Search

Objective: To observed the effect of a curcumin-based vaginal gel combined with electroporation for the treatment of vulvovaginal candidiasis (VVC) caused by Candida albicans. Methods: Temperature-sensitive in situ gels (ISG) were prepared using poloxamers 407 and 188 as matrices. The mass ratio of poloxamer 407 and poloxamer 188 was 7:1 with a gelation temperature of approximately 29°C and gelation time of 2.5 min. Results: Electroporation increased the transmucosal permeability of the model drug, doxorubicin and improved the antifungal effects of curcumin. In vitro antifungal experiments showed that the number of fungal colonies in curcumin ISG combined with electroporation was lower than that in pure curcumin ISG. In vivo pharmacodynamic experiments showed that, compared to the model group, curcumin ISG with electroporation inhibited the growth of C. albicans, alleviated vaginal mucosal edema, and reduced the inflammatory response. Conclusion: Curcumin ISG combined with electroporation has substantial potential for the efficient clinical treatment of VVC.

Abstract Background Agonistic monoclonal antibodies targeting 4-1BB/CD137 have shown preclinical promise, but their clinical development has been limited by severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. Methods A novel anti-MSLN×4-1BB bispecific antibody (bsAb) was generated via antibody engineering, and its affinity and activity were detected via enzyme-linked immunosorbent assay (ELISA), flow cytometry, and T-cell activation and luciferase reporter assays. In vivo antitumour activity was assessed by establishing humanized mice bearing human MSLN-expressing MC38 (MC38/hMSLN) or CT26 (CT26/hMSLN) cells, and safety was further evaluated in cynomolgus monkeys. Results We generated two humanized anti-MSLN×4-1BB bsAbs (HK013-G1/G4) by fusing an anti-4-1BB scFv to the C-terminus of an anti-MSLN VHH with an intact Fc fragment from human IgG1 or IgG4. The two bsAbs were able to block the binding of CA125 to MSLN and stimulate 4-1BB signaling pathway, which was strictly dependent on MSLN expression. In particular, HK013-G1 retained Fc function and induced ADCC effect in tumour cells, whereas HK013-G4 did not. Strikingly, HK013-G1 showed superior antitumour activity to HK013-G4 both in vitro and in vivo and remained effective even in the presence of soluble MSLN. HK013-G1 enhanced antitumour immunity and induced durable antigen-specific immune memory to prevent rechallenged tumour growth, even at a dose as low as 1 mg/kg. Furthermore, HK013-G1 did not induce nonspecific production of proinflammatory cytokines and showed good tolerability up to the highest tested dose (30 mg/kg weekly) for 5 weeks, with no HK013-G1-related adverse effects observed in cynomolgus monkeys. In addition, the mean half-life of HK013-G1 was approximately 61 and 97 h at single doses of 3 and 30 mg/kg, respectively. Conclusion The optimal anti-MSLN×4-1BB bsAb HK013-G1 exhibited synergistic antitumour effects by inducing an ADCC effect (innate immunity) and stimulating the 4-1BB signaling pathway (adaptive immunity) upon cross-bridging with MSLN with no systemic toxicity, which may offer the promise of an improved therapeutic window relative to that of 4-1BB agonists.

Abstract Background Rectal cancer is a common cancer worldwide and lacks effective prognostic markers. The development of prognostic markers by computational pathology methods has attracted increasing attention. This paper aims to construct a prognostic signature from whole slide images for predicting progression-free survival (PFS) of rectal cancer through an unsupervised artificial intelligence algorithm. Methods A total of 238 patients with rectal cancer from two datasets were collected for the development and validation of the prognostic signature. A tumor detection model was built by transfer learning. Then, on the basis of the tumor patches recognized by the tumor detection model, a convolutional autoencoder model was built for decoding the tumor patches into deep latent features. Next, on the basis of the deep latent features, the tumor patches were divided into different clusters. The cluster number and other hyperparameters were optimized by a nested cross-validation method. The percentage of each cluster from the patient’s tumor patches, which is hereafter called PCF, was calculated for prognostic signature construction. The prognostic signature was constructed by Cox proportional hazard regression with L2 regularization. Finally, bioinformatic analysis was performed to explore the underlying biological mechanisms of the PCFs. Results The accuracy of the tumor detection model in distinguishing tumor patches from non-tumor patches achieved 99.3%. The optimal cluster number was determined to be 9. Therfore, 9 PCFs were calculated to construct the prognostic signature. The prognostic signature achieved a concordance index of 0.701 in the validation cohort. The Kaplan-Meier survival curves showed the prognostic signature had good risk stratification ability. Through the bioinformatic analysis, several PCF-associated genes were identified. These genes were enriched in various gene ontology terms. Conclusion The developed prognostic signature can effectively predict PFS in patients with rectal cancer and exploration of the underlying biological mechanisms may help to promote its clinical translation.

AIM: To quantify the severity and frequency of ocular pain in Tibetan plateau patients with dry eye, and to evaluate the related factors affecting ocular pain. METHODS: A retrospective study included 160 cases of dry eye disease (DED) patients who were treated from July 2022 to June 2023. Age, gender, occupation, illness course, anxiety, plateau duration, plateau protection, ocular surface disease index scale (OSDI), break-up time (BUT), Schirmer I test (SIT), conjunctivitis, history of ophthalmic medication, autoimmune disease, the workload of daily near vision range, smoking and overnight stay were obtained via comprehensive ophthalmic assessment, and their duration was followed up. Logistic regression analysis was used to determine the related factors affecting ocular pain. RESULTS: Totally 77.5% (124/160) of DED patients had ocular pain, of which the severity of ocular pain was mild, moderate, and severe in 30.0%, 36.3%, and 11.3% of patients, respectively. Frequency of ocular pain was reported occasional, half the time, frequent, and persistent pain in 19.4%, 36.9%, 16.9%, and 4.4%. OSDI score was 19.67±5.70 (13 to 36), and the level of pain was lowly correlated with OSDI (rs=0.316, P0.05). CONCLUSION: Ocular pain is a common complaint in high-altitude DED patients during the pandemic. Anxiety, eye protection, and adequate sleep during the epidemic period are significantly associated with the severity and frequency of ocular pain in patients with plateau DED, while symptoms of DED have relatively little influence on them.

