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Manipulating spin polarization orientation is challenging but crucial for field-free spintronic devices. Although such manipulation has been demonstrated in a limited number of antiferromagnetic metal-based systems, the inevitable shunting effects from the metallic layer can reduce the overall device efficiency. In this study, we propose an antiferromagnetic insulator-based heterostructure NiO/Ta/Pt/Co/Pt for such spin polarization control without any shunting effect in the antiferromagnetic layer. We show that zero-field magnetization switching can be realized and is related to the out-of-plane component of spin polarization modulated by the NiO/Pt interface. The zero-field magnetization switching ratio can be effectively tuned by the substrates, in which the easy axis of NiO can be manipulated by the tensile or compressive strain from the substrates. Our work demonstrates that the insulating antiferromagnet based heterostructure is a promising platform to enhance the spin-orbital torque efficiency and achieve field-free magnetization switching, thus opening an avenue towards energy-efficient spintronic devices. Electrically switching perpendicular magnetized ferromagnets using spin-orbit torques without assisting magnetic fields is a major goal for spintronics. Recently, several works have proposed using out-of-plane spin polarized currents to achieve this, but these rely on antiferromagnetic metals with low Neel temperatures. Here, Wang et al show that such out-of-plane spin polarization driven switching can be achieved using the interface of an antiferromagnetic insulator and a heavy metal.

Special delivery for siRNAs The therapeutic potential of gene silencing with siRNAs (short interfering RNAs) is great — in theory. In practice many obstacles will need to be overcome before it becomes a practical proposition, and one of those is the safe delivery of the siRNA to its target tissue. A new delivery system described in this issue may prove to be a significant step towards that end. siRNAs designed to silence expression of the enzyme MAP4k4 in macrophages were encapsulated in micrometre-sized β1,3- D -glucan particles and administered orally to mice. The encapsulated siRNA increased survival rates in mice with lipopolysaccharide-induced inflammation — a common model for inflammatory diseases — and suppressed systemic inflammation. The method is up to 250 times more potent in vivo than previously reported forms of systemic siRNA delivery. Encapsulated small interfering RNA nanoparticles are shown to silence a kinase mediator of inflammatory responses in mice in vitro and in vivo . Gene silencing by double-stranded RNA, denoted RNA interference, represents a new paradigm for rational drug design 1 . However, the transformative therapeutic potential of short interfering RNA (siRNA) has been stymied by a key obstacle—safe delivery to specified target cells in vivo 2 . Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes 3 . Here we report the engineering of β1,3- d -glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo . Oral gavage of mice with GeRPs containing as little as 20 μg kg -1 siRNA directed against tumour necrosis factor α (Tnf-α) depleted its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum Tnf-α levels. Screening with GeRPs for inflammation genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting Tnf-α and interleukin-1β production. This technology defines a new strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease.

Cytochrome P450 enzymes (CYPs) play a crucial role in phase I metabolic reactions. The activity of CYPs would affect therapeutic efficacy and may even induce toxicity. Given the complex components of traditional Chinese medicine, it is important to understand the effect of active ingredients on CYPs activity to guide their prescription. This study aimed to evaluate the effect of polyphyllin H on the activity of CYPs major isoforms providing a reference for the clinical prescription of polyphyllin H and its source herbs. The effects of polyphyllin H were evaluated in pooled human liver microsomes using probe substrates of CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 to determine their activities. The Lineweaver‐Burk was used to model the inhibition, and a time‐dependent inhibition experiment was performed to understand the characteristics of the inhibition. Polyphyllin H significantly suppressed the activity of CYP1A2, 2D6, and 3A4 with IC50 values of 6.44, 13.88, and 4.52 μM, respectively. The inhibition of CYP1A2 and 2D6 was best fitted with a competitive model, yielding the inhibition constant (Ki) values of 3.18 and 6.77 μM, respectively. The inhibition of CYP3A4 was fitted with the non‐competitive model with the Ki value of 2.38 μM. Moreover, the inhibition of CYP3A4 was revealed to be time‐dependent with the inhibition parameters inhibition constant (KI) and inactivation rate constant (Kinact) values of 2.26 μM−1 and 0.045 min−1. Polyphyllin H acted as a competitive inhibitor of CYP1A2 and 2D6 and a non‐competitive and time‐dependent inhibitor of CYP3A4.

