Bioactive daphnane diterpenes from the flower buds of Daphne genkwa (Thymelaeaceae).

Four diterpenes of the daphnane type were isolated from a methanol extract of the flower buds of Daphne genkwa, the two of them were new structures named genkwadanes J (1) and K (2). Their structures were determined based on analysis of their 1D- and 2D-NMR, HRESIMS and ECD calculations. Among the isolates, the cytotoxicity was assessed via the MTT method using the K562, MCF-7 and HeLa cancer cell lines, the positive control was taxol. Compounds 1 and 3 exhibited appreciable cytotoxic activity against the K562 cancer cell line with IC50 values between 6.58 and 5.33 µM. Compounds 2 and 4 showed noteworthy inhibitory effects against the MCF-7 cell line with IC50 values of 3.25 and 2.56 µM, respectively. All compounds showed weak cytotoxicities to the Hela cell line with IC50 values in the range of 20.19-55.23 µM.

[Clinical anatomy of the free latissimus dorsi myocutaneous flap and its application in the restoration of giant defects of the head and neck].

PURPOSE: To investigate the feasibility and effect of free latissimus dorsi myocutaneous flap in the reconstruction of giant head and neck defects. METHODS: Free latissimus dorsi myocutaneous flap on the cadaver was simulated dissected, and measured by Image-Pro Plus 6.0 to assess the feasibility of repairing giant head and neck defects. Between May 2011 and September 2022, seven patients with giant head and neck defects of different causes repaired with the latissimus dorsi myocutaneous flap were retrospectively analyzed. RESULTS: The diameter of the initiating thoracodorsal artery was (4.03±0.56) mm, and the mean lengths of the arteriolar and venous pedicles of the latissimus dorsi myocutaneous flaps obtained from human specimens were (85.5±10.5) mm and (104±4.2) mm, respectively. Among 7 patients, 5 cases had scalp defects, the remaining 2 cases had neck defects. There were no substantial postoperative problems in the donor site, and all seven latissimus dorsi myocutaneous flaps were successfully transplanted. CONCLUSIONS: For the treatment of considerable head and neck deformities, the latissimus dorsi myocutaneous flap is an optimal muscle flap due to its abundance of tissue, enough length of vascular pedicles, and sufficient venous drainage.

B Cell Epigenetic Modulation of IgA Response by 5-Azacytidine and IgA Nephropathy.

BACKGROUND: IgA nephropathy is an important global cause of kidney failure. Dysregulation of IgA production is thought to play a key role in IgA nephropathy pathogenesis, however, little is known about the epigenetic mechanisms such as RNA 5- methylcytosine (5mC) modification in regulating IgA synthesis. METHODS: To decipher the role of RNA 5mC in regulation of IgA class switch, the miR-23b-/- and LCWE induced Kawasaki disease mice were treated with 5-azacytidine. Trdmt1-/- and double Trdmt1-/-/ miR-23b-/- mice, Aid-/- mice or Aid-/-/ miR-23b-/- mice were also employed. RESULTS: We showed that miR-23b down regulated expression of Transfer RNA Aspartic Acid Methyltransferase 1 (Trdmt1) and consequently reduced 5-methylcytosine (m5C) RNA modification and IgA synthesis in B cells. Inhibition of m5C RNA modification normalised serum IgA levels and ameliorated progression of the IgA nephropathy-like kidney disease in miR-23b-/- and Kawasaki disease mice while mesangial IgA and C3 deposition failed to develop in Trdmt1-/-miR-23b-/- mice. By contrast, increased m5C RNA modification resulted in an exaggerated IgA nephropathy phenotype. miR-23b regulation of serum IgA levels and the development of an IgA nephropathy-like kidney disease in miR-23b-/- and Kawasaki disease mice is likely mediated through TRDMT1 driven 5-methylcytosine RNA modification in B cells, resulting in impaired activation-induced cytidine deaminase activity and IgA class switch recombination. CONCLUSIONS: This study revealed TRDMT1 induced RNA 5mC methylation regulate IgA class switch and inhibition of RNA 5mC by 5-Azacytidine could ameliorate progression of IgA nephropathy.

The Effect of Unhealthy Food Packaging Information Boundaries on Consumer Purchasing Intentions.

