Real-world evidence of combined treatment of biologics and exclusive enteral nutrition in patients with ileum-dominant Crohn's disease: A multicenter study.

BACKGROUND & AIMS: Although biologics were prescribed to achieve and maintain clinical remission of active Crohn's disease (CD), almost half of patients experienced a loss of response or intolerance. Here, we investigated the efficacy of combined treatment of biologics and 16-weeks exclusive enteral nutrition (EEN) in moderate-to-severe CD patients with small intestine lesions. METHODS: This was a real-world, multicenter retrospective study, from October 2016 to March 2023, medical records of patients registered at three IBD centers were reviewed for patients with ileal or ileocolonic CD in moderate-to-severe activity. All patients received treatment of biologics with concomitant 16-week EEN (BioEEN) or biologics alone (Bio). The clinical outcomes and endoscopic outcomes were assessed at week 16 and 52. RESULTS: There was no statistically significant difference between Bio (97 patients) and BioEEN group (100 patients) at baseline for demographic and clinical characteristics. Compared to treatment with biologics alone, patients with BioEEN treatment achieved higher rates of clinical response (95.0% vs. 66.0%), clinical remission (87.0% vs. 52.6%), endoscopic response (91.4% vs. 47.4%) including mucosal healing (85.7% vs. 23.7%) at week 16. The superiority of BioEEN sustained in maintenance, with 84.7% (vs. 49.1%) clinical response, 77.8% (vs. 38.6%) clinical remission, 69.2% (vs. 32.6%) endoscopic response and 51.9% (vs. 18.6%) mucosal healing at week 52. CONCLUSIONS: Combined treatment of biologics and 16-week EEN was an efficient therapeutic strategy with affirmative effectiveness for small intestine diseases of active CD.

Improvement of thermostability and catalytic efficiency of xylanase from Myceliophthora thermophilar by N-terminal and C-terminal truncation.

Introduction: Extracting xylanase from thermophilic filamentous fungi is a feasible way to obtain xylanase with good thermal stability. Methods: The transcriptomic data of Myceliophthora thermophilic destructive ATCC42464 were differentially expressed and enriched. By comparing the sequences of Mtxylan2 and more than 10 xylanases, the N-terminal and C-terminal of Mtxylan2 were truncated, and three mutants 28N, 28C and 28NC were constructed. Results and discussion: GH11 xylan Mtxylan2 was identified by transcriptomic analysis, the specific enzyme activity of Mtxylan2 was 104.67 U/mg, and the optimal temperature was 65°C. Molecular modification of Mtxylan2 showed that the catalytic activity of the mutants was enhanced. Among them, the catalytic activity of 28C was increased by 9.3 times, the optimal temperature was increased by 5°C, and the residual enzyme activity remained above 80% after 30 min at 50-65°C, indicating that redundant C-terminal truncation can improve the thermal stability and catalytic performance of GH11 xylanase.

Preliminary investigation on the causes of red tides in Qinhuangdao coastal areas in 2022.

To explore the causes of red tides in Qinhuangdao coastal water, we conducted surveys on both water quality and red tides during April to September of 2022 and analyzed the relationships between main environmental factors and red tide organisms through the factor analysis and canonical correspondence analysis. The results showed that there were eight red tides along the coast of Qinhuangdao in 2022, with a cumulative blooming area of 716.1 km2. The red tides could be divided into three kinds based on the major blooming organisms and occurrence time, Noctiluca scintillans bloom, diatom-euglena (Skeletonema costatum, Eutreptiella gymnastica, Pseudo-nitzschia spp.) bloom, and dinoflagellate (Scrippsiella trochoidea and Ceratium furca) bloom. Seasonal factor played roles mainly during July to September, while inorganic nutrients including nitrogen and phosphorus influenced the blooms mainly in April and July. The canonical correspondence analysis suggested that N. scintillans preferred low temperature, and often bloomed with high concentrations of ammonium nitrogen and dissolved inorganic phosphorus. S. costatum, E. gymnastica, and Pseudo-nitzschia spp. could tolerate broad ranges of various environmental factors, but favored high temperature and nitrogen-rich seawater. C. furca and S. trochoidea had higher survival rate and competitiveness in phosphate-poor waters. Combined the results from both analyses, we concluded that the causes for the three kinds of red tide processes in Qinhuangdao coastal areas in 2022 were different. Adequate diet algae and appropriate water temperature were important factors triggering and maintaining the N. scintillans bloom. Suitable temperature, salinity and eutrophication were the main reasons for the diatom-euglena bloom. The abundant nutrients and seawater disturbance promoted the germination of S. trochoidea cysts, while phosphorus limitation caused the blooming organism switched to C. furca and maintained the bloom hereafter.

