Electrical-Controllable Antiferromagnet-Based Tunnel Junction.

An electrical-controllable antiferromagnet tunnel junction is a key goal in spintronics, holding immense promise for ultradense and ultrastable antiferromagnetic memory with high processing speed for modern information technology. Here, we have advanced toward this goal by achieving an electrical-controllable antiferromagnet-based tunnel junction of Pt/Co/Pt/Co/IrMn/MgO/Pt. The exchange coupling between antiferromagnetic IrMn and Co/Pt perpendicular magnetic multilayers results in the formation of an interfacial exchange bias and exchange spring in IrMn. Encoding information states "0" and "1" is realized through the exchange spring in IrMn, which can be electrically written by spin-orbit torque switching with high cyclability and electrically read by antiferromagnetic tunneling anisotropic magnetoresistance. Combining spin-orbit torque switching of both exchange spring and exchange bias, a 16 Boolean logic operation is successfully demonstrated. With both memory and logic functionalities integrated into our electrically controllable antiferromagnetic-based tunnel junction, we chart the course toward high-performance antiferromagnetic logic-in-memory.

Direct 1,6-Difluoromethylation of 3-Methyl-4-nitro-5-styryl Isoxazoles by Photoredox-Promoted Radical Addition.

The photoredox-catalyzed 1,6-difluoromethylation of 3-methyl-4-nitro-5-styrylisoxazole with HCF2SO2Na has been developed. Structurally diverse difluoromethylated products were obtained in good yields, and their further transformations were also investigated. The di-, tri-, and monofluoromethylation of the substrates were compared, and the yield of the difluoromethylation was the highest. DFT calculations revealed that in the difluoromethylation reaction the CF2H radical was nucleophilic, and the transition state activation energy was the lowest.

[Sesquiterpenes from stems of Schisandra henryi var. henryi].

The dried stems of Schisandra henryi var. henryi were extracted with 95% ethanol and the extracts were further subjected to partition, affording the ethyl acetate extracts(EtOAc Extrs.).The EtOAc Extrs.were separated and purified with silica gel and octadecyl-silylated silica gel column chromatography, preparative HPLC and preparative TLC. Thirteen known compounds were obtained and identified by spectral methods including MS and NMR, all of which were elucidated as t-cadinol(1), cadinane-4ß,5α,10ß-triol(2), cadinane-5α, 10α-diol-2-ene(3), oxyphyllenodiols A(4), 1ß, 4ß-dihydroxyeudesman-11-ene(5), cyperusol C(6), (7R)-opposit-4(15)-ene-1ß,7-diol(7), dysodensiol E(8), epi-guaidiol A(9), aromadendrane-4ß,10ß-diol(10), tricyclohumuladiol(11), caryolane-1,9ß-diol(12), and guaidiol A(13). Compounds 3, 5-10, and 13 were separated from the genus for the first time, while compounds 1-13 were separated from this species for the first time.

AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF-ß receptor II signaling.

The generation of CD4⁺Foxp3⁺ Treg cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent studies have shown Treg-cell plasticity when Th-related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of Treg cells are poorly understood. Here, using mice with a T-cell-specific deletion of the transforming growth factor-ß receptor 2 (Tgfbr2⁻/⁻ mice), we identify the restriction of AKT activation as a key event for the control of Treg-cell stability in Th1 inflammation. AKT regulation was evident in thymic CD4⁺Foxp3⁺ Treg cells before they egressed to peripheral tissues. CD4⁺Foxp3⁺ thymocytes from mice with the Tgfbr2 deletion expressed high levels of CXCR3 and T-bet, and produced IFN-γ and TNF-α. Thymic Tgfbr2⁻/⁻ Treg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN-γ both in natural and inducible Treg cells. Inhibition of AKT activity markedly attenuated the expression of IFN-γ and TNF-α in thymic Tgfbr2⁻/⁻ Treg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF-ß signaling maintained Treg-cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of Treg cells to a Th1 phenotype.

