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Abstract Sowing date and soil fertility are very important factors in the overwintering and production performance of alfalfa (Medicago sativa L.), yet there’s a knowledge gap in knowledge on how late-seeded alfalfa responds to phosphorus (P) fertilization. A field study was conducted in Inner Mongolia from 2020 to 2022 using a split-plot design. The main plots consisted of five sowing dates (31 July, 8, 16, and 24 August, and 1 September), while the subplots involved five P application rates (0, 40, 70, 100, and 130 kg P2O5 ha−1). Throughout the growing seasons, the overwintering rate, root traits, forage yield, and yield components were measured. The results revealed a consistent decrease in overwintering ability and productivity with the delayed sowing. This reduction in overwintering rate was mainly due to diminished root traits, while the decrease in forage yield was largely associated with a reduction in plants per square meter. However, P fertilizer application to late-seeded alfalfa demonstrated potential in enhancing the diameter of both the crown and taproot, thus strengthening the root system and improving the overwintering rate, the rate of increase ranges from 11.6 to 49%. This adjustment could also improve the shoots per square meter and mass per shoot, increasing by 9.4–31.3% and 15.0–27.1% respectively in 2 years, which can offset the decline in forage yield caused by late sowing and might even increase the forage yield. Regression and path analysis indicated that alfalfa forage yield is primarily affected by mass per shoot rather than shoots per square meter. This study recommended that the sowing of alfalfa in similar regions of Inner Mongolia should not be later than mid-August. Moreover, applying P fertilizer (P2O5) at 70.6–85.9 kg ha−1 can enhance the forage yield and persistence of late-seeded alfalfa. Therefore, appropriate late sowing combined with the application of P fertilizer can be used as an efficient cultivation strategy for alfalfa cultivation after a short-season crop harvest in arid and cold regions.

Abstract Background Compared with moderate-intensity continuous training (MICT), high-intensity interval training (HIIT) has at least a comparable effect on inhibiting an increase in fat. However, few studies have been conducted to examine the effects of detraining on body fat in rats fed a high-fat diet. The present study aimed to compare the effects of 10 weeks of HIIT or MICT as well as 6 weeks of detraining on body fat in rats fed a high-fat diet. Methods After being fed a high-fat diet for 8 weeks, 54 female rats were randomly assigned to six groups: (1) CON-10, sedentary control for 10 weeks; (2) MICT-10, 10 weeks of MICT; (3) HIIT-10, 10 weeks of HIIT; (4) CON-16, sedentary control for 16 weeks; (5) MICT-16, 10 weeks of MICT followed by 6 weeks of training cessation; and (6) HIIT-16, 10 weeks of HIIT followed by 6 weeks of training cessation. The training was performed 5 days/week. The subcutaneous adipose tissue (inguinal; SCAT), visceral adipose tissue (periuterine; VAT) and serum lipid profile were analysed after 10 or 16 weeks. Adipose tissue triglyceride lipase (ATGL) protein expression in VAT was assessed by western blotting. Results HIIT-10 and MICT-10 prevented the increase in SCAT, VAT and serum lipid levels seen in the CON group. During the 6-week detraining period, HIIT continued to prevent the increase in adipose tissue mass observed in the CON group, whereas MICT at least maintained this inhibition. The inhibition of fat mass increase was mainly the result of preventing adipocyte hypertrophy. The HIIT-10 and HIIT-16 groups showed the highest ATGL protein expression. Conclusions HIIT has a comparable effect to MICT on inhibiting fat accumulation in female rats; however, the inhibition of SCAT and VAT increase by HIIT is superior to MICT after short-term training cessation. Graphical Abstract

Abstract To assess the health utility value (HUV) of Rheumatoid Arthritis (RA) patients and its influencing factors in China. A cross-sectional survey was conducted in 8 tertiary hospitals across four capital-cities. The demographic characteristics, patient-reported outcomes including the HUV got by EQ-5D-5L, clinical characteristics, and clinician-reported outcomes of 171 RA patients were collected both from themselves and their physicians. Both the univariate and multivariate analyses were used to assess the potential factors of EQ-5D-5L HUV of the patients. The mean age of the patients was 50.7 years, with female being 64.9% (n = 111). The mean HUV and EQ visual analogue scale score of all patients were 0.586 and 47.3, respectively. The univariate analysis showed that the patients who were female, older, living in rural areas, with lower education level, advanced disease stage, higher the patient's assessment of arthritis pain visual analogue scale (PtAAP-VAS), the patient's global assessment of disease activity visual analogue scale (PtGADA-VAS), and the Physician’s global assessment of disease activity visual analogue scale (PhGADA-VAS) scores had significantly lower EQ-5D-5L HUVs. The multivariate analysis further suggested that older age, female, higher body mass index and higher PtGADA-VAS score were statistically significantly related to lower HUVs. The study provided the HUVs for RA patients with different characteristics and outcomes, which could be used in the economic evaluation of interventions for the RA patients. The identified factors could also assist the health care managing and improving the health-related quality of life on RA patients.

Aberrant expression of cyclin-dependent kinase 5 (Cdk5) has been reported in pituitary adenomas. However, the role of Cdk5 in the tumorigenesis remains unclear. We show that prenatal p25-activated Cdk5 phosphorylates minichromosome maintenance protein 2 (Mcm2), enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-located melanotrope-originated pituitary tumorigenesis. In a mouse model with CaMKII promoter-driven transgenic induction of p25, we observed intermediate lobe-originated pituitary adenoma producing non-functional proopiomelanocortin (POMC)-derived peptides under persistent p25 overexpression. Single-cell RNA sequencing revealed Mcm2 may play an important role during tumor progression. Subsequently, Mcm2 was identified as a potential phosphorylated substrate of Cdk5, mediating the tumorous proliferation of melanotrope cells. Silencing Cdk5 or Mcm2 suppressed cell proliferation and colony formation in the 293T cell lines. Therefore, our findings provide a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveil a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis.

The rhizome of Corydalis decumbens is a traditional Chinese medicine commonly utilized in the clinical treatment of acute ischemic stroke. Numerous phytochemical and biological investigations have demonstrated that protoberberine alkaloids from C. decumbens exhibit diverse pharmaceutical activities against various diseases. Sinometumine E (SE), a protoberberine alkaloid isolated from C. decumbens for the first time, is characterized by a complex 6/6/6/6/6/6 hexacyclic skeleton. In the current study, we investigated the protective effects of SE on endothelial cell injury and its angiogenesis effects in zebrafish. The results suggested that SE showed significant anti-ischemic effects on OGD/R-induced HBEC-5i and HUVECs cell ischemia/reperfusion injury model. Furthermore, it promoted angiogenesis in PTK787-induced, MPTP-induced, and atorvastatin-induced vessel injury models of zebrafish, while also suppressing hypoxia-induced locomotor impairment in zebrafish. Transcriptome sequencing analysis provided a sign that SE likely to promotes angiogenesis through the HIF-1/VEGF signaling pathway to exert anti-ischemic effects. Consistently, SE modulated several genes related to HIF-1/VEGF signal pathway, such as hif-1, vegf, vegfr-2, pi3k, erk, akt and plcγ. Molecular docking analysis revealed that VEGFR-2 exhibited high binding affinity with SE, and western blot analysis confirmed that SE treatment enhanced the expression of VEGFR-2. In conclusion, our study profiled the angiogenic activities of SE in vitro and in vivo. The key targets and related pathways involved in anti-ischemic effects of SE, shedding light on the pharmacodynamic components and mechanisms of Corydalis decumbens, and provides valuable insights for identifying effective substances for the treatment of ischemic stroke.