Dimerized Nonfused Electron Acceptor Based on a Thieno[3,4-c]pyrrole-4,6-dione Core for Organic Solar Cells.

In this work, the first dimerized nonfused electron acceptor (NFEA), based on thieno[3,4-c]pyrrole-4,6-dione as the core, has been designed and synthesized. The dimerized acceptor and its single counterpart exhibit similar energy levels but different absorption spectra due to their distinct aggregation behavior. The dimerized acceptor-based organic solar cells (OSCs) demonstrate a higher power conversion efficiency of 11.05%, accompanied by enhanced thermal stability. This improvement is attributed to the enhancement of the short-circuit current density and fill factor, along with an increase in the glass transition temperature. Characterizations of exciton dynamics and film morphology reveal that a dimerized acceptor-based device possesses an enhanced exciton dissociation efficiency and a well-established charge transport pathway, explaining its improved photovoltaic performance. All these results indicate that the dimerized NFEA as a promising candidate can achieve efficiency-stability-cost balance in OSCs.

Wireless Technologies in Flexible and Wearable Sensing: from Materials Design, System Integration to Applications.

Wireless and wearable sensors attract considerable interest in personalized healthcare by providing a unique approach for remote, non-contact, and continuous monitoring of various health-related signals without interference with daily life. Recent advances in wireless technologies and wearable sensors have promoted practical applications due to their significantly improved characteristics, such as reduction in size and thickness, enhancement in flexibility and stretchability, and improved conformability to the human body. Currently, most researches focus on active materials and structural designs for wearable sensors, with just a few exceptions reflecting on the technologies for wireless data transmission. This review provides a comprehensive overview of the state-of-the-art wireless technologies and related studies on empowering wearable sensors. The emerging functional nanomaterials utilized for designing unique wireless modules are highlighted, which include metals, carbons, and MXenes. Additionally, the review outlines the system-level integration of wireless modules with flexible sensors, spanning from novel design strategies for enhanced conformability to efficient transmitting data wirelessly. Furthermore, the review introduces representative applications for remote and non-invasive monitoring of physiological signals through on-skin and implantable wireless flexible sensing systems. Finally, the challenges, perspectives, and unprecedented opportunities for wireless and wearable sensors are discussed. This article is protected by copyright. All rights reserved.

Quantifying the mitigating effect of organic matter on heavy metal availability in soils with different manure applications: A geochemical modelling study.

Manure is one of the main sources of heavy metal (HM) pollution on farmlands. It has become the focus of global ecological research because of its potential threat to human health and the sustainability of food systems. Soil pH and organic matter are improved by manure and play pivotal roles in determining soil HM behavior. Geochemical modeling has been widely used to assess and predict the behavior of soil HMs; however, there remains a research gap in manure applications. In this study, a geochemical model (LeachXS) coupled with a pH-dependent leaching test with continuously simulations over a broad pH range was used to determine the effects and pollution risks of pig or cattle manure separate application on soil HMs distribution. Both pig and cattle manure applications led to soil pH reduction in alkaline soils and increased organic matter content. Pig manure application resulted in a potential 90.5-156.0 % increase in soil HM content. Cattle manure did not cause significant HM contamination. The leaching trend of soil HMs across treatments exhibited a V-shaped change, with the lowest concentration at pH = 7, gradually increasing toward strong acids and bases. The dissolved organic matter-bound HM content directly increased the HM availability, especially for Cu (up to 8.4 %) after pig manure application. However, more HMs (Cr, Cu, Zn, Ni) were in the particulate organic matter-bound state than in other solid phases (e.g., Fe-Al(hydr) oxides, clay minerals), which inhibited the HMs leaching by more than 19.3 % after cattle manure application. Despite these variations, high HM concentrations introduced by pig manure raised the soil contamination risk, potentially exceeding 40 times at pH ±1. When manure is returned to the field, reducing its HM content and mitigating possible pollution is necessary to realize the healthy and sustainable development of circular agriculture.

