Exploring antiviral effect and mechanism of Jinye Baidu granules（JYBD）against influenza A virus through network pharmacology and in vitro and invivo experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinye Baidu granules (JYBD) have been used to treat acute respiratory tract infections and demonstrated clinical efficacy for the treatment of emerging or epidemic respiratory viruses such as SARS-CoV-2 and influenza virus. AIM OF THE STUDY: This study is to investigate the antiviral effect of JYBD against influenza A viruses (IAV) in vitro and in vivo and elucidate its underlying mechanism. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography connected with Orbitrap mass spectrometer (UHPLC-Orbitrap MS) was employed to describe the chemical profile of JYBD. The potential pathways and targets involved in JYBD against IAV infection were predicted by network pharmacology. The efficacy and mechanism of JYBD were validated through both in vivo and in vitro experiments. Moreover, combination therapy with JYBD and the classic anti-influenza drugs was also investigated. RESULTS: A total of 126 compounds were identified by UHPLC-Orbitrap MS, of which 9 compounds were unambiguously confirmed with reference standards. JYBD could significantly inhibit the replication of multiple strains of IAV, especially oseltamivir-resistant strains. The results of qRT-PCR and WB demonstrated that JYBD could inhibit the excessive induction of pro-inflammatory cytokines induced by IAV infection and regulate inflammatory response through inhibiting JAK/STAT, NF-κB and MAPK pathways. Moreover, both JYBD monotherapy or in combination with oseltamivir could alleviate IAV-induced severe lung injury in mice. CONCLUSIONS: JYBD could inhibit IAV replication and mitigate virus-induced excessive inflammatory response. Combinations of JYBD and neuraminidase inhibitors conferred synergistic suppression of IAV both in vitro and in vivo. It might provide a scientific basis for clinical applications of JYBD against influenza virus infected diseases.

A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer.

BACKGROUND: Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib. METHODS: This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics. RESULTS: Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAFnon-V600-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively. CONCLUSIONS: Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect. CLINICALTRIALS: gov identifier: NCT02974725.

An Aggregation-Induced Emissive Platinum(II) Metallacycle as the Energy Donor of Rhodols for Ratiometric Detection of Hydrazine.

Industry-produced hydrazine (N2H4) is released into the environment, posing a major risk to human health and the ecosystem. Therefore, it is imperative to develop an effective and convenient method for the detection of N2H4. Herein, artificial light-harvesting systems (ALHSs) for N2H4 detection were constructed by applying an aggregation-induced emission-active platinum(II) metallacycle (TPEMc) as the energy donor and rhodols (P1, P2, and P3) as the energy acceptors. The ratiometric fluorescence probes based on ALHSs for N2H4 showed obvious signal amplification and lower limits of detection compared to those of rhodols (P1, P2, P3) alone. The TPEMc-rhodols systems clearly demonstrated a noticeable increase in fluorescence intensity at 550 nm and an obvious fluorescent color shift from cyan to yellow in the presence of N2H4. Fascinatingly, N2H4 could be visually and quantitatively detected in water by the TPEMc-rhodol systems paired with smartphone RGB analysis. Therefore, the combination of platinum(II) metallacycle with rhodols is a promising strategy for simple, sensitive, and visual detection of N2H4.

UV-Induced Reaction Pathways in Bromoform Probed with Ultrafast Electron Diffraction.

