ORC1 enhances repressive epigenetic modifications on HIV-1 LTR to promote HIV-1 latency.

The human immunodeficiency virus type 1 (HIV-1) reservoir consists of latently infected cells which present a major obstacle to achieving a functional cure for HIV-1. The formation and maintenance of HIV-1 latency have been extensively studied, and latency-reversing agents (LRAs) that can reactivate latent HIV-1 by targeting the involved host factors are developed; however, their clinical efficacies remain unsatisfactory. Therefore, it is imperative to identify novel targets for more potential candidates or better combinations for LRAs. In this study, we utilized CRISPR affinity purification in situ of regulatory elements system to screen for host factors associated with the HIV-1 long terminal repeat region that could potentially be involved in HIV-1 latency. We successfully identified that origin recognition complex 1 (ORC1), the largest subunit of the origin recognition complex, contributes to HIV-1 latency in addition to its function in DNA replication initiation. Notably, ORC1 is enriched on the HIV-1 promoter and recruits a series of repressive epigenetic elements, including DNMT1 and HDAC1/2, and histone modifiers, such as H3K9me3 and H3K27me3, thereby facilitating the establishment and maintenance of HIV-1 latency. Moreover, the reactivation of latent HIV-1 through ORC1 depletion has been confirmed across various latency cell models and primary CD4+ T cells from people living with HIV-1. Additionally, we comprehensively validated the properties of liquid-liquid phase separation (LLPS) of ORC1 from multiple perspectives and identified the key regions that promote the formation of LLPS. This property is important for the recruitment of ORC1 to the HIV-1 promoter. Collectively, these findings highlight ORC1 as a potential novel target implicated in HIV-1 latency and position it as a promising candidate for the development of novel LRAs. IMPORTANCE: Identifying host factors involved in maintaining human immunodeficiency virus type 1 (HIV-1) latency and understanding their mechanisms prepares the groundwork to discover novel targets for HIV-1 latent infection and provides further options for the selection of latency-reversing agents in the "shock" strategy. In this study, we identified a novel role of the DNA replication factor origin recognition complex 1 (ORC1) in maintaining repressive chromatin structures surrounding the HIV-1 promoter region, thereby contributing to HIV-1 latency. This discovery expands our understanding of the non-replicative functions of the ORC complex and provides a potential therapeutic strategy for HIV-1 cure.

The construction of modular universal chimeric antigen receptor T (MU-CAR-T) cells by covalent linkage of allogeneic T cells and various antibody fragments.

BACKGROUND: Chimeric antigen receptor-T (CAR-T) cells therapy is one of the novel immunotherapeutic approaches with significant clinical success. However, their applications are limited because of long preparation time, high cost, and interpersonal variations. Although the manufacture of universal CAR-T (U-CAR-T) cells have significantly improved, they are still not a stable and unified cell bank. METHODS: Here, we tried to further improve the convenience and flexibility of U-CAR-T cells by constructing novel modular universal CAR-T (MU-CAR-T) cells. For this purpose, we initially screened healthy donors and cultured their T cells to obtain a higher proportion of stem cell-like memory T (TSCM) cells, which exhibit robust self-renewal capacity, sustainability and cytotoxicity. To reduce the alloreactivity, the T cells were further edited by double knockout of the T cell receptor (TCR) and class I human leukocyte antigen (HLA-I) genes utilizing the CRISPR/Cas9 system. The well-growing and genetically stable universal cells carrying the CAR-moiety were then stored as a stable and unified cell bank. Subsequently, the SDcatcher/GVoptiTag system, which generate an isopeptide bond, was used to covalently connect the purified scFvs of antibody targeting different antigens to the recovered CAR-T cells. RESULTS: The resulting CAR-T cells can perform different functions by specifically targeting various cells, such as the eradication of human immunodeficiency virus type 1 (HIV-1)-latenly-infected cells or elimination of T lymphoma cells, with similar efficiency as the traditional CAR-T cells did. CONCLUSION: Taken together, our strategy allows the production of CAR-T cells more modularization, and makes the quality control and pharmaceutic manufacture of CAR-T cells more feasible.

An Axially Chiral Styrene-Phosphine Ligand for Pd-Catalyzed Asymmetric N-Alkylation of Indoles.

An efficient palladium-catalyzed enantioselective direct N-alkylation of indoles using a novel type of axially chiral styrene-phosphine ligand SJTU-PHOS-1 was developed. This reaction demonstrated good functional group compatibility and a wide range scope of substrates in mild conditions. Moreover, the DFT calculations expounded the coordination mode of the metal catalyst and the axially chiral styrene-phosphine ligand in the enantioselectivity control.

