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Ustekinumab biosimilars have expanded treatment options for moderate-to-severe plaque psoriasis, but pooled evidence is needed to determine whether they achieve therapeutic equivalence to reference ustekinumab during the initial randomized comparative period before protocol-defined switching. The aim of this systematic review was to assess the therapeutic equivalence of ustekinumab biosimilars versus reference ustekinumab during the pre-switch period in adults with moderate-to-severe plaque psoriasis. We searched PubMed, Embase, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and trial registries from inception to 15 October 2025 for phase III randomized clinical trials comparing ustekinumab biosimilars or follow-on biologics with reference ustekinumab and reporting comparative data before switching. Data were extracted independently by two reviewers. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random-effects meta-analysis with Hartung-Knapp-Sidik-Jonkman 95% confidence intervals (CIs) was performed. The primary outcome was 75% improvement in Psoriasis Area and Severity Index (PASI 75) response at week 12, analyzed using risk differences with a prespecified equivalence margin of ± 10%. Nine randomized trials including 4532 participants were analyzed. At week 12, the pooled risk difference for PASI 75 was 0.02 (95% CI -0.02 to 0.05), meeting the prespecified ± 10% equivalence criterion, with low between-study heterogeneity (I2 statistic = 6%). Equivalence-consistent estimates were also observed for PASI 90 (risk difference - 0.01, 95% CI - 0.06 to 0.03) and PASI 100 (risk difference 0.00, 95% CI - 0.03 to 0.03). Treatment-emergent adverse events were comparable through week 28 (risk difference 0.01, 95% CI - 0.04 to 0.06). At week 12, anti-drug antibody detection was lower in biosimilar arms (risk difference - 0.14, 95% CI - 0.23 to - 0.04), which may partly reflect assay variability rather than clinically meaningful differences. No material differences were observed in short-term pre-switch clinical response, patient-reported quality of life, or safety. During the initial randomized comparative period, ustekinumab biosimilars met prespecified therapeutic equivalence criteria for PASI 75 and showed equivalence-consistent results for PASI 90 and PASI 100, with comparable short-term safety versus reference ustekinumab. These findings provide pooled reassurance across standard and stringent skin-clearance outcomes during a clinically relevant early treatment window. PROSPERO (CRD420251166323). Registered October 12, 2025. Plaque psoriasis is a long-term inflammatory skin disease that affects millions of people worldwide. Although biologic treatments such as ustekinumab are effective, their high cost can limit patient access. Biosimilars are medicines designed to be highly similar to original biologic products. In this study, we combined results from nine clinical trials involving 4532 participants to compare ustekinumab biosimilars with the reference medicine. We focused on the first 12 weeks of treatment to allow a direct comparison before any planned treatment changes or switching occurred. Our analysis showed that biosimilars and the reference medicine produced very similar results for skin improvement, including both standard and more demanding levels of clearance. Short-term safety results were also similar between groups. Although antibody detection was lower in patients receiving biosimilars, this did not lead to differences in efficacy or safety. Overall, these findings suggest that ustekinumab biosimilars perform similarly to the reference medicine during the initial treatment period and may help support their clinical use and improve access to these therapies.
The Global Lung Function Initiative (GLI) has recently introduced race-neutral reference equations for pulmonary function tests, replacing traditional ethnic-specific equations. However, the clinical impact of this transition in Northeast Asian patients with idiopathic pulmonary fibrosis (IPF) remains unclear. We evaluated the implications of switching from the ethnic-specific equations to the race-neutral GLI equations in 903 Korean patients newly diagnosed with IPF between 2005 and 2020. Per cent predicted values of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) were calculated using both equations and used to derive the baseline gender-age-physiology (GAP) index scores. We then compared the prognostic performance of GAP staging derived from each equation in predicting all-cause mortality. Additionally, we assessed the clinical impacts of 1-year absolute declines in FVC and DLCO % predicted, as determined by each equation. The race-neutral GLI equations yielded higher FVC % predicted and lower DLCO % predicted values compared with the ethnic-specific equations, resulting in GAP stage reclassification in 203 of 903 patients (22.5%), predominantly toward lower stages. Despite these differences, the agreement in GAP staging between the two equations was substantial (Cohen's kappa 0.628) and their predictive performance for mortality did not significantly differ (C-index 0.686 vs 0.684; p=0.598). One-year absolute declines in FVC and DLCO % predicted were similarly associated with increased mortality, regardless of reference equation used. In Northeast Asian patients with IPF, race-neutral GLI equations resulted in reclassification of GAP stage for some patients but did not affect the overall prognostic performance of the GAP index in predicting mortality.