Existing studies have examined unhealthy food packaging information, mainly focusing on aspects such as the content, color, and text, whilst paying less attention to the boundaries of information. This paper investigates unhealthy foods through three experiments, revealing that the presence (vs. absence) of packaging information boundaries on unhealthy foods has a negative impact on consumers' purchasing intentions (p = 0.040) (Experiment 1). The feeling of constraint mediates this effect (ß = -0.078, CI: [-0.1911, -0.0111]) (Experiment 2). Additionally, consumers with an independent self-construal exhibit reduced purchasing intentions when unhealthy food packaging information boundaries are present (vs. absent) (p < 0.001), whereas those with an interdependent self-construal show increased purchasing intentions under the same conditions (p = 0.024) (Experiment 3). This paper reveals the psychological mechanism and boundary conditions of unhealthy food packaging information boundaries affecting consumers' purchasing intention and provides practical inspiration for government policy-making related to unhealthy food packaging.

Hematopoietic stem and progenitor cell membrane-coated vesicles for bone marrow-targeted leukaemia drug delivery.

Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin ß2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia.

Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma.

The expression dysregulation of microRNAs (miRNA) has been widely reported during cancer development, however, the underling mechanism remains largely unanswered. In the present work, we performed a systematic integrative study for genome-wide DNA methylation, copy number variation and miRNA expression data to identify mechanisms underlying miRNA dysregulation in lower grade glioma. We identify 719 miRNAs whose expression was associated with alterations of copy number variation or promoter methylation. Integrative multi-omics analysis revealed four subtypes with differing prognoses. These glioma subtypes exhibited distinct immune-related characteristics as well as clinical and genetic features. By construction of a miRNA regulatory network, we identified candidate miRNAs associated with immune evasion and response to immunotherapy. Finally, eight prognosis related miRNAs were validated to promote cell migration, invasion and proliferation through in vitro experiments. Our study reveals the crosstalk among DNA methylation, copy number variation and miRNA expression for immune regulation in glioma, and could have important implications for patient stratification and development of biomarkers for immunotherapy approaches.

Sunlight-powered sustained flight of an ultralight micro aerial vehicle.

Limited flight duration is a considerable obstacle to the widespread application of micro aerial vehicles (MAVs)1-3, especially for ultralightweight MAVs weighing less than 10 g, which, in general, have a flight endurance of no more than 10 min (refs. 1,4). Sunlight power5-7 is a potential alternative to improve the endurance of ultralight MAVs, but owing to the restricted payload capacity of the vehicle and low lift-to-power efficiency of traditional propulsion systems, previous studies have not achieved untethered sustained flight of MAVs fully powered by natural sunlight8,9. Here, to address these challenges, we introduce the CoulombFly, an electrostatic flyer consisting of an electrostatic-driven propulsion system with a high lift-to-power efficiency of 30.7 g W-1 and an ultralight kilovolt power system with a low power consumption of 0.568 W, to realize solar-powered sustained flight of an MAV under natural sunlight conditions (920 W m-2). The vehicle's total mass is only 4.21 g, within 1/600 of the existing lightest sunlight-powered aerial vehicle6.

Polydopamine-coated bioactive glass for immunomodulation and odontogenesis in pulpitis.

Preserving vital pulp in cases of dental pulpitis is desired but remains challenging. Previous research has shown that bioactive glass (BG) possesses notable capabilities for odontogenic differentiation. However, the immunoregulatory potential of BG for inflamed pulp is still controversial, which is essential for preserving vital pulp in the context of pulpitis. This study introduces a novel approach utilizing polydopamine-coated BG (BG-PDA) which demonstrates the ability to alleviate inflammation and promote odontogenesis for vital pulp therapy. In vitro, BG-PDA has the potential to induce M2 polarization of macrophages, resulting in decreased intracellular reactive oxygen species levels, inhibition of pro-inflammatory factor, and enhancement of anti-inflammatory factor expression. Furthermore, BG-PDA can strengthen the mitochondrial function in macrophages and facilitate odontogenic differentiation of human dental pulp cells. In a rat model of pulpitis, BG-PDA exhibits the capacity to promote M2 polarization of macrophages, alleviate inflammation, and facilitate dentin bridge formation. This study highlights the notable immunomodulatory and odontogenesis-inducing properties of BG-PDA for treating dental pulpitis, as evidenced by both in vitro and in vivo experiments. These results imply that BG-PDA could serve as a promising biomaterial for vital pulp therapy.