For many chemical reactions, it remains notoriously difficult to predict and experimentally determine the rates and branching ratios between different reaction channels. This is particularly the case for reactions involving short-lived intermediates, whose observation requires ultrafast methods. The UV photochemistry of bromoform (CHBr3) is among the most intensely studied photoreactions. Yet, a detailed understanding of the chemical pathways leading to the production of atomic Br and molecular Br2 fragments has proven challenging. In particular, the role of isomerization and/or roaming and their competition with direct C-Br bond scission has been a matter of continued debate. Here, gas-phase ultrafast megaelectronvolt electron diffraction (MeV-UED) is used to directly study structural dynamics in bromoform after single 267 nm photon excitation with femtosecond temporal resolution. The results show unambiguously that isomerization contributes significantly to the early stages of the UV photochemistry of bromoform. In addition to direct C-Br bond breaking within <200 fs, formation of iso-CHBr3 (Br-CH-Br-Br) is observed on the same time scale and with an isomer lifetime of >1.1 ps. The branching ratio between direct dissociation and isomerization is determined to be 0.4 ± 0.2:0.6 ± 0.2, i.e., approximately 60% of molecules undergo isomerization within the first few hundred femtoseconds after UV excitation. The structure and time of formation of iso-CHBr3 compare favorably with the results of an ab initio molecular dynamics simulation. The lifetime and interatomic distances of the isomer are consistent with the involvement of a roaming reaction mechanism.

n-changing population of Rydberg states by low-energy electron-Rydberg collisions.

Inelastic n-changing collisions play an important role in the evolution of Rydberg atoms into ultracold plasmas. However, for the initially intermediate n (n ∼ 40) Rydberg states, these collisions can hardly be observed due to the low electron temperature in ultracold plasmas. In this work, we designed an experimental scheme to facilitate collisions between free electrons at 1.5 eV and intermediate n Rydberg atoms. Using the field ionization technique, we measured the state distributions resulting from the evolution of initially cold rubidium atoms in the 45P3/2 Rydberg state. The experimentally obtained probability of inelastic collisions excitation agrees well with the Monte Carlo simulation results. In addition, our experimental results indicate that the n-changing population induced by hot electrons is significant for lower nP Rydberg states. Our work plays a significant role in calculating the rates of electron-ion three-body recombination in ultracold plasmas.

Mitigative Effect and Mechanism of Caffeic Acid Combined with Umbilical Cord-Mesenchymal Stem Cells on LPS-Induced Mastitis.

Mastitis is an inflammation of the mammary gland tissue that can lead to decreased milk production and altered milk composition, carrying serious implications for the safety of dairy products. Although both caffeic acid (CA) and umbilical cord-mesenchymal stem cells (UC-MSCs) showed potential anti-inflammatory and immunomodulatory properties, little is known about their combined roles in treating mastitis. Here, we report the combined effects and mechanisms of CA and UC-MSCs on lipopolysaccharide (LPS)-induced mastitis. Based on the network pharmacological analysis, the potential relevant genes involved in the alleviating effects of CA on LPS-induced mastitis were inferred. In LPS-treated mammary epithelial cells, CA or/and UC-MSC conditioned medium (UC-MSC-CM) inhibited the phosphorylation of p65, p50, p38, IκB, and MKK3/6 proteins and the expression of downstream inflammatory factors TNF-α, IL-1ß, IL-6, IL-8, and COX-2. Additionally, CA or/and hydrogel-loaded UC-MSCs also suppressed the activation of the above inflammatory pathway, leading to the alleviation of pathological damages in the LPS-induced mouse mastitis model. UC-MSCs exhibited more significant effects than CA, and the combined treatment of both was more effective. Our study sheds light on the synergistic and complementary effects of CA and UC-MSCs in alleviating mastitis, offering clues for understanding the regulation of the p38-MAPK/NF-κB↔TNF-α signal transduction loop in the tumor necrosis factor (TNF) pathway as a potential mechanism. This study provides a theoretical basis for developing a novel antibiotic alternative treatment of mastitis that may contribute to reducing economic losses in animal husbandry and protecting public health safety.

Androgen-ablative therapies inducing CXCL8 regulates mTORC1/SREBP2-dependent cholesterol biosynthesis to support progression of androgen receptor negative prostate cancer cells.