To analyze the metabolic differences in Wangdu peppers, this study employed high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) to detect chemical components and perform non-targeted metabolomics analysis on five different varieties of Wangdu peppers: Yan Jiao (YJ), La Yan (LY), Guo Ta (GT), Yan Jiao 110 (YJA), and Re La (RL). Machine learning was used to classify and identify the differential metabolites screened. First, HPLC was used to measure the content of capsaicin, dihydrocapsaicin, and Vitamin C (VC) in the five pepper varieties. Then, GC-MS was used for non-targeted metabolite analysis of the five peppers. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were employed to identify differential metabolites and metabolic pathways. Machine learning methods were used to identify the different pepper varieties based on the differential metabolites. In the five pepper varieties, Re La had the highest content of capsaicin and dihydrocapsaicin, at 533.897±62.187 μg/g and 264.526±28.532 μg/g, respectively. Yan Jiao had the highest VC content at 146.9±0.029 mg/100 g. OPLS-DA identified 16 differential metabolites, including organic acids such as quinic acid and aconitic acid, which were higher in Yan Jiao, D-sorbitol, which was highest in La Yan, citric acid, D-fructose, D-mannose, and lactic acid, which were most enriched in Guo Ta, D-tagatose and amino acids, which were highest in Yan Jiao 110, and glucose and inositol, which were most abundant in Re La. KEGG pathway enrichment analysis indicated that the differential metabolic pathways mainly included galactose metabolism, fructose and mannose metabolism, the citric acid cycle, starch and sucrose metabolism, glyoxylate and dicarboxylate metabolism, and pyruvate metabolism. Finally, three machine learning methods—random forest (RF), XGBoost, and backpropagation (BP) neural networks were used to classify and validate the differential metabolites of the five pepper varieties. The established classification models achieved accuracies of 100%, 92.9%, and 78.6%, respectively, demonstrating their utility in identifying pepper varieties. These results would provide fundamental data for the quality evaluation, variety improvement, and comprehensive utilization of Wangdu peppers.

Abstract Plants such as herbs, vegetables, fruits, and cereals are closely related to human life. Developing effective testing methods to ensure their safety and quantify their active components are of significant importance. Recently, nanomaterials with enzyme-like activity (known as nanozymes) have been widely developed in various assays, including colorimetric, fluorescence, chemiluminescence, and electrochemical analysis. This review presents the latest advances in analyzing phytochemicals and hazardous substances in plant samples based on nanozymes, including some active ingredients, organophosphorus pesticides, heavy metal ions, and mycotoxins. Additionally, the current shortcomings and challenges of the actual sample analysis were discussed.

Abstract Reading digital information from highly dense but lightweight DNA medium nowadays relies on time-consuming next-generation sequencing. Nanopore sequencing holds the promise to overcome the efficiency problem, but high indel error rates lead to the requirement of large amount of high quality data for accurate readout. Here we introduce Composite Hedges Nanopores, capable of handling indel rates up to 15.9% and substitution rates up to 7.8%. The overall information density can be doubled from 0.59 to 1.17 by utilizing a degenerated eight-letter alphabet. We demonstrate that sequencing times of 20 and 120 minutes are sufficient for processing representative text and image files, respectively. Moreover, to achieve complete data recovery, it is estimated that text and image data require 4× and 8× physical redundancy of composite strands, respectively. Our codec system excels on both molecular design and equalized dictionary usage, laying a solid foundation approaching to real-time DNA data retrieval and encoding.

In this work, we report a counter-intuitive activation of abnormal grain growth (AGG) in randomly-oriented fine grains (FGs) in an L-PBF Al–Mg–Sc–Zr alloy, which is unlikely from perspectives of curvature-driven grain growth, crystallographic texture or strain-induced boundary migration. The observed spontaneous AGG is understood in light of the growth instability of an arbitrary grain in an evolving particle-pinned polycrystalline aggregation. A generalized criterion for AGG is hence proposed, which efficaciously explains the observed susceptibility of FGs to AGG, the presence of multiple AGG activation sites, and the asynchrony of AGG activation.

ABSTRACT Introduction Multitasking during flights leads to a high mental workload, which is detrimental for maintaining task performance. Electroencephalography (EEG) power spectral analysis based on frequency‐band oscillations and microstate analysis based on global brain network activation can be used to evaluate mental workload. This study explored the effects of a high mental workload during simulated flight multitasking on EEG frequency‐band power and microstate parameters. Methods Thirty‐six participants performed multitasking with low and high mental workloads after 4 consecutive days of training. Two levels of mental workload were set by varying the number of subtasks. EEG signals were acquired during the task. Power spectral and microstate analyses were performed on the EEG. The indices of four frequency bands (delta, theta, alpha, and beta) and four microstate classes (A–D) were calculated, changes in the frequency‐band power and microstate parameters under different mental workloads were compared, and the relationships between the two types of EEG indices were analyzed. Results The theta‐, alpha‐, and beta‐band powers were higher under the high than under the low mental workload condition. Compared with the low mental workload condition, the high mental workload condition had a lower global explained variance and time parameters of microstate B but higher time parameters of microstate D. Less frequent transitions between microstates A and B and more frequent transitions between microstates C and D were observed during high mental workload conditions. The time parameters of microstate B were positively correlated with the delta‐, theta‐, and beta‐band powers, whereas the duration of microstate C was negatively correlated with the beta‐band power. Conclusion EEG frequency‐band power and microstate parameters can be used to detect a high mental workload. Power spectral analyses based on frequency‐band oscillations and microstate analyses based on global brain network activation were not completely isolated during multitasking.

