Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity.

Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.

High carrier mobility along the [111] orientation in Cu2O photoelectrodes.

Solar fuels offer a promising approach to provide sustainable fuels by harnessing sunlight1,2. Following a decade of advancement, Cu2O photocathodes are capable of delivering a performance comparable to that of photoelectrodes with established photovoltaic materials3-5. However, considerable bulk charge carrier recombination that is poorly understood still limits further advances in performance6. Here we demonstrate performance of Cu2O photocathodes beyond the state-of-the-art by exploiting a new conceptual understanding of carrier recombination and transport in single-crystal Cu2O thin films. Using ambient liquid-phase epitaxy, we present a new method to grow single-crystal Cu2O samples with three crystal orientations. Broadband femtosecond transient reflection spectroscopy measurements were used to quantify anisotropic optoelectronic properties, through which the carrier mobility along the [111] direction was found to be an order of magnitude higher than those along other orientations. Driven by these findings, we developed a polycrystalline Cu2O photocathode with an extraordinarily pure (111) orientation and (111) terminating facets using a simple and low-cost method, which delivers 7 mA cm-2 current density (more than 70% improvement compared to that of state-of-the-art electrodeposited devices) at 0.5 V versus a reversible hydrogen electrode under air mass 1.5 G illumination, and stable operation over at least 120 h.

CCR7 Chemokine Receptor-Inducible lnc-Dpf3 Restrains Dendritic Cell Migration by Inhibiting HIF-1α-Mediated Glycolysis.

CCR7 chemokine receptor stimulation induces rapid but transient dendritic cell (DC) migration toward draining lymph nodes, which is critical for the initiation of protective immunity and maintenance of immune homeostasis. The mechanisms for terminating CCR7-mediated DC migration remain incompletely understood. Here we have identified a long non-coding RNA lnc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation upregulated lnc-Dpf3 via removing N6-methyladenosine (m6A) modification to prevent RNA degradation. DC-specific lnc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1α transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. lnc-Dpf3 directly bound to HIF-1α and suppressed HIF-1α-dependent transcription of the glycolytic gene Ldha, thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible lnc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.

Adult Connective Tissue-Resident Mast Cells Originate from Late Erythro-Myeloid Progenitors.

Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin ß7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development.

Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis.

Immunotherapy is a promising approach for treating metastatic breast cancer (MBC), offering new possibilities for therapy. While checkpoint inhibitors have shown great progress in the treatment of metastatic breast cancer, their effectiveness in patients with bone metastases has been disappointing. This lack of efficacy seems to be specific to the bone environment, which exhibits immunosuppressive features. In this study, we elucidate the multiple roles of the sialic acid-binding Ig-like lectin (Siglec)-15/sialic acid glyco-immune checkpoint axis in the bone metastatic niche and explore potential therapeutic strategies targeting this glyco-immune checkpoint. Our research reveals that elevated levels of Siglec-15 in the bone metastatic niche can promote tumor-induced osteoclastogenesis as well as suppress antigen-specific T cell responses. Next, we demonstrate that antibody blockade of the Siglec-15/sialic acid glyco-immune checkpoint axis can act as a potential treatment for breast cancer bone metastasis. By targeting this pathway, we not only aim to treat bone metastasis but also inhibit the spread of metastatic cancer cells from bone lesions to other organs.

Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO.

Excessive activation of dendritic cells (DCs) leads to the development of autoimmune and inflammatory diseases, which has prompted a search for regulators of DC activation. Here we report that Rhbdd3, a member of the rhomboid family of proteases, suppressed the activation of DCs and production of interleukin 6 (IL-6) triggered by Toll-like receptors (TLRs). Rhbdd3-deficient mice spontaneously developed autoimmune diseases characterized by an increased abundance of the TH17 subset of helper T cells and decreased number of regulatory T cells due to the increase in IL-6 from DCs. Rhbdd3 directly bound to Lys27 (K27)-linked polyubiquitin chains on Lys302 of the modulator NEMO (IKKγ) via the ubiquitin-binding-association (UBA) domain in endosomes. Rhbdd3 further recruited the deubiquitinase A20 via K27-linked polyubiquitin chains on Lys268 to inhibit K63-linked polyubiquitination of NEMO and thus suppressed activation of the transcription factor NF-κB in DCs. Our data identify Rhbdd3 as a critical regulator of DC activation and indicate K27-linked polyubiquitination is a potent ubiquitin-linked pattern involved in the control of autoimmunity.