The King Ratsnake (Elaphe carinata), a widely distributed non-colubrine snake in East Asia, exhibits a remarkable capacity for broad-spectrum venom resistance, enabling it to prey on other snakes, including lethal viperid and elapid species. Despite its ecological and physiological significance, the genetic basis of this trait remains largely unknown. Here, we present a chromosome-level genome assembly of E. carinata, generated using PacBio HiFi long-read sequencing, Illumina short-read data, and RNA-seq-supported by a synteny-based scaffolding approach using the closely related Elaphe schrenckii. The 1.62 Gb assembly (contig N50 = 2.77 Mb, scaffold N50 = 143.07 Mb) achieves 97.3% BUSCO completeness, with over 90% of sequences anchored into 18 pseudochromosomes. Repetitive sequences account for 53.19% of the genome, with LINE elements being the most abundant. We annotated 19,750 protein-coding genes, of which 99.2% were functionally assigned using integrated evidence from homology, transcriptomics, and ab initio predictions. This high-quality genomic resource provides a foundation for exploring colubrid evolution, venom resistance mechanisms, and the development of novel antivenom therapies.
This study aimed to establish Diagnostic criteria for kidney Yang deficiency syndrome in male infertility(referred to as "this criteria"). A preliminary questionnaire item pool was constructed through literature retrieval, in combination with male infertility-related textbooks, existing national standards, guidelines, and expert consensus documents, as well as expert interviews and group discussions. Two rounds of questionnaire surveys were conducted using the Delphi method to standardize the diagnostic criteria item pool and complete item supplementation and screening. Expert questionnaires were collected using the analytic hierarchy process(AHP) to statistically determine item weights and diagnostic thresholds. Finally, a diagnostic test was conducted by enrolling 105 participants to evaluate the diagnostic criteria, with sensitivity, specificity, accuracy, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio used as indicators of diagnostic efficacy at the established threshold. Based on the results of expert discussions, this criteria was established. After systematic literature screening, 66 articles were included. By incorporating textbooks, national standards, and consensus documents, all items were summarized, merged, and classified, resulting in an initial diagnostic criteria item pool of 39 items. The first round of the Delphi method retained 29 important items, and the second round retained 18 important items. AHP identified three levels of item weights, i.e., high, medium, and low. The primary symptoms for diagnosing kidney Yang deficiency syndrome in MI were finally determined as aversion to cold, soreness and weakness of the lower back and knees, a pale and swollen tongue, and a thin white tongue coating. The secondary symptoms were decreased libido, cold sensation in the lower abdomen or genital region, increased nocturnal urination, and a deep and weak pulse or a deep and slow pulse. Patients presenting all primary symptoms were diagnosed with this syndrome; patients presenting two primary symptoms together with any two manifestations from the secondary symptoms, physical signs, or pulse conditions were also diagnosed with this syndrome. After establishment of this criteria, 105 MI patients from the Department of Andrology, Xiyuan Hospital of China Academy of Chinese Medical Sciences were enrolled. Eligible participants were diagnosed using both the evaluated this criteria and the reference diagnostic criteria. The diagnostic efficacy of this criteria showed a sensitivity of 0.91, specificity of 0.88, and accuracy of 0.89. This study established Diagnostic criteria for kidney Yang deficiency syndrome in male infertility and completed clinical validation, providing a reference basis for the clinical diagnosis of MI with kidney Yang deficiency syndrome.