The potential applications of Acer truncatum Bunge seed oil in the food and medical industries are constrained by its susceptible fatty acid composition, which is prone to oxidation. In this study, rice bran protein (RBP) was employed as an emulsifier for the fabrication of Acer truncatum Bunge seed oil Pickering emulsion. The impact of antioxidant-phytic acid (PA) on the stability of Pickering emulsion and the underlying mechanisms were further investigated. The findings indicate that PA is capable of interacting with RBP, resulting in a change in its spatial conformation. When the PA concentration was increased from 0 to 0.01 % (w/v), the number of α-helices of RBP-PA particles decreased by 5 %, the number of β-sheets and interfacial adsorbed proteins increased by 2.89 % and 39.83 %. Additionally, and the surface hydrophobicity was increased from 50 ± 3.63 (a.u.) to 429 ± 20.03 (a.u.), and the range of the particle size distribution was reduced from 1 to 10 μm to 295–459 nm, and the zeta potential decreased from −23.43 ± 0.46 mV to −53.4 ± 1.35 mV. The Acer truncatum Bunge seed oil Pickering emulsion, containing 0.01 % PA, exhibits favourable static stability and lipid oxidative stability, allowing for storage at room temperature for a period exceeding 50 days.

ABSTRACT: H9N2 avian influenza virus is a significant poultry pathogen that provides internal genes for multiple zoonotic subtypes of avian influenza, presenting a severe threat to public health. The isolation rate of H9N2 in poultry has increased annually in recent years. In this study, a recombinant Herpesvirus of Turkeys (HVT) vaccine expressing H9-HA was constructed using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. In the construction of HVT-EGFP-HA recombinant virus, nonhomologous end joining (NHEJ) is a much more efficient strategy compare to Homology-directed recombination (HDR). HVT-HA demonstrated stability and consistent replication with the parent strain. Subcutaneous injection and in-ovo injection of HVT-HA induced different levels of immune response. Compared to in-ovo injection of HVT-HA, subcutaneous injection induced significantly higher neutralizing serum antibodies. This finding is supported by the significantly higher CD4+ T cell response in Peripheral blood mononuclear cell Peripheral blood mononuclear cell (PBMC) in the subcutaneous injection group. However, in-ovo injection of HVT-HA resulted in significantly higher neutralizing antibodies in the Harderian glands. In addition, it significantly inhibited viral shedding after intranasal exposure to H9N2. This phenomenon could be attributed to the mucosal immunity present in the Hadrian gland. Thus, our findings indicate that the in-ovo injection of the HVT-HA recombinant vaccine is a promising method to inhibit the transmission of H9N2 via the upper respiratory tract in chickens.

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of cancer pathogenesis, influencing various cellular processes and contributing to tumorigenesis. Sphingolipid metabolism has garnered interest as a potential target for cancer therapy owing to its considerable diagnostic and prognostic value. Recent studies have demonstrated that lncRNAs regulate tumor-associated metabolic reprogramming via sphingolipid metabolism. However, the precise nature of the interactions between lncRNAs and sphingolipid metabolism remains unclear. This review summarizes the key roles of lncRNAs and sphingolipid metabolism in tumorigenesis. We emphasize that the interaction between lncRNAs and sphingolipid metabolism influences their impact on both cancer prognosis and drug resistance. These findings suggest that lncRNA-sphingolipid metabolism interaction holds great potential as a newl target for cancer treatment.

Subcutaneous injection is the preferred route of administration for many antibody therapeutics for reasons that include its speed and convenience. However, the small volume limit (typically [Formula: see text]2 mL) for subcutaneous delivery often necessitates antibody formulations at high concentrations (commonly ≥100 mg/mL), which may lead to physicochemical problems. For example, antibodies with large hydrophobic or charged patches can be prone to self-interaction giving rise to high viscosity. Here, we combined X-ray crystallography with computational modeling to predict regions of an anti-glucagon receptor (GCGR) IgG1 antibody prone to self-interaction. An extensive mutational analysis was undertaken of the complementarity-determining region residues residing in hydrophobic surface patches predicted by spatial aggregation propensity, in conjunction with residue-level solvent accessibility, averaged over conformational ensembles from molecular dynamics simulations. Dynamic light scattering (DLS) was used as a medium throughput screen for self-interaction of ~ 200 anti-GCGR IgG1 variants. A negative correlation was found between the viscosity determined at high concentration (180 mg/mL) and the DLS interaction parameter measured at low concentration (2–10 mg/mL). Additionally, anti-GCGR variants were readily identified with reduced viscosity and antigen-binding affinity within a few fold of the parent antibody, with no identified impact on overall developability. The methods described here may be useful in the optimization of other antibodies to facilitate their therapeutic administration at high concentration.

Plasma homocysteine (Hcy) is an amino acid causing vascular injury. It is closely associated with endothelial cell injury, vascular smooth muscle proliferation, inflammatory responses, thrombosis and vascular calcification. An elevated level of Hcy may affect normal function of renal vasculature and glomeruli, thereby accelerating the progression of chronic kidney disease to end-stage renal disease. In maintenance hemodialysis (MHD) patients, the incidence of hyperhomocysteinemia (HHcy) is 33 folds that of normal individuals so that it becomes a common yet complex health issue. For accurately identifying HHcy and improving patient prognosis, this review summarized the common causes of HHcy in MHD patients and introduced various preventive and therapeutic measures.

Objective: To find a viable alternative to reduce the number of doses required for the patients with post-traumatic stress disorder (PTSD), and to improve efficacy and patient compliance. Methods: In this study, we used ginger oil, a phytochemical with potential therapeutic properties, to prepare ginger oil patches. High-performance liquid chromatography (HPLC) was used to quantify the main active component of ginger oil, 6-gingerol. Transdermal absorption experiments were conducted to optimize the various pressure-sensitive adhesives and permeation enhancers, including their type and concentration. Subsequently, the ginger oil patches were optimized and subjected to content determination and property evaluations. A PTSD mouse model was established using the foot-shock method. The therapeutic effect of ginger oil patches on PTSD was assessed through pathological sections, behavioral tests, and the evaluation of biomarkers such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), and melatonin (MT). Results: The results demonstrated that ginger oil patches exerted therapeutic effects against PTSD by inhibiting inflammatory responses and modulating MT and BDNF levels. Pharmacokinetic experiments revealed that ginger oil patches maintained a stable blood drug concentration for at least one day, addressing the rapid metabolism drawback of 6-gingerol and enhancing its therapeutic efficacy. Conclusions: Ginger oil can be prepared as a transdermal drug patch that meets these requirements, and the bioavailability of the prepared patch is better than that of oral administration. It can improve PTSD with good patient compliance and ease of administration. Therefore, it is a promising therapeutic formulation for the treatment of PTSD.