Sizable spin-to-charge conversion in PLD-grown amorphous (Mo, W)Te2-xfilms.

We report on the spin-to-charge conversion (SCC) in Mo0.25W0.75Te2-x(MWT)/Y3Fe5O12(YIG) heterostructures at room temperature. The centimeter-scale amorphous MWT films are deposited on liquid-phase-epitaxial YIG by pulsed laser deposition technique. The significant SCC voltage is measured in the MWT layer with a sizable spin Hall angle of ∼0.021 by spin pumping experiments. The control experiments by inserting MgO or Ag layer between MWT and YIG show that the SCC is mainly attributed to the inverse spin Hall effect rather than the thermal or interfacial Rashba effect. Our work provides a novel spin-source material for energy-efficient topological spintronic devices.

Synthesis of a Bi3+-Doped Cs2HfCl6 Double Perovskite with Highly Efficient Blue Light Emission at Room Temperature.

Lead-free perovskites have been widely studied due to their environmental friendliness and high stability. In this study, Bi3+-doped Cs2HfCl6 has been synthesized at room temperature. Different from the emission of the Cs2HfCl6 host (452 nm), Bi3+:Cs2HfCl6 can produce a bright blue emission at an excitation wavelength of 350 nm, which is derived from the 3P1 → 1S0 transition of Bi ions and accompanied by the properties of self-trapped excitons. Moreover, 7%Bi3+:Cs2HfCl6 shows excellent stability with the photoluminescence quantum yield reaching up to 69.08%. Meanwhile, a light-emitting diode that is close to pure white light has been fabricated by using 7%Bi3+:Cs2HfCl6, which has a high color rendering index of 92.5. These results show that Bi3+:Cs2HfCl6 would be a potential candidate in the field of inorganic luminescent materials.

Efficient Broadband Yellow-Green Emission of Vacancy Halide Double Perovskites Through the Ion-Exchanged Strategy.

Broadband high-efficiency luminescent materials have become a hot spot in lead-free perovskite research. There are relatively few broadband yellow-green phosphors with both ultraviolet and blue excitation ranges, which make them more suitable for phosphor-converted white LEDs. Through the ion-exchanged strategy, Cs2Hf1-xTexCl6 (CH1-xTxC) vacancy halide double perovskites were successfully prepared at room temperature. Using different excitation ranges of CH1-xTxC, two types of high-quality white LEDs are obtained. By combining density functional theory calculations and experiments, it is proved that this bright broadband yellow-green emission (photoluminescence quantum yield of 83.46%) is not only derived from the ion transitions of Te4+ but also exhibits the inherent characteristics of self-trapped exciton emission. Our results not only broaden the application fields of lead-free halide perovskites but also provide further insights into the luminescence mechanism.

A turn-on fluorescent probe based on quinoline and coumarin for rapid, selective and sensitive detection of hypochlorite in water samples.

A fluorescent probe L-Cu2+ based on quinoline, coumarin and Cu2+ has been synthesized and characterized for hypochlorite determination. After copper ion was added to the solution of ligand L, the fluorescence quenching at 490 nm might result from a ligand-metal charge transfer (LMCT) process and its strong coordination ability for Cu2+ . In the presence of hypochlorite, the structure of ligand L was destroyed to form 7-(diethylamino)-coumarin-3-carboxylic acid, and the fluorescence was restored at 460 nm. In this case, L-Cu2+ complex could be used as a fluorescent probe to detect hypochlorite, with the advantages of rapid, selective, wide linear range and low detection limit.

Colorimetric sensing of iodide ions based on unmodified gold nanoparticles and the distinctive antiaggregation-to-aggregation process.

A highly sensitive and selective colorimetric analysis method based on unmodified gold nanoparticles (AuNPs) to detect iodide ions (I- ) in solution in the presence of hexadecyl trimethyl ammonium bromide (CTAB) and mercury ions (Hg2+ ) has been successfully developed. Hg2+ could form a gold amalgam with AuNPs to protect AuNPs from CTAB-induced aggregation caused by the electrostatic attraction between CTAB and citrate ion-covered AuNPs. When a mixture of Hg2+ and I- was added to the solution of AuNPs, the formation of the HgI2 complex destroyed the protection of Hg2+ for AuNPs, which led to the aggregation of AuNPs accompanied with the change in colour of the solution from red to grey black and decrease in the absorbance of AuNPs at 520 nm. There was a good linear relationship between A520nm and I- concentration from 0 to 800 nM with a low limit of detection (LOD) of 4.2 nM. Furthermore, this simple and reliable colorimetric sensor has been applied successfully to the detection of I- in practical samples.

