Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

In-situ Ultrafast Construction of Zinc Tungstate Interface Layer for Highly Reversible Zinc Anodes.

Constructing artificial solid electrolyte interface on the Zn anode surface is recognized as an appealing method to inhibit zinc dendrites and side reactions, whereas the current techniques are complex and time-consuming. Here, a robust and zincophilic zinc tungstate (ZnWO4) layer has been in situ constructed on the Zn anode surface (denoted as ZWO@Zn) by an ultrafast chemical solution reaction. Comprehensive characterizations and theoretical calculations demonstrate that the ZWO layer can effectively modulate the interfacial electric field distribution and promote the Zn2+ uniform diffusion, thus facilitating the uniform Zn2+ nucleation and suppressing zinc dendrites. Besides, ZWO layer can prevent direct contact between the Zn/water and increase the hydrogen evolution reaction overpotential to eliminate side reactions. Consequently, the in-situ constructed ZWO layer facilitates remarkable reversibility in the ZWO@Zn||Ti battery, achieving an impressive Coulombic efficiency of 99.36% under 1.0 mA cm-2, unprecedented cycling lifespan exceeding 1800 h under 1.0 mA cm-2 in ZWO@Zn||ZWO@Zn battery, and a steady and reliable operation of the overall ZWO@Zn||VS2 battery. The work provides a simple, low cost, and ultrafast pathway to crafting protective layers for driving advancements in aqueous zinc-metal batteries.

Anxiety and depression in nasopharyngeal carcinoma patients and network analysis to identify central symptoms: A cross-sectional study from a high-incidence area.

PURPOSE: To determine the prevalence of anxiety and depression in patients with nasopharyngeal carcinoma (NPC) and to identify central symptoms and bridge symptoms among psychiatric disorders. METHODS: This cross-sectional study recruited patients with NPC in Guangzhou, China from May 2022, to October 2022. The General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were used for screening anxiety and depression, respectively. Network analysis was conducted to evaluate the centrality and connectivity of the symptoms of anxiety, depression, quality of life (QoL) and insomnia. RESULTS: A total of 2806 respondents with complete GAD-7 and PHQ-9 scores out of 3828 were enrolled. The incidence of anxiety in the whole population was 26.5% (depression, 28.5%; either anxiety or depression, 34.8%). Anxiety was highest at caner diagnosis (34.2%), while depression reached a peak at late-stage radiotherapy (48.5%). Both moderate and severe anxiety and depression were exacerbated during radiotherapy. Coexisting anxiety and depression occurred in 58.3% of those with either anxiety or depression. The generated network showed that anxiety and depression symptoms were closely connected; insomnia was strongly connected with QoL. "Sad mood", "Lack of energy", and "Trouble relaxing" were the most important items in the network. Insomnia was the most significant bridge item that connected symptom groups. CONCLUSION: Patients with NPC are facing alarming disturbances of psychiatric disorders; tailored strategies should be implemented for high-risk patients. Besides, central symptoms (sad mood, lack of energy, and trouble relaxing) and bridge symptoms (insomnia) may be potential interventional targets in future clinical practice.

Study on the Low Plastic Behavior of Expansion Deformation of Austenitic Stainless Steel.

The plastic deformation of TWIP steel is greatly inhibited during the expansion process. The stress-strain curves obtained through expansion experiments and observations of fracture morphology confirmed the low plastic behavior of TWIP steel during expansion deformation. Through an analysis of the mechanical expansion model, it was found that the expansion process has a lower stress coefficient and a faster strain rate than stretching, which inhibits the plasticity of TWIP steel during expansion deformation. Using metallographic microscopy, transmission electron microscopy, and EBSD to observe the twin morphology during expansion deformation and tensile deformation, it was found that expansion deformation has a higher twin density, which is manifested in a denser twin arrangement and a large number of twin deliveries in the microscopic morphology. During the expansion deformation process, dislocation slips are hindered by twins, the free path of the slips is reduced, and dislocations accumulate significantly. The accumulation area is the initial point of crack expansion. The results show that the significant dislocation accumulation caused by the delivery of a large number of twins under expansion deformation is the main reason for the decrease in the plasticity of TWIP steel.

[Research progress on pathogenic mechanism of sepsis-induced liver injury and treatment with traditional Chinese medicine and its active components].