Chicken feedlot revisited: Co-dispersal of antibiotic and metal resistome under banning in-feed veterinary antibiotics.

Intensive livestock farming has been implicated as a notorious hotspot for antibiotic resistance genes (ARGs) due to the excessive or inappropriate use of in-feed antibiotics over the past few decades. Since China implemented a ban on the use of antibiotics in animal feed since 2020, the dissemination of ARGs in the vicinity of feedlots has remained unclear. This study presents a case study that aims to investigate the dispersal of antibiotics and ARGs from a chicken feedlot (established in 2020) to the adjacent aquatic and soil environments. Comparing the sample collected from upstream area, the water and sediment samples from midstream and downstream areas showed an increase in total antibiotic residues and metal content (Cu and Zn) by 4.2-5.3 fold and 1.3-22.6 fold, respectively. The downstream water samples exhibited a 2.49-2.93-fold increase in the abundance of ARGs and a 1.48-1.75-fold increase in the abundance of metal resistance genes (MRGs). The results of Pearson correlation and metagenome-assembled genome revealed a tendency for the co-occurrence of ARGs and MRGs. The dissemination of ARGs and MRGs is primarily driven by tetracycline, tylosin, Cu, and, Mn, with mobile genetic elements playing a more significant role than bacterial communities. These findings shed light on the overlooked co-dispersal pattern of ARGs and MRGs in the environment surrounding feedlots, particularly in the context of banning in-feed veterinary antibiotics.

Myeloid TGF-ß signaling contributes to colitis-associated tumorigenesis in mice.

Myeloid cells have a critical role in maintaining intestinal homeostasis and regulating the development of inflammatory bowel disease and colitis-associated cancer (CAC). However, the signaling pathways that control the function of colonic myeloid cells in these pathological processes are still poorly defined. In this study, we demonstrate that transforming growth factor-ß (TGF-ß) signaling in colonic myeloid cells is significantly involved in the development of CAC. Myeloid TGF-ß receptor II (Tgfbr2)-deficient mice showed reduced susceptibility to chemically induced colitis-associated tumorigenesis, as evidenced by decreases in number and size of tumors. Myeloid Tgfbr2 deficiency markedly decreased the production of interleukin-6 and tumor necrosis factor-α, two proinflammatory cytokines that are essential for colonic tumorigenesis; in addition, a marked increase in the proportions of Foxp3+CD4+ regulatory T cells was observed in the colonic lamina propria in the initial stage of CAC. Loss of myeloid Tgfbr2 was associated with a decrease in the presence of F4/80 positive macrophages and a downregulation of phosphorylated STAT3, proliferative cell nuclear antigen and cyclin D1 expression in colonic adenoma tissues. TGF-ß enhanced macrophage recruitment, at least in part, through modulating the expression of the chemokine (C-C motif) receptor 2 (CCR2) ligands in tumor environment and the CCR2 signaling in macrophages. Collectively, these results suggest that myeloid TGF-ß signaling modulates intestinal inflammation and significantly promotes tumorigenesis in the development of colitis-associated colon cancer.

(Z)-3ß-(2-Chloro-anilino)-17(20)-pregnene.

In the pregnene fragment of the title compound, C27H38ClN, the three six-membered rings exhibit chair conformations and the five-membered ring has a distorted envelope form with the fused C atom not bearing a methyl group as the flap atom. The amino group is involved in the formation of an intra-molecular N-H⋯Cl hydrogen bond. The crystal packing exhibits no short inter-molecular contacts.

Application of hinokitiol potassium salt for wood preservative.

The decay of wood and other cellulosic materials by fungi cause significant economic loss. The widely used chromated copper arsenate was prohibited for the environmental impact and safety of arsenic and chromium. It was found that natural product hinokitiol (HK) had fungicidal and insecticidal activities, and its toxicity was bearable for the environment. We described the practical synthesis of HK-K salt. According to the GB/T18261-2000 and LY/T1283-1998, wood preservative performance of HK-K salt was tested. The results showed that the best inhibitory concentration of HK-K salt was 50 mg/L, for which the prevention effectiveness on mold is better, the killed value is between 0 and 1, and the corrosion-resistant for wood-rotting fungi is grade A.