Abstract Blood flow infections (BSIs) is common occurrences in intensive care units (ICUs) and are associated with poor prognosis. The study aims to identify risk factors and assess mortality among BSI patients admitted to the ICU at Shanghai Ruijin hospital north from January 2022 to June 2023. Additionally, it seeks to present the latest microbiological isolates and their antimicrobial susceptibility. Independent risk factors for BSI and mortality were determined using the multivariable logistic regression model. The study found that the latest incidence rate of BSI was 10.11%, the mortality rate was 35.21% and the mean age of patients with BSI was 74 years old. Klebsiella pneumoniae was the predominant bacterial isolate. Logistic multiple regression revealed that tracheotomy, tigecycline, gastrointestinal bleeding, shock, length of hospital stay, age and laboratory indicators (such as procalcitonine and hemoglobin) were independent risk factors for BSI. Given the elevated risk associated with use of tracheotomy and tigecycline, it underscores the importance of the importance of cautious application of tracheostomy and empirical antibiotic management strategies. Meanwhile, the independent risk factors of mortality included cardiovascular disease, length of hospital stay, mean platelet volume (MPV), uric acid levels and ventilator. BSI patients exhibited a significant decrease in platelet count, and MPV emerged as an independent factor of mortality among them. Therefore, continuous monitoring of platelet-related parameters may aid in promptly identifying high-risk patients and assessing prognosis. Moreover, monitoring changes in uric acid levels may serve as an additional tool for prognostic evaluation in BSI patients.

Objective: To explore the new treatment strategies for radiation proctitis, which is the most common complication of pelvic tumor malignancies. Methods: Four cases of patients with severe radiation proctitis were treated with high-dosage vitamin C (VC, 12–24 ​g/d, iv) combined with cyclooxygenase-2 (cyclooxygenase-2, COX-2) inhibitors. Results: For these four cases, the diarrhea, hematochezia, tenesmus, pain, and other symptoms were significantly improved. The edema of the rectal wall is also significantly improved in the imaging review. Conclusion: The high-dosage VC combined with the treatment of severe radiation proctitis is safe and effective.

ObjectiveThis study compared the effects of Flywheel Resistance Squat Training (FRST) vs. Traditional Resistance Squat Training (TRST) on lower body strength in female collegiate basketball players.MethodsNineteen participants were randomly assigned to either the FRST group (n = 9) or the TRST group (n = 10) through a random number draw. Both groups underwent a 6-week intervention with training sessions conducted twice a week. The FRST group utilized an inertia of 0.075 kg ·m2, while another group trained at 80% of their one-repetition maximum (1RM). Each training session consisted of 4 sets of 8 repetitions with a 3-minute rest between sets. Both groups performed standardized warm-ups and stretches before and after each training session. The effectiveness of the training methods was assessed through the Countermovement Jump (CMJ), Reactive Strength Index (RSI), Eccentric Utilization Ratio, Running Vertical Jump, and 1RM squat.ResultsThe FRST and TRST groups showed differences within groups in both CMJ and 1RM squat (p < 0.01), with the FRST group demonstrating moderate effect sizes in CMJ (Hedges’ g = 0.59) and 1RM (Hedges’ g = 1.01). However, there were no differences between groups (p > 0.05). The Eccentric Utilization Ratio showed a small effect size (p = 0.78; ηp2=0.01). Additionally, Reactive Strength Index and Running Vertical Jump exhibited low test-retest reliability.ConclusionThe two groups did not exhibit a statistically significant difference. Nonetheless, both FRST and TRST demonstrated positive effects on 1RM squat and CMJ performance compared to baseline values for each method. Therefore, flywheel resistance training can be considered an effective alternative to traditional resistance training for enhancing strength levels in female basketball players.

Objective: The purpose of this study was to compare the impact of unilateral (U) and bilateral (B) contrast training on lower limb explosiveness, agility, and balance in college basketball athletes.Methods: Twenty male college basketball players were randomly assigned to either a unilateral group (U, n = 10) or a bilateral group (B, n = 10). Both groups underwent an 8week strength training program, with sessions held twice a week. The unilateral group performed six Bulgarian split squats and ten reverse lunge jump squats, while the bilateral group performed six barbell rear squats and ten double-leg vertical jumps. To comprehensively assess the training effects, the study utilized one-repetition maximum (1RM), countermovement jump (CMJ), 20m sprint, and single-leg hop tests to evaluate explosive power; the 505 and t-test to assess change-of-direction ability; and the Y-balance test (YBT) to evaluate dynamic balance. Paired sample t-tests were used to evaluate within-group changes, and a 2 (pre- and post-) × 2 (experimental and control groups) repeated measures analysis of variance (ANOVA) was used to assess between-group differences.Results: Within-group comparisons indicated that both unilateral and bilateral contrast training significantly improved all performance metrics. Between-group comparisons revealed that bilateral training was superior to unilateral training in improvements in 1RM and CMJ (p > 0.05) (growth rate of 1RM: B: 8.4%, U: 5.15%; growth rate of CMJ: B: 15.63%, U: 6.74%). Unilateral training showed greater improvements in the 20m sprint, dominant leg single-leg hop, YBT left, and YBT right (p > 0.05) (growth rate of 20m sprint: B: 5.43%, U: 10.41%; growth rate of advantage foot touch high: B: 4.56%, U: 9.35%; growth rate of YBT left: B: 3.77%, U: 8.53%; growth rate of YBT right: B: 4.72%, U: 13.8%). Unilateral training also significantly outperformed bilateral training in non-dominant leg single-leg hop, t-test, 505 left, and 505 right improvements (p < 0.05).Conclusion: Unilateral contrast training may offer advantages for enhancing change-of-direction ability and explosive power in the non-dominant leg, and it may also provide benefits for improving short-distance sprinting ability, explosive power in the dominant leg, and dynamic balance. In contrast, bilateral contrast training appears to be more effective for enhancing bilateral explosive power and may be more advantageous for increasing maximal strength.