We aimed to explore the population pharmacokinetics and pharmacodynamics (popPK/PD) of ciprofol in paediatric patients and to provide references for dose optimisation of ciprofol as initiation and maintenance dosages in paediatric patients. Anaesthesia was induced with ciprofol at doses of 0.6 mg kg-1 or 0.9 mg kg-1 in paediatric patients (n=88; 0.08-15 yr; weight, 4.2-71.0 kg) undergoing cardiac or thoracic surgery. Blood samples were collected using opportunistic blood sampling, and ciprofol concentration was determined by a validated analytical method. A popPK/PD model of ciprofol was developed. The relationship between bispectral index (BIS) and drug concentration was characterised by an effect compartment model in children younger than 3 yr of age. A two-compartment model with body weight and an empirical maturation process as covariates optimally characterised ciprofol PK. The recommended induction dose was 0.6 mg kg-1. Maintenance of anaesthesia which targeted an optimal BIS range of 40-60 using simulation-based, weight-stratified infusion regimens was recommended as follows: 1.4 mg kg-1 h-1 for patients weighing 0-5 kg, 1.2 mg kg-1 h-1 for those weighing 5-30 kg, and 1.0 mg kg-1 h-1 for patients weighing >30 kg, with escalation to higher doses only under continuous BIS monitoring to avoid oversedation. A ciprofol induction dose of 0.6 mg kg-1 followed by a weight-stratified maintenance infusion of 1.0-1.4 mg kg-1 h-1 is recommended for paediatric anaesthesia. Extrapolation to children 3 yr of age and older assumed similarity in PD response, and potential inaccuracy in this age group is cautioned. ChiCTR2600118090.
To assess the prevalence of Mycobacterium tuberculosis infection among foreign-born individuals entering prison and to evaluate the performance of the tuberculin skin test (TST) in vaccinated individuals (Bacillus Calmette-Guérin vaccine, BCG), using interferon gamma release assays (IGRAS) as the reference standard. We conducted a prospective observational study including foreign-born individuals admitted to prisons in Catalonia (Spain) between 1 March 2023 and 30 June 2023. A TST was performed if there was no prior positive TST or prior TB infection, or if the TST was negative for more than 1 year. Current TB was excluded by clinical and radiological evaluation. BCG vaccination status was assessed using medical records, identification of a vaccination scar, and the BCG World Atlas. TST positivity was analysed according to BCG vaccination status. Among BCG-vaccinated individuals with a positive TST, IGRA results were used to estimate the positive predictive value (PPV) of the TST overall and by TST induration diameter. Among 1075 foreign-born individuals admitted during the study period, 32 (3.0%) had a previous diagnosis of active TB. Of the remaining 1043, 86.4% were classified as BCG-vaccinated. Overall, 45.2% had a positive TST, with no significant difference between vaccinated individuals and unvaccinated individuals (46.1% vs. 39.9%; p = 0.08). Among BCG-vaccinated individuals with a positive TST, IGRA testing was performed in 71%, yielding an overall TST PPV of 65%. The PPV increased with induration diameter, from 51.6% (10-14 mm) to 81.8% (≥ 20 mm). Foreign-born individuals entering prison show a high prevalence of M. tuberculosis infection. In BCG-vaccinated individuals, the TST shows limited predictive value, particularly at lower induration thresholds. While further studies are needed, these findings support the preferential use of IGRA-based strategies for LTBI screening in this setting.
Rapid and accurate assessment of bacterial concentration is essential, yet conventional methods remain constrained by low detection sensitivity at low concentrations with long processing times. Optical density (OD₆₂₅) measurements report a detection sensitivity value of approximately of 93% for high concentrations of [Formula: see text] CFU/mL. Plate count assays under similar bacteria parameters exhibit 62% and require > 24 h for incubation and colony enumeration. In this study, we introduce the dielectrophoretic (DEP)-based crossover frequency (fx0 ) method as a quantitative, frequency-based metric for rapid bacterial concentration assessment, varying concentrations of initial, 1:10, 1:100, and 1:1000 representing bacteria parameter of [Formula: see text]. The initial concentration, 1.5 × 10⁸ CFU mL, yielded an OD₆₂₅ of 0.12, an average plate count of 320 CFU, and an fx0 of 4.5 MHz, corresponding to the densest bacterial population. At a 1:10 concentration, these values decreased to OD₆₂₅ = 0.08, 220 CFU, andfx0 = 3.23 MHz. Further dilution to 1:100 concentration yielded OD₆₂₅ = 0.05, 186 CFU, and fx0 = 2.50 MHz, while the most dilute sample at 1:1000 concentration