Effect of Chemical Composition on the Thermoplastic Formability and Nanoindentation of Ti-Based Bulk Metallic Glasses.

A series of Ti41Zr25Be34-xNix (x = 4, 6, 8, 10 at.%) and Ti41Zr25Be34-xCux (x = 4, 6, 8 at.%) bulk metallic glasses were investigated to examine the influence of Ni and Cu content on the viscosity, thermoplastic formability, and nanoindentation of Ti-based bulk metallic glasses. The results demonstrate that Ti41Zr25Be30Ni4 and Ti41Zr25Be26Cu8 amorphous alloys have superior thermoplastic formability among the Ti41Zr25Be34-xNix and Ti41Zr25Be34-xCux amorphous alloys due to their low viscosity in the supercooled liquid region and wider supercooled liquid region. The hardness and modulus exhibit obvious variations with increasing Ni and Cu content in Ti-based bulk metallic glasses, which can be attributed to alterations in atomic density. Optimal amounts of Ni and Cu in Ti-based bulk metallic glasses enhance thermoplastic formability and mechanical properties. The influence of Ni and Cu content on the hardness of Ti-based bulk metallic glasses is discussed from the perspective of the mean atomic distance.

Integrating Targeted Metabolomics and Targeted Proteomics to Study the Responses of Wheat Plants to Engineered Nanomaterials.

This manuscript presents a multiomics investigation into the metabolic and proteomic responses of wheat to molybdenum (Mo)- and copper (Cu)-based engineered nanomaterials (ENMs) exposure via root and leaf application methods. Wheat plants underwent a four-week growth period with a 16 h photoperiod (light intensity set at 150 µmol·m-2·s-1), at 22 °C and 60% humidity. Six distinct treatments were applied, including control conditions alongside exposure to Mo- and Cu-based ENMs through both root and leaf routes. The exposure dosage amounted to 6.25 mg of the respective element per plant. An additional treatment with a lower dose (0.6 mg Mo/plant) of Mo ENM exclusively through the root system was introduced upon the detection of phytotoxicity. Utilizing LC-MS/MS analysis, 82 metabolites across various classes and 24 proteins were assessed in different plant tissues (roots, stems, leaves) under diverse treatments. The investigation identified 58 responsive metabolites and 19 responsive proteins for Cu treatments, 71 responsive metabolites, and 24 responsive proteins for Mo treatments, mostly through leaf exposure for Cu and root exposure for Mo. Distinct tissue-specific preferences for metabolite accumulation were revealed, highlighting the prevalence of organic acids and fatty acids in stem or root tissues, while sugars and amino acids were abundant in leaves, mirroring their roles in energy storage and photosynthesis. Joint-pathway analysis was conducted and unveiled 23 perturbed pathways across treatments. Among these, Mo exposure via roots impacted all identified pathways, whereas exposure via leaf affected 15 pathways, underscoring the reliance on exposure route of metabolic and proteomic responses. The coordinated response observed in protein and metabolite concentrations, particularly in amino acids, highlighted a dynamic and interconnected proteomic-to-metabolic-to-proteomic relationship. Furthermore, the contrasting expression patterns observed in glutamate dehydrogenase (upregulation at 1.38 ≤ FC ≤ 1.63 with high Mo dose, and downregulation at 0.13 ≤ FC ≤ 0.54 with low Mo dose) and its consequential impact on glutamine expression (7.67 ≤ FC ≤ 39.60 with high Mo dose and 1.50 ≤ FC ≤ 1.95 with low Mo dose) following Mo root exposure highlighted dose-dependent regulatory trends influencing proteins and metabolites. These findings offer a multidimensional understanding of plant responses to ENMs exposure, guiding agricultural practices and environmental safety protocols while advancing knowledge on nanomaterial impacts on plant biology.