Abstract A new idea to alleviate environmental pollution is the development of low-cost adsorbents using natural minerals and fishery wastes to treat high concentrations of heavy metal pollutants in acid mine drainage (AMD). Adsorbent morphology, adsorptive and regenerative capacity, and application potential are limiting factors for their large-scale use. Oyster shells capable of releasing alkalinity were loaded on the surface of lignite to develop two composite adsorbents with different morphologies (powdery and globular) for the treatment of AMD containing Pb(II) and Cd(II). The results show that the ability of the adsorbent to treat AMD is closely related to its morphologies. The pseudo-second-order kinetic model and the Langmuir model are suitable to describe the adsorption process of OS-M(P), and the maximum adsorption saturation capacities of Pb(II) and Cd(II) are 332.6219 mg/g and 318.9854 mg/g, respectively. The pseudo-second-order kinetic model and the Freundlich model are suitable to describe the adsorption process of OS-M(G). A synergistic result of electrostatic adsorption, neutralization precipitation, ion exchange and complex reaction is achieved in the removal of Pb(II) and Cd(II) by two morphologies of adsorbents. The regeneration times (5 times) and recovery rate (75.75%) of OS-M(G) are higher than those of OS-M(P) (3 times) and recovery rate (20%). The ability of OS-M(G) to treat actual AMD wastewater is still better than that of OS-M(P). OS-M(G) can be used as a promising environmentally friendly adsorbent for the long-term remediation of AMD. This study provides a comprehensive picture of resource management and reuse opportunities for natural mineral and fishery wastes.

Abstract Background The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. Methods HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan–Meier method was utilised to analyse progression-free survival (PFS). Results This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5–22.1) versus 9.2 months (95% CI: 7.5–13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4–18.2) versus 22.2 months (95% CI: 18.3–NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9–NA) versus 8.3 months (95% CI: 6.7–13.8)]. Conclusions HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. Trial registration NCT03534453. Registered at May 23, 2018.

Abstract Background The retrieval of inferior vena cava (IVC) filter is essential for preventing complications associated with the device. Advanced techniques have been developed to improve the success rate of retrieving tip-embedded filters. The forceps technique is frequently used to address this issue. Case presentation We present a case study of two patients who underwent a successful tip-embedded IVC filter retrieval using a modified forceps technique, which has not been previously reported. This technique involves using a wire loop under the filter tip and a forceps to grasp the filter shoulder. By pulling the wire loop and pushing the forceps in counterforce, the filter tip is straightened and aligned with the vascular sheath. The vascular sheath can then dissect the filter tip out from the caval wall and get inside the sheath to complete the retrieval. Conclusions The modified forceps technique we present here offers a new solution for the complex retrieval of IVC filters.

Immune checkpoint inhibitors (ICIs) have changed the treatment mode of lung cancer, extending the survival time of patients unprecedentedly. Once patients respond to ICIs, the median duration of response is usually longer than that achieved with cytotoxic or targeted drugs. Unfortunately, there is still a large proportion of lung cancer patients do not respond to ICI. Effective biomarkers are crucial for identifying lung cancer patients who can benefit from them. The first predictive biomarker is programmed death-ligand 1 (PD-L1), but its predictive value is limited to specific populations. With the development of single-cell sequencing and spatial imaging technologies, as well as the use of deep learning and artificial intelligence, the identification of predictive biomarkers has been greatly expanded. In this review, we will dissect the biomarkers used to predict ICIs efficacy in lung cancer from the tumor-immune microenvironment and host perspectives, and describe cutting-edge technologies to further identify biomarkers.

BackgroundPaper mulberry is a promising alternative fodder source due to its high protein and the abundance of active components. However, paper mulberry often faces susceptibility to contamination during silage fermentation, and there is a need to improve the quality of silage fermentation of paper mulberry through exotic additives. Sea buckthorn pomace (BP) is a feed additive containing antimicrobial and antioxidant substances that help to enhance silage fermentation. Therefore, the objective of this study was to evaluate the effects of BP and Lactiplantibacillus as additives on silage fermentation and bacterial community of paper mulberry.ResultsThe results showed that BP and Lactiplantibacillus significantly reduced the pH and ammonium nitrogen content of paper mulberry silage (P < 0.05) and significantly increased the content of lactic acid and acetic acid (P < 0.05), resulting in more residual water-soluble carbohydrate and crude protein contents and less fiber content relative to the control. The key microorganisms in paper mulberry silage fermentation are Lactiplantibacillus pentosus and Weissella cibaria. Among these, Lactiplantibacillus favored a rapid increase in Lactiplantibacillus pentosus abundance during the pre-silage fermentation period, whereas BP favored the promotion of Lactiplantibacillus pentosus growth, resulting in higher contents of lactic and acetic acid than those of the control.ConclusionsSimultaneously adding Lactiplantibacillus and BP can effectively improve the quality of paper mulberry silage and increase the abundance of beneficial microorganisms in paper mulberry silage.

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized gastrointestinal cancer treatment, yet the absence of reliable biomarkers hampers precise patient response prediction.MethodsWe developed and validated a genomic mutation signature (GMS) employing a novel artificial intelligence network to forecast the prognosis of gastrointestinal cancer patients undergoing ICIs therapy. Subsequently, we explored the underlying immune landscapes across different subtypes using multiomics data. Finally, UMI-77 was pinpointed through the analysis of drug sensitization data from the Genomics of Drug Sensitivity in Cancer (GDSC) database. The sensitivity of UMI-77 to the AGS and MKN45 cell lines was evaluated using the cell counting kit-8 (CCK8) assay and the plate clone formation assay.ResultsUsing the artificial intelligence network, we developed the GMS that independently predicts the prognosis of gastrointestinal cancer patients. The GMS demonstrated consistent performance across three public cohorts and exhibited high sensitivity and specificity for 6, 12, and 24-month overall survival (OS) in receiver operating characteristic (ROC) curve analysis. It outperformed conventional clinical and molecular features. Low-risk samples showed a higher presence of cytolytic immune cells and enhanced immunogenic potential compared to high-risk samples. Additionally, we identified the small molecule compound UMI-77. The half-maximal inhibitory concentration (IC50) of UMI-77 was inversely related to the GMS. Notably, the AGS cell line, classified as high-risk, displayed greater sensitivity to UMI-77, whereas the MKN45 cell line, classified as low-risk, showed less sensitivity.ConclusionThe GMS developed here can reliably predict survival benefit for gastrointestinal cancer patients on ICIs therapy.

Invasive aspergillosis (IA) is the most severe type of Aspergillus infection. Yunnan has developed agriculture, and the proportion of triazole-resistant A. fumigatus induced by triazole fungicides is much higher than that in other regions of China. Inhalation of triazole-resistant A. fumigatus is one of the main factors inducing IA. We gathered five strains of A. fumigatus from the sputum or bronchoalveolar lavage fluid (BALF) of patients with IA in Yunnan. Subsequent testing showed that all of these strains were resistant to triazoles and harboured mutations in the tandem repeat sequence of the cyp51A promoter region, suggesting that they may be triazole-resistant A. fumigatus present in the environment.