Engineering small-molecule and protein drugs for targeting bone tumors.

Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and death. Currently, treatments such as chemotherapy, hormone therapy, and radiation therapy are used to treat bone cancer, but they often only shrink or slow tumor growth and do not eliminate cancer completely. The bone microenvironment contributes unique signals that influence cancer growth, immunogenicity, and metastasis. Traditional cancer therapies have limited effectiveness due to off-target effects and poor distribution on bones. As a result, therapies with improved specificity and efficacy for treating bone tumors are highly needed. One of the most promising strategies involves the targeted delivery of pharmaceutical agents to the site of bone cancer by introduction of bone-targeting moieties, such as bisphosphonates or oligopeptides. These moieties have high affinities to the bone hydroxyapatite matrix, a structure found exclusively in skeletal tissue, and can enhance the targeting ability and efficacy of anticancer drugs when combating bone tumors. This review focuses on the engineering of small molecules and proteins with bone-targeting moieties for the treatment of bone tumors.

Excitonic van der Waals Metasurfaces for Resonant Wavefront Shaping at Deep Subwavelength Thickness Scale.

Dielectric phase gradient metasurfaces have emerged as promising candidates to shrink bulky optical elements to subwavelength thickness scale based on dielectric meta-atoms. These meta-atoms strongly interact with light, thus offering excellent phase manipulation of incident light. However, to fulfill 2π phase control using meta-atoms, the metasurface thickness, to date, is limited to the order of 102 nm. Here, we present the thickness scaling down of phase gradient metasurfaces to <λ/20 by using excitonic van der Waals metasurfaces. High-refractive-index enabled by exciton resonances and symmetry-breaking nanostructures in the patterned layered tungsten disulfide (WS2) corporately enable quasibound states in the continuum in WS2 metasurfaces, which consequently yield complete phase regulation of 2π with the thickness down to 35 nm. To illustrate the concept, we have experimentally demonstrated beam steering, focusing, and holographic display using WS2 metasurfaces. We envision our results unveiling new venues for ultimate thin phase gradient metasurfaces.

Polarization-Controlled Exciton-Polaritons in WS2 Strongly Coupled with Low-Symmetry Photonic Crystal Nanostructures.

Atomically thin transition metal dichalcogenides (TMDs) with ambient stable exciton resonances have emerged as an ideal material platform for exciton-polaritons. In particular, the strong coupling between excitons in TMDs and optical resonances in anisotropic photonic nanostructures can form exciton-polaritons with polarization selectivity, which offers a new degree of freedom for the manipulation of the light-matter interaction. In this work, we present the experimental demonstration of polarization-controlled exciton-polaritons in tungsten disulfide (WS2) strongly coupled with polarization singularities in the momentum space of low-symmetry photonic crystal (PhC) nanostructures. The utilization of polarization singularities can not only effectively modulate the polarization states of exciton-polaritons in the momentum space but also facilitate or suppress their far field coupling capabilities by tuning the in-plane momentum. Our results provide new strategies for creating polarization-selective exciton-polaritons.

Associations between ticagrelor use and the risk of infections: A Mendelian randomization study.

AIMS: We conducted a Mendelian randomization (MR) study to elucidate the anti-infective effects of ticagrelor. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) associated with serum levels of ticagrelor or its major metabolite AR-C124910XX (ARC) in the PLATelet inhibition and patient Outcomes trial were selected as genetic proxies for ticagrelor exposure. Positive control analyses indicated that genetically surrogated serum ticagrelor levels (six SNPs) but not ARC levels (two SNPs) were significantly associated with lower risks of coronary heart disease. Therefore, the six SNPs were used as genetic instruments for ticagrelor exposure, and the genome-wide association study data for five infection outcomes were derived from the UK Biobank and FinnGen consortium. The two-sample MR analyses based on inverse variance-weighted methods indicated that genetic liability to ticagrelor exposure could reduce the risk of bacterial pneumonia (odds ratio [OR]: 0.82, 95% confidence interval [CI]: 0.71-0.95, P = 8.75E-03) and sepsis (OR: 0.83, 95% CI: 0.73-0.94, P = 3.69E-03); however, no causal relationship between ticagrelor exposure and upper respiratory infection, pneumonia, and urinary tract infection was detected. Extensive sensitivity analyses corroborated these findings. CONCLUSION: Our MR study provides further evidence for the preventive effects of ticagrelor on bacterial pneumonia and sepsis.