Sepsis is a systemic inflammatory response syndrome caused by infection, with high morbidity and mortality. Sepsis-induced liver injury(SILI) is one of the manifestations of sepsis-induced multiple organ syndrome. At present, there is no recommended pharmacological intervention for the treatment of SILI. traditional Chinese medicine(TCM), based on the holism and dialectical treatment concept, shows the therapeutic characteristics of multi-target and multi-pathway and can comprehensively prevent and treat SILI by interfering with inflammatory factors, inflammatory signaling pathways, and anti-oxidative stress and inhibiting apoptosis. This article reviewed the experimental studies on the treatment of SILI with TCM to clarify its pathogenic mechanism and therapeutic characteristics, so as to provide more ideas and directions for the development or preparation of new drugs.

CRISPR-Cas9 screening identifies INTS3 as an anti-apoptotic RNA-binding protein and therapeutic target for colorectal cancer.

Growing evidences indicate that RNA-binding proteins (RBPs) play critical roles in regulating the RNA splicing, polyadenylation, stability, localization, translation, and turnover. Abnormal expression of RBPs can promote tumorigenesis. Here, we performed a CRISPR screen using an RBP pooled CRISPR knockout library and identified 27 potential RBPs with role in supporting colorectal cancer (CRC) survival. We found that the deletion/depletion of INTS3 triggered apoptosis in CRC. The in vitro experiments and RNA sequencing revealed that INTS3 destabilized pro-apoptotic gene transcripts and contributed to the survival of CRC cells. INTS3 loss delayed CRC cells growth in vivo. Furthermore, delivery of DOTAP/cholesterol-mshINTS3 nanoparticles inhibited CRC tumor growth. Collectively, our work highlights the role of INTS3 in supporting CRC survival and provides several novel therapeutic targets for treatment.

Molecular Mechanism of Resistance to Alternaria alternata Apple Pathotype in Apple by Alternative Splicing of Transcription Factor MdMYB6-like.

As a fruit tree with great economic value, apple is widely cultivated in China. However, apple leaf spot disease causes significant damage to apple quality and economic value. In our study, we found that MdMYB6-like is a transcription factor without auto-activation activity and with three alternative spliced variants. Among them, MdMYB6-like-ß responded positively to the pathogen infection. Overexpression of MdMYB6-like-ß increased the lignin content of leaves and improved the pathogenic resistance of apple flesh callus. In addition, all three alternative spliced variants of MdMYB6-like could bind to the promoter of MdBGLU H. Therefore, we believe that MdMYB6-like plays an important role in the infection process of the pathogen and lays a solid foundation for breeding disease-resistant cultivars of apple in the future.

The Phylogeny and Taxonomy of Cryptothecia (Arthoniaceae, Ascomycota) and Myriostigma (Arthoniaceae, Ascomycota), including Three New Species and Two New Records from China.

Cryptothecia and Myriostigma are important elements of crustose lichen communities in tropical to subtropical forests, but little research has been done on these two genera in China. Morphological and molecular phylogenetic approaches to investigate species diversity of Cryptothecia and Myriostigma from Southern China were carried out in this study. We find five species of Cryptothecia and Myriostigma in our study, including three new species (M. flavescens, M. hainana and M. laxipunctata) and two new records (C. bartlettii and C. inexspectata). In addition, a phylogenetic tree based on mtSSU, RPB2 and nLSU illustrates the placement of the five species and supports the delimitation of the three new taxa. Detailed descriptions of morphological, ecological and chemical characteristics and illustrations are provided for every species. A key to all known Chinese Cryptothecia and Myriostigma species is also provided.

Mitochondria complex I deficiency in Candida albicans arrests the cell cycle at S phase through suppressive TOR and PKA pathways.

How mutations in mitochondrial electron transport chain (ETC) proteins impact the cell cycle of Candida albicans was investigated in this study. Using genetic null mutants targeting ETC complexes I (CI), III (CIII), and IV (CIV), the cell cycle stages (G0/G1, S phase, and G2/M) were analyzed via fluorescence-activated cell sorting (FACS). Four CI null mutants exhibited distinct alterations, including extended S phase, shortened G2/M population, and a reduction in cells size exceeding 10 µM. Conversely, CIII mutants showed an increased population in G1/G0 phase. Among four CI mutants, ndh51Δ/Δ and goa1Δ/Δ displayed aberrant cell cycle patterns correlated with previously reported cAMP/PKA downregulation. Specifically, nuo1Δ/Δ and nuo2Δ/Δ mutants exhibited increased transcription of RIM15, a central hub linking cell cycle with nutrient-dependent TOR1 and cAMP/PKA pathways and Snf1 aging pathway. These findings suggest that suppression of TOR1 and cAMP/PKA pathways or enhanced Snf1 disrupts cell cycle progression, influencing cell longevity and growth among CI mutants. Overall, our study highlights the intricate interplay between mitochondrial ETC, cell cycle, and signaling pathways.

