for the postoperative follow-up. Capanna criteria for bone cyst was used for postoperative evaluation of three methods. RESULTS: All cases accomplished the follow-up. The effective rate of the ABM + ESIN group was significantly higher than that of the ABM group (P < 0.05), and the cure rates of the ESIN group and the ABM + ESIN group were higher than that of the ABM group (P < 0.05, respectively). The cure time in the ESIN group was lower than that of the other two groups (P < 0.05, respectively). The times for admission were 2.0 ± 0.0 in the ESIN group, 5.7 ± 1.9 in the ABM group, and 4.7 ± 2.4 in the ABM + ESIN group (P < 0.05 when compared with each other). CONCLUSIONS: The method of ABM combined with ESIN for children's bone cyst has the highest effective rate and curative rate. For the individual method, ESIN has a higher effective rate and curative rate than that of ABM. Meanwhile, it has the fewest time of hospitalization.

Enantioselective Allylic Alkylation with 4-Alkyl-1,4-dihydro-pyridines Enabled by Photoredox/Palladium Cocatalysis.

Highly regio- and enantioselective allylic alkylation has been achieved enabled by the merger of photoredox and palladium catalysis. In this dual catalytic process, alkyl radicals generated from 4-alkyl-1,4-dihydropyridines act as the coupling partners of the π-allyl palladium complexes. The generality of this method has been illustrated through the reaction of a variety of allyl esters with 4-alkyl-1,4-dihydropyridines. This mechanistically novel strategy expands the scope of the traditional Pd-catalyzed asymmetric allylic alkylation reaction and serves as its alternative and potential complement.

Inheritance, Realized Heritability, and Biochemical Mechanisms of Malathion Resistance in Bactrocera dorsalis (Diptera: Tephritidae).

To better characterize the resistance development and therefore establish effective pest management strategies, this study was undertaken to investigate the inheritance mode and biochemical mechanisms of malathion resistance in the oriental fruit fly, Bactrocera dorsalis (Hendel), which is one of the most notorious pests in the world. After 22 generations of selection with malathion, the malathion-resistant (MR) strain of B. dorsalis developed a 34-fold resistance compared with a laboratory susceptible strain [malathion-susceptible (MS)]. Bioassay results showed that there was no significant difference between the LD50 values of malathion against the progenies from both reciprocal crosses (F(1)-SR and F(1)-RS). The degree of dominance values (D) was calculated as 0.39 and 0.32 for F(1)-RS and F(1)-SR, respectively. The logarithm dosage-probit mortality lines of the F(2) generation and progeny from the backcross showed no clear plateaus of mortality across a range of doses. In addition, Chi-square analysis revealed significant differences between the mortality data and the theoretical expectations. The realized heritability (h(2)) value was 0.16 in the laboratory-selected resistant strain of B. dorsalis. Enzymatic activities identified significant changes of carboxylesterases, cytochrome P450 (general oxidases), and glutathione S-transferases in MR compared with the MS strain of B. dorsalis. Taken together, this study revealed for the first time that malathion resistance in B. dorsalis follows an autosomal, incompletely dominant, and polygenic mode of inheritance and is closely associated with significantly elevated activities of three major detoxification enzymes.

[Advances in the research of pharmacogenomics of tamoxifen].

Tamoxifen (TAM) is the most common nonsteroidal antiestrogen agent, which has been widely used in the prevention of recurrence of estrogen or progesterone receptor-positive breast cancer in patients. It is metabolized by cytochrome P450 oxidases to its active metabolite (4-hydroxytamoxifen, 4-OH-TAM) and endoxifen (EDF), which played a critical role in the therapy. 4-OH-TAM and EDF have 30- to 100-fold more potency than TAM in the suppression of estrogen-dependent breast cancer cell proliferation. CYP3A4 and CYP2D6, as the key drug-metabolizing enzymes in those metabolic actions, are known to have several alleles. Genetic polymorphisms of CYP2D6 and CYP3A4 will influence the plasma concentrations of active TAM metabolites and clinical outcomes for breast cancer patients treated with TAM. The genetic polymorphisms of drug transporters, involved in the disposition of active TAM metabolites, also have the potential to influence the plasma concentrations of active TAM metabolites and clinical outcome for the treatment of breast cancer. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of TAM with the metabolite concentration, efficacy and adverse effects of TAM, which provides a fundamental reference for further pharmacogenomic study and clinical use of TAM.

Catalytic Chemo-, E/Z-, and Enantioselective Cyclizations of o-Hydroxybenzyl Alcohols with Dimedone-Derived Enaminones.

A catalytic chemo-, E/Z-, and enantioselective cyclization of o-hydroxybenzyl alcohols with dimedone-derived enaminones has been established, which not only realized a chemoselective C1,2 cyclization of enaminones but also achieved the catalytic asymmetric construction of the biologically important tetrahydroxanthene framework with high E/Z- and enantioselectivities (all >95:5 E/Z, up to 98% yield, 97:3 er). This approach not only represents the first catalytic asymmetric C1,2 cyclization of enaminones with o-hydroxybenzyl alcohols but also provides an efficient strategy for constructing oxygenous heterocyclic frameworks with optical purity.