ABSTRACT The dissemination of antibiotic resistance genes (ARGs) through plasmids is a major mechanism for the development of bacterial antimicrobial resistance. The adaptation and evolution mechanisms of multidrug-resistant (MDR) plasmids with their hosts are not fully understood. Herein, we conducted experimental evolution of a 244 kb MDR plasmid (pJXP9) under various conditions including no antibiotics and mono- or combinational drug treatments of colistin (CS), cefotaxime (CTX), and ciprofloxacin (CIP). Our results showed that long-term with or without positive selections for pJXP9, spanning approximately 600 generations, led to modifications of the plasmid-encoded MDR and conjugative transfer regions. These modifications could mitigate the fitness cost of plasmid carriage and enhance plasmid maintenance. The extent of plasmid modifications and the evolution of plasmid-encoded antibiotic resistance depended on treatment type, particularly the drug class and duration of exposure. Interestingly, prolonged exposure to mono- and combinational drugs of CS and CIP resulted in a substantial loss of the plasmid-encoded MDR region and antibiotic resistance, comparable to the selection condition without antibiotic. By contrast, combinational treatment with CTX contributed to the maintenance of the MDR region over a long period of time. Furthermore, drug selection was able to maintain and even amplify the corresponding plasmid-encoded ARGs, with co-selection of ARGs in the adjacent regions. In addition, parallel mutations in chromosomal arcA were also found to be associated with pJXP9 plasmid carriage among endpoint-evolved clones from diverse treatments. Meanwhile, arcA deletion improved the persistence of pJXP9 plasmid without drugs. Overall, our findings indicated that plasmid-borne MDR region deletion and chromosomal arcA inactivation mutation jointly contributed to co-adaptation and co-evolution between MDR IncHI2 plasmid and Salmonella Typhimurium under different drug selection pressure.IMPORTANCEThe plasmid-mediated dissemination of antibiotic resistance genes has become a significant concern for human health, even though the carriage of multidrug-resistant (MDR) plasmids is frequently associated with fitness costs for the bacterial host. However, the mechanisms by which MDR plasmids and bacterial pairs evolve plasmid-mediated antibiotic resistance in the presence of antibiotic selections are not fully understood. Herein, we conducted an experimental evolution of a large multidrug-resistant plasmid in a Salmonella enterica Typhimurium host under single and combinatorial drug selection pressures. Our results show the adaptive evolution of plasmid-encoded antibiotic resistance through alterations of the MDR region in the plasmid, in particular substantial loss of the MDR region, in response to different positive selections, especially mono- and combinational drugs of colistin and ciprofloxacin. In addition, strong parallel mutations in chromosomal arcA were associated with pJXP9 carriage in Salmonella Typhimurium from diverse treatments. Our results thus highlight promoting the loss of the plasmid’s MDR region could offer an alternative approach for combating plasmid-encoded antibiotic resistance.

ObjectiveThis meta-analysis examines the impact of different combinations of plyometric training (complexity, training volume, and rest intervals) on immediate vertical jump and sprint performance in athletes.MethodsA systematic search was conducted in four databases, and Cochrane guidelines were used to evaluate the quality of included studies. Review Manager 5.4 software was employed to analyze outcome measures. Nineteen randomized controlled trials involving 293 participants were included.ResultsSingle plyometric training-induced post-activation potentiation (PAP) had a slight positive effect on vertical jump performance [SMD = −0.24, 95% CI (−0.38, −0.1), P = 0.0009]. Optimal results were observed with rest intervals of 0.3–4 min (SMD = 0.30, P = 0.0008). Sprint performance showed slight improvement [SMD = 0.27, 95% CI (0.03, 0.52), P = 0.03]. Complex plyometric training had a moderate effect on vertical jump performance [SMD = 0.58, 95% CI (−0.86, −0.23), P = 0.002], with the best outcomes seen with rest intervals exceeding 8 min (SMD = 0.77). Sprint performance also improved significantly [SMD = 0.8, 95% CI (0.01, 1.59), P = 0.05]. Single-session plyometric training did not significantly enhance vertical jump performance [SMD = −0.19, 95% CI (−0.41, −0.02), P = 0.07], but had a notable effect on sprint performance [SMD = 0.8, 95% CI (0.01, 1.59), P = 0.05], particularly with rest intervals exceeding 8 min (SMD = 0.77). Multiple-session plyometric training improved vertical jump (SMD = 0.43, 95% CI [0.01, 1.59), P = 0.00001 < 0.05], with optimal effects observed at rest intervals of 5–7 min (SMD = 0.64). Sprint performance also improved [SMD = 0.46, 95% CI (0.01, 0.81), P = 0.01 < 0.05].ConclusionPlyometric training as an activation method has significant enhancing effects, depending on training complexity, volume, and rest intervals.

Walnut dreg protein hydrolysates (WDPHs) exhibit a variety of biological activities, however, the cyclooxygenase-2 (COX-2) inhibitory peptide of WDPHs remain unclear. The aim of this study was to rapidly screen for such peptides in WDPHs through a combination of in silico and in vitro analysis. In total, 1262 peptide sequences were observed by nano liquid chromatography/tandem mass spectrometry (nano LC-MS/MS) and 4 novel COX-2 inhibitory peptides (AGFP, FPGA, LFPD, and VGFP) were identif ied. Enzyme kinetic data indicated that AGFP, FPGA, and LFPD displayed mixed-type COX-2 inhibition, whereas VGFP was a non-competitive inhibitor. This is mainly because the peptides form hydrogen bonds and hydrophobic interactions with residues in the COX-2 active site. These results demonstrate that computer analysis combined with in vitro evaluation allows for rapid screening of COX-2 inhibitory peptides in walnut protein dregs.

Abstract Background Community medical institutions play a vital role in China’s healthcare system. While the number of these institutions has increased in recent years, their construction contents remain insufficient. The potential of community medical institutions in preventing, screening, diagnosing, and treating non-communicable chronic diseases (NCDs) has not been fully utilized. This study aims to assess the status of construction contents in community medical institutions in Southwest China and examine how these contents influence the medical choices of NCD patients. Methods Descriptive statistics were used to evaluate the construction content of community medical institutions. Multiple-sets of multinomial logistic regression were employed to analyze the associations and marginal impacts between construction content and medical choices. Shapley value analysis was applied to determine the contribution and ranking of these impacts. Results Descriptive statistics revealed satisfactory construction contents in community medical institutions. Notably, factors such as service attitude, nursing services, expert consultations, charging standards, medical equipment, medical examinations, privacy protection, and referrals significantly influenced medical choices. Among these, service attitude, charging standards, and privacy protection had the most significant marginal improvement effects on NCD patients’ choices, with improvements of 12.7%, 10.2%, and 5.9%, respectively. The combined contribution of privacy protection, medical examinations, service attitude, charging standards, and nursing services to medical choices exceeded 80%. Conclusion Optimizing the service contents of community institutions can encourage NCD patients to seek medical care at grassroots hospitals. This study addresses crucial gaps in existing literature and offers practical insights for implementing new medical reform policies, particularly in underdeveloped regions of Southwest China focusing on hierarchical diagnosis and treatment.