Treatment with androgen-ablative therapies effectively inhibited androgen receptor (AR)-positive (AR+) prostate cancer (PCa) cell subtypes, but it resulted in an increase in AR-negative (AR-) PCa cell subtypes. The present study aimed to investigate the debated mechanisms responsible for the changing proportion of cell types, identifying CXCL8 as a synthetic essential effector of AR- PCa cells. AR- PCa cells were found to be susceptible to CXCL8 depletion or inhibition, which impaired their survival. Mechanistically, androgen-ablative therapies resulted in the suppression of AR signaling, leading to the upregulation of CXCL8 gene transcription. CXCL8, in turn, activated the mTORC1 pathway, which increased de novo cholesterol synthesis by activating sterol regulatory element-binding protein-2 (SREBP2). Together, these results suggested that the CXCL8-mTORC1-SREBP2 axis contributed to the exacerbation of tumorigenicity in AR- PCa cells under androgen-ablative therapies.

IL-17A-neutralizing antibody ameliorates inflammation and fibrosis in rosacea by antagonizing the CXCL5/CXCR2 axis.

Rosacea is a chronic inflammatory skin disorder that can lead to fibrosis. However, the mechanisms underlying fibrosis in the later stages of rosacea have been less thoroughly investigated. Interleukin-17A (IL-17A) has been implicated in both inflammation and organ fibrosis; however, the effectiveness and mechanism of IL-17A-neutralizing antibodies in the later stages of rosacea-related fibrosis remain unclear. In this study, we induced rosacea-like lesions in mice using LL-37 and administered IL-17A-neutralizing antibodies. The results indicated that the IL-17A-neutralizing antibodies alleviated skin damage, reduced skin thickness, and decreased the secretion of inflammatory factors (TNF-α, CAMP, TLR4, P-NF-kB), angiogenesis-related factors (CD31, VEGF), and the TGF-ß1 signaling pathway, along with factors associated with epithelial-mesenchymal transition and the deposition of fibrosis-related proteins (COL1) in the rosacea-like mouse models. Furthermore, the IL-17A-neutralizing antibodies effectively diminished the expression of IL-17, IL-17R, CXCL5, and CXCR2 in the skin. Our findings demonstrate that IL-17A-neutralizing antibodies inhibit the activation of the CXCL5/CXCR2 axis in rosacea-like skin tissue, thereby ameliorating inflammation and fibrosis associated with the condition.

Recent advances in correlative cryo-light and electron microscopy.

Correlative light and electron microscopy (CLEM) pipelines serve to integrate the imaging modalities of fluorescence light microscopy (FLM) and cryogenic electron microscopy (cryo-EM) to produce contextually relevant high-resolution structural snapshots of biological systems. Innovations in sample preparation, instrumentation, imaging, and data processing have advanced the field of cryo-EM. This review focuses on prior work and recent developments in the field of cryo- EM that support further integration of technologies for correlative microscopy workflows.

A burrowing annelid from the early Cambrian.

Soft-bodied fossils of annelids from the Cambrian are relatively rare but provide vital insights into the early evolution and diversification of annelids. Here we describe a new annelid, Xiaoshibachaeta biodiversa gen. et sp. nov., from the early Cambrian (Stage 3) Xiaoshiba biota of Kunming, Yunnan Provence, China. This worm is obliquely oriented in the sediment, and is characteristic of a cephalic cage-like structure formed by the anteriorly directed parapodia and long chaetae of chaetiger 1, strongly suggesting an endobenthic lifestyle. This first report of an annelid worm from the Xiaoshiba biota provides the earliest known plausible evidence of burrowing behaviour in Annelida. Phylogenetic analyses recover X. biodiversa in the polytomy with other crown-group Annelida, indicating that the evolution of cephalic cage in Annelida is most likely convergent.

The influence of the personality traits of newly graduated nurses on the knowledge, skills and professional self-efficacy in standardized training: a cross-sectional study.