Exploring genetic codon expansion for unnatural amino acid incorporation in filamentous fungus Aspergillus nidulans.

Genetic code expansion technology allows the incorporation of unnatural amino acids (UAAs) into proteins, which is useful in protein engineering, synthetic biology, and gene therapy. Despite its potential applications in various species, filamentous fungi remain unexplored. This study aims to address this gap by developing these techniques in Aspergillus nidulans. We introduced an amber stop codon into a specific sequence within the reporter gene expressed in A. nidulans and replaced the anticodon of the fungal tRNATyr with CUA. This resulted in the synthesis of the target protein, confirming the occurrence of amber suppression in the fungus. When exogenous E. coli tRNATyrCUA (Ec. tRNATyrCUA) and E. coli tyrosyl-tRNA (Ec.TyrRS) were introduced into A. nidulans, they successfully synthesized the target protein via amber suppression and were shown to be orthogonal to the fungal translation system. By replacing the wild-type Ec.TyrRS with a mutant with a higher affinity for the UAA O-methyl-L-tyrosine, the fungal system was able to initiate the synthesis of the UAA-labeled protein (UAA-protein). We further increased the expression level of the UAA-protein through several rational modifications. The successful development of a genetic code expansion technique for A. nidulans has introduced a potentially valuable approach to the study of fungal protein structure and function.

Long-Term Efficacy and Safety of Stapokibart in Adults with Moderate-to-Severe Atopic Dermatitis: An Open-Label Extension, Nonrandomized Clinical Trial.

BACKGROUND: Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials. OBJECTIVE: We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis. METHODS: Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300 mg every 2 weeks up to 52 weeks. Efficacy outcomes included the proportions of patients with ≥ 50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale. RESULTS: In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week 52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥ 2-point reduction was achieved in 39.3% of patients at week 16, increasing to 58.9% at week 52. The proportions of patients with ≥ 3-point and ≥ 4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week 52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events. CONCLUSIONS: Long-term treatment with stapokibart for 52 weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021).

Prediction of protein secondary structure by the improved TCN-BiLSTM-MHA model with knowledge distillation.

Secondary structure prediction is a key step in understanding protein function and biological properties and is highly important in the fields of new drug development, disease treatment, bioengineering, etc. Accurately predicting the secondary structure of proteins helps to reveal how proteins are folded and how they function in cells. The application of deep learning models in protein structure prediction is particularly important because of their ability to process complex sequence information and extract meaningful patterns and features, thus significantly improving the accuracy and efficiency of prediction. In this study, a combined model integrating an improved temporal convolutional network (TCN), bidirectional long short-term memory (BiLSTM), and a multi-head attention (MHA) mechanism is proposed to enhance the accuracy of protein prediction in both eight-state and three-state structures. One-hot encoding features and word vector representations of physicochemical properties are incorporated. A significant emphasis is placed on knowledge distillation techniques utilizing the ProtT5 pretrained model, leading to performance improvements. The improved TCN, achieved through multiscale fusion and bidirectional operations, allows for better extraction of amino acid sequence features than traditional TCN models. The model demonstrated excellent prediction performance on multiple datasets. For the TS115, CB513 and PDB (2018-2020) datasets, the prediction accuracy of the eight-state structure of the six datasets in this paper reached 88.2%, 84.9%, and 95.3%, respectively, and the prediction accuracy of the three-state structure reached 91.3%, 90.3%, and 96.8%, respectively. This study not only improves the accuracy of protein secondary structure prediction but also provides an important tool for understanding protein structure and function, which is particularly applicable to resource-constrained contexts and provides a valuable tool for understanding protein structure and function.

Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types.

As the most abundant messenger RNA (mRNA) modification in mRNA, N  6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the function and role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A sequencing (m6A-seq) and RNA sequencing samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called "m6A-express", we predicted m6A-regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin, and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A for cancer precision medicine for patients with different cancer types.

Demineralization activating highly-disordered lignite-derived hard carbon for fast sodium storage.