Dynamically changed HSP70 after reperfusion following cerebral infarction in human and rats: correlation with p38 MAPK.

We aimed to clarify the correlation between dynamic change of blood HSP70 and the prognosis of thrombolysis in human and rats, so as to explain the neuroprotection and early warning role of HSP70 in cerebral ischemia-reperfusion. Forty-two patients with acute ischemic stroke were divided into two groups according to the time from onset to thrombolytic therapy: 0 h-3 h (27 patients) and 3-4.5 h group (15 patients). The level of HSP70 in serum before and after thrombolysis was detected by ELISA. Furthermore, a rat model was also used to mimic the ischemic stroke and reperfusion. Peripheral blood of rat samples was collected to detect the level of HSP70 using Elisa. Several signal proteins from MAPK signaling pathway including JNK, p38, ERK (p42/44) were detected at different time points by Western blot of brain tissue. Patients who underwent thrombolytic therapy within 0-3 h had the highest HSP70 level at 1 h after thrombolysis. The higher HSP70 after thrombolysis, the better the patient prognosis. NIHSS scores showed HSP70 was positively correlated with cerebral ischemia. The levels of ERK family (p42/44 MAPK) and p-JNK were decreased gradually along with the time suffering cerebral ischemia. P-ERK, JNK, p-p38 had dynamic changes with increased ischemic time in the middle cerebral artery occlusion model. Dynamic change of HSP70 level in blood may be a biological index that reflects the functional condition of cell survival for cerebral ischemia and estimating the prognostic conditions. Importantly, HSP70 levels in blood were positively correlated with the p38 MAPK pathway in brain tissue.

Double Perovskite Single Crystals with High Laser Irradiation Stability for Solid-State Laser Lighting and Anti-counterfeiting.

Laser lighting devices, comprising an ultraviolet (UV) laser chip and a phosphor material, have emerged as a highly efficient approach for generating high-brightness light sources. However, the high power density of laser excitation may exacerbate thermal quenching in conventional polycrystalline or amorphous phosphors, leading to luminous saturation and the eventual failure of the device. Here, for the first time, we raise a single-crystal (SCs) material for laser lighting considering the absence of grain boundaries that scatter electrons and phonons, achieving high thermal conductivity (0.81 W m-1 K-1) and heat-resistance (575 °C). The SCs products exhibit a high photoluminescence quantum yield (89%) as well as excellent stability toward high-power lasers (>12.41 kW/cm2), superior to all previously reported amorphous or polycrystalline matrices. Finally, the laser lighting device was fabricated by assembling the SC with a UV laser chip (50 mW), and the device can maintain its performance even after continuous operation for 4 h. Double perovskite single crystals doped with Yb3+/Er3+ demonstrated multimodal luminescence with the irradiation of 355 and 980 nm lasers, respectively. This characteristic holds significant promise for applications in spectrally tunable laser lighting and multimodal anticounterfeiting.

Ethylenedioxythiophene-based Small Molecular Donor with Multiple Conformation Locks for Organic Solar Cells with Efficiency of 19.3.