Decreased levels of serum nesfatin-1 in patients with preeclampsia.

CONTEXT: Nesfatin-1 is implicated to possess an anti-inflammatory effect. OBJECTIVE: The aim of our study is to investigate whether abnormal serum levels of nesfatin-1 are associated with the presence and severity of preeclampsia. METHODS: A total of 120 women with preeclampsia and 92 women with uncomplicated pregnancies were enrolled in this study. RESULTS: Women with preeclampsia showed significantly reduced levels of serum nesfatin-1 levels than women with uncomplicated pregnancies. Serum nesfatin-1 levels were significantly decreased in women with severe preeclampsia compared with women with mild preeclampsia. CONCLUSION: Decreased serum nesfatin-1 levels are associated with the presence and severity of preeclampsia.

[Epidemiologic investigation of cardiac arrest and current research status on its risk factors analysis].

Cardiac arrest most commonly occurs outside of the hospital, known as out-of-hospital cardiac arrest (OHCA), and is an important global health problem. Approximately 40% of cardiac arrest has no clear cause. Hereditary arrhythmias and cardiomyopathies factors contribute to cardiac arrest. The identification of genetic factors for cardiac arrest after its occurrence is of great value not only for the individual, but also for relatives who may be at risk for the disease in their family. In the United States, there are over 350 000 cases of OHCA and over 200 000 cases of in-hospital cardiac arrest (IHCA) each year, and in Western Europe, cardiac arrest accounts for 15%-20% of all adult natural deaths and 50% of all cardiovascular deaths. In order to reduce the burden caused by cardiac arrest within society, it is essential to further understand its etiological factors, such as incidence in different regions, risk factors, and populations at higher risk. For each individual, cardiac arrest is the result of a complex interaction of genetic and acquired factors. Understanding the complex interplay of pathogenic factors in cardiac arrest and the development of individualized prevention and treatment approaches requires the collection of clinical data from cardiac arrest populations and multimodal analysis in order to identify epidemiological features and risk factors for cardiac arrest. Recently, cardiac arrest-related data are being collected and integrated in Europe in different regions and populations. As a result of the commitment to the creation of large datasets of clinical information on cardiac arrest populations, the knowledge of the pathology of cardiac arrest pathogenesis as well as risk factors is steadily increasing. This article reviews the epidemiologic data of cardiac arrest in recent years and the associated risk factors, thus providing ideas for developing better strategies for the prevention and treatment of cardiac arrest.

Long Noncoding RNA SOX2OT Ameliorates Sepsis-Induced Myocardial Injury by Inhibiting Cellular Pyroptosis Through Mediating the EZH2/Nrf-2/NLRP3 Signaling Pathway.

Objective: Cellular pyroptosis is a pro-inflammatory mode of programmed cell death that has been identified in recent years, and studies have shown that the LncRNA SOX2OT regulates myocardial injury during sepsis, but the exact regulatory mechanism is unclear. The aim of this study was to assess the role of SOX2OT in regulating cardiomyocyte injury during sepsis cardiomyopathy. Methods: Rat cardiomyocytes, C57BL/6 mice, and transgenic mice were divided into four groups: control, LPS, LPS+ knockout LncRNA SOX2OT, and LPS+ overexpression LncRNA SOX2OT. Inflammatory factor levels were detected by qPCR. Associated proteins and gene expression were detected by Western blotting and qPCR. Dual luciferase was used to detect the target genes of SOX2OT. Nrf2 and EZH2 knockdown and overexpression cell lines were established, and the expression of related genes was detected by qPCR. Results: Results In this study, we found that SOX2OT knockdown exacerbated LPS-induced levels of inflammatory factors and procalcitoninogen (PCT), and increased the expression of pyroptosis-related proteins and LDH. The results of dual luciferase reporter gene assay showed that EZH2 is the target gene of SOX2OT, and overexpression of SOX2OT decreased the expression of EZH2; we also found that knockdown of EZH2 in H9c2 cells decreased the expression of Nrf2, which was positively correlated with the expression level of NLRP3. Further in vivo results showed that overexpression of SOX2OT attenuated SIMD (sepsis-induced myocardial dysfunction), as evidenced by improved myocardial structural integrity and reduced inflammatory cell infiltration. The expression of pyroptosis-related proteins and LDH was significantly increased in the mice in the LPS group; this effect was reversed by overexpression of SOX2OT, and potentiated by knockdown of SOX2OT. Conclusion: Our data reveal a novel mechanism by which SOX2OT inhibits cardiomyocyte sepsis through the EZH2/Nrf-2/NLRP3 pathway, thereby attenuating septic myocardial injury, which may contribute to the development of new therapeutic strategies.