Mass Spectrometry Imaging for the Characterization of C═C Localization in Unsaturated Lipid Isomers at the Single-Cell Level.

Unsaturated lipids with carbon-carbon double bonds (C═C) have been implicated in the pathogenesis of various diseases. While mass spectrometry imaging (MSI) has been employed to map the distribution of lipid isomers in tissue sections, the identification of lipid C═C positional isomers at the single-cell level using MSI poses a significant challenge. In this study, we developed a novel approach utilizing ToF-SIMS in conjunction with the Paternò-Büchi (P-B) photochemical reaction to characterize the C═C localization in unsaturated lipid isomers at the single-cell level. The P-B reaction was employed to produce adduct products, which were subsequently subjected to collision-induced dissociation by the primary ion beam of ToF-SIMS to generate characteristic ion pairs indicative of the presence of C═C bonds. Utilizing this approach, lipid isomers in brain and skeletal tissues from mice, as well as different cell lines, were visualized at single-cell resolution. Furthermore, distinct variations in the composition of FA 18:1 isomers across different microregions and cell types were revealed. Our P-B ToF-SIMS approach enables the accurate identification and characterization of complex lipid structures with remarkable spatial resolution and can be helpful in understanding the physiological role of these C═C positional isomers.

Chiral absorption enhancement via critically coupled resonances in atomically thin photonic crystal exciton-polaritons.

Atomically thin transition metal dichalcogenides (TMDS) offer a promising route to the scaling down of optoelectronic devices to the ultimate thickness limit. But the weak light-matter interaction caused by their atomically thin nature makes them inevitably rely on external photonic structures to enhance optical absorption. Here, we report chiral absorption enhancement in atomically thin tungsten diselenide (WSe2) using chiral resonances in photonic crystal (PhC) nanostructures patterned directly in WSe2 itself. We show that the quality factors (Q factors) of the resonances grow exponentially as the PhC thickness approaches atomic limit. As such, the strong interaction of high Q factor photonic resonance with the coexisting exciton resonance in WSe2 results into self-coupled exciton-polaritons. By balancing the light coupling and absorption rates, the incident light can critically couple to chiral resonances in WSe2 PhC exciton-polaritons, leading to the theoretically limited 50% optical absorptance with over 84% circular dichroism (CD).

A Prussian blue analog-based copper-aluminum layered double hydroxide for cesium removal from water: fabrication, density functional theory-based molecular modeling, and the adsorption mechanism.

A new type of adsorbent, a Prussian blue analog-based copper-aluminum layered double hydroxide (PBA@CuAl-LDH), was successfully synthesized using a one-step method for the removal of radioactive Cs+ from wastewater. The adsorption performance, characteristics and the underlying adsorption mechanism of PBA@CuAl-LDH were systematically examined. The results showed that PBA@CuAl-LDH exhibited excellent adsorption performance, with a maximum adsorption capacity of 109.2 mg g-1. Over 85% of PBA@CuAl-LDH can be recycled, and the material exhibited only a 6.6% loss in adsorption performance. The adsorption process was well-fitted using the pseudo-second-order kinetic model and the Freundlich isotherm model, revealing the surface heterogeneity of the composite adsorbent. A molecular model of PBA@CuAl-LDH was constructed by combining density functional theory and multiple instrumental characterization techniques. Our results indicate that PBA crystals can be generated between layers and on the surface. Ion exchange was revealed as the main adsorption mechanism of Cs+ by PBA@CuAl-LDH. Specifically, the interstitial spaces of the PBA crystals generated between the layers and on the surface played an important role in ion exchange. These findings provide concrete theoretical support for radioactive pollution control and have significant value in directing the fabrication of cesium removal materials and their future engineering application.