In order to clarify the characteristic compounds and establish the authenticity evaluation method of heptapleurum honey, high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (HPLC-Q/TOF-MS/MS) was used to qualitative and quantitative analysis of characteristic compounds in heptapleurum honey. Five compounds were identified including 4-(1'-cyclodiethyl ether-3'-butanediol)-3,5,5-trimethyl-2-cyclohexenone (Unedone B), 3,4,5-trimethoxy cinnamyl alcohol, 4-(1'2'-dihydroxy-3'epoxypropane) -3,5,5-2-cyclohexenone (Unedone C), trans, trans abscisic acid, and cis, trans abscisic acid. Notably, 3,4,5-trimethoxy cinnamyl alcohol was first found in honey, and it could be a marker of heptapleurum honey. Moreover, 10 raw heptapleurum honey samples with different geographic origins were collected to establish HPLC fingerprint. The authenticity of six commercial heptapleurum honey samples were evaluated by combining characteristic compound with HPLC fingerprint. The results demonstrated that three brands of sample were genuine pure heptapleurum honey, two brands of sample might be mixed with other honeys. A brand sample did not contain characteristic compound and were significantly different with the standard fingerprints of heptapleurum honey. It was inferred that the sample was not heptapleurum honey. This study provides theoretical reference for the authenticity evaluation of heptapleurum honey.

Organic fertilizers are widely used to improve soil quality. However, their potential for ensuring the safe production of vegetables in soils with varying levels of heavy metals pollution remains inadequately explored. Here, we conducted a pot experiment to investigate the effects of substituting chemical fertilizers with organic fertilizer on the HMs accumulation in water spinach by simulating soils with different levels of HMs pollution. The results showed that the organic fertilizer significantly increased the soil pH, cation exchange capacity (CEC), and organic matter (OM). Furthermore, it led to a reduction in the soil DTPA–Cd and DTPA–Pb levels by 3.3–20.6% and 22.4–47.3%, respectively, whereas the DTPA–As levels increased by 0.07–7.7 times. The organic fertilizer effectively reduced the Cd and Pb content in water spinach below the safety limits when the added Cd content in the soil was less than 2 mg/kg and the Pb content was equal to or less than 90 mg/kg. However, its efficacy in reducing As accumulation in water spinach was limited, emphasizing the need for caution when using organic fertilizers in As-contaminated soils. Our results provide valuable insights for the scientific and precise utilization of organic fertilizers, thereby contributing to the safe production of vegetables.

Bioremediation of acid mine drainage (AMD) was often challenged by poor tolerance of sulfate-reducing bacteria (SRB) to heavy metals and low bioactivity. The highly active immobilized particles with Fe0/Fe2+ enhanced SRB (Fe0/2+-SRB) were prepared by the microorganism immobilization technique. Three dynamic columns were constructed to investigate the adsorption capacity of Fe0/2+-SRB for Mn2+ under varying adsorption layer heights, inflow velocity, and initial Mn2+ concentrations. The role of each matrix material in the immobilized particles was explored, the mechanism of AMD remediation by Fe0/2+-SRB was revealed, and the adaptability of Fe0/2+-SRB to AMD under various initial conditions was investigated. The results showed that the prepared Fe0/2+-SRB exhibited a well-developed surface pore structure. When the adsorption layer height was 200 mm, the influent flow rate was 5 × 10−5 m3/s, and the initial manganese ion concentration was 10 mg/L, the maximum dynamic adsorption capacities (qe) of Mn2+ for each dynamic column were 7.8430, 4.7627, and 8.7677 mg/g, respectively. Compared to dynamic columns 1# and 2#, dynamic column 3# showed the best performance in treating AMD, and the Thomas model effectively described the adsorption kinetics of Mn2+ by Fe0/2+-SRB(3#). Microstructural analysis indicated that chemical adsorption, ion exchange, dissimilation–reduction reaction, and surface complexation occurred between the various matrix materials in Fe0/2+-SRB(3#). Mn2+ was primarily removed in the form of metal sulfide (MnS), and Fe0/Fe2+ could promote the dissimilatory reduction of SO42− by SRB to form S2−. Fe0/2+-SRB(3#) was able to adapt to AMD with initial conditions of pH was 2~4, SO42− < 2500 mg/L, and Mn2+ < 20 mg/L. The research results provide new insights into the remediation of AMD, using a combined microbial-adsorption technology.

A low-cost composite adsorption material has been synthesized from fishery wastes and natural minerals to address challenges such as ecological balance destruction caused by high concentrations of Pb and Cd in acid mine drainage (AMD), unreasonable use of low-caloric lignite, and environmental pollution caused by idle accumulation of oyster shells. This new adsorbent can effectively treat AMD by improving acidity and adsorbing Pb2+ and Cd2+. In this study, oyster shell-modified lignite composite in globular shape (OSL-G) was synthesized by using pyrolyzed oyster shell and lignite, with the addition of bentonite adhesive. The adsorption properties of OSL-G on AMD were evaluated, and the potential mechanism of OSL-G repairing AMD was explored. The results showed that when the mass ratio of oyster shell to lignite was 1:1, oyster shell-modified lignite composite (OSL) was synthesized at 900 °C for 20 min. When the adhesive content was 15.50 %, the roasting temperature was 640 °C, and the roasting time was 2.35 h, OSL-G was synthesized and the adsorption effect was the best. The OSL-G could effectively treat AMD with pH 4 ∼ 5 and initial Pb2+ and Cd2+ concentrations of 10 mg/L within 600 min at a dosage of 4 g/L. The OSL-G adsorption process followed the quasi-second-order kinetic model and the Freundlich model. The maximum adsorption saturation capacities of Pb2+ and Cd2+ were 107.2821 mg/g and 8.3777 mg/g at 298.15 K, respectively. The adsorption process was a multistep controlled spontaneous endothermic process. The potential mechanism was mainly the adsorption-condensation coexistence results of electrostatic adsorption, neutralization precipitation, ion exchange, and surface complexation. The removal rates of Pb2+ and Cd2+ of the recovered OSL-G (ROSL-G) were still high, reaching 57.26 % and 50.38 % after 5 times of adsorption–desorption, respectively. The applicability of ROSL-G after adsorption–desorption for other heavy metal components in AMD proved its good application potential. This study suggested that OSL-G can be used as a promising environmentally friendly adsorbent for AMD. This study provided a broad picture of the management and reuse possibilities of fishery wastes and natural mineral resources, and addressed established, current, and potential strategic needs, particularly in terms of sustainability challenges and ecological civilization construction.

BackgroundThe incidence of deep vein thrombosis (DVT) in the lower extremities is increasing in the younger population. However, there are fewer reported comparisons in the literature for lower extremity DVT.MethodsPatients aged 0.05). The incidence of lower-extremity DVT post-thrombotic syndrome and thrombus recurrence was higher in the young group than in the middle-aged group at 1 year postoperatively (PTS: 78.57% vs. 33.3%, P

Abstract Background Although the candy-plug technique has been reported to be useful for the treatment of post-dissection aortic aneurysm, the stent graft needs be to customized to accommodate the size of vascular occluders. Case presentation We present a case of a persistent false lumen successfully treated with endovascular stent-graft and atrial septal defect occluder in a patient with Stanford Type B dissection. A covered stent graft was implanted into the false cavity through a distal rupture, and an atrial septal defect occluder was inserted into the covered stent to seal of the false cavity. Decreased aneurysmal diameter and false lumen thrombosis were noted by CT scan at 6-month follow-up. Conclusions Our case showed that combined use of a stent graft and atrial septal defect occluder is safe, technically feasible and effective in sealing of the false lumen in post-dissection aortic aneurysm patients with previously failed false lumen thrombosis.