Regioselective Electrooxidative [3+2] Annulation between Indole and Aniline Derivatives to Construct Functionalized Indolo[2,3-b]indoles.

A protocol for the electrooxidative [3+2] annulation to generate indolo[2,3-b]indoles in an undivided cell is reported. It exhibits good yields with excellent regioselectivities and tolerates various functional groups without external chemical oxidants. Cyclic voltammetry and density functional theory calculations indicate that the [3+2] annulation is initiated by the simultaneous anodic oxidation of indole and aniline derivatives, and the step to determine the rate relies on the combination of radical cations.

Cooperative Cu/azodiformate system-catalyzed allylic C-H amination of unactivated internal alkenes directed by aminoquinoline.

Aliphatic allylic amines are common in natural products and pharmaceuticals. The oxidative intermolecular amination of C(sp3)-H bonds represents one of the most straightforward strategies to construct these motifs. However, the utilization of widely internal alkenes with amines in this transformation remains a synthetic challenge due to the inefficient coordination of metals to internal alkenes and excessive coordination with aliphatic and aromatic amines, resulting in decreasing the reactivity of the catalyst. Here, we present a regioselective Cu-catalyzed oxidative allylic C(sp3)-H amination of internal olefins with azodiformates to these problems. A removable bidentate directing group is used to control the regiochemistry and stabilize the π-allyl-metal intermediate. Noteworthy is the dual role of azodiformates as both a nitrogen source and an electrophilic oxidant for the allylic C-H activation. This protocol features simple conditions, remarkable scope and functional group tolerance as evidenced by >40 examples and exhibits high regioselectivity and excellent E/Z selectivity.

Harmonizing international quality standards for Andrographis paniculata: A comparative analysis of content determination methods across pharmacopeias.

The quality standards for Andrographis paniculata, a widely used medicinal herb, exhibited significant variations across different pharmacopeias. In this study, we compared the HPLC content determination methods and total lactone content of A. paniculata samples from different regions, as specified in the Chinese (CP), United States (USP), European (EP), Thai (TP), and Indian pharmacopeias (IP), as well as the Hong Kong Chinese Materia Medica Standards (HK). We aimed to assess the differences and similarities among these pharmacopeias and harmonized international quality standards for A. paniculata. The analysis revealed variations in sample preparation, liquid chromatographic conditions, fingerprint profiles, and total lactone content among the different pharmacopeias. Specifically, the CP and HK methods exhibited superior sample preparation and chromatographic separation. Further comparing the content of 20 A. paniculata samples with the CP, USP, EP and HK methods showed consistent determinations for the same components, indicating similar detection capabilities. The discrepancies in total lactone content primarily stemmed from differences in the number and types of detected compounds. Moreover, the acceptance criteria exhibited a stringency in the order CP > HK > EP > USP. In conclusion, this comparison analysis of content determination in CP, USP, HK, EP, TP and IP provided a scientific foundation for the international standardization and trade regulations of A. paniculata. It also served as a valuable reference for the development of international quality standards for other medicinal herbs, facilitating the harmonization of global pharmaceutical standards.

The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2.

Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19.IMPORTANCEIn addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

Defect-induced helicity dependent terahertz emission in Dirac semimetal PtTe2 thin films.

Nonlinear transport enabled by symmetry breaking in quantum materials has aroused considerable interest in condensed matter physics and interdisciplinary electronics. However, achieving a nonlinear optical response in centrosymmetric Dirac semimetals via defect engineering has remained a challenge. Here, we observe the helicity dependent terahertz emission in Dirac semimetal PtTe2 thin films via the circular photogalvanic effect under normal incidence. This is activated by a controllable out-of-plane Te-vacancy defect gradient, which we unambiguously evidence with electron ptychography. The defect gradient lowers the symmetry, which not only induces the band spin splitting but also generates the giant Berry curvature dipole responsible for the circular photogalvanic effect. We demonstrate that the THz emission can be manipulated by the Te-vacancy defect concentration. Furthermore, the temperature evolution of the THz emission features a minimum in the THz amplitude due to carrier compensation. Our work provides a universal strategy for symmetry breaking in centrosymmetric Dirac materials for efficient nonlinear transport.

Modification of Mg/Al-LDH by vanadate: effects on tribological properties and corrosion resistance.