Plant viruses seriously disrupt crop growth and development, and classic protein-targeted antiviral drugs could not provide complete protection against them. It is urgent to develop antiviral compounds with novel targets. Photodynamic therapy shows potential in controlling agricultural pests, but nonselective damage from reactive oxygen species (ROS) unexpectedly affects healthy tissues. A G-quadruplex (G4)-forming sequence in the tobacco mosaic virus (TMV) genome was identified to interfere the RNA replication in vitro , and affect the proliferation of TMV in tobacco. N -methyl mesoporphyrin IX stabilizing the G4 structure exhibited inhibition against viral proliferation, which was comparable to the inhibition effect of ribavirin. This indicated that G4 could work as an antiviral target. The large conjugate planes shared by G4 ligands and photosensitizers (PSs) remind us that the PSs could work as antiviral agents by targeting G4 in the genome of TMV. Chlorin e6 (Ce6) was identified to stabilize the G4 structure in the dark and selectively cleave the G4 sequence by producing ROS upon LED-light irradiation, leading to 92.2% inhibition against TMV in vivo , which is higher than that of commercial ningnanmycin. The inhibition of Ce6 was lost against the mutant variants lacking the G4-forming sequence. These findings indicated that the G-quadruplex in the TMV genome worked as an important structural element regulating viral proliferation, and could act as the antiviral target of photodynamic therapy.

Glutamine and glutamate have been widely explored as potential therapeutic targets in acute myeloid leukemia (AML). In addition to its bioenergetic role in leukemia cell proliferation, L‐glutamate is a neurotransmitter that acts on glutamate receptors. However, the role of glutamate receptors in AML is largely understudied. Here, we comprehensively analyze the genomic and transcriptomic alterations of glutamate receptor genes in AML using publicly available data. We investigated the frequency of mutations in the glutamate receptor genes and whether an association exist between the presence of these mutations and clinical and molecular characteristics or patient's clinical outcome. We also assessed the dysregulation of glutamate receptor gene expression in AML with and without mutations and whether gene dysregulation is associated with clinical outcomes. We found that 29 (14.5%) of 200 patients with AML had a mutation in at least one glutamate receptor gene. The DNMT3A mutations were significantly more frequent in patients with mutations in at least one glutamate receptor gene compared with patients without mutations (13 of 29 [44.8%] vs. 41 of 171 [23.9%], p value: 0.02). Notably, patients with mutations in at least one glutamate receptor gene survived shorter than patients without mutations; however, the results did not reach statistical significance (overall survival: 15.5 vs. 19.0 months; p value: 0.10). Mutations in the glutamate receptor genes were not associated with changes in gene expression and the transcriptomic levels of glutamate receptor genes were not associated with clinical outcome.

Increasing numbers of SARS-CoV-2-positive (SARS-CoV-2 pos ) subjects are detected at silent SARS-CoV-2 infection stage (SSIS). Yet, SSIS represents a poorly examined time-window wherein unknown immunity patterns may contribute to the fate determination towards persistently asymptomatic or overt disease. Here, we retrieved blood samples from 19 asymptomatic and 12 presymptomatic SARS-CoV-2 pos subjects, 47 age/gender-matched patients with mild or moderate COVID-19 and 27 normal subjects, and interrogated them with combined assays of 44-plex CyTOF, RNA-seq and Olink. Notably, both asymptomatic and presymptomatic subjects exhibited numerous readily detectable immunological alterations, while certain parameters including more severely decreased frequencies of CD107a low classical monocytes, intermediate monocytes, non-classical monocytes and CD62L hi CD8 + T naïve cells, reduced plasma STC1 level but an increased frequency of CD4 + NKT cells combined to distinguish the latter. Intercorrelation analyses revealed a particular presymptomatic immunotype mainly manifesting as monocytic overactivation and differentiation blockage, a likely lymphocyte exhaustion and immunosuppression, yielding mechanistic insights into SSIS fate determination, which could potentially improve SARS-CoV-2 management.

Background Agarwood is an expensive resinous heartwood derived from Aquilaria plants that is widely used in traditional medicines, incense and perfume. Only wounded trees can produce agarwood, and the huge demand for the agarwood products has led all Aquilaria spp. being endangered and listed in the Appendix II of the CITES ( http://www.cites.org ). The major components of agarwood are sesquiterpenes and phenylethyl chromones. Owing to a lack of genomic information, the molecular basis of wound-induced sesquiterpenes biosynthesis and agarwood formation remains unknown. Results To identify the primary genes that maybe related to agarwood formation, we sequenced 2 cDNA libraries generated from healthy and wounded A. sinensis (Lour.) Gilg. A total of 89,137 unigenes with an average length of 678.65 bp were obtained, and they were annotated in detail at bioinformatics levels. Of those associated with agarwood formation, 30 putatively encoded enzymes in the sesquiterpene biosynthesis pathway, and a handful of transcription factors and protein kinases were related to wound signal transduction. Three full-length cDNAs of sesquiterpene synthases ( ASS1-3 ) were cloned and expressed in Escherichia coli , and enzyme assays revealed that they are active enzymes, with the major products being δ-guaiene. A methyl jasmonate (MJ) induction experiment revealed that the expression of ASS was significantly induced by MJ, and the production of sesquiterpenes was elevated accordingly. The expression of some transcription factors and protein kinases, especially MYB4 , WRKY4 , MPKK2 and MAPK2 , was also induced by MJ and coordinated with ASS expression, suggesting they maybe positive regulators of ASS . Conclusions This study provides extensive transcriptome information for Aquilaria spp . and valuable clues for elucidating the mechanism of wound-induced agarwood sesquiterpenes biosynthesis and their regulation.