Carboxyl position-directed structure diversity in zirconium-tricarboxylate frameworks.

Herein, three tritopic carboxylic acids were used to construct three Zr-MOFs, HIAM-4033, HIAM-4034, and HIAM-4035, to investigate the effect of carboxyl position on the MOF structures. The results showed that HIAM-4033 and HIAM-4034 possess (3,9)-c models with different underlying nets, whereas HIAM-4035 exhibits the same underlying net as UiO-68. Nanosized HIAM-4033 exhibits excellent sensitivity and selectivity for detecting aromatic acids, such as benzoic acid and 2-fluorobenzoic acid, compared with aliphatic acids and inorganic acids. This study offers new insights into achieving an organic linker directed structure evolution of Zr-MOFs, which might facilitate the discovery of unprecedented underlying nets.

12α-Hy-droxy-3,27-dioxooleanano-28,13-lactone.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(30)H(44)O(5). They comprise a triterpenoid skeleton of five six-membered rings and a five-membered lactone ring. The five six-membered rings are all trans-fused. In both independent mol-ecules the D rings adopt a slightly distorted half-chair conformation due the presence of the lactone ring while the other four six-membered rings all adopt chair conformations. The characteristic carbon-carbon double bond of the oleanoic skeleton is absent. Inter-molecular O-H⋯O hydrogen bonds between the hy-droxy and carbonyl groups occur in the crystal structure.

A Potential In Vitro 3D Cell Model to Study Vascular Diseases by Simulating the Vascular Wall Microenvironment and Its Application.

BACKGROUND: Current in vitro vascular models are too simple compared with the real vascular environment. In this research, a novel in vitro 3D vascular disease model that simulated the vascular microenvironment was introduced. METHODS: This model was mainly established by low shear stress and co-culture of endothelial cells and smooth muscle cells. Characterization and reproduction of the pathological state of the 3D model were determined. The effect of two clinical drugs was verified in this model. The difference of drug screening between a traditional oxidative-damaged cell model and this 3D model was determined by HPLC. RESULTS: This model presented many disease markers of vascular diseases: abnormal cellular shape, higher endothelial cell apoptotic rate and smooth muscle cell migration rate, decreased superoxide dismutase level, and increased malondialdehyde and platelet-derived growth factor level. The drugs effectively reduced the disease indices and relieved the damage caused by low shear stress. Compared to the traditional oxidative-damaged cell model, this 3D model screened different active components of Salviae Miltiorrhizae extract, and it is closer to clinical studies. CONCLUSIONS: These results suggest that the 3D vascular disease model is a more efficient and selective in vitro study and drug screening platform for vascular diseases than previously reported in vitro vascular disease models.

Rational Design of High-Performance Keratin-Based Hemostatic Agents.

Keratins are considered ideal candidates as hemostatic agents, but the development lags far behind their potentials due to the poorly understood hemostatic mechanism and structure-function relations, owing to the composition complexity in protein extracts. Here, it is shown that by using a recombinant synthesis approach, individual types of keratins can be expressed and used for mechanism investigation and further high-performance keratin hemostatic agent design. In the comparative evaluation of full-length, rod-domain, and helical segment keratins, the α-helical contents in the sequences are identified to be directly proportional to keratins' hemostatic activities, and Tyr, Phe, and Gln residues at the N-termini of α-helices in keratins are crucial in fibrinopeptide release and fibrin polymerization. A feasible route to significantly enhance the hemostatic efficiency of helical keratins by mutating Cys to Ser in the sequences for enhanced water wettability through soluble expression is then further presented. These results provide a rational strategy to design high-efficiency keratin hemostatic agents with superior performance over clinically used gelatin sponge in multiple animal models.

3ß-Acet-oxy-12-oxoolean-28-oic acid benzyl ester.