Trophic transfer of antibiotics in the benthic-pelagic coupling foodweb in a macrophyte-dominated shallow lake: The importance of pelagic-benthic coupling strength and baseline organism.

In lake ecosystems, pelagic-benthic coupling strength (PBCS) is closely related to foodweb structure and pollutant transport. However, the trophic transfer of antibiotics in a benthic-pelagic coupling foodweb (BPCFW) and the manner in which PBCS influences the trophic magnification factor (TMFs) of antibiotics is still not well understood in the whole lake. Herein, the trophic transfer behavior of 12 quinolone antibiotics (QNs) in the BPCFW of Baiyangdian Lake were studied during the period of 2018-2019. It was revealed that 24 dominant species were contained in the BPCFW, and the trophic level was 0.42-2.94. Seven QNs were detected in organisms, the detection frequencies of ofloxacin (OFL), flumequine (FLU), norfloxacin (NOR), and enrofloxacin (ENR) were higher than other QNs. The ∑QN concentration in all species was 11.3-321 ng/g dw. The TMFs for ENR and NOR were trophic magnification, while for FLU/OFL it was trophic dilution. The PBCS showed spatial-temporal variation, with a range of 0.6977-0.7910. The TMFs of ENR, FLU, and OFL were significantly positively correlated with PBCS. Phytoplankton and macrophyte biomasses showed indirect impact on the TMFs of QNs by directly influencing the PBCS. Therefore, the PBCS was the direct influencing factor for the TMFs of chemicals.

Constructing Highly Stable Zinc Metal Anodes via Induced Zn(002) Growth.

The nonuniform electric field at the surface of a zinc (Zn) anode, coupled with water-induced parasitic reactions, exacerbates the growth of Zn dendrites, presenting a significant impediment to large-scale energy storage in aqueous Zn-ion batteries. One of the most convenient strategies for mitigating dendrite-related issues involves controlling crystal growth through electrolyte additives. Herein, we present thiamine hydrochloride (THC) as an electrolyte additive capable of effectively stabilizing the preferential deposition of the Zn(002) plane. First-principles calculations reveal that THC tends to adsorb on Zn(100) and Zn(101) planes and is capable of inducing the deposition of Zn ion onto the (002) plane and the preferential growth of the (002) plane, resulting in a flat and compact deposition layer. A THC additive not only effectively suppresses dendrite growth but also prevents the generation of side reactions and hydrogen evolution reaction. Consequently, the Zn||Zn symmetric battery exhibits long-term cycling stability of over 3000 h at 1 mA cm-2/1 mAh cm-2 and 1000 h at 10 mA cm-2/10 mAh cm-2. Furthermore, the NH4V4O10||Zn full battery also displays excellent cycling stability and a high reversible capacity of 210 mAh g-1 after 1000 cycles at 1 A g-1, highlighting a significant potential for practical applications.

Hollow Layered Iron-Based Prussian Blue Cathode with Reduced Defects for High-Performance Sodium-Ion Batteries.

Fe-based Prussian blue (Fe-PB) analogues have emerged as promising cathode materials for sodium-ion batteries, owing to their cost-effectiveness, high theoretical capacity, and environmental friendliness. However, their practical application is hindered by [Fe(CN)6] defects, negatively impacting capacity and cycle stability. This work reports a hollow layered Fe-PB composite material using 1,3,5-benzenetricarboxylic acid (BTA) as a chelating and etching agent by the hydrothermal method. Compared to benzoic acid, our approach significantly reduces defects and enhances the yield of Fe-PB. Notably, the hollow layered structure shortens the diffusion path of sodium ions, enhances the activity of low-spin Fe in the Fe-PB lattice, and mitigates volume changes during Na-ion insertion/extraction into/from Fe-PB. As a sodium-ion battery cathode, this hollow layered Fe-PB exhibits an impressive initial capacity of 95.9 mAh g-1 at a high current density of 1 A g-1. Even after 500 cycles, it still maintains a considerable discharge capacity of 73.1 mAh g-1, showing a significantly lower capacity decay rate (0.048%) compared to the control sample (0.089%). Moreover, the full cell with BTA-PB-1.6 as the cathode and HC as the anode provides a considerable energy density of 312.2 Wh kg-1 at a power density of 291.0 W kg-1. This research not only enhances the Na storage performance of Fe-PB but also increases the yield of products obtained by hydrothermal methods, providing some technical reference for the production of PB materials using the low-yield hydrothermal method.