showed OD₆₂₅ = 0.011, 80 CFU, and fx0 = 0.71 MHz, reflecting reduced cell density and conductivity. Detection sensitivity analysis from the response normalization equation for OD₆₂₅, plate count, and fx0 experimental achieved values of 53.6%, 59.15%, and 60.69%, respectively. Based on the increasing trend of OD₆₂₅, plate count, and DEP-based fx0 values with respect to each method, we plotted a linear fit , OD₆₂₅ (R2 = 0.963), plate count (R2 = 0.949) and DEP-based fx0 (R2 = 0.981). The plotted line serves as a reference for the expected values of OD₆₂₅, plate count, and DEP-based fx0 at the selected medium conductivity (σₘ) for the following evaluation tests. We introduced high σₘ values of 0.8 S/m, 0.6 S/m, 0.4 S/m, and 0.2 S/m, and low σₘ values of 0.08 S/m, 0.06 S/m, 0.04 S/m, and 0.02 S/m in the evaluation test to observe the deviation between the plotted line of the expected trend and the actual measured values. We calculated the deviations between expected and measured values and produced a mean deviation of 116% for OD₆₂₅, 49% for plate count, and 60% for DEP-based fx0 with p < 0.05, indicating a strong linear relationship between expected values and actual values measured of every method, thus demonstrating trend agreement within the tested conductivity range, while also revealing nonlinear deviations at elevated conductivity. This paper aims to study the correlation between DEP-based fx0 OD₆₂₅ and plate count by assessing the detection sensitivity value of each method, reliability, and evaluation based on linear regression of expected and measured values under the same experimental conditions for Staphylococcus aureus concentration assessment. The results showed that DEP-based fx0 was potentially superior in detection sensitivity, with a conductivity-associated correlation based on linear regression analysis.
This study adopted an integrated strategy combining serum transitional component screening, network pharmacology prediction, and animal experiment verification to systematically explore the core active components and mechanism of action of Yinxing Yangnao Formula(YYF) in the treatment of vascular dementia(VD), aiming to provide solid experimental evidence for the modernization of this classical TCM prescription. With the use of ultra-high performance liquid chromatography-Orbitrap high-resolution mass spectrometry(UPLC-Orbitrap-HRMS), a total of 97 chemical components were identified from the YYF extract by combining accurate mass-to-charge ratio, characteristic fragmentation ions of MS/MS, comparison with reference standards, and matching with literature databases. Furthermore, 27 serum transitional components were captured through the analysis of YYF-containing serum from rats, which were inferred as the key material basis for the in vivo pharmacodynamic effects of YYF. The potential targets of the serum transitional components were predicted using the SwissTargetPrediction database, and VD-related disease targets were screened from authoritative databases including GeneCard, OMIM, and GEO with the keyword dementia vascular. A total of 275 common targets were obtained with the Jvenn online tool. The "drug-component-target-disease" network was constructed using Cytoscape 3.9.1 software, and core active components such as isoscopoletin, jaceosidin, catalpol, senkyunolide F, and bilobalide were screened out. The protein-protein interaction(PPI) network was constructed via the STRING database, identifying key regulatory targets including the phosphatidylinositol 3-kinase family, sarcoma, protein tyrosine phosphatase, non-receptor type 11, Janus kinase 2, and protein tyrosine kinase 2. Gene Ontology(GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis revealed that the core targets were mainly enriched in biological processes such as oxidative stress, neurological function, and immune and inflammatory responses, involving phosphoinositide 3-kinase-protein kinase B(PI3K-Akt), mitogen-activated protein kinase(MAPK), and Janus kinase-signal transducer and activator of transcription 3(JAK-STAT3) signaling pathways. Molecular docking results showed that bilobalide had a good binding effect with core targets. Verification experiments on VD rat models demonstrated that YYF might exert the therapeutic effect by alleviating oxidative stress through modulating the serum levels of superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), and malondialdehyde(MDA). This study preliminarily clarified the material basis, pharmacological effects, and underlying mechanism of YYF in the treatment of VD, providing a direction and basis for subsequent research on the complete regulatory chain of "drug-target-pathway-phenotype".
Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.