The mol-ecule of title compound, C(39)H(56)O(5), contains five fused six-membered rings, four of which (rings A, B, D and E) adopt a chair conformation, while the other (ring C) has a half chair conformation. The acet-oxy and carb-oxy-benzyl groups occupy equatorial positions.

Nanoparticle encapsulated core-shell hydrogel for on-site BMSCs delivery protects from iron overload and enhances functional recovery.

The local microenvironment may influence the success of stem cell therapy. Iron overload occurs in many hemorrhagic injuries due to hemolysis and hemoglobin degradation, which not only mediates local cell injury, but also induces damage to the transplanted cells. Here, an injectable nanoparticle encapsulated core-shell hydrogel was fabricated for simultaneous iron overload clearance and bone marrow mesenchymal stem cells (BMSCs) transplantation following intracerebral hemorrhage (ICH). The iron chelator-loaded low-molecular-weight keratin hydrogel with quick degradation property was selected as the outer shell to eliminate iron overload, and BMSCs implantation with high-molecular-weight keratin hydrogel was selected as the inner core. The epidermal growth factor and the basic fibroblast growth factor were entrapped within the poly (lactic-co-glycolic acid) (PLGA) nanoparticle, which was then encapsulated into the core hydrogel to support the BMSC growth and differentiation. The core-shell hydrogel can be easily formed by programmed injections, and the core-shell hydrogel displayed a strong protective effect against the toxicity of hemoglobin in cell experiments. Furthermore, more BMSCs survived in the core-shell hydrogel group in vivo as compared to that in the core hydrogel group and the vehicle group. Less iron deposition and ventricular enlargement, lower brain water content, and faster neurological recovery were also observed. The data demonstrated that this core-shell hydrogel is an effective strategy for promoting transplanted cell survival under the condition of an iron overload.

Triterpenes from Astilbe chinensis.

Six new triterpenes, 3beta,6beta-dihydroxyurs-12-en-27-oic acid (1), 3beta,6beta,24-trihydroxyurs-12-en-27-oic acid (2), 3beta,6beta,7alpha-trihydroxyurs-12-en-27-oic acid (3), 3beta-acetoxy-6beta-hydroxyurs-12-en-27-oic acid (4), 3beta,6beta,24-trihydroxyolean-12-en-27-oic acid (5), and 3beta,6beta,7alpha-trihydroxyolean-12-en-27-oic acid (6), were isolated from the rhizomes of Astilbe chinensis. Their structures were elucidated on the basis of 1D- and 2D-NMR analyses and HR-MS experiments. The isolated compounds exhibited significant cytotoxic activities against the SK-N-SH and HL-60 cell lines.

Human Hair Keratin Hydrogels Alleviate Rebleeding after Intracerebral Hemorrhage in a Rat Model.

Surgery is an important therapeutic strategy for intracerebral hemorrhage (ICH) in the clinic and is theoretically beneficial for the outcome of ICH by decreasing hematoma, reducing nervous tissue damage, and removing harmful chemicals. However, the outcome of ICH surgery is always unsatisfactory due to postoperative rebleeding. We hypothesized that the injection of hemostatic agents in situ after aspiration surgery could immediately activate hemostasis once rebleeding occurs. Therefore, keratin hydrogels (K-gels) were easily prepared as a hemostatic material via a rehydration method and had a porous structure. Collagenase was injected into the basal lamina to mimic ICH rebleeding, and the K-gels were then injected into the same injured site after 2 h for hemostatic therapy. The hematoma volume was significantly reduced by K-gel treatment, indicating that in situ infusion of the K-gels inhibited hematoma enlargement when rebleeding occurred. Moreover, brain damage, including cell apoptosis, neuroinflammatory reactions, and neurological deficits, was also relieved after K-gel treatment. These results suggested that in situ injection of the K-gels into the hematoma area after ICH surgery improves the therapeutic outcome by stopping postoperative rebleeding. K-gels have great potential for clinical hemostatic application because of their excellent hemostatic properties and biocompatibility.