BACKGROUND: New graduate nurses often have certain potential safety hazards for patients due to insufficient knowledge and lack of clinical practice ability. To address these challenges, China has implemented a standardized training strategy. The improvements in the quality of this training involve not only the intervention of teaching methods but also the consideration of personality traits. METHODS: The application software based on the BFI-2 Chinese scale was utilized to administer personality tests to nursing students; nursing students were invited to scan the QR code and voluntarily fill in a questionnaire, including basic information, personality test results, and a professional self-efficacy test scale; offline paper-based theoretical examination results of nursing students were collected before and after training. The data was then analyzed using SPSS software version 26.0, which involved descriptive analysis, one-way between-groups analysis of variance (ANOVA) and Spearman correlation analysis. RESULTS: Based on the data, there were no observable differences in the theoretical results before and after training across different personality traits. In terms of skill assessment, conscientiousness exhibited the highest score at 78.91 ± 2.98 points, while negative emotionality showed the lowest score at 74.59 ± 2.12 points. These differences between different personality traits are statistically significant (P < 0.001). In terms of professional self-efficacy, conscientiousness scored the highest at 98.48 ± 12.69, while negative emotionality scored the lowest at 85.89 ± 11.71, with significant differences between different personality traits (P < 0.001). Professional self-efficacy was negatively correlated with agreeableness (r = -0.150, P = 0.044) and positively correlated with conscientiousness (r = -0.310, P < 0.001). Skill scores were negatively correlated with negative emotionality (r = -0.257, P < 0.001) and positively correlated with conscientiousness (r = 0.182, P = 0.014). CONCLUSIONS: This study shows that personality traits affect the skills test results and professional self-efficacy of nursing students. Conscientiousness scored the highest in this study, while negative emotionality scored the lowest. Therefore, personalized training plans are recommended to improve the quality of care for such nursing students and to further enhance patient safety.

Tannic Acid Film Based on One-Dimensional Supramolecular Self-Assembly for Electrical Conductivity and Oil-Water Separation.

Tannic acid is widely regarded as one of the most promising natural polyphenolic compounds. However, current research predominantly focuses on the utilization of its phenolic hydroxyl groups, with limited exploration of the functional potential of its aromatic structure. Herein, one-dimensional nanofibers based on supramolecular self-assembly were successfully prepared through the simple alkylation reaction of tannic acid and the π-π stacking of aromatic structures. These fibers, with lengths reaching tens of micrometers and an average height of 10 nm, were clearly observed using SEM and AFM. A film with excellent electrical conductivity (σ = 37.9 µS/cm) was fabricated by vacuum filtering the organic suspension of these fibers, which was 100-fold higher than that of the TA film. Additionally, the hydrophobic and lipophilic properties of Bn-TA were further investigated through oil-water separation experiments, where the Bn-TA membrane displayed excellent separation efficiency and durability, maintaining stable performance over multiple cycles. This strategy presents opportunities for the high-value utilization of tannic acid.

Immunogenicity, safety, and persistence induced by triple- and standard-strength four-dose hepatitis B vaccination regimens in hemodialysis patients: A multicenter, randomized, parallel-controlled trial in Six cities in Shanxi Province.