Ternary organic solar cells (T-OSCs) represent an efficient strategy for enhancing the performance of OSCs. Presently, the majority of high-performance T-OSCs incorporates well-established Y-acceptors or donor polymers as the third component. In this study, a novel class of conjugated small molecules has been introduced as the third component, demonstrating exceptional photovoltaic performance in T-OSCs. This innovative molecule comprises ethylenedioxythiophene (EDOT) bridge and 3-ethylrhodanine as the end group, with the EDOT unit facilitating the creation of multiple conformation locks. Consequently, the EDOT-based molecule exhibits two-dimensional charge transport, distinguishing it from the thiophene-bridged small molecule, which displays fewer conformation locks and provides one-dimensional charge transport. Furthermore, the robust electron-donating nature of EDOT imparts the small molecule with cascade energy levels relative to the electron donor and acceptor. As a result, OSCs incorporating the EDOT-based small molecule as the third component demonstrate enhanced mobilities, yielding a remarkable efficiency of 19.3%, surpassing the efficiency of 18.7% observed for OSCs incorporating thiophene-based small molecule as the third component. The investigations in this study underscore the excellence of EDOT as a building block for constructing conjugated materials with multiple conformation locks and high charge carrier mobilities, thereby contributing to elevated photovoltaic performance in OSCs.

Single-virus-sensitive barcode qPCR mediated by the aggregation of gold nanoparticle probes.

Herein, we developed a gold nanoparticle (GNP)-mediated barcode qPCR strategy with a sensitivity for a single virus particle per reaction for the detection of influenza virus H3N2. The analysis of the results for pure virus and real virus samples show that GNP-mediated barcode qPCR is ∼16 times more sensitive than conventional qPCR, demonstrating the potential to reduce false negatives and improve early diagnosis of viral infections.

Caproicibacter sp. BJN0012, a potential new species isolated from cellar mud for caproic acid production from glucose.

Acids play a crucial role in enhancing the flavor of strong-aroma Baijiu, and among them, caproic acid holds significant importance in determining the flavor of the final product. However, the metabolic synthesis of caproic acid during the production process of Baijiu has received limited attention, resulting in fluctuations in caproic acid content among fermentation batches and generating production instability. Acid-producing bacteria found in the cellar mud are the primary microorganisms responsible for caproic acid synthesis, but there is a lack of research on the related microbial resources and their metabolic properties. Therefore, it is essential to identify and investigate these acid-producing microorganisms from cellar mud to ensure stable caproic acid synthesis. In this study, a unique strain was isolated from the cellar mud, exhibiting a 98.12 % similarity in its 16 S rRNA sequence and an average nucleotide identity of 79.57 % with the reference specie, together with the DNA-DNA hybridization of 23.20 % similarity, confirming the distinct species boundaries. The strain was able to produce 1.22 ± 0.55 g/L caproic acid from glucose. Through genome sequencing, annotation, and bioinformatics analysis, the complete pathway of caproic acid synthesis from glucose was elucidated, and the catalytic mechanism of the key thiolase for caproic acid synthesis was investigated. These findings provide useful fundamental data for revealing the metabolic properties of caproic acid-producing bacteria found in cellar mud.

Electrical Conductivities and Conduction Mechanism of Lithium-Doped High-Entropy Oxides at Different Temperature and Pressure Conditions.

Li-doped high-entropy oxides (Li-HEO) are promising electrode materials for Li-ion batteries. However, their electrical conduction in a wide range of temperatures and/or at high pressure is unknown, hindering their applications under extreme conditions. Especially, a clear understanding of the conduction mechanism is needed. In this work, we determined the carrier type of several Li-doped (MgCoNiCuZn)O semiconductor compounds and measured their electrical conduction at temperatures 79-773 K and/or at pressures up to 50 GPa. Three optical band gaps were uncovered from the UV-vis-NIR absorption measurements, unveiling the existence of defect energy levels near the valence band of p-type semiconductors. The Arrhenius-like plot of the electrical conductivity data revealed the electronic conduction in three temperature regions, i.e., the ionization region from 79 to 170 K, the extrinsic region from ∼170 to 300 K, and the intrinsic region at ≥300 K. The closeness of the determined electronic band gap and the second optical band gap suggests that the conduction electrons in the intrinsic region originate from a thermal excitation from the defect energy levels to the conduction band, which determines the electronic conductivity. It was also found that at or above room temperature, ionic conduction coexists with electronic conduction with a comparable magnitude at ambient pressure and that the intrinsic conduction mechanism also operates at high pressures. These findings provide us a fundamental understanding of the band structure and conduction mechanism of Li-HEO, which would be indispensable to their applications in new technical areas.