Abstract Background Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. Methods We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. Results Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. Conclusions We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

Abstract Defence against pathogens relies on intracellular nucleotide-binding, leucine-rich repeat immune receptors (NLRs) in plants. Hormone signaling including abscisic acid (ABA) pathways are activated by NLRs and play pivotal roles in defence against different pathogens. However, little is known about how hormone signaling pathways are activated by plant immune receptors. Here, we report that a plant NLR Sw-5b mimics the behavior of the ABA receptor and directly employs the ABA central regulator PP2C-SnRK2 complex to activate an ABA-dependent defence against viral pathogens. PP2C4 interacts with and constitutively inhibits SnRK2.3/2.4. Behaving in a similar manner as the ABA receptor, pathogen effector ligand recognition triggers the conformational change of Sw-5b NLR that enables binding to PP2C4 via the NB domain. This receptor-PP2C4 binding interferes with the interaction between PP2C4 and SnRK2.3/2.4, thereby releasing SnRK2.3/2.4 from PP2C4 inhibition to activate an ABA-specific antiviral immunity. These findings provide important insights into the activation of hormone signaling pathways by plant immune receptors.

Alternative splicing of ddx4 (DEAD-box helicase 4), a key germline marker gene, has been reported to generate sex-specific transcripts in zebrafish gonads. The biological functions and regulatory mechanisms of the ddx4 ovary-specific transcript (ddx4-L) during oogenesis remain unclear. In this study, we found that ddx4-L mutants, in which ddx4-L was specifically deleted, had enlarged ovaries but laid fewer eggs, along with having a lower fertilization rate compared to WT controls. RNA-seq analysis was performed to detect the changes in gene expression between WT and ddx4-L mutant ovaries. A total of 524 upregulated and 610 downregulated DEGs were identified. GO and GSEA enrichment analyses showed that genes involved in fertilization and reproduction biological processes were significantly downregulated. More specifically, we observed a remarkable reduction in Sycp1, a core component of synaptonemal complex, in ddx4-L mutant ovaries at both the mRNA and protein levels. In addition, the expressions of transposon elements, as well as the events of alternative splicing, alternative polyadenylation, and RNA editing, were analyzed based on the RNA-seq data. We found that the deletion of ddx4-L resulted in derepression of DNA transposons in zebrafish ovaries, possibly causing genome instability. In conclusion, our work demonstrates that the ovary-specific ddx4 transcript plays important roles in oocyte meiosis and DNA transposon repression, which extends our understanding of the biological functions and regulatory mechanisms of sex-specific alternative splicing in zebrafish oogenesis and reproduction.

Abstract N‐methyl‐D‐aspartate receptor (NMDAR)‐positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE‐718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first‐in‐human, phase I, double‐blind, dose‐finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single‐ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple‐ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open‐label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once‐daily dosing. Following single and multiple doses in healthy participants, median terminal half‐life was 8–118 h, and the median time to reach maximum plasma concentration was 4–7 h. Exposures were dose‐proportional after single dose (6–46 ng/mL) and more than dose‐proportional after multiple doses (6–41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.

Improving the nutrient content of red soils in southern China is a priority for efficient rice production there. To assess the effectiveness of oilseed rape as green manure for the improvement of soil phosphorus nutrient supply and rice yield in red soil areas, a long-term field plot experiment was conducted comparing two species of rape, Brassica napus (BN) and Brassica juncea (BJ). The effects of returning oilseed rape on soil phosphorus availability, phosphorus absorption, and yield of subsequent rice under rice–green manure rotation mode were analyzed, using data from the seasons of 2020 to 2021. The study found that compared with winter fallow treatment (WT) and no-tillage treatment (NT), the soil available phosphorus content of BN was increased, and that of BJ was significantly increased. The content of water-soluble inorganic phosphorus of BJ increased, and that of BN increased substantially. Compared with the WT, the soil organic matter content and soil total phosphorus content of BN significantly increased, as did the soil available potassium content of BJ, and the soil total phosphorus content of BJ was significantly increased compared with NT. The soil particulate phosphorus content of BJ and BN was significantly increased by 14.00% and 16.00%, respectively. Compared with the WT, the phosphorus activation coefficient of BJ was significantly increased by 11.41%. The rice plant tiller number under the green manure returning treatment was significantly increased by 43.16% compared with the winter fallow treatment. The green manure returning measures increased rice grain yield by promoting rice tiller numbers; BN increased rice grain yield by 9.91% and BJ by 11.68%. Based on these results, returning oilseed rape green manure could augment the phosphorus nutrients of red soil and promote phosphorus availability. Rice–oilseed rape green manure rotation could increase rice grain yield.