BACKGROUND: Hemodialysis (HD) patients represent a high-risk group for hepatitis B infection. It is crucial to administer hepatitis B vaccination and stimulate higher and more sustained levels of anti-HBs. Our aim is to enhance the immunogenicity and persistence by implementing high-dose and prolonged hepatitis B vaccine schedule regimen in HD patients. METHODS: We conducted this multicenter, randomized, parallel-controlled trial between July 2020 and February 2023 at 11 hospitals in Shanxi province, China. A total of 504 HD patients were enrolled. All participants randomly allocated in a ratio of 1:1:1 to receive recombinant HBV vaccine of 3 standard doses (20 µg) at 0-1-6 months (IM20×3 group), 4 standard doses at 0-1-2-6 months (IM20×4 group), or 4 triple doses (60 µg) at 0-1-2-6 months (IM60×4 group). RESULTS: The vaccine-elicited antibody response peaked at month 7. The follow-up outcomes ranging from month 7 to 30 revealed that the response rates of anti-HBs decreased from 85.9% (134/156) to 33.0% (33/100) in IM20×3 group, from 92.5% (135/146) to 53.9% (56/104) in IM20×4 group and from 95.4% (145/152) to 57.3% (55/96) in IM60×4 group. The duration of vaccine-induced response with 75% of patients maintained protective antibody were 21.0 months in IM20×3 group, 25.7 months in IM20×4 group (vs. IM20×3 group, P=0.056) and 29.2 months in IM60×4 group (vs. IM20×3 group, P=0.034). All the adverse reactions were mild. CONCLUSIONS: The four-triple-dose hepatitis B vaccination regimens could enhance the immunogenicity and 2-year duration in HD patients.The trial was registered with Clinical Trials.gov, number NCT03962881. https://classic.clinicaltrials.gov/ct2/show/NCT03962881?term=NCT03962881&draw=2&rank=1.

Effect of occlusion site on the effectiveness and safety of endovascular thrombectomy for large ischemic cores: A cohort study.

BACKGROUND: Recent clinical trials have shown that patients with large ischemic cores have better outcomes with endovascular thrombectomy (EVT) compared with standard medical treatment (SMT) alone.We aim to assess whether the relationship between EVT and improvements in clinical outcomes varies depending on the location of the occlusive sites. METHODS: This study is a subgroup analysis conducted within a prospective, nationwide, multi-center registry. The cohort included patients with acute large vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 0 to 5 within 24 hours from last known well. We utilized the adjusted common odds ratio for a shift toward better outcome on the modified Rankin Scale after EVT compared with SMT alone as the primary outcome. Safety outcomes included symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 745 patients with large ischemic cores were included: 272(36.5%) with internal carotid artery occlusion, 392(52.6%) with M1 segment of the middle cerebral artery occlusion, and 81(11.0%) with M2 segment of the middle cerebral artery occlusion. The adjusted common odds ratios were as follows: 1.98 (95% CI, 1.01-3.89) for ICA occlusions, 2.09 (95% CI, 1.35-3.23) for M1 occlusions, and 1.13 (95% CI, 0.43-2.94) for M2 occlusions. There was no significant treatment-by-occlusion site interaction observed (P=0.69). However, the incidence of sICH was significantly greater in all groups receiving EVT than in those receiving SMT alone. Additionally, we observed that the secondary outcomes and subgroup analyses were generally consistent with the main outcomes. CONCLUSIONS: In this study, we found that patients with internal carotid artery and M1 occlusion demonstrated a better outcome with EVT, while the benefit for patients with M2 occlusion remains uncertain.

Bulk high-temperature superconductivity in pressurized tetragonal La2PrNi2O7.

The Ruddlesden-Popper (R-P) bilayer nickelate, La3Ni2O7, was recently found to show signatures of high-temperature superconductivity (HTSC) at pressures above 14 GPa (ref. 1). Subsequent investigations achieved zero resistance in single-crystalline and polycrystalline samples under hydrostatic pressure conditions2-4. Yet, obvious diamagnetic signals, the other hallmark of superconductors, are still lacking owing to the filamentary nature with low superconducting volume fraction2,4,5. The presence of a new 1313 polymorph and competing R-P phases obscured proper identification of the phase for HTSC6-9. Thus, achieving bulk HTSC and identifying the phase at play are the most prominent tasks. Here we address these issues in the praseodymium (Pr)-doped La2PrNi2O7 polycrystalline samples. We find that substitutions of Pr for La effectively inhibit the intergrowth of different R-P phases, resulting in a nearly pure bilayer structure. For La2PrNi2O7, pressure-induced orthorhombic to tetragonal structural transition takes place at Pc ≈ 11 GPa, above which HTSC emerges gradually on further compression. The superconducting transition temperatures at 18-20 GPa reach T c onset = 82.5 K and T c zero = 60 K , which are the highest values, to our knowledge, among known nickelate superconductors. Importantly, bulk HTSC was testified by detecting clear diamagnetic signals below about 75 K with appreciable superconducting shielding volume fractions at a pressure of above 15 GPa. Our results not only resolve the existing controversies but also provide directions for exploring bulk HTSC in the bilayer nickelates.