Abstract Objectives To investigate the optimal parameters of spectral CT for preferably visualizing the periprosthetic vasculature and metal artifact reduction (MAR) in total hip arthroplasty (THA). Methods A total of 34 THA of 30 patients were retrospectively included. Image reconstructions included conventional image (CI), CI combined with MAR (CIMAR), and virtual monoenergetic images (VMI) combined with MAR (VMIMAR) at 50–120 keV. The attenuation and standard deviation of the vessel and artifact, and the width of artifact were measured. Qualitative scoring was evaluated including the vascular contour, the extent of artifact, and overall diagnostic evaluation. Results The attenuation, noise of the vessel and artifact, and the width of artifact decreased as the energy level increased (p

Heat stress inhibits plant growth and productivity. Among the main regulators, B-box zinc-finger (BBX) proteins are well-known for their contribution to plant photomorphogenesis and responses to abiotic stress. Our research pinpoints that SlBBX31, a BBX protein harboring a conserved B-box domain, serves as a suppressor of plant growth and heat tolerance in tomato (Solanum lycopersicum L.). Overexpressing (OE) SlBBX31 in tomato exhibited yellowing leaves due to notable reduction in chlorophyll content and net photosynthetic rate (Pn). Furthermore, the pollen viability of OE lines obviously decreased and fruit bearing was delayed. This not only affected the fruit setting rate and the number of plump seeds but also influenced the size of the fruit. These results indicate that SlBBX31 may be involved in the growth process of tomato, specifically in terms of photosynthesis, flowering, and the fruiting process. Conversely, under heat-stress treatment, SlBBX31 knockout (KO) plants displayed superior heat tolerance, evidenced by their improved membrane stability, heightened antioxidant enzyme activities, and reduced accumulation of reactive oxygen species (ROS). Further transcriptome analysis between OE lines and KO lines under heat stress revealed the impact of SlBBX31 on the expression of genes linked to photosynthesis, heat-stress signaling, ROS scavenging, and hormone regulation. These findings underscore the essential role of SlBBX31 in regulating tomato growth and heat-stress resistance and will provide valuable insights for improving heat-tolerant tomato varieties.

B-box (BBX) proteins, a subfamily of zinc-finger transcription factors, are involved in various environmental signaling pathways. In this study, we conducted a comprehensive analysis of BBX family members in Brassica crops. The 482 BBX proteins were divided into five groups based on gene structure, conserved domains, and phylogenetic analysis. An analysis of nonsynonymous substitutions and (Ka)/synonymous substitutions (Ks) revealed that most BBX genes have undergone purifying selection during evolution. An analysis of transcriptome data from rapeseed (Brassica napus) organs suggested that BnaBBX3d might be involved in the development of floral tissue-specific RNA-seq expression. We identified numerous light-responsive elements in the promoter regions of BnaBBX genes, which were suggestive of participation in light signaling pathways. Transcriptomic analysis under shade treatment revealed 77 BnaBBX genes with significant changes in expression before and after shading treatment. Of these, BnaBBX22e showed distinct expression patterns in yellow- vs. black-seeded materials in response to shading. UPLC-HESI-MS/MS analysis revealed that shading influences the accumulation of 54 metabolites, with light response BnaBBX22f expression correlating with the accumulation of the flavonoid metabolites M46 and M51. Additionally, BnaBBX22e and BnaBBX22f interact with BnaA10.HY5. These results suggest that BnaBBXs might function in light-induced pigment accumulation. Overall, our findings elucidate the characteristics of BBX proteins in six Brassica species and reveal a possible connection between light and seed coat color, laying the foundation for further exploring the roles of BnaBBX genes in seed development.

ABSTRACT Suaeda as a halophyte with wide adaptability of salinization level plays an important role in saline soil improvement and management. To some extent, the strong salt tolerance of Suaeda is influenced by rhizobacteria. However, the effect of different Suaeda species and salinization level on the microbial community diversity still unknown. In our study, high-throughput sequencing technology was used to explore the difference in the bacterial and archaeal community diversity of Suaeda altissima and Suaeda dendroides rhizosphere under high (EC, 8–16 dS/m) and severe (EC > 16 dS/m) saline soil. The result showed that complex soil environment and Suaeda species co-shaped bacterial and archaeal community structure, and pH was one of the most important driving factors. In addition, the increase of soil salinity significantly decreased the complexity of bacterial and archaeal co-occurrence network. We explored Halomonas and Candidatus Nitrocosmicus as core microorganisms in the Suaeda rhizosphere, which may play a key ecological role in improving salt tolerance and promoting growth of Suaeda. Our study improves the macroscopic understanding of the interrelationships between soil environments-microbes-plants. IMPORTANCE Suaeda play an important ecological role in reclamation and improvement of agricultural saline soil due to strong salt tolerance. At present, research on Suaeda salt tolerance mainly focuses on the physiological and molecular regulation. However, the important role played by microbial communities in the high-salinity tolerance of Suaeda is poorly studied. Our findings have important implications for understanding the distribution patterns and the driving mechanisms of different Suaeda species and soil salinity levels. In addition, we explored the key microorganisms that played an important ecological role in Suaeda rhizosphere. We provide a basis for biological improvement and ecological restoration of salinity-affected areas.

This study first employed ultrasonic-assisted fermentation of seaweed foot material with Lactiplantibacillus plantarum to produce Porphyra yezoensis sauce. The aim was to examine L. plantarum's growth and metabolism of nutritional components at different growth stages under low- (133.99 W/L) and high-ultrasonic power densities (169.17 W/L). After 24-h fermentation, L. plantarum exhibited a 21.32 % increase in the sonicated P. yezoensis sauce at 133.99 W/L and the logarithmic growth phase compared to that at 169.17 W/L. In addition, compared to the non-sonicated sauce, total phenolic and flavonoid contents increased by around 58 % and 27 % in sonicated sauce at 133.99 W/L, reaching 92.38 mg GEA/g DW and 111.08 mg RE/g DW, respectively. Principal Component Analysis (PCA) of the evaluation criteria for different fermentation stages under 133.99 W/L power ultrasonication revealed that the P. yezoensis sauce generated more phenolic compounds and exhibited stronger antioxidant capabilities in the sonicated sample at the logarithmic phase of L. plantarum. Compared to the traditional treated P. yezoensis sauce, the content of free amino acids was significantly increased in sonicated sauce, especially for logarithmic phase. Finally, GC-IMS analysis demonstrated that the ultrasonication at logarithmic phase released more volatile compounds compared to the non-sonicated sauce. This led to a reduction in the fishy odour of the Porphyra yezoensis sauce and an improved release of favourable flavour compounds.

ABSTRACT Cryptococcus gattii (C. gattii) is emerging as a life-threatening fungus worldwide. However, few data were available in China. In this study, 27 isolates and 32 patient information were collected from several hospitals in China, together with previously reported data (80 cases), to describe the geographic distribution of C. gattii. Molecular identification and genetic diversity analysis of the isolates were conducted using multilocus sequence typing, while the microbiological and virulence characteristics were explored through in vitro phenotypic tests and in vivo animal experiments. The findings revealed that patients infected with C. gattii were mainly immunocompetent males, with most showing symptoms of central nervous system involvement. Isolated strains were predominantly distributed in tropical and subtropical regions, with VGI genotype predominance. These strains exhibited marked genetic diversity, identifying 25 distinct sequence types (STs) among the 57 isolates (available data), including three novel STs (ST565, ST567, and ST568). In vitro assays unveiled significant differences between VGI and VGII in growth capacity at 39°C, capsule diameter, melanin production, UV resistance, and antioxidative capacity, with VGII displaying greater resilience. Integrating animal experiments and clinical prognosis showed that pathogenicity did not directly correlate with in vitro virulence phenotypes or molecular genotypes, underscoring virulence’s complexity. Furthermore, histopathological analysis suggested that lung tissue damage might primarily contribute to mouse mortality, particularly with more pathogenic strains causing extensive lung tissue damage. Our study has the potential to provide valuable data for a comprehensive understanding of the microbiological characteristics of C. gattii in China. IMPORTANCE Our study indicates that the molecular typing of Cryptococcus gattii is unrelated to virulence. The integration of animal experiments and clinical prognosis demonstrated that pathogenicity did not exhibit a direct correlation with in vitro virulence phenotypes or molecular genotypes, emphasizing the intricate nature of virulence. In conclusion, our research holds the potential to provide valuable insights into understanding the microbiological attributes of C. gattii in China.