Sublethal and transgenerational effects of lufenuron on the biological traits of Panonychus citri (McGregor) (Acari: Tetranychidae).

The citrus red mite, Panonychus citri (McGregor), is a globally important pest that has developed severe resistance to various pesticides. Lufenuron has been widely used in the control of the related pests in citrus orchard ecosystem. In this study, the susceptibilities of egg, larva, deutonymph and female adult of P. citri to lufenuron was determined, and the LC50 values were 161.354 mg/L, 49.595 mg/L, 81.580 mg/L, and 147.006 mg/L, respectively. Life-table analysis indicated that the fecundities were significantly increased by 11.86% and 26.84% after the mites were treated with LC20 concentrations of lufenuron at the egg or deutonymph stages, respectively. After eggs were treated with lufenuron, the immature stage and longevity were also affected, and resulted in a significant increase in r, R0 and λ. After exposure of female adults to LC20 of lufenuron, the fecundity and longevity of F0 generation significantly decreased by 31.99% and 10.94%, respectively. Furthermore, the expression level of EcR and Vg was significantly inhibited upon mites was treated with lufenuron. However, lufenuron exposure has a positive effect on fecundity and R0 in F1 generation, the expression of all reproduction-related genes was significantly up-regulated. In conclusion, there was a stimulating effect on the offspring population. Our results will contribute to the assessment of the resurgence of P. citri in the field after the application of lufenuron and the development of integrated pest control strategies in citrus orchards.

A Novel Waveform Optimization Method for Orthogonal-Frequency Multiple-Input Multiple-Output Radar Based on Dual-Channel Neural Networks.

The orthogonal frequency-division multiplexing (OFDM) mode with a linear frequency modulation (LFM) signal as the baseband waveform has been widely studied and applied in multiple-input multiple-output (MIMO) radar systems. However, its high sidelobe levels after pulse compression affect the target detection of radar systems. For this paper, theoretical analysis was performed, to investigate the causes of high sidelobe levels in OFDM-LFM waveforms, and a novel waveform optimization design method based on deep neural networks is proposed. This method utilizes the classic ResNeXt network to construct dual-channel neural networks, and a new loss function is employed to design the phase and bandwidth of the OFDM-LFM waveforms. Meanwhile, the optimization factor is exploited, to address the optimization problem of the peak sidelobe levels (PSLs) and integral sidelobe levels (ISLs). Our numerical results verified the correctness of the theoretical analysis and the effectiveness of the proposed method. The designed OFDM-LFM waveforms exhibited outstanding performance in pulse compression and improved the detection performance of the radar.

Soil organic matter degradation and methylmercury dynamics in Hg-contaminated soils: Relationships and driving factors.

Biodegradation of soil organic matter (SOM), which involves greenhouse gas (GHG) emissions, plays an essential role in the global carbon cycle. Over the past few decades, this has become an important research focus, particularly in natural ecosystems. SOM biodegradation significantly affects contaminants in the environment, such as mercury (Hg) methylation, producing highly toxic methylmercury (MeHg). However, the potential link between GHG production from SOM turnover in contaminated soils and biogeochemical processes involving contaminants remains unclear. In this study, we investigated the dynamics of GHG, MeHg production, and the relationship between biogeochemical processes in soils from two typical Hg mining sites. The two contaminated soils have different pathways, explaining the significant variations in GHG and MeHg production. The divergence of the microbial communities in these two biogeochemical processes is essential. In addition to the microbial role, abiotic factors such as Hg species can significantly affect MeHg production. On the other hand, we found an inverse relationship between CH4 and MeHg, suggesting that carbon emission reduction policies and management could inadvertently increase the MeHg levels. This highlights the need for an eclectic approach to organic carbon sequestration and contaminant containment. These findings suggest that it is difficult to establish a general pattern to describe and explain the SOM degradation and MeHg production in contaminated soils within the specific scenarios. However, this study provides a case study and helpful insights for further understanding the links between environmental risks and carbon turnover in Hg mining areas.

Highly Promiscuous Flavonoid Di-O-glycosyltransferases from Carthamus tinctorius L.