Dynamics of Polymer Films on Polymer-Grafted Substrates: A Molecular Dynamics Simulation.

For substrate-supported polymer films, the tails of adsorbed chains are generally assumed to play important roles in the propagation of the substrate's effect inside polymer films. The effects of the grafting density and the rigidity of substrate-grafted polymers, the simplest model for the adsorbed tails, on the diffusivity of film polymers are investigated by performing molecular dynamics simulations. An optimal grafting density σo, around the critical grafting density for the transition from "mushroom" to "brush", is found with the most pronounced suppression of diffusivity on the film polymers; i.e., the penetration of the film polymers into the grafting layer reaches the maximum. However, at high grafting density, the crowded and vertically stretched brush excludes the coil-like film polymers, and the suppression is thus reduced. At σo, with an increase in the rigidity of the grafted polymers, the suppression is increased quickly at low rigidity but slowly at high rigidity. The dynamic suppression is attributed to the combination of the conformation change from stretching at low rigidity to tilted orientation at high rigidity and decelerated mobility induced by the rigidity. The stretching conformation enhances, whereas the tilted conformation weakens the interpenetration between the grafted polymers and the film polymers. Our results reflect the importance of both conformational variation and interchain interaction in the interface region.

Incidence and Risk Factors for Toxic Shock Syndrome After Endoscopic Sinus Surgery: A Systematic Review.

OBJECTIVE: Toxic shock syndrome (TSS) is a rare but serious complication after sinonasal surgery and a commonly cited consideration for prescribing antibiotics when nasal packing or stents are placed. Most reports are limited to case reports or small series. The aim of this systematic review was to describe the incidence, risk factors, and clinical course of patients who developed TSS as a complication of endoscopic sinus surgery (ESS) and/or septoplasty. DATA SOURCES: A systematic review was conducted using MEDLINE, EMBASE, CINAHL, Web of Science, and Cochrane Library databases. REVIEW METHODS: Eligibility criteria were patients of any age who developed TSS as a complication of ESS and/or septoplasty. RESULTS: Twenty-five studies were included in the final review. Seventy cases were identified over 38 years (1982-2020). The pooled incidence of TSS after sinonasal surgery was 0.0003 (0.0002-0.0004, 95% confidence interval, CI) or 30 per 100,000 persons. Among 33 patients with single-subject data, mean age was 33.8 years (29.73-37.87, 95% CI). Seventeen (51.5%) patients had nasal packing, 3 (9.1%) had stents, 5 (15.2%) had both, 7 (21.2%) had none. Fourteen (42.4%) patients had nonabsorbable packing and 5 (15.2%) had absorbable packing. Sixteen (48%) patients received peri-operative antibiotics. Thirty-two (97%) patients had full recovery. CONCLUSION: The incidence of TSS after sinonasal surgery is very rare. TSS can occur with and without nasal packing and prophylactic antibiotics were not protective. Outcomes were favorable with appropriate recognition and management. Further study is needed to determine which patients are most at risk for TSS.

Specific depressive symptoms, body mass index and diabetes in middle-aged and older Chinese adults: Analysis of data from the China Health and Retirement Longitudinal Study (CHARLS).