BackgroundLimited studies have explored the association between sexual factors [age at first sexual intercourse (AFS) and lifetime number of sexual partners (LNSP)] and cardiovascular diseases (CVDs), leaving the causality inconclusive.MethodsWe performed a bi-directional Mendelian randomization (MR) study to investigate the causality between sexual factors and CVDs, including coronary artery disease, myocardial infarction, atrial fibrillation (AF), heart failure (HF), and ischemic stroke (IS). Single-nucleotide polymorphisms (SNPs) for sexual factors were extracted from the UK Biobank. Statistics for each CVD were derived from two different databases. MR estimates were calculated per outcome database and were combined through meta-analysis. Several complementary sensitivity analyses were also performed.ResultsThe primary analysis suggested that AFS was causally associated with the risk of CVDs; the odds ratios (ORs) ranged from 0.686 [95% confidence interval (CI), 0.611–0.770] for HF to 0.798 (95% CI, 0.719–0.886) for AF. However, the association between AFS and IS (OR, 0.844; 95% CI, 0.632–1.126) was not consistent in the meta-analysis after excluding SNPs related to confounders. Moreover, non-significant associations were found between LNSP and CVDs. Reverse direction MR analysis showed that CVDs were not associated with sexual factors.ConclusionsGenetic evidence suggested that AFS was causally associated with the risk of CVDs except for IS, whereas non-significant association of LNSP with CVDs was detected. Further investigation into AFS could be warranted in preventing the progression of CVDs.

Selective phosphorus removal from aquatic media has become an ideal strategy to mitigate eutrophication and meet increasingly stringent discharge requirements. To achieve phosphorus control and resource utilization of low-calorific-value lignite, iron and magnesium salts were used to functionalize lignite, and iron–magnesium functionalized lignite (called IM@BC) was prepared for phosphate recovery from water media. The adsorption properties of IM@BC were systematically evaluated, especially the influence of ambient pH and co-existing ions. The kinetic, isothermal, and thermodynamic adsorption behaviors of IM@BC were analyzed. The adsorption mechanism was revealed by microscopic characterization. The potential application of phosphate-containing IM@BC (P-IM@BC) was explored. The results show that IM@BC has a strong phosphate adsorption capacity, and the maximum adsorption capacity is 226.22 mgP/g at pH = 3. Co-existing CO32− inhibits phosphate adsorption, while coexisting Ca2+ and Mg2+ enhance the effect. At the initial adsorption stage, the amount of phosphate adsorbed by IM@BC continues to increase, and the adsorption equilibrium state is gradually reached after 24 h. The adsorption process conforms to the pseudo-second-order kinetic model (PSO) and Langmuir isothermal adsorption model, and the adsorption process is mainly chemical adsorption. The phosphate absorption capacity is positively correlated with temperature (283.15 K~313.15 K), and the adsorption process is spontaneous, endothermic, and entropy-increasing. Its adsorption mechanism includes electrostatic attraction, ion exchange, surface precipitation, and coordination exchange. IM@BC can efficiently recover phosphate from actual phosphorus-containing wastewater with a recovery efficiency of up to 90%. P-IM@BC slowly releases phosphate from pH 3 to 11. Plant growth experiments showed that P-IM@BC could be used as a slow-release fertilizer to promote the root growth of cowpeas. The novelty of this work lies in the development of a highly efficient phosphate recovery adsorbent, which provides a feasible method of phosphorus control in water media and resource utilization of lignite.

This study is aimed to explore the feasibility of ultrasound on enhancing the fermentation properties of ginkgo kernel juice by Lactiplantibacillus plantarum Y2. Specifically, ultrasound at 20 kHz and different intensities (mild ultrasound intensity-84.42 W/L, moderate ultrasound intensity-115.50 W/L, high ultrasound intensity-173.88 W/L) with a pulse mode were applied to facilitate the fermentation process. The number of viable cells of Lactiplantibacillus plantarum Y2 increased by 5.06, 5.05 and 2.19% in the sonicated groups at 173.88, 115.50 and 84.42 W/L, compared with the non-sonicated juice after 24-h fermentation. Furthermore, mild intensity ultrasonication improved the permeability of the cell membrane, which is beneficial for the metabolism of phenolics, amino acids and organic acids. Ultrasonication increased in-vitro antioxidant activity of fermented ginkgo kernel juice by promoting the metabolism of phenolic acids, such as ferulic acid, chlorogenic and caffeic acids. At the end of fermentation, the sonicated group at 84.42 W/L has the maximum consumptions of total sugars and proteins (increased by 12.52 and 18.73%). Moreover, the reduction rate of the poison material 4′-O-methylpyridoxine (MPN) in ginkgo kernel juice increased by more than 16.40% with ultrasound treatment at 173.88 W/L after the fermentation for 48 h. Overall, ultrasound can improve the metabolizations of Lactobacillus plantarum and reduce the toxic substances, which promoted the nutritional value and flavors of ginkgo kernel juice.

Stanniocalcin 2 (STC2) is identified as a glycosylated peptide hormone and estrogen-responsive gene in cancer cells. STC2 participates in angiogenesis, cell development, cytoprotection, and calcium and phosphate regulation during the development of cancer. The role of STC2 in endometrial cancer (EC) remains unclear. The data from the bioinformatic and immunohistochemical analysis showed that STC2 was upregulated in the EC tissues. The EC cells were treated with 17β-estradiol (E2), and 0.1 μmol/L E2 increased the expression of STC2 in the EC cells. E2 also increased cell viability, promoted proliferation, and inhibited apoptosis of EC. However, the knockdown of STC2 decreased cell viability, reduced proliferation, and promoted apoptosis of E2-stimulated EC. Moreover, silencing of STC2 attenuated E2-induced downregulation of phosphorylated-AMP-activated protein kinase (AMPK) in the EC cells. The loss of STC2 reduced E2-stimulated tumor growth EC in vivo. In conclusion, STC2 deficiency suppressed E2-stimulated proliferation and tumor growth of EC through the activation of AMPK signaling.

Peripheral nerve injury (PNI) is a common surgical disease. In recent years, with the development of tissue engineering materials, nerve guidance conduit (NGC) is expected to replace autologous nerve transplantation and become a new method for the treatment of PNI. In this work, we developed a multifunctional silk fibroin (SF)/gelatin-tyramine (GT) composite hydrogel conduit with flexible adjustable size by using a diffusion-driven cross-linking method. Furthermore, the ZIF-8 nanoparticles loaded with miR-29a (miR-29a@ZIF-8) delivery system was constructed and compounded into SF/GT hydrogel conduit to enhance its bioactivity and neural repair effects through sustained miR-29a release. In vitro cell experiments showed that SF/GT hydrogel conduit could significantly promote the myelination of Schwann cells (SCs), neuronal differentiation and axon extension of PC12 ​cells. In addition, it was worth mentioning that SF/GT hydrogel conduit could also regulate the immune microenvironment of nerve regeneration by promoting the transformation of macrophages from M1 phenotype to M2 phenotype, indicating a potential application as nerve guidance conduit in peripheral nerve repair.