Kauniolide, a parthenolide derivative, serves as a key biosynthetic intermediate for various guaianolide-type sesquiterpenoids, such as agrabin, lactucin, and lactupicrin. However, its chemical synthesis is often hampered by demanding reaction conditions and high reagent consumption, which severely limit further development and application. To address this, this study employed systematic metabolic engineering strategies to construct an efficient yeast cell factory for kauniolide production. First, the biosynthetic pathway genes for costunolide-the direct precursor of kauniolide(HaGAS, TpGAO, TpCOS, AaCPR)-were heterologously expressed in a lab-engineered yeast chassis strain with high farnesyl pyrophosphate(FPP) production. This initial strain produced costunolide at a titer of 6.1 mg·L~(-1). Subsequently, the co-expression of AaADH1, AaALDH1, and AaCYB5 was implemented to enhance the germacrene A acid synthesis and promote electron transfer, thereby boosting the catalytic efficiency of the key cytochrome P450 enzymes. This modification increased the costunolide titer to 71.5 mg·L~(-1). To optimize the conversion of costunolide to kauniolide, a promoter compatibility screen for the TpKLS gene was conducted. Among the tested promoters(P_(GAL1), P_(TDH3), P_(TEF1), P_(TPI1), P_(sptGAL2), and P_(skGAL2)), the strain harboring the P_(skGAL2)-driven TpKLS construct showed the highest performance, achieving a kauniolide titer of 28.2 mg·L~(-1). Furthermore, to further enhance the pathway flux, the catalytic efficiency of the TpKLS enzyme was improved through semi-rational design coupled with computer-aided design. The best-performing mutant, TpKLS~(V204R), exhibited a 2.7-fold higher catalytic activity compared to the wild-type enzyme. The final engineered strain, when cultivated in shake-flask fermentation, produced costunolide and kauniolide at titers of 35.0 and 71.1 mg·L~(-1), respectively. The kauniolide titer represents the highest level reported to date in a yeast system. In conclusion, this study successfully constructed an efficient yeast cell factory for kauniolide by reconstructing and optimizing its heterologous biosynthetic pathway. It provides a solid technical foundation and a valuable reference for the scalable biosynthesis of kauniolide and the exploration of its downstream derivatives.
This paper aims to establish the fingerprint and multi-component quantitative determination methods of raw and stir-fried Bupleuri Radix, explore the dynamic change rules of the processing procedure combined with chemometrics, screen quality markers, and provide a scientific basis for formulating the quality standard of stir-fried Bupleuri Radix. The fingerprints of raw and stir-fried Bupleuri Radix were established by high performance liquid chromatography(HPLC). The contents of saikosaponin A(SSA), saikosaponin B_1(SSB_1), saikosaponin B_2(SSB_2), saikosaponin C(SSC), saikosaponin D(SSD), and ethanol-soluble extractive were determined. The chromaticity values of the samples were determined by an electronic eye. By employing chemometrics, the chromaticity value, five components, and ethanol-soluble extractive content of the samples during the processing procedure were analyzed by hierarchical clustering analysis(HCA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA). Finally, based on the five principles of quality markers, the variable importance of projection(VIP) value, artificial neural network, and random forest algorithm were employed to establish the prediction model of stir-fried Bupleuri Radix processing degree, and the quality markers of stir-fried Bupleuri Radix were explored. RESULTS:: show that the color of Bupleuri Radix changes from light yellow to brown after being stir-fried. The similarity of fingerprints between raw and stir-fried Bupleuri Radix is high(>0.940), indicating that the overall change trend of main chemical components in the stir-fried procedure of Bupleuri Radix is basically the same. A total of 14 common peaks are calibrated, and five of them are identified, which are No.3(SSC), No.4(SSA), No.6(SSD), No.13(SSB_2), and No.14(SSB_1). Quantitative analysis was conducted, showing that the contents of SSA, SSC, and SSD gradually decreased after being stir-fried, while the contents of SSB_1 and SSB_2 gradually increased. The processing procedure can be divided into three stages: the early stage(0-6 min), the middle stage(8-14 min), and the late stage(16-20 min) according to the comprehensive ethanol-soluble extractive, the contents of five components, and chromaticity values. The fingerprints and multi-component content determination methods of raw and stir-fried Bupleuri Radix established in this study are accurate and reliable, and SSA, SSB_1, SSB_2, and SSD can be used as quality markers in the processing procedure of stir-fried Bupleuri Radix, which provides a scientific basis and reference for formulating the quality standard of stir-fried Bupleuri Radix.