ABSTRACT Salmonella 4,[5],12:i:-, a monophasic variant of Salmonella Typhimurium, has emerged as a global cause of multidrug-resistant salmonellosis and has become endemic in many developing and developed countries, especially in China. Here, we have sequenced 352 clinical isolates in Guangdong, China, during 2009–2019 and performed a large-scale collection of Salmonella 4,[5],12:i:- with whole genome sequencing (WGS) data across the globe, to better understand the population structure, antimicrobial resistance (AMR) genomic characterization, and transmission routes of Salmonella 4,[5],12:i:- across Guangdong. Salmonella 4,[5],12:i:- strains showed broad genetic diversity; Guangdong isolates were found to be widely distributed among the global lineages. Of note, we identified the formation of a novel Guangdong clade (Bayesian analysis of population structure lineage 1 [BAPS1]) genetically diversified from the global isolates and likely emerged around 1990s. BAPS1 exhibits unique genomic features, including large pan-genome, decreased ciprofloxacin susceptibility due to mutation in gyrA and carriage of plasmid-mediated quinolone resistance (PMQR) genes, and the multidrug-resistant IncHI2 plasmid. Furthermore, high genetic similarity was found between strains collected from Guangdong, Europe, and North America, indicating the association with multiple introductions from overseas. These results suggested that global dissemination and local clonal expansion simultaneously occurred in Guangdong, China, and horizontally acquired resistance to first-line and last-line antimicrobials at local level, underlying emergences of extensive drug and pan-drug resistance. Our findings have increased the knowledge of global and local epidemics of Salmonella 4,[5],12:i:- in Guangdong, China, and provided a comprehensive baseline data set essential for future molecular surveillance.IMPORTANCESalmonella 4,[5],12:i:- has been regarded as the predominant pandemic serotype causing diarrheal diseases globally, while multidrug resistance (MDR) constitutes great public health concerns. This study provided a detailed and comprehensive genome-scale analysis of this important Salmonella serovar in the past decade in Guangdong, China. Our results revealed the complexity of two distinct transmission modes, namely global transmission and local expansion, circulating in Guangdong over a decade. Using phylogeography models, the origin of Salmonella 4,[5],12:i:- was predicted from two aspects, year and country, that is, Salmonella 4,[5],12:i:- emerged in 1983, and was introduced from the UK, and subsequently differentiated into the local endemic lineage circa 1991. Additionally, based on the pan-genome analysis, it was found that the gene accumulation rate in local endemic BAPS 1 lineage was higher than in other lineages, and the horizontal transmission of MDR IncHI2 plasmid associated with high resistance played a major role, which showed the potential threat to public health.

Seven samples of Wuyi rock tea (cv. Shuixian) stored for different times (0, 5, 10, 15, 20, 25, and 30 years) were collected to investigate the effect of storage time on the flavor quality of Wuyi rock tea by the combined use of sensory evaluation, non-volatile and volatile composition analysis and chemometrics methods. The results showed that the transformation of the flavor quality of Wuyi rock tea during storage was divided into three stages: 0–5, 10–15, and 20–30 years. As the storage time increased, the taste gradually transformed from mellow to stale, and a sour taste appeared at the middle stage of storage and then faded away at the late stage. The aroma gradually changed from flowery and fruity to aged, woody and herbal. A significant decrease in the content of tea polyphenols, catechins-like and theaflavins and an increase in the content of soluble sugars were the major reasons for the taste changes. Changes in the contents of 15 characteristic volatiles, including indole, trans-nerolidol, dihydroactinidiolide, hotrienol, α-terpineol, methyl salicylate, β-ionone, and (Z)-hexanoic acid-3-hexenyl ester, were the key factors affecting the aroma changes. This study provides a scientific reference for the storage and consumption of Wuyi rock tea.

Abstract For 800 Gbps/λ and beyond optical transmission systems, frequency-dependent impairments (FDI) degrade coherent optical transceiver (CO-TRx) performance severely. Calibration and compensation of such FDI in factories includes amplitude/phase frequency response (AFR/PFR), skew, and ripple for both transmitters(Tx) and receivers (Rx). However, due to the polarization rotation and phase rotation effects in optical link, the separation and extraction of FDI from different polarization or I/Q tributaries is challenging. Here we report a FDI calibration method based on orthogonal separation scheme and frequency domain analysis. The proposal can simultaneously characterize and separate the Tx/Rx sides FDI including AFR, PFR, and time skew of four tributaries. Finally, the effectiveness is demonstrated by transmitting a 96 GBuad Nyquist-16QAM signal on a 64 GBaud-class CO-TRx.

Abstract Hereditary predisposition play an important role in thrombosis, especially in younger patients. Here we studied a young patient who experienced three different episodes of severe thromboses, some of which were life-threatening (pulmonary artery thrombosis, portal and mesenteric vein thrombosis, and arterial thrombosis of the lower leg). Blood levels of clotting related indicators were assessed. We screened 35 genes linked to thrombosis. We discovered a 756 kb duplication that spanned the F9 gene in region q27.1 of the X chromosome. The repeat includes the full F9 gene, thus, the patient had two functional copies of FIX with the FIX activity 192%. An identical repetition was found in the patient’s mother. Both the patient and his mother had high, but variable, plasma FIX activities that promote coagulation. The patient’s frequent, severe thrombolic events maybe attributed to the duplication of a big portion of the F9 gene and lupus anticoagulant positive.

Abstract Intercropping has the potential to improve plant nutrition as well as crop yield. However, the exact mechanism promoting improved nutrient acquisition and the role the rhizosphere microbiome may play in this process remains poorly understood. Here, we use a peanut/maize intercropping system to investigate the role of root-associated microbiota in iron nutrition in these crops, combining microbiome profiling, strain and substance isolation and functional validation. We find that intercropping increases iron nutrition in peanut but not in maize plants and that the microbiota composition changes and converges between the two plants tested in intercropping experiments. We identify a Pseudomonas secreted siderophore, pyoverdine, that improves iron nutrition in glasshouse and field experiments. Our results suggest that the presence of siderophore-secreting Pseudomonas in peanut and maize intercropped plays an important role in iron nutrition. These findings could be used to envision future intercropping practices aiming to improve plant nutrition.

Phospholipase C zeta (PLCζ) is a key sperm-borne oocyte-activating factor that triggers Ca2+ oscillations and the subsequent block to polyspermy following gamete fusion. Mutations in PLCZ1, the gene encoding PLCζ, cause male infertility and intracytoplasmic sperm injection (ICSI) fertilization failure; and PLCζ expression and localization patterns are significantly correlated with ICSI fertilization rate (FR). However, in conventional in vitro fertilization (cIVF), whether and how sperm PLCζ affects fertilization remain unclear. Herein, we identified one previously reported and two novel PLCZ1 mutations associated with polyspermy in vitro that are characterized by excessive sperm–zona binding and a delay in pronuclei (PN) formation. Immunofluorescence staining and oocyte activation testing revealed that virtually all spermatozoa from patients lacked functional PLCζ and were thus unable to evoke Ca2+ oscillations. ICSI with an artificial oocyte activation treatment successfully rescued the polyspermic phenotype and resulted in a live birth. Furthermore, we analyzed PLCζ in an additional 58 males after cIVF treatment in the Reproductive and Genetic Hospital of CITIC-Xiangya (Changsha, China) between February 2019 and January 2022. We found that the proportion of spermatozoa that expressed PLCζ was positively correlated with both 2PN rate and total FR. The optimal cutoff value below which males were likely to experience low FR (total FR ≤30%) after cIVF was 56.7% for the proportion of spermatozoa expressing PLCζ. Our study expands the mutation and the phenotypic spectrum of PLCZ1 and further suggests that PLCζ constitutes a promising biomarker for identifying low FRs cases in cIVF due to sperm-related oocyte activation deficiency and that sperm PLCζ analysis may benefit the wider male population and not only men with ICSI failure.