Craniotomy is an invasive operation with great trauma and many complications, and patients undergoing craniotomy should enter the ICU for monitoring and treatment. Based on electronic medical records (EMR), the discovery of high-risk multi-biomarkers rather than a single biomarker that may affect the length of ICU stay (LoICUS) can provide better decision-making or intervention suggestions for clinicians in ICU to reduce the high medical expenses of these patients and the medical burden as much as possible. The multi-biomarkers or medical decision rules can be discovered according to some interpretable predictive models, such as tree-based methods. Our study aimed to develop an interpretable framework based on real-world EMRs to predict the LoICUS and discover some high-risk medical rules of patients undergoing craniotomy. The EMR datasets of patients undergoing craniotomy in ICU were separated into preoperative and postoperative features. The paper proposes a framework called Rules-TabNet (RTN) based on the datasets. RTN is a rule-based classification model. High-risk medical rules can be discovered from RTN, and a risk analysis process is implemented to validate the rules discovered by RTN. The performance of the postoperative model was considerably better than that of the preoperative model. The postoperative RTN model had a better performance compared with the baseline model and achieved an accuracy of 0.76 and an AUC of 0.85 for the task. Twenty-four key decision rules that may have impact on the LoICUS of patients undergoing craniotomy are discovered and validated by our framework. The proposed postoperative RTN model in our framework can precisely predict whether the patients undergoing craniotomy are hospitalized for too long (more than 15 days) in the ICU. We also discovered and validated some key medical decision rules from our framework.

Aspergillus luchuensis, an industrially important member of Aspergillus species belonging to section Nigri used in fermentation in East Asia, was isolated from an immunocompromised patient with probable invasive pulmonary aspergillosis who failed voriconazole therapy in China. This isolate showed non-wild-type susceptibility to itraconazole, voriconazole, isavuconazole, and posaconazole. A G1378A mutation in cyp51A, resulting in the G441S amino acid substitution, which is the homolog to G448S conferring triazole-resistance in A. fumigatus, was detected in the A. luchuensis isolate.

Abstract Background Diagnosing partial subscapularis (SSC) tendon tears still faces challenges. A failure rate of massive posterosuperior rotator cuff tear repair will be highly increased when extending more than one-third of SSC tendon. This study aims to investigate the quantitative indicators and features of partial SSC tears on conventional shoulder MRI and improve the preoperative diagnostic accuracy. Materials and methods Four hundred and thirty-seven patients underwent MRI and arthroscopy were retrospectively reviewed; 89 patients with partial SSC tears in case group and 50 patients with normal SSC in control group were included. Six MRI features with the explicit definition of some quantitative indicators were evaluated. Results Fissure sign showed the highest diagnostic efficiency for the partial SSC tears, with a specificity of 92%, sensitivity of 75.3%, and accuracy of 81.3%. Thinning of SSC, fluid collection under the coraco-glenoid arch (CGA), and combined SSP complete tear also showed high specificity of 86%, 80%, and 80%, respectively, while the sensitivity and accuracy were moderate, with a sensitivity of 38.2%, 50.6%, and 48.3%, respectively, an accuracy of 55.4%, 61.2%, and 59.7%, respectively. The specificity, sensitivity, and accuracy of lesser tuberosity cysts were all moderate with values of 68%, 56.2%, and 60%, respectively. However, fat accumulation under the CGA showed no significant difference between the partial SSC tears group and the control group. Conclusion Several specific MRI features with quantitative indicators defined in this study can be used to improve the accuracy of preoperative MRI diagnosis of partial SSC tears.

Low responsiveness to chemotherapy is an important cause of poor prognosis in pancreatic cancer. Smoking is a high‐risk factor for pancreatic cancer and cancer resistance to gemcitabine; however, the underlying mechanisms remain unclear. 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) is the main metabolite of tobacco burning and has been shown to be associated with cancer development and chemoresistance. However, in pancreatic cancer, its mechanism remains poorly understood. In this study, we found that NNK promoted stemness and gemcitabine resistance in pancreatic cancer cell lines. Moreover, NNK increased autophagy and elevated the expression levels of the autophagy‐related markers autophagy‐related gene 5 (ATG5), autophagy‐related gene 7 (ATG7), and Beclin1. Furthermore, the results showed that NNK‐promoted stemness and gemcitabine resistance was partially dependent on the role of NNK in cell autophagy, which is mediated by the β2‐adrenergic receptor (β2AR)‐Akt axis. Finally, we proved that NNK intervention could not only activate β2AR, but also increase its expression, making β2AR and Akt form a feedback loop. Overall, these findings show that the NNK‐induced β2AR‐Akt feedback loop promotes stemness and gemcitabine resistance in pancreatic cancer cells.

Abstract The metabolic syndrome (MetS) has been well linked with coronary heart disease (CHD) in the general population, but studies have rarely explored their association among patients with stroke. We examine prevalence of MetS and its association with CHD in patients with first-ever ischemic stroke. This hospital-based study included 1851 patients with first-ever ischemic stroke (mean age 61.2 years, 36.5% women) who were hospitalized into two university hospitals in Shandong, China (January 2016–February 2017). Data were collected through interviews, physical examinations, and laboratory tests. MetS was defined following the National Cholesterol Education Program (NCEP) criteria, the International Diabetes Federation (IDF) criteria, and the Chinese Diabetes Society (CDS) criteria. CHD was defined following clinical criteria. Data were analyzed using binary logistic regression models. The overall prevalence of MetS was 33.4% by NECP criteria, 47.2% by IDF criteria, and 32.5% by CDS criteria, with the prevalence being decreased with age and higher in women than in men (p

ObjectiveThe study aims to develop a mapping algorithm from the Pediatric Quality of Life Inventory™ 4. 0 (Peds QL 4.0) onto Child Health Utility 9D (CHU-9D) based on the cross-sectional data of functional dyspepsia (FD) children and adolescents in China.MethodsA sample of 2,152 patients with FD completed both the CHU-9D and Peds QL 4.0 instruments. A total of six regression models were used to develop the mapping algorithm, including ordinary least squares regression (OLS), the generalized linear regression model (GLM), MM-estimator model (MM), Tobit regression (Tobit) and Beta regression (Beta) for direct mapping, and multinomial logistic regression (MLOGIT) for response mapping. Peds QL 4.0 total score, Peds QL 4.0 dimension scores, Peds QL 4.0 item scores, gender, and age were used as independent variables according to the Spearman correlation coefficient. The ranking of indicators, including the mean absolute error (MAE), root mean squared error (RMSE), adjusted R2, and consistent correlation coefficient (CCC), was used to assess the predictive ability of the models.ResultsThe Tobit model with selected Peds QL 4.0 item scores, gender and age as the independent variable predicted the most accurate. The best-performing models for other possible combinations of variables were also shown.ConclusionThe mapping algorithm helps to transform Peds QL 4.0 data into health utility value. It is valuable for conducting health technology evaluations within clinical studies that have only collected Peds QL 4.0 data.

ObjectiveThis research aimed to develop the more accurate mapping algorithms from health assessment questionnaire disability index (HAQ-DI) onto EQ-5D-5L based on Chinese Rheumatoid Arthritis patients.MethodsThe cross-sectional data of Chinese RA patients from 8 tertiary hospitals across four provincial capitals was used for constructing the mapping algorithms. Direct mapping using Ordinary least squares regression (OLS), the general linear regression model (GLM), MM-estimator model (MM), Tobit regression model (Tobit), Beta regression model (Beta) and the adjusted limited dependent variable mixture model (ALDVMM) and response mapping using Multivariate Ordered Probit regression model (MV-Probit) were carried out. HAQ-DI score, age, gender, BMI, DAS28-ESR and PtAAP were included as the explanatory variables. The bootstrap was used for validation of mapping algorithms. The average ranking of mean absolute error (MAE), root mean square error (RMSE), adjusted R2 (adjR2) and concordance correlation coefficient (CCC) were used to assess the predictive ability of the mapping algorithms.ResultsAccording to the average ranking of MAE, RMSE, adjR2, and CCC, the mapping algorithm based on Beta performed the best. The mapping algorithm would perform better as the number of variables increasing.ConclusionThe mapping algorithms provided in this research can help researchers to obtain the health utility values more accurately. Researchers can choose the mapping algorithms under different combinations of variables based on the actual data.