Lignite, as one of the coal materials, has been considered a promising precursor for hard carbon anodes in sodium-ion batteries (SIBs) owing to its low cost and high carbon yield. Nevertheless, hard carbon directly derived from lignite pyrolysis typically exhibits highly ordered microstructure with narrow interlayer spacing and relatively unreactive interfacial properties, owing to the abundance of polycyclic aromatic hydrocarbons and inert aromatic rings within its molecular composition. Herein, an innovative demineralization activating strategy is established to simultaneously modulate the interfacial properties and the microstructure of lignite-derived carbon for the development of high-performance SIBs. Demineralization process not only creates numerous void spaces in the matrix of lignite precursor to assist aromatic hydrocarbon rearrangement, thereby reducing the ordering and expanding interlayer spacing, but also exposes more interfacial oxygen-containing functional groups to effectively increasing the sodium storage active sites. As a result, the optimal demineralized lignite-derived hard carbon (DLHC 1300) delivers a high reversible capacity of 335.6 mAh g-1 at 30 mA g-1, superior rate performance of 246.3 mAh g-1 at 6 A g-1 and nearly 100 % capacity retention after 1100 cycles at 1A g-1. Furthermore, the optimized DLHC 1300 material functions as an outstanding anode in sodium ion full cells. This work significantly advances the development of low-cost, high-performance commercial hard carbon anodes for SIBs.

Optimization of Porous Structures of Carbon Matrices for Loading Red Phosphorus to Achieve High-Capacity and Long-Life Anodes for All-Solid-State Lithium-Ion Batteries.

All-solid-state lithium-ion batteries (ASSLIBs) using sulfide electrolytes and high-capacity alloy-type anodes have attracted sizable interest due to their potential excellent safety and high energy density. Encapsulating insulating red phosphorus (P) inside nanopores of a carbon matrix can adequately activate its electrochemical alloying reaction with lithium. Therefore, the porosity of the carbon matrix plays a crucial role in the electrochemical performance of the resulting red P/carbon composites. Here, we use zeolite-templated carbon (ZTC) with monodisperse micropores and mesoporous carbon (CMK-3) with uniform mesopores as the model hosts of red P. Our results reveal that micropores enable more effective pore utilization for the red P loading, and the P@ZTC material can achieve a record-high content (65.0 wt %) of red P confined within pores. When used as an anode of ASSLIBs, the P@ZTC electrode delivers an ultrahigh capacity of 1823 mA h g-1 and a high initial Coulombic efficiency of 87.44%. After 400 deep discharge-charge cycles (running over 250 days) at 0.2 A g-1, the P@ZTC electrode still holds a reversible capacity of 1260 mA h g-1 (99.92% capacity retention per cycle). Moreover, a P@ZTC||LiNi0.8Co0.1Mn0.1O2 full cell can deliver a reversible areal capacity of over 3 mA h cm-2 at 0.1C after 100 cycles.

Epidemiological characteristics of syphilis in mainland China, 2004 to 2019.

OBJECTIVES: Syphilis is a globally prevalent sexually transmitted infection. This study aimed to elucidate the epidemiological characteristics of syphilis in China from 2004 to 2019. METHODS: Incidence data for syphilis across 31 provinces in mainland China were obtained from the Data Center of China Public Health Science for the period from 2004 to 2019. Epidemiological methods and the Chi-squared test were used to analyze the temporal, regional, and disease stage distributions of syphilis. RESULTS: In total, 5,527,399 syphilis cases were reported in China from 2004 to 2019, with an average annual prevalence of 25.7063 per 100,000 population and overall increasing trend. In terms of regional distribution, high-incidence provinces included Shanghai, Zhejiang, Fujian, Guangxi, Guangdong, Xinjiang, Ningxia, and Qinghai. The proportion of latent syphilis increased from 20.41% in 2004 to 82.95% in 2019, with an upward trend each year. CONCLUSIONS: Syphilis incidence exhibited an overall increasing trend in China, and latent syphilis was predominant. Syphilis incidences considerably varied among regions, and syphilis was detected from coastal to inland provinces. Thus, syphilis prevention and control programs should be tailored according to the specific epidemiological characteristics of each region.

IRF8 maintains mononuclear phagocyte and neutrophil function in acute kidney injury.