[Transplacental transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia of MDCKII/MDCKII-BCRP cell line].

To study the transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia, MDCKII-BCRP and MDCKII cell models was used. MDCKII-BCRP and MDCKII cell monolayer model was used to investigate the bi-direction transport of sotalol, propranolol, propafenone, procainamide and flecainide. Drug concentrations were measured by HPLC-UV or chemiluminescence. The apparent permeability coefficient (P(app)), efflux rate (R(E)) and net efflux rate (R(net)) were calculated. Drugs with R(net) greater than 1.5 were further investigated using cellular accumulation experiments with or without a BCRP inhibitor. The R(net) of sotalol, propranolol, propafenone and procainamide were less than 1.5, while R(net) of flecainide with concentrations of 20 and 5 µmol x L(-1) were 1.6 and 1.9, respectively. The results showed that the transport of flecainide on MDCKII-BCRP cell monolayer could be mediated by BCRP; and the affinity increased when the concentration of flecainide decreased. Cellular accumulation experiments further suggested that accumulation of flecainide in MDCKII-BCRP cells was significantly lower than that in MDCKII cells in a concentration-dependent manner. BCRP inhibitor quercetin (50 µmol x L(-1)) significantly increased the accumulation of flecainide in MDCKII-BCRP cells (P < 0.05). Our preliminary data showed that flecainide but not sotalol, propranolol, propafenone or procainamide can be a substrate of BCRP. Thus the effect of flecainide may be affected by the BCRP in the maternal placental trophoblast membrane layer when treating fetal tachyarrhythmia.

[A New Method to Decline the SWC Effect on the Accuracy for Monitoring SOM with Hyperspectral Technology].

Soil organic matter (SOM) is one of the most important indexes to reflect the soil fertility, and soil moisture is a main factor to limit the application of hyperspectral technology in monitoring soil attributes. To study the effect of soil moisture on the accuracy for monitoring SOM with hyperspectral remote sensing and monitor the SOM quickly and accurately, SOM, soil water content (SWC) and soil spectrum for 151 natural soil samples in winter wheat field were measured and the soil samples were classified with the method of traditional classification of SWC and Normalized Difference Soil Moisture Index (NSMI) based on the hyperspectral technology. Moreover, the relationship among SWC, SOM and NSMI were analyzed. The results showed that the accuracy of spectral monitor for SOM among the classifications were significantly different, its accuracy was higher than the soils (5%-25%) which was not classified. It indicated that the soil moisture affected the accuracy for monitoring the SOM with hyperspectral technology and the study proved that the most beneficent soil water content for monitoring the SOM was less 10% and higher 20%. On the other hand, the four models for monitoring the SOM by the hyperspectral were constructed by the classification of NSMI, and its accuracy was higher than the classification of SWC. The models for monitoring the SOM by the classification of NSMI were calibrated with the validation parameters of R², RMSE and RPD, and it showed that the four models were available and reliable to quickly and conveniently monitor the SOM by heperspectral. However, the different classifiable ways for soil samples mentioned in the study were naturally similar as all soil samples were classified again with another way. Namely, there may be another optimal classifiable way or method to overcome and eliminate the SWC effect on the accuracy for monitoring SOM. The study will provide some theoretical technology to monitor the SWC and SOM by remote sensing.

Catalytic asymmetric inverse-electron-demand oxa-Diels-Alder reaction of in†situ generated ortho-quinone methides with 3-methyl-2-vinylindoles.

The first catalytic asymmetric inverse-electron-demand (IED) oxa-Diels-Alder reaction of ortho-quinone methides, generated in situ from ortho-hydroxybenzyl alcohols, has been established. By selecting 3-methyl-2-vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho-hydroxybenzyl alcohols as precursors of dienes and 3-methyl-2-vinylindoles as dienophiles, as well as the hydrogen-bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa-Diels-Alder reaction.

Organocatalytic arylation of 3-indolylmethanols via chemo- and regiospecific C6-functionalization of indoles.

An organocatalytic arylation of 3-indolylmethanols has been established via chemo- and regiospecific C6-functionalization of 2,3-disubstituted indoles, leading to the production of bisindolyloxindoles containing an all-carbon quaternary stereocenter in high yields (up to 99% yield). This reaction not only represents the first catalytic arylation of 3-indolylmethanols using 2,3-disubstituted indoles as aromatic nucleophiles but also serves as a good example of direct catalytic C6-functionalization of indoles, which have been scarcely investigated. Besides, this approach also provides an efficient method to access a biologically important 3,3'-disubstituted oxindole framework and a 3',6-linked bisindole skeleton. Furthermore, the investigation of the activation mode suggested that the dual activation of an ion pair and H-bond between the substrates and the catalyst cooperatively contributed to the success of the reaction.

Organocatalytic asymmetric arylative dearomatization of 2,3-disubstituted indoles enabled by tandem reactions.