IntroductionAlfalfa (Medicago sativa L.) is a highly nutritious leguminous forage that plays an essential role in animal husbandry. In the middle and high latitudes of the northern hemisphere, there are problems with its low rates of overwintering and production. The application of phosphate (P) is an important measure to improve the cold resistance and production of alfalfa, but little is known about the mechanism of P in improving the cold resistance of alfalfa.MethodsThis study integrated the transcriptome and metabolome to explain the mechanism of alfalfa in response to low-temperature stress under two applications of P (50 and 200 mg kg-1) and a control of none applied.ResultsThe application of P fertilizer improved the root structure and increased the content of soluble sugar and soluble protein in the root crown. In addition, there were 49 differentially expressed genes (DEGs) with 23 upregulated and 24 metabolites with 12 upregulated when 50 mg kg-1 of P was applied. In contrast, there were 224 DEGs with 173 upregulated and 12 metabolites with 6 upregulated in the plants treated with 200 mg kg-1 of P compared with the Control Check (CK). These genes and metabolites were significantly enriched in the biosynthesis of other secondary metabolites and the metabolic pathways of carbohydrates and amino acids. The integration of the transcriptome and metabolome indicated that P affected the biosynthesis of N-acetyl-L-phenylalanine, L-serine, lactose, and isocitrate during the period of increasing cold. It could also affect the expression of related genes that regulate cold tolerance in alfalfa.DiscussionOur findings could contribute to a deeper understanding of the mechanism that alfalfa uses to tolerate cold and lay a theoretical foundation for breeding alfalfa that is highly efficient at utilizing phosphorus.

Abstract Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. However, the molecular mechanism of PNI remains unclear. The present study aimed to investigate the mechanism that HGF/c-Met pathway facilitates the PNI of pancreatic cancer. In this study, we confirmed that c-Met expression was correlated with PNI in pancreatic cancer tissues. Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI. Activating the HGF/c-Met signaling pathway also enhanced the migration and invasion ability of cancer cells to facilitate cancer cells invading nerves. Mechanistically, HGF/c-Met signaling pathway can active the mTOR/NGF axis to promote the PNI of pancreatic cancer. Additionally, we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo. Taken together, our findings suggest a supportive mechanism of the HGF/c-Met signaling pathway in promoting PNI by activating the mTOR/NGF axis in pancreatic cancer. Blocking the HGF/c-Met signaling pathway may be an effective target for the treatment of PNI.

Abstract We previously reported that ibandronate (IBAN) could improve endothelial function in spontaneously hypertensive rats. However, the mechanism by which IBAN improves endothelial function is unclear. The IBAN-induced autophagic process in vitro experiments were determined by detection of LC3, Beclin1, and P62 protein levels via western blotting. The autophagy flux was detected by confocal microscopy and transmission electron microscopy. For in vivo experiments, spontaneously hypertensive rats were orally administered with IBAN. Utilizing angiotensin II (Ang II) to stimulate the human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) as a model of endothelial cell injury in hypertension, we found that IBAN promoted autophagy and protected cell viability in Ang II-treated-endothelial cells while these effects could be reversed by autophagy inhibitor. In terms of mechanism, IBAN treatment decreased the levels of Rac1 and mammalian target of rapamycin (mTOR) pathway. Activating either Rac1 or mTOR could reverse IBAN-induced autophagy. Furthermore, the in vivo experiments also indicated that IBAN promotes autophagy by downregulating Rac1-mTOR. Taken together, our results firstly revealed that IBAN enhances autophagy via inhibiting Rac1-mTOR signaling pathway, and thus alleviates Ang II-induced injury in endothelial cells.

Background: The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear. Methods: A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization. Results: There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P

Ultra-high-performance concrete (UHPC)-filled duct connection is an innovative solution for joining assembled structures, in which the anchorage performance of the rebar and UHPC filled in bellows plays a critical role in determining the overall connection effectiveness. To establish a reliable anchorage length and a bond–slip relationship between rebar and UHPC within a bellow, a total of 16 specimens were conducted, and pullout tests were carried out. Two parameters were considered, including the diameter ratio (D/d), representing the proportion of the diameter of the bellow D to the diameter of the steel bar d, and anchorage length (L). By analyzing the failure modes, load versus deflection curves, and steel strain data, the influences of the diameter ratio and anchorage length on the anchorage performance were discussed. The test results showed that the failure mode changed from rebar pullout to rebar breakage as the anchorage length increased from 3 d to over 10 d. The reliable anchorage length of the rebar was recommended to be at least 10 d with a diameter ratio (D/d) of 2.4. Moreover, a fitting bond–slip model was proposed based on the experimental bond–slip curves between the rebar and UHPC interface within the bellows with high precision. These findings constitute a crucial basis for the comprehensive stress analysis of assembled structures connected using UHPC grouted in bellows.

Periodontitis and inflammatory bowel diseases (IBD) are inflammatory diseases of the gastrointestinal tract that share common features of microbial-induced ecological dysregulation and host immune inflammatory response. The close relationship between periodontitis and IBD is characterized by a higher prevalence of IBD in patients with periodontitis and a higher prevalence and severity of periodontitis in patients with IBD, indicating that periodontitis and IBD are different from the traditional independent diseases and form an “Oral-Gut” axis between the two, which affect each other and thus form a vicious circle. However, the specific mechanisms leading to the association between the two are not fully understood. In this article, we describe the interconnection between periodontitis and IBD in terms of microbial pathogenesis and immune dysregulation, including the ectopic colonization of the gut by pathogenic bacteria associated with periodontitis that promotes inflammation in the gut by activating the host immune response, and the alteration of the oral microbiota due to IBD that affects the periodontal inflammatory response. Among the microbial factors, pathogenic bacteria such as Klebsiella, Porphyromonas gingivalis and Fusobacterium nucleatum may act as the microbial bridge between periodontitis and IBD, while among the immune mechanisms, Th17 cell responses and the secreted pro-inflammatory factors IL-1β, IL-6 and TNF-α play a key role in the development of both diseases. This suggests that in future studies, we can look for targets in the “Oral-Gut” axis to control and intervene in periodontal inflammation by regulating periodontal or intestinal flora through immunological methods.

BackgroundBletilla striata is one of the commonly used traditional Chinese medicine. B. striata polysaccharides (BP) and oligosaccharides (BO) are one of the main components of B. striata, which have been proved to have a variety of biological activities. However, the digestion and fermentation characteristics of BP and BO are still unclear.MethodsThe study evaluated different prebiotic effects of BP and BO by in vitro simulating digestion and gut microbiota fermentation.ResultsThe results show that the simulating saliva partly degraded BP, but had no effect on BO. The molecular weights of BP and BO remained basically unchanged in gastric and intestinal digestion. In addition, BP and BO could be rapidly degraded and utilized by gut microbiota. During in vitro fermentation, the growth rates of the BP and BO groups were higher than that of the Control group and the pH value and total carbohydrate content in BP group and BO group decreased significantly. Although the reducing sugar level in the BO group decreased rapidly, it remained at a low level in the BP group. Both BP and BO improved the composition and structure of gut microbiota, indicative of the upregulated abundances of Streptococcus and Veillonella, and the downregulated populations of Escherichia and Bacteroides. There were differences in the SCFA production by gut microbiota and antioxidant activities between the BP and BO groups. The fermentation broth of the BP group displayed a stronger suppression of O2-, but a higher scavenging effect on DPPH for the BO group.ConclusionsBP and BO displayed different digestion and fermentation characteristics in vitro due to their distinct polymerization degrees. The study point towards the potential of BP and BO as prebiotics in the application to human diseases by selectively regulating gut microbiota in the future.