Immune cells are key players in acute tissue injury and inflammation, including acute kidney injury (AKI). Their development, differentiation, activation status, and functions are mediated by a variety of transcription factors, such as interferon regulatory factor 8 (IRF8) and IRF4. We speculated that IRF8 has a pathophysiologic impact on renal immune cells in AKI and found that IRF8 is highly expressed in blood type 1 conventional dendritic cells (cDC1s), monocytes, monocyte-derived dendritic cells (moDCs) and kidney biopsies from patients with AKI. In a mouse model of ischemia‒reperfusion injury (IRI)-induced AKI, Irf8 -/- mice displayed increased tubular cell necrosis and worsened kidney dysfunction associated with the recruitment of a substantial amount of monocytes and neutrophils but defective renal infiltration of cDC1s and moDCs. Mechanistically, global Irf8 deficiency impaired moDC and cDC1 maturation and activation, as well as cDC1 proliferation, antigen uptake, and trafficking to lymphoid organs for T-cell priming in ischemic AKI. Moreover, compared with Irf8 +/+ mice, Irf8 -/- mice exhibited increased neutrophil recruitment and neutrophil extracellular trap (NET) formation following AKI. IRF8 primarily regulates cDC1 and indirectly neutrophil functions, and thereby protects mice from kidney injury and inflammation following IRI. Our results demonstrate that IRF8 plays a predominant immunoregulatory role in cDC1 function and therefore represents a potential therapeutic target in AKI.

Heparin-Functionalized Bioactive Glass to Harvest Endogenous Growth Factors for Pulp Regeneration.

Pulp and periapical diseases can lead to the cessation of tooth development, resulting in compromised tooth structure and functions. Despite numerous efforts to induce pulp regeneration, effective strategies are still lacking. Growth factors (GFs) hold considerable promise in pulp regeneration due to their diverse cellular regulatory properties. However, the limited half-lives and susceptibility to degradation of exogenous GFs necessitate the administration of supra-physiological doses, leading to undesirable side effects. In this research, a heparin-functionalized bioactive glass (CaO-P2O5-SiO2-Heparin, abbreviated as PSC-Heparin) with strong bioactivity and a stable neutral pH is developed as a promising candidate to addressing challenges in pulp regeneration. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis reveal the successful synthesis of PSC-Heparin. Scanning electron microscopy and X-ray diffraction show the hydroxyapatite formation can be observed on the surface of PSC-Heparin after soaking in simulated body fluid for 12 h. PSC-Heparin is capable of harvesting various endogenous GFs and sustainably releasing them over an extended duration by the enzyme-linked immunosorbent assay. Cytological experiments show that developed PSC-Heparin can facilitate the adhesion, migration, proliferation, and odontogenic differentiation of stem cells from apical papillae. Notably, the histological analysis of subcutaneous implantation in nude mice demonstrates PSC-Heparin is capable of promoting the odontoblast-like layers and pulp-dentin complex formation without the addition of exogenous GFs, which is vital for clinical applications. This work highlights an effective strategy of harvesting endogenous GFs and avoiding the involvement of exogenous GFs to achieve pulp-dentin complex regeneration, which may open a new horizon for regenerative endodontic therapy.

GutUDB: A comprehensive multiomics database for intestinal diseases.

Gut Universe Database (GutUDB) provides a comprehensive, systematic, and practical platform for researchers, and is dedicated to the management, analysis, and visualization of knowledge related to intestinal diseases. Based on this database, eight major categories of omics data analyses are carried out to explore the genotype-phenotype characteristics of a certain intestinal disease. The first tool for comprehensive omics data research on intestinal diseases will help each researcher better understand intestinal diseases.

Duck pan-genome reveals two transposon insertions caused bodyweight enlarging and white plumage phenotype formation during evolution.

Structural variations (SVs) are a major source of domestication and improvement traits. We present the first duck pan-genome constructed using five genome assemblies capturing ∼40.98 Mb new sequences. This pan-genome together with high-depth sequencing data (∼46.5×) identified 101,041 SVs, of which substantial proportions were derived from transposable element (TE) activity. Many TE-derived SVs anchoring in a gene body or regulatory region are linked to duck's domestication and improvement. By combining quantitative genetics with molecular experiments, we, for the first time, unraveled a 6945 bp Gypsy insertion as a functional mutation of the major gene IGF2BP1 associated with duck bodyweight. This Gypsy insertion, to our knowledge, explains the largest effect on bodyweight among avian species (27.61% of phenotypic variation). In addition, we also examined another 6634 bp Gypsy insertion in MITF intron, which triggers a novel transcript of MITF, thereby contributing to the development of white plumage. Our findings highlight the importance of using a pan-genome as a reference in genomics studies and illuminate the impact of transposons in trait formation and livestock breeding.