Comparative effectiveness of several adjuvant therapies after hepatectomy for hepatocellular carcinoma patients with microvascular invasion.

BACKGROUND: For resectable hepatocellular carcinoma (HCC), radical hepatectomy is commonly used as a curative treatment. However, postoperative recurrence significantly diminishes the overall survival (OS) of HCC patients, especially with microvascular invasion (MVI) as an independent high-risk factor for recurrence. While some studies suggest that postoperative adjuvant therapy may decrease the risk of recurrence following liver resection in HCC patients, the specific role of adjuvant therapies in those with MVI remains unclear. AIM: To conduct a network meta-analysis (NMA) to evaluate the efficacy of various adjuvant therapies and determine the optimal adjuvant regimen. METHODS: A systematic literature search was conducted on PubMed, EMBASE, and Web of Science until April 6, 2023. Studies comparing different adjuvant therapies or comparing adjuvant therapy with hepatectomy alone were included. Hazard ratios (HRs) with 95% confidence intervals were used to combine data on recurrence free survival and OS in both pairwise meta-analyses and NMA. RESULTS: Fourteen eligible trials (2268 patients) reporting five different therapies were included. In terms of reducing the risk of recurrence, radiotherapy (RT) [HR = 0.34 (0.23, 0.5); surface under the cumulative ranking curve (SUCRA) = 97.7%] was found to be the most effective adjuvant therapy, followed by hepatic artery infusion chemotherapy [HR = 0.52 (0.35, 0.76); SUCRA = 65.1%]. Regarding OS improvement, RT [HR: 0.35 (0.2, 0.61); SUCRA = 93.1%] demonstrated the highest effectiveness, followed by sorafenib [HR = 0.48 (0.32, 0.69); SUCRA = 70.9%]. CONCLUSION: Adjuvant therapy following hepatectomy may reduce the risk of recurrence and provide a survival benefit for HCC patients with MVI. RT appears to be the most effective adjuvant regimen.

Prediction of risk factors for linezolid-induced thrombocytopenia based on neural network model.

Background: Based on real-world medical data, the artificial neural network model was used to predict the risk factors of linezolid-induced thrombocytopenia to provide a reference for better clinical use of this drug and achieve the timely prevention of adverse reactions. Methods: The artificial neural network algorithm was used to construct the prediction model of the risk factors of linezolid-induced thrombocytopenia and further evaluate the effectiveness of the artificial neural network model compared with the traditional Logistic regression model. Results: A total of 1,837 patients receiving linezolid treatment in a hospital in Xi 'an, Shaanxi Province from 1 January 2011 to 1 January 2021 were recruited. According to the exclusion criteria, 1,273 cases that did not meet the requirements of the study were excluded. A total of 564 valid cases were included in the study, with 89 (15.78%) having thrombocytopenia. The prediction accuracy of the artificial neural network model was 96.32%, and the AUROC was 0.944, which was significantly higher than that of the Logistic regression model, which was 86.14%, and the AUROC was 0.796. In the artificial neural network model, urea, platelet baseline value and serum albumin were among the top three important risk factors. Conclusion: The predictive performance of the artificial neural network model is better than that of the traditional Logistic regression model, and it can well predict the risk factors of linezolid-induced thrombocytopenia.

Temporal Profile of the Microbial Community and Volatile Compounds in the Third-Round Fermentation of Sauce-Flavor baijiu in the Beijing Region.