BackgroundIntestinal inflammation and periodontitis influence the development of each other through the bidirectional relationship. As the intestinal microbiome metabolite, trimethylamine-N-oxide (TMAO) could contribute to chronic inflammation in the gut by influencing the gut microbial composition and intestinal immunity. Increased circulating TMAO levels often accompany clinical findings in patients with experimental periodontitis. However, the role of TMAO in the bidirectional relationship between intestinal inflammation and periodontitis remains unclear. Thus, we explored whether TMAO influences the periodontitis process by affecting intestinal immunity and microbial composition in this article.MethodsPeriodontitis was induced by unilateral ligation of the first molar in mice, and 3,3-dimethyl-1-butanol (DMB) was used as an inhibitor to reduce TMAO circulating. Twenty-five BALB/c mice were randomly assigned to five study sets (n = 5/group): no periodontitis with DMB (Control group), periodontitis (P) group, periodontitis with TMAO (P+TMAO) group, periodontitis with TMAO and DMB (P+TMAO+DMB) group, and periodontitis with DMB (P+DMB) group. The effect of TMAO was determined by assessing changes in intestinal histology, intestinal flora composition, periodontal tissue, and periodontal pro-inflammatory factors at ten days.ResultsThe outcomes indicated a marked improvement in the intestinal inflammation severity, and intestinal flora diversity was reduced. Firmicutes number and the ratio of Firmicutes/Bacteroidetes were improved in the P+TMAO group. In addition, the alveolar bone resorption and the degree of periodontal tissue inflammation were more severe in the P+TMAO group than in other groups. Immunohistochemistry showed higher levels of TGF-β and IL-1β expression in the periodontal tissues of P+TMAO.ConclusionsOur data suggest that TMAO could influence periodontal immunity and promote periodontal inflammation by affecting the intestinal microenvironment, revealing TMAO may affect the development of periodontitis through the bidirectional relationship of the oral-gut axis.

BackgroundPredicting type 2 chronic rhinosinusitis with nasal polyps (CRSwNP) may help for selection of appropriate surgical procedures or pharmacotherapies in advance. However, an accurate non-invasive method for diagnosis of type 2 CRSwNP is presently unavailable.MethodsTo optimize the technique for collecting nasal secretion (NasSec), 89 CRSwNP patients were tested using nasal packs made with four types of materials. Further, Th2low and Th2highCRSwNP defined by clustering analysis in another 142 CRSwNP patients using tissue biomarkers, in the meanwhile, inflammatory biomarkers were detected in NasSec of the same patients collected by the selected nasal pack. A diagnostic model was established by machine learning algorithms to predict Th2highCRSwNP using NasSecs biomarkers.ResultsConsidering the area under receiver operating characteristic curve (AUC) for IL-5 in NasSec, nasal pack in polyvinyl alcohol (PVA) was superior to other materials for NasSec collection. When Th2low and Th2highCRSwNP clusters were defined, logistic regression and decision tree model for prediction of Th2highCRSwNP demonstrated high AUCs values of 0.92 and 0.90 respectively using biomarkers of NasSecs. Consequently, the pre-pruned decision tree model; based on the levels of IL-5 in NasSec (≤ 15.04 pg/mL), blood eosinophil count (≤ 0.475*109/L) and absence of comorbid asthma; was chosen to define Th2lowCRSwNP from Th2highCRSwNP for routine clinical use.ConclusionsTaken together, a decision tree model based on a combination of NasSec biomarkers and clinical features can accurately define type 2 CRSwNP patients and therefore may be of benefit to patients in receiving appropriate therapies in daily clinical practice.

Acute pancreatitis is a common gastrointestinal disease characterized by inflammation of the exocrine pancreas and manifesting itself through acute onset of abdominal pain. It is frequently associated with organ failure, pancreatic necrosis, and death. Mounting evidence describes monocytes - phagocytic, antigen presenting, and regulatory cells of the innate immune system - as key contributors and regulators of the inflammatory response and subsequent organ failure in acute pancreatitis. This review highlights the recent advances of dynamic change of numbers, phenotypes, and functions of circulating monocytes as well as their underling regulatory mechanisms with a special focus on the role of lipid modulation during acute pancreatitis.

Abstract Introduction Immune cells and molecules are considered as clinical biomarkers and potential targets for immunotherapy. Analyses of the composition of peripheral blood cells hold promise for providing a basis for diagnosing and prognosis lung cancer. In this study, we assessed correlations between immune cell subset profiles in peripheral blood and disease prognosis in patients with lung cancer. Methods One hundred and thirteen patients with lung cancer and 99 age‐matched healthy people were enrolled in this study. The percentage and cell count of monocytes, neutrophils, T cells, B cells, natural killer (NK), and NKT cells in peripheral blood were analyzed by flow cytometry or peripheral blood analyzer. Serum cytokines and colony‐stimulating factors were detected by enzyme‐linked immunosorbent assay (ELISA). Results A reduction in antitumor NK cells (p

Inflammatory damage from bacterial biofilms usually causes the failure of tooth implantation. A promising solution for this challenge is to use an implant surface with a long-term, in-depth and efficient antibacterial feature. In this study, we developed an ultrasound-enhanced antibacterial implant surface based on Au nanoparticle modified TiO2 nanotubes (AuNPs-TNTs). As an artificial tooth surface, films based on AuNPs-TNTs showed excellent biocompatibility. Importantly, compared to bare titania surface, a larger amount of reactive oxygen radicals was generated on AuNPs-TNTs under an ultrasound treatment. For a proof-of-concept application, Porphyromonas gingivalis (P. gingivalis) was used as the model bacteria; the as-proposed AuNPs-TNTs exhibited significantly enhanced antibacterial activity under a simple ultrasound treatment. This antibacterial film offers a new way to design the surface of an artificial implant coating for resolving the bacterial infection induced failure of dental implants.

IntroductionCurrent evidence indicates endovascular intervention is a safe and effective treatment for peripheral artery disease of the lower extremity. However, the clinical outcome of endovascular intervention for femoropopliteal lesions has been shown to be affected by the status of tibial runoff. It remains unclear whether endovascular intervention for tibial runoff is associated with additional benefits.Methods and analysisThis prospective, multicenter, real-world observational study is carried out from January 2021 to December 2022 in 8 designated centers across China with an estimated sample size of 1200 patients with severe femoropopliteal disease. The pre-procedural status of tibial runoff is evaluated with the modified SVS score and categorized as good (SVS 10). Whether the patient will be treated with endovascular intervention for tibial runoff is determined by the treating vascular surgeons. Patients are dichotomized into the intervention group and the non-intervention group, with each group further divided into the good, compromised and poor tibial run-off subgroup, yielding 6 subgroups in total. Patients within various subgroups are compared with regard to the primary patency rate of the femoropopliteal artery, changes in quality of life, changes of Rutherford category, improvement of the Wound, Ischemia, and Foot Infection Classification, and incidence of major adverse events over 24-months follow-up. The results of this study may provide important information to help vascular sspecialists to decide whether the tibial runoff should be endovascularly intervened and which patient population benefits most from tibial runoff intervention.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04675632?id=NCT04675632&draw=2&rank=1, NCT04675632.