Selenium alleviates the adverse effects of microplastics on kale by regulating photosynthesis, redox homeostasis, secondary metabolism and hormones.

Kale is a functional food with anti-cancer, antioxidant, and anemia prevention properties. The harmful effects of the emerging pollutant microplastic (MP) on plants have been widely studied, but there is limited research how to mitigate MP damage on plants. Numerous studies have shown that Se is involved in regulating plant resistance to abiotic stresses. The paper investigated impact of MP and Se on kale growth, photosynthesis, reactive oxygen species (ROS) metabolism, phytochemicals, and endogenous hormones. Results revealed that MP triggered a ROS burst, which led to breakdown of antioxidant system in kale, and had significant toxic effects on photosynthetic system, biomass, and accumulation of secondary metabolites, as well as a significant decrease in IAA and a significant increase in GA. Under MP supply, Se mitigated the adverse effects of MP on kale by increasing photosynthetic pigment content, stimulating function of antioxidant system, enhancing secondary metabolite synthesis, and modulating hormonal networks.

Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier.

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment, significantly curtailing the efficacy of these treatments and, in some cases, resulting in fatal consequences. Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis, the paucity of effective treatments for such damage is evident. In our study, we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells, thereby fortifying the integrity of the intestinal mucus barrier. This enhanced barrier function serves to resist microbial invasion and subsequently reduces the inflammatory response. Importantly, this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs. Mechanistically, E. copr up-regulates the expression of AUF1, leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells. An especially significant finding is that E. copr activates the AhR pathway, thereby promoting the expression of AUF1. In summary, our results strongly indicate that E. copr enhances the intestinal mucus barrier, effectively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUF1 pathway, consequently enhancing Muc2 mRNA stability.

Predictive nomogram for bone metastases in lung cancer based on monocyte infiltration.

The presence of bone metastases (BM) in patients with lung cancer is indicative of a worse prognosis. The present study aims to investigate the risk factors associated with BM in patients with lung cancer. Patients with lung cancer admitted to the First Affiliated Hospital of Anhui Medical University between June 2019 and September 2021 were enrolled in this study. A nomogram was constructed based on the outcomes derived from univariate and multivariate analyses. Concordance index, calibration plots, receiver operating characteristic curves, and decision curve analysis were used to evaluate the nomogram. To substantiate the influence of monocytes on lung cancer BM, various assays, including cell co-culture, Transwell, wound-healing assays, and immunohistochemistry and immunofluorescence staining, were conducted. Statistical analyses were performed using SPSS 22.0 software and GraphPad Prism 7.0. A total of 462 eligible patients were enrolled, comprising 220 with BM and 242 without. Multivariate analysis revealed that histological type, medical history, monocyte percentage, and LDH (Lactate Dehydrogenase) and ALP (Alkaline Phosphatase) levels were independent risk factors for BM in lung cancer. Transwell and wound-healing assays indicated that co-culture with monocytes significantly enhanced the migration and invasion capabilities of A549 cells in vitro. Immunohistochemistry and immunofluorescence analyses demonstrated a noteworthy increase in monocyte infiltration in the primary lesions of patients with lung cancer with BM. In conclusion, this study successfully constructed and validated a precise, straightforward, and cost-effective prognostic nomogram for patients with lung cancer with BM.

In situ fluoro-oxygen codoped graphene layer for high-performance lithium metal anode.