Gas expansion induced by formation uplift plays a crucial role in gas accumulation and secondary reservoir charging. However, in tight sandstones, macroscopic experiments fail to accurately characterize gas saturation changes due to the presence of small pore-throat networks and strong heterogeneity. To address this, we conducted a series of pore-scale analyses, including mercury intrusion, gas adsorption, and NMR, complemented by laser spectrometry and fluid inclusion measurements. Results showed that, as a typical tight sandstone, 87.53% of rigid minerals ensured effective elastic expansion of the reservoir, providing mineral foundation for natural gas expansion. Morphological methods enhanced the full-scale pore-throat radius distribution for various experimental techniques, and the full-scale pore-throat radius distribution based on the T2 spectrum was established by a combined interpolation fitting method. Under the condition of a pressure difference of 8 MPa, the core experiment measured a natural gas expansion averaged rate of 10.98%, confirming from an experimental perspective the formation of natural gas reservoirs caused by formation uplifting. As the pressure difference increased, the contribution of microscopic geological factors to natural gas expansion became more significant. Large pores, homogeneous pore-throats, and abundant clay minerals are effective promoters of natural gas expansion, and the reservoir formation effect of natural gas expansion in the eastern part of the study area is more pronounced. This study provides experimental evidence for the formation of tight gas reservoirs through expansion, and the related results help improve the recovery rate of tight gas and other field work.

Background: The coronary microvascular dysfunction has attracted more and more attention in recent years, but there is still a lack of effective treatment. Shexiang Baoxin Pill is one of the commonly used drugs for the treatment of coronary artery disease in China. More recently, some studies found that it has the effect of improving coronary microvascular function. Objective: To evaluate the effects of Shexiang Baoxin Pill for coronary microvascular function. Methods: Databases including MEDLINE, Web of Science, CNKI, Wanfang, The Cochrane Library, EMbase, VIP and CBM were searched from inception to June 2021 to screen out relevant clinical studies. The 2019 version 2 of the Cochrane risk of bias tool (RoB2) were used to assess the methodological quality of the included studies. RevMan 5.3 software was used for meta-analysis. Results: Eleven studies meeting the criteria were included, with a total of 1,075 patients. The results of meta-analysis showed that compared with conventional treatment alone, combination of Shexiang Baoxin Pill and conventional treatment can further increase the coronary flow reserve (CFR) [mean difference (MD) = 0.43, 95%CI (0.28, 0.58), p < 0.000 01], decrease the index of microvascular resistance (IMR) [MD = −4.23, 95%CI (−5.49, −2.97), p < 0.000 01], increase serum nitric oxide (NO) [MD = 11.96, 95%CI (2.74, 21.18), p = 0.001] and decrease serum hypersensitive C-reactive protein (hs-CRP) [MD = −2.49, 95%CI (−3.08, −1.90), p < 0.000 01], but did not increase the time of duration on the exercise testing (TET) [MD = 3.64, 95%CI (−1.17, 8.45), p = 0.14]. In terms of safety, a total of 10 patients developed adverse reactions in the intervention group and 17 patients developed adverse reactions in the control group. Conclusion: Current evidence suggests that Shexiang Baoxin Pill may be effective in the improvement of coronary microvascular function when used in combination with conventional treatment. However, due to the low quality of the included studies, lack of placebo control and high heterogeneity among different studies, we should take a cautious attitude towards this conclusion. Moreover, the safety of Shexiang Baoxin Pill remains uncertain, more high-quality clinical studies are needed to verify the efficacy and safety of this drug in the future. Systematic Review Registration: [website], identifier [registration number: CRD42021265113].

Conventional ground survey data are very accurate, but expensive. Airborne lidar data can reduce the costs and effort required to conduct large-scale forest surveys. It is critical to improve biomass estimation and evaluate carbon stock when we use lidar data. Bayesian methods integrate prior information about unknown parameters, reduce the parameter estimation uncertainty, and improve model performance. This study focused on predicting the independent tree aboveground biomass (AGB) with a hierarchical Bayesian model using airborne LIDAR data and comparing the hierarchical Bayesian model with classical methods (nonlinear mixed effect model, NLME). Firstly, we chose the best diameter at breast height (DBH) model from several widely used models through a hierarchical Bayesian method. Secondly, we used the DBH predictions together with the tree height (LH) and canopy projection area (CPA) derived by airborne lidar as independent variables to develop the AGB model through a hierarchical Bayesian method with parameter priors from the NLME method. We then compared the hierarchical Bayesian method with the NLME method. The results showed that the two methods performed similarly when pooling the data, while for small sample sizes, the Bayesian method was much better than the classical method. The results of this study imply that the Bayesian method has the potential to improve the estimations of both DBH and AGB using LIDAR data, which reduces costs compared with conventional measurements.