Safflower (Carthamus tinctorius L.) has been recognized for its medicinal value, but there have been limited studies on the glycosyltransferases involved in the biosynthesis of flavonoid glycosides from safflower. In this research, we identified two highly efficient flavonoid O-glycosyltransferases, CtOGT1 and CtOGT2, from safflower performing local BLAST alignment. By constructing a prokaryotic expression vector, we conducted in vitro enzymatic reactions and discovered that these enzymes were capable of catalyzing two-step O-glycosylation using substrates such as kaempferol, quercetin, and eriodictyol. Moreover, they exhibited efficient catalytic activity towards various compounds, including flavones (apigenin, scutellarein), dihydrochalcone (phloretin), isoflavones (genistein, daidzein), flavanones (naringenin, glycyrrhizin), and flavanonols (dihydrokaempferol), leading to the formation of O-glycosides. The broad substrate specificity of these enzymes is noteworthy. This study provides valuable insights into the biosynthetic pathways of flavonoid glycosides in safflower. The discovery of CtOGT1 and CtOGT2 enhances our understanding of the enzymatic processes involved in synthesizing flavonoid glycosides in safflower, contributing to the overall comprehension of secondary metabolite biosynthesis in this plant species.

[Functional characterization of ent-kaurane-type diterpenoid synthases from Stellera chamaejasme].

Sequential catalysis by ent-copalyl diphosphate(CPS) and ent-kaurene synthase(KS) is a critical step for plants to initiate the biosynthesis of gibberellin with geranylgeranyl pyrophosphate(GGPP) as the substrate. This study mined the transcriptome data of Stellera chamaejasme and cloned two key diterpene synthase genes, SchCPS and SchKS, involved in the gibberellin pathway. The two genes had the complete open reading frames of 2 595 bp and 1 701 bp, encoding two hydrophilic proteins composed of 864 and 566 amino acid residues and with the relative molecular mass of 97.9 kDa and 64.6 kDa and the theoretical isoelectric points of 5.61 and 6.12, respectively. Sequence comparison and phylogenetic tree showed that SchCPS contained LHS, PNV, and DxDD motifs conserved in the CPS family and was categorized in the TPS-c subfamily, while SchKS contained DDxxD, NSE/DTE and PIx motifs conserved in the KS family and was categorized in the TPS-e subfamily. Functional validation showed that SchCPS catalyzed the protonation and cyclization of GGPP to ent-CPP, while SchKS acted on ent-CPP dephosphorylation and re-cyclization to ent-kaurene. In this study, the full-length sequences of SchCPS and SchKS were cloned and functionally verified for the first time, which not only enriched the existing CPS and KS gene libraries but also laid a foundation for the cloning and biosynthesis pathway analysis of more genes involved in the synthesis of active components in S. chamaejasme.

[Cloning and functional analysis of 3ß-hydroxysteroid dehydrogenase gene involved in biosynthesis of digitoxin].

Digitoxin, an important secondary metabolite of Digitalis purpurea, is a commonly used cardiotonic in clinical practice. 3ß-Hydroxysteroid dehydrogenase(3ßHSD) is a key enzyme involved in the biosynthesis of digitoxin. It belongs to the short-chain dehydrogenase/reductase(SDR) family, playing a role in the biosynthesis of cardiac glycosides by oxidizing and isomerizing the precursor sterol. In this study, two 3ßHSD genes were cloned from D. purpurea. The results showed that the open reading frame(ORF) of Dp3ßHSD1 was 780 bp, encoding 259 amino acid residues. The ORF of Dp3ßHSD2 was 774 bp and encoded 257 residues. Dp3ßHSD1/2 had the cofactor binding site TGxxxA/GxG and the catalytic site YxxxK. In vitro experiments confirmed that Dp3ßHSD1/2 catalyzed the generation of progesterone from pregnenolone, and Dp3ßHSD1 had stronger catalytic capacity than Dp3ßHSD2. The expression level of Dp3ßHSD1 was much higher than that of Dp3ßHSD2 in leaves, and digitoxin was only accumulated in leaves. The results implied that Dp3ßHSD1 played a role in the dehydrogenation of pregnenolone to produce progesterone in the biosynthesis of digitoxin. This study provides a reference for further exploring the biosynthetic pathway of cardiac glycosides in D. purpurea.