We hypothesized that the respiratory exercises have uniform effects on ventilation in healthy subjects but the effects varied in patients with chronic obstructive pulmonary disease (COPD). In this study, a total of 30 healthy volunteers and 9 patients with COPD were included. Data were recorded continuously during (1) diaphragmatic breathing; (2) pursed lip breathing with full inhalation; (3) pursed lip combining diaphragmatic breathing. The sequence of the three breathing exercises was randomized using machine generated random permutation. Spatial and temporal ventilation distributions were evaluated with electrical impedance tomography. Results showed that, tidal volume was significantly larger during various breathing exercises compared to quiet tidal breathing, in both healthy and COPD (p

Beryllium is a lightweight metal that is toxic to humans. The critical health effects related to beryllium exposure are liver toxicity, immune system toxicity, and chronic beryllium disease (CBD). This study investigated the effects of occupational beryllium exposure on liver and lung function and hematologic parameters among beryllium smelter workers. A cross-sectional study was performed by comparing 65 exposed workers and 34 non-exposed workers. Health information was collected through questionnaire surveys and biochemical tests. The concentration of urinary beryllium was determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The findings indicated that the urinary beryllium levels of the exposed workers and the controls were 0.48 (0.115, 1.19) μg/mL and 0.0125 (0.005, 0.005) μg/mL, respectively (p < 0.001). Compared with the controls, the exposed workers showed a significant increase in serum alanine aminotransferase (ALT) level, hemoglobin (HGB) concentration, white blood cell (WBC) count, red blood cell (RBC) count, and systolic and diastolic blood pressure (SBP, DBP) (p < 0.05). Furthermore, the HGB concentration and ALT level were significantly correlated with the concentration of beryllium in urine (p < 0.05). The exposed workers had increased urinary concentrations of beryllium, in contrast to the control subjects. Moreover, the urinary beryllium levels among the exposed workers are much higher than that in the Chinese general population. Beryllium-exposed workers may be at risk of liver and hematologic impairments.

Abstract Frequency control is considered to be an important function of multi‐terminal HVDC (MTDC) systems. Sharing frequency containment reserves (FCRs) among interconnected AC systems using HVDC technology is particularly attractive in the European context. However, coordination of the contribution between systems with different sizes, quality requirements, and dynamic characteristics requires harmonized rules and well‐defined control strategies. If the controllers are not properly designed, they can lead to disproportional supports, noncompliance with the existing regulation framework, or even degradation of the frequency quality. This paper presents a general analytical methodology for assessing the compliance of MTDC grid control solutions to the essential requirements of the FCR framework, and then examines three different implementation solutions as illustrative examples to validate the method. Through this process, the interaction mechanisms behind each solution are analytically clarified. The performance analyses are then confirmed using load‐frequency models of CE, Nordic, and GB systems coupled with a three‐terminal DC system. It is revealed that, while certain control solutions result in insufficient performance with respect to the desired FCR provision, the newly proposed distributed solution for each pair of converters is the most compliant with the existing framework thanks to the highest degrees of freedom.

Impaired differentiation of megakaryocytes constitutes the principal etiology of thrombocytopenia. The signal transducer and activator of transcription 3 (STAT3) is a crucial transcription factor in regulating megakaryocyte differentiation, yet the precise mechanism of its activation remains unclear. PALLD, an actin-associated protein, has been increasingly recognized for its essential functions in multiple biological processes. This study revealed that megakaryocyte/plateletspecific knockout of PALLD in mice exhibited thrombocytopenia due to diminished platelet biogenesis. In megakaryocytes, PALLD deficiency led to impaired proplatelet formation and polyploidization, ultimately weakening their differentiation for platelet production. Mechanistic studies demonstrated that PALLD bound to STAT3 and interacted with its DNA-binding domain (DBD) and Src homology 2 (SH2) domain via Immunoglobulin domain 3 (Ig3). Moreover, the absence of PALLD attenuated STAT3 Y705 phosphorylation and impeded STAT3 nuclear translocation. Based on the PALLD-STAT3 binding sequence, we designed a peptide C-P3, which can facilitate megakaryocyte differentiation and accelerate platelet production in vivo. In conclusion, this study highlights the pivotal role of PALLD in megakaryocyte differentiation and proposes a novel approach for treating thrombocytopenia by targeting the PALLD-STAT3 interaction.

Objective In this article, we investigate how chronic noncommunicable disease (CND) patients evaluate the medical service, and what obstacles exist in this process, which is useful for hospitals to improve efficiency and enhance patient satisfaction. Methods Based on the total number of CND patients in China, 7 CNDs were selected as the evaluation objects, and then selected the Haodaifu website as the data source, crawled 15,682 medical service reviews, then the 9 themes were analyzed by the LDA theme model. The evaluation index system of six indicators was constructed based on quality management theory. The binary long short-term memory model was used to analyze the sentiment, and the entropy-valued, TOPSIS and gray correlation model was implemented for medical service quality evaluation; the barrier model was used to find out the key factors limiting medical services. Results (a) Hypertension was rated at a good level in the degree of gray correlation closeness, bronchitis was rated at a low level and the rest were at an intermediate level. (b) The first two overall barriers were the hospitalization process and registration services which occupy about 30%, respectively. This implies that hospitals should focus on providing registration services and inpatient settings in the future. Conclusion To promote hospitals to provide better services for patients with CNDs and improve patient satisfaction with medical care. And it is necessary to optimize medical services fundamentally by optimizing the inpatient process and improving the registration process to improve efficiency.