In this study, Mg/Al layered double hydroxide (LDH) composite coatings were prepared on the surface of anodized 1060 aluminum alloy by an in situ growth method, and then the vanadate anions were embedded in the interlayer corridor of LDH by an ion exchange process. The morphology, structure and composition of the composite coatings were investigated using scanning electron microscopy, energy dispersive spectroscopy, X-ray diffractometry and Fourier transform infrared spectroscopy. Ball-and-disk friction wear experiments were carried out to measure the coefficient of friction, the amount of wear, and the morphology of the worn surface. The corrosion resistance of the coating is studied using dynamic potential polarisation (Tafel) and electrochemical impedance spectroscopy (EIS). The results showed that the LDH composite coating with unique layered nanostructure as a solid lubricating film can effectively improve the friction and wear reduction performance of the metal substrate. Chemical modification treatment by embedding vanadate anions in the LDH coating leads to the change of LDH layer spacing and the increase of interlayer channels, resulting in the best friction and wear reduction and corrosion resistance of the LDH coating. Finally, the mechanism of hydrotalcite coating as a solid lubricating film for friction and wear reduction is proposed.

Comparative biochemical characterization of mammalian-derived CYP11A1s with cholesterol side-chain cleavage activities.

Steroid drugs, the second largest class of pharmaceuticals after antibiotics, have shown significant anti-inflammatory, anti-allergic, and endocrine-regulating effects. A group of cytochrome P450 enzymes, namely, CYP11A1 isoenzymes from different organisms are capable of converting cholesterol into pregnenolone, which is a pivotal reaction in both steroid metabolism and (bio)synthetic network of steroid products. However, the low activity of CYP11A1s greatly restricts the industrial application of these cholesterol side-chain cleavage enzymes. Herein, we investigate ten CYP11A1 enzymes of different origins and in vitro characterize two CYP11A1s with a relatively higher expression level from Capra hircus and Sus scrofa, together with the CYP11A1s from Homo sapiens and Bos taurus as references. Towards five selected sterol substrates with different side chain structures, S. scrofa CYP11A1 displays relatively higher activities. Through redox partners combination screening, we reveal the optimal redox partner pair of S. scrofa adrenodoxin and C. hircus adrenodoxin reductase. Moreover, the semi-rational mutagenesis for the active sites and substrate entrance channels of human and bovine CYP11A1s is performed based on comparative analysis of their crystal structures. The mutant mBtCYP11A1-Q377A derived from mature B. taurus CYP11A1 shows a 1.46 times higher activity than the wild type enzyme. These results not only demonstrate the tunability of the highly conserved CYP11A1 isoenzymes, but also lay a foundation for the following engineering efforts on these industrially relevant P450 enzymes.

Axially chiral styrene-based organocatalysts and their application in asymmetric cascade Michael/cyclization reaction.

An axially chiral styrene-based organocatalyst, featuring a combination of axially chiral styrene-based structure and a pyrrole ring, has been designed and synthesized. This catalyst demonstrates remarkable capabilities in producing a wide range of densely substituted spirooxindoles that feature an alkyne-substituted quaternary stereogenic center. These spirooxindoles are generated through mild cascade Michael/cyclization reactions, resulting in high conversion rates and exceptional enantioselectivity. Our catalytic model, based on experiments, X-ray structure analysis and DFT calculations suggests that chiral matched π-π interactions and multiple H-bonds between the organocatalyst and substrates play significant roles in controlling the stereoselectivity of the reaction.

Light-Induced Mott-Insulator-to-Metal Phase Transition in Ultrathin Intermediate-Spin Ferromagnetic Perovskite Ruthenates.

Light control of emergent quantum phenomena is a widely used external stimulus for quantum materials. Generally, perovskite strontium ruthenate SrRuO3 has an itinerant ferromagnetism with a low-spin state. However, the phase of intermediate-spin (IS) ferromagnetic metallic state has never been seen. Here, by means of UV-light irradiation, a photocarrier-doping-induced Mott-insulator-to-metal phase transition is shown in a few atomic layers of perovskite IS ferromagnetic SrRuO3- δ . This new metastable IS metallic phase can be reversibly regulated due to the convenient photocharge transfer from SrTiO3 substrates to SrRuO3- δ ultrathin films. These dynamical mean-field theory calculations further verify such photoinduced electronic phase transformation, owing to oxygen vacancies and orbital reconstruction. The optical manipulation of charge-transfer finesse is an alternative pathway toward discovering novel metastable phases in strongly correlated systems and facilitates potential light-controlled device applications in optoelectronics and spintronics.