Sauce-flavor baijiu produced in the Beijing and Guizhou regions has regional characteristic flavors, but the differences in flavor compounds and reasons for their formation remain unclear. The sauce-flavor baijiu brewing process involves several rounds of fermentation. In this study, we investigated the temporal distribution of microbial communities and flavor substances during the third round of sauce-flavor baijiu fermentation in the Beijing region, and we then compared and analyzed the differences of flavor substances and microorganisms in the fermented grains of sauce-flavor baijiu in the Beijing and Guizhou regions. It was found that 10 bacterial genera and 10 fungal genera were dominant in the fermented grains. The acidity of the fermented grains had a significant driving effect on the microbial community succession. A total of 81 volatile compounds were identified and quantified in the fermented grains, of which esters and alcohols were relatively abundant. The differences in 30 microbial community compositions and their resulting differences in terms of the fermentation parameters of fermented grains are responsible for the differences in the profiles of flavor compounds between sauce-flavor baijiu produced in the Beijing and Guizhou regions.

Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx.

To date, several molecules have been found to facilitate iron influx, while the types of iron influx channels remain to be elucidated. Here, Piezo1 channel was identified as a key iron transporter in response to mechanical stress. Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells (NPCs). Importantly, Piezo1-induced iron influx was independent of the transferrin receptor (TFRC), a well-recognized iron gatekeeper. Furthermore, pharmacological inactivation of Piezo1 profoundly reduced iron accumulation, alleviated mitochondrial ROS, and suppressed ferroptotic alterations in stimulation of mechanical stress. Moreover, conditional knockout of Piezo1 (Col2a1-CreERT Piezo1flox/flox) attenuated the mechanical injury-induced intervertebral disc degeneration (IVDD). Notably, the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout (cDKO) mice (Col2a1-CreERT Piezo1flox/flox/Gpx4flox/flox). These findings suggest that Piezo1 is a potential determinant of iron influx, indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.

Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins.

Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and the recently emerged BA.2.86 and JN.1. Receptor binding and immune evasion are recognized as two major drivers for evolution of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the underlying mechanism of interplay between two factors remains incompletely understood. Herein, we determined the structures of human ACE2 complexed with BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5 RBDs. Based on the ACE2/RBD structures of these sub-variants and a comparison with the known complex structures, we found that R346T substitution in the RBD enhanced ACE2 binding upon an interaction with the residue R493, but not Q493, via a mechanism involving long-range conformation changes. Furthermore, we found that R493Q and F486V exert a balanced impact, through which immune evasion capability was somewhat compromised to achieve an optimal receptor binding. We propose a "two-steps-forward and one-step-backward" model to describe such a compromise between receptor binding affinity and immune evasion during RBD evolution of Omicron sub-variants.

Genetic fusion of CCL11 to antigens enhances antigenicity in nucleic acid vaccines and eradicates tumor mass through optimizing T-cell response.

Nucleic acid vaccines have shown promising potency and efficacy for cancer treatment with robust and specific T-cell responses. Improving the immunogenicity of delivered antigens helps to extend therapeutic efficacy and reduce dose-dependent toxicity. Here, we systematically evaluated chemokine-fused HPV16 E6/E7 antigen to improve the cellular and humoral immune responses induced by nucleotide vaccines in vivo. We found that fusion with different chemokines shifted the nature of the immune response against the antigens. Although a number of chemokines were able to amplify specific CD8 + T-cell or humoral response alone or simultaneously. CCL11 was identified as the most potent chemokine in improving immunogenicity, promoting specific CD8 + T-cell stemness and generating tumor rejection. Fusing CCL11 with E6/E7 antigen as a therapeutic DNA vaccine significantly improved treatment effectiveness and caused eradication of established large tumors in 92% tumor-bearing mice (n = 25). Fusion antigens with CCL11 expanded the TCR diversity of specific T cells and induced the infiltration of activated specific T cells, neutrophils, macrophages and dendritic cells (DCs) into the tumor, which created a comprehensive immune microenvironment lethal to tumor. Combination of the DNA vaccine with anti-CTLA4 treatment further enhanced the therapeutic effect. In addition, CCL11 could also be used for mRNA vaccine design. To summarize, CCL11 might be a potent T cell enhancer against cancer.