Because traditional lithium-ion batteries have been unable to meet the energy density requirements of various emerging fields, lithium-metal batteries (LMBs), known for their high energy density, are considered promising next-generation energy storage batteries. However, a series of problems, including low coulombic efficiency and low safety caused by dendrites, limit the application of lithium metal batteries. Herein, fluoro-oxygen codoped graphene (FGO) was used to modify the copper current collector (FGO@Cu). FGO-coated current collector provides more even nucleation sites to reduce the local effective current density. FGO is partly reduced during cycling and helps form stable LiF-rich SEI. Moreover, graphene's oxygen and fluorine functional groups reconstruct the current density distribution, promoting uniform lithium plating. The FGO@Cu current collector demonstrates superior properties than commercial Cu foil. The FGO@Cu delivers a 97% high CE for over 250 cycles at 1 mA cm-2. The FGO@Cu symmetrical battery cycled at 1 mA cm-2 for over 650 h. LiFePO4 fuel cell with a lithium-plated FGO@Cu collector as an anode exhibits superior cycling stability.

Confined growth of Ultrathin, nanometer-sized FeOOH/CoP heterojunction nanosheet arrays as efficient self-supported electrode for oxygen evolution reaction.

Self-supported electrodes, featuring abundant active species and rapid mass transfer, are promising for practical applications in water electrolysis. However, constructing efficient self-supported electrodes with a strong affinity between the catalytic components and the substrate is of great challenge. In this study, by combining the ideas of in-situ construction and space-confined growth, we designed a novel self-supported FeOOH/cobalt phosphide (CoP) heterojunctions grown on a carefully modified commercial Ni foam (NF) with three-dimensional (3D) hierarchically porous Ni skeleton (FeOOH/CoP/3D NF). The specific porous structure of 3D NF directs the confined growth of FeOOH/CoP catalyst into ultra-thin and small-sized nanosheet arrays with abundant edge active sites. The active FeOOH/CoP component is stably anchored on the rough pore wall of 3D NF support, leading to superior stability and improved conductivity. These structural advantages contributed to a highly facilitated oxygen evolution reaction (OER) activity and enhanced durability of the FeOOH/CoP/3D NF electrode. Herein, the FeOOH/CoP/3D NF electrode afforded a low overpotential of 234 mV at 10 mA cm-2 (41 mV smaller than FeOOH/CoP grown on unmodified Ni foam) and high stability for over 90 h, which is among the top reported OER catalysts. Our study provides an effective idea and technique for the construction of active and robust self-supported electrodes for water electrolysis.

A Highly Stable Microporous Calcium-Based MOF for C2H2/CO2 Separation with Low Regenerative Energy.

Most of the porous materials used for acetylene/carbon dioxide separation have the problems of poor stability and high energy requirements for regeneration, which significantly hinder their practical application in industries. Here, we report a novel calcium-based metal-organic framework (NKM-123) with excellent chemical stability against water, acids, and bases. Additionally, it has exceptional thermal stability, retaining its structural integrity at temperatures up to 300 °C. This material exhibits promising potential for separating C2H2 and CO2 gases. Furthermore, it demonstrates an adsorption heat of 29.3 kJ mol-1 for C2H2, which is lower than that observed in the majority of MOFs used for C2H2/CO2 separations. The preferential adsorption of C2H2 over that of CO2 is confirmed by dispersion-corrected density functional theory (DFT-D) calculations. In addition, the potential of industrial feasibility of NKM-123 for C2H2/CO2 separation is confirmed by transient breakthrough tests. The robust cycle performance and structural stability of NKM-123 during multiple breakthrough tests show great potential in the industrial separation of light hydrocarbons.

Fabrication of polysaccharide-coated oleanolic acid-curcumin-coassembled nanoparticles (OA/Cur NPs): Enhancement of colloidal stability and water solubility.

Natural terpenoid carriers, such as oleanolic acid (OA), can enhance the water solubility and stability of hydrophobic compounds such as curcumin (Cur). However, improving the colloidal stability of nanoparticle emulsions and resolving the redispersion problem of freeze-dried nanoparticle powders remain significant challenges. In this study, we fabricated coassembled oleanolic acid-curcumin nanoparticles (OA/Cur NPs) and applied a polysaccharide surface coating method to improve their colloidal stability and water solubility. The results showed that the optimal ratio of Cur/OA for preparing OA/Cur NPs was 4:10, resulting in a high encapsulation efficiency (EE) of Cur (75.2%). Additionally, TEM, contact angle tests, Turbiscan TOWER optical stability analysis of the polysaccharide-coated OA/Cur NP emulsions and redispersion tests of their lyophilized powders verified the advantages of carboxymethyl chitosan/ß-cyclodextrin (CMC/ß-CD) coating over other polysaccharides. This study indicated that polysaccharide coating is an effective method for enhancing the colloidal stability, water solubility, and redispersibility of OA/Cur NPs.