BACKGROUND: This study examined the association between specific depressive symptoms and incident diabetes, and whether overweight or obesity mediates this relationship among middle-aged and older adults in China. METHODS: In a nationally representative prospective cohort study of 11,893 middle-aged and older Chinese adults without baseline diabetes, we used Cox models to assess the association between depressive symptoms and diabetes. The quantile g-computation (qgcomp) model evaluated the contribution of 10 specific depressive symptoms to diabetes risk, and a two-stage regression method explored the mediation effect of overweight or obesity. RESULTS: Over a median follow-up of 7.1 years, 1314 cases of diabetes were identified. Elevated depressive symptoms were associated with increased diabetes risk (HR 1.23; 95 % CI 1.09-1.38). Eight out of 10 depressive symptoms were significantly associated to diabetes, with loneliness (weight = 18 %; HR 1.23; 95 % CI 1.10-1.39), restless sleep (weight = 17 %; HR 1.16; 95 % CI 1.04-1.29), and bother (weight = 15 %; HR 1.19; 95 % CI 1.07-1.33) being the primary contributors. Mediation analysis showed that overweight and obesity reduced the depression-diabetes risk association by 8.21 % and 12.61 %, respectively. LIMITATIONS: Diagnosis of diabetes was self-reported. CONCLUSIONS: Eight out of ten specific depressive symptoms were associated to diabetes, overweight and obesity may partially mitigate the effect of depressive symptoms on diabetes among middle-aged and older adults in China. CLINICAL IMPLICATIONS: Our results highlight the importance of tailoring diabetes prevention and management strategies according to specific depressive symptoms among middle-aged and older adults in China.

VvbZIP22 regulates quercetin synthesis to enhances cold resistance in grape.

Grapes are one of the important fruit crops widely cultivated in the world, with high nutritional and economic value. However, with the intensification of global warming, extreme low temperature has seriously affected the development of the grape industry. Quercetin is a highly antioxidant active substance that can enhance the tolerance of plants to external environmental stress, but its function and mechanism in response to low-temperature stress in grapes are still unclear. Here, we found that grapes accumulate more quercetin under low-temperature stress, and exogenous quercetin can significantly improve the cold resistance of grapes. The key quercetin synthesis gene VvFLS1 (flavanol synthase 1) is up-regulated after low-temperature treatment, and overexpression of VvFLS1 increases quercetin content and enhances the cold resistance of grape. Yeast one-hybrid and dual luciferase reporter systems demonstrate that VvbZIP22 (basic-leucine zipper 22) directly binds to the VvFLS1 promoter, and VvbZIP22 has cold-induced expression characteristics. Overexpression of VvbZIP22 significantly improves the cold resistance of grape. The above results indicate that quercetin plays an important role in the response of grapes to low-temperature stress. Under low temperature, VvbZIP22 can mediate quercetin synthesis through regulating VvFLS1, alleviate oxidative damage, and improve the cold resistance of grapes.

In situ crystalline structure of the human eosinophil major basic protein-1.

Eosinophils are white blood cells that participate in innate immune responses and have an essential role in the pathogenesis of inflammatory and neoplastic disorders. Upon activation, eosinophils release cytotoxic proteins such as major basic protein-1 (MBP-1) from cytoplasmic secretory granules (SGr) wherein MBP-1 is stored as nanocrystals. How the MBP-1 nanocrystalline core is formed, stabilized, and subsequently mobilized remains unknown. Here, we report the in-situ structure of crystalline MBP-1 within SGrs of human eosinophils. The structure reveals a mechanism for intragranular crystal packing and stabilization of MBP-1 via a structurally conserved loop region that is associated with calcium-dependent carbohydrate binding in other C-type lectin (CTL) proteins. Single-cell and single-SGr profiling correlating real-space three-dimensional information from cellular montage cryo-electron tomography (cryo-ET) and microcrystal electron diffraction (MicroED) data obtained from non-activated and IL33-activated eosinophils revealed activation-dependent crystal expansion and extrusion of expanded crystals from SGr. These results suggest that MBP-1 crystals play a dynamic role in the release of SGr contents. Collectively, this research demonstrates the importance of in-situ macromolecular structure determination.