Cyclophilin A is an important mediator of platelet function by regulating integrin αIIbß3 bidirectional signalling.

Cyclophilin A (CyPA) is an important mediator in cardiovascular diseases. It possesses peptidyl-prolyl cis-trans isomerase activity (PPIase) and chaperone functions, which regulate protein folding, intracellular trafficking and reactive oxygen species (ROS) production. Platelet glycoprotein receptor αIIbß3 integrin activation is the common pathway for platelet activation. It was our objective to understand the mechanism by which CyPA-regulates αIIbß3 activation in platelets. Mice deficient for CyPA (CyPA-/-) had prolonged tail bleeding time compared to wild-type (WT) controls despite equivalent platelet numbers. In vitro studies revealed that CyPA-/- platelets exhibited dramatically decreased thrombin-induced platelet aggregation. In vivo, formation of occlusive thrombi following FeCl3 injury was also significantly impaired in CyPA-/- mice compared with WT-controls. Furthermore, CyPA deficiency inhibited flow-induced thrombus formation in vitro. Flow cytometry demonstrated that thrombin-induced ROS production and αIIbß3 activation were reduced in CyPA-/- platelets. Coimmunoprecipitation studies showed ROS-dependent increased association of CyPA and αIIbß3. This association was dependent upon the PPIase activity of CyPA. Significantly, fibrinogen-platelet binding, platelet spreading and cytoskeleton reorganisation were also altered in CyPA-/- platelets. Moreover, CyPA deficiency prevented thrombin-induced αIIbß3 and cytoskeleton association. In conclusion, CyPA is an important mediator in platelet function by regulation of αIIbß3 bidirectionalsignalling through increased ROS production and facilitating interaction between αIIbß3 and the cell cytoskeleton.

A potential model for drug screening by simulating the effect of shear stress in vivo on endothelium.

The purpose of this paper was to research the potential of a dynamic cell model in drug screening by studying the influence of microvascular wall shear stress on the drug absorption of endothelial cells compared to that in the static state. The cells were grown and seeded on gelatin-coated glass slides and were pretreated with extracts of Salviae miltiorrhizae (200 µg/ml) for 1 h. Then oxidative stress damage was produced by H2O2 (300 µmol/l) for 0.5 h under the 1.5 dyn/cm2 shear stress incorporated in a parallel plate flow chamber. Morphological analysis was conducted with an inverted microscope and image analysis software, and high performance liquid chromatography-mass spectrometry was used for the detection of active compounds. We compared the drug absorption in the dynamic group with that in the static group. In the dynamic model, five compounds and two new metabolite peaks were detected. However, in the static model, four compounds were absorbed by cells, and one metabolite peak was found. This study indicated that there were some effects on the absorption and metabolism of drugs under the microvascular shear stress compared to that under stasis. We infer that shear stress in the microcirculation situation in vivo played a role in causing the differences between drug screening in vitro and in vivo.

Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.

Emerging evidence suggests that tumor-initiating cells (TICs) are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC) cells. Reactive oxygen species (ROS) initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

The screening toolbox of bioactive substances from natural products: a review.

Hunting lead compounds from natural products plays a vital role in finding successful drug candidates. The efficiency of screening campaigns is mainly determined by the validity of selected screening models. To screen desired lead compounds, researchers have developed a plethora of experimental screening models. However, the considerable diversity of screening models from animal models, tissue models, to cell models and so on, may cause some trouble in choosing the suitable one. This review provides a toolbox of experimental screening models that have been used to discover new drug candidates from natural products. Two screening indexes are designed for different research directions in this screening toolbox. Index I is proposed from the direction of screening different objective substance populations, including plant extracts, active fractions and pure compounds; index Π is according to screening different drug properties, including pharmacological properties, pharmacokinetic properties and affinity binding properties. We hope that the abbreviated bibliographies will help readers to quickly retrieve useful information by two screening indexes and provide certain reference value for choosing more appropriate screening models. Finally, we discuss ways of improving model systems, as well as future directions.