The organocatalytic asymmetric arylative dearomatization of indoles was achieved through two tandem approaches involving 2,3-disubstituted indoles and quinone imine ketals. One approach utilized the enantioselective cascade 1,4 addition/alcohol elimination reaction, the other employed the one-pot tandem arylative dearomatization/transfer hydrogenation sequence. In both cases, enantiomerically pure indole derivatives that bear an all-carbon quaternary stereogenic center were generated in high yields and excellent stereoselectivities (all d.r.>95:5, up to 99% ee).

Mesenchymal stem cells-derived extracellular vesicle-incorporated H19 attenuates cardiac remodeling in rats with heart failure.

Cardiac remodeling is manifested by hypertrophy and apoptosis of cardiomyocytes, resulting in the progression of cardiovascular diseases. Long noncoding RNAs (lncRNAs) serve as modifiers of cardiac remodeling. In this study, we aimed to explore the molecular mechanism of H19 shuttled by mesenchymal stem cells (MSC)-derived extracellular vesicles (EV) in cardiac remodeling upon heart failure (HF). Using the GEO database, H19, microRNA (miR)-29b-3p, and CDC42 were screened out as differentially expressed biomolecules in HF. H19 and CDC42 were elevated, and miR-29b-3p was decreased after MSC-EV treatment in rats subjected to ligation of the coronary artery. MSC-EV alleviated myocardial injury in rats with HF. H19 downregulation exacerbated myocardial injury, while miR-29b-3p inhibitor alleviated myocardial injury. By contrast, CDC42 downregulation aggravated the myocardial injury again. PI3K/AKT pathway was activated by MSC-EV. These findings provide insights into how H19 shuttled by EV mitigates cardiac remodeling through a competitive endogenous RNA network regarding miR-29b-3p and CDC42.

TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice.

Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHAGABA→dCA3CaMKIIα→DLSGABA circuit for the development of potential therapeutic strategies in depression.

The small peptide VISP1 acts as a selective autophagy receptor regulating plant-virus interactions.

Selective macroautophagy/autophagy is tightly regulated by cargo receptors that recruit specific substrates to the ATG8-family proteins for autophagic degradation. Therefore, identification of selective receptors and their new cargoes will improve our understanding of selective autophagy functions in plant development and stress responses. We have recently demonstrated that the small peptide VISP1 acts as a selective autophagy receptor to mediate degradation of suppressors of RNA silencing (VSRs) of several RNA and DNA viruses. Moreover, VISP1 induces symptom recovery through fine-tuning the balance of plant immunity and virus pathogenicity. Our findings provide new insights into the double-edged sword roles of selective autophagy in plant-virus interactions.

Effects of ZSM-5 zeolite on pyrolysis of polystyrene: from stabilizing to catalyzing.

Nonisothermal pyrolysis measurements of polystyrene (PS)/ZSM-5 zeolite hybrids are conducted in N2 and thermogravimetric results have been kinetically analyzed with different isoconversional methods. Experimental results show that the addition of 5 and 10 wt.% ZSM-5 zeolite has increased the initial pyrolysis temperature of PS while the addition of 20 and 30 wt.% ZSM-5 zeolite can significantly decrease the initial pyrolysis temperature of PS. Elevated activation energy is resulted by adding low zeolite amount whereas reduced activation energy is obtained by adding high ZSM-5 amounts. The effect of zeolite ZSM-5 on PS pyrolysis can thus be observed to transfer from stabilizing to catalyzing. Furthermore, the pyrolysis mechanism functions of PS/zeolite hybrids are determined by integrating the master plots method with a new compensation effect method, and the most appropriate reaction models are found to be F0.92, F0.85, F0.56 and A1.32 for describing the pyrolysis of the PS/ZSM-5 hybrids with a zeolite loading of 5, 10, 20 and 30 wt.%, respectively. With the kinetic parameters thus available, the temperature-dependent mass conversion curves have been recast, leading to satisfactory simulations for PS/ZSM-5 hybrids.

A selective autophagy receptor VISP1 induces symptom recovery by targeting viral silencing suppressors.

Selective autophagy is a double-edged sword in antiviral immunity and regulated by various autophagy receptors. However, it remains unclear how to balance the opposite roles by one autophagy receptor. We previously identified a virus-induced small peptide called VISP1 as a selective autophagy receptor that facilitates virus infections by targeting components of antiviral RNA silencing. However, we show here that VISP1 can also inhibit virus infections by mediating autophagic degradation of viral suppressors of RNA silencing (VSRs). VISP1 targets the cucumber mosaic virus (CMV) 2b protein for degradation and attenuates its suppression activity on RNA silencing. Knockout and overexpression of VISP1 exhibit compromised and enhanced resistance against late infection of CMV, respectively. Consequently, VISP1 induces symptom recovery from CMV infection by triggering 2b turnover. VISP1 also targets the C2/AC2 VSRs of two geminiviruses and enhances antiviral immunity. Together, VISP1 induces symptom recovery from severe infections of plant viruses through controlling VSR accumulation.