Under the "Dual Carbon" goals, reducing carbon emissions from contaminated site remediation is urgent. However, most existing studies have focused on Cd, Pb, and other heavy metals, and research on the remediation of Cr(VI) has long centered primarily on removal efficiency and risk management. There is a relative lack of research specifically addressing carbon emissions accounting and reduction strategies for sites contaminated with Cr(VI). This study, therefore, presents the first comprehensive carbon emissions assessment for Cr(VI) contaminated site remediation and explores emission mitigation pathways based on a project in East China. A life cycle assessment (LCA) was applied to define system boundaries and compile inventories for chemical washing, chemical reduction, and chemical washing combined with reduction. The carbon footprint was calculated using Emission Factor Methods, with key factors identified via contribution and sensitivity analyses. Mitigation potential was assessed through technical and energy system optimization and their integration, resulting in targeted strategies. Results show that treating 1 m3 of Cr(VI)-contaminated soil emits 407.75, 27.52, and 227.27 kg CO2eq, respectively. The remediation stage dominates emissions for washing (63.77%) and combined (57.37%), while wastewater treatment dominates for reduction (57.78%). Technical, energy, and coupled optimizations reduce emissions by 24-30%, 2-24%, and 31-48%, respectively. Key measures include improving reagent efficiency, controlling transport distance, recycling water, and selecting suitable techniques. This study focuses on the application, based on the case studies from the East China region. It considers the soil pollution situation of Cr(VI), calculates the total carbon emissions during the entire life cycle of the remediation process, and conducts a comprehensive analysis of contribution rates, sensitivity, and emission reduction potential. This provides a reference for the formulation of carbon reduction strategies in the remediation process of similar contaminated sites.
This study compared the terpenoids among different varieties of Chrysanthemi Flos and explored the molecular mechanisms underlying their accumulation, aiming to provide a basis for elucidating the material basis responsible for the differences in taste, flavor, and efficacy among different varieties. Secondary metabolites of two Chrysanthemi Flos varieties- "Hangju" and "Huaiju" -were analyzed by metabolomics. Key genes were identified from the transcriptome data, and gene expression levels were determined by qRT-PCR. A total of 21 terpenoid-related differential metabolites were identified in "Hangju" and "Huaiju" via metabolomics analysis, including eucalyptol, camphor, γ-terpinene, and α-terpineol. Transcriptomics analysis yielded 21 differentially expressed genes associated with terpenoid biosynthesis. Correlation analysis revealed that ten genes had significantly positive correlations with multiple highly accumulated differential terpenoids in "Huaiju". The qRT-PCR validation showed that the expression trends of the eight enzyme genes involved in terpenoid biosynthesis were consistent with those obtained from transcriptome sequencing in "Hangju" and "Huaiju". This study elucidates the differences in terpenoids and their accumulation mechanisms between the two varieties. It lays a foundation for further revealing the material basis underlying the differences in taste, flavor, and the wind-dispersing and heat-clearing efficacy of the two varieties, as well as for clarifying the regulation of key enzyme genes on differential terpenoids. The results provide a reference for the genetic improvement and high-value utilization of Chrysanthemi Flos germplasm resources.
This study aimed to explore the prescription patterns of TCM in the treatment of cerebral small vessel disease(CSVD) based on latent structure model combined with association rules and provide a reference for clinical diagnosis and treatment based on syndrome differentiation. Multiple databases including PubMed, EMbase, Cochrane Library, CNKI, Wanfang, VIP, SinoMed, ITMCTR, and ChiCTR were searched from their inception to November 17, 2025. Literature related to TCM prescriptions for CSVD was selected, and a database of TCM prescriptions was established using Microsoft Excel 2019. Lantern 5.0 and Rstudio were used to conduct latent structure analysis and association rule analysis on high-frequency TCMs with a frequency >4.00% to explore the prescription patterns of TCM in the treatment of CSVD. A total of 126 TCM prescriptions involving 164 TCMs and 1 313 total frequencies were included. High-frequency TCMs included Chuanxiong Rhizoma, Pheretima, Astragali Radix, Acori Tatarinowii Rhizoma, and Salviae Miltiorrhizae Radix et Rhizoma, with the main efficacy shown by tonic TCMs and blood-activating and stasis-resolving TCMs. Latent structure analysis identified 12 latent variables, 24 latent classes, 6 comprehensive clustering models, and 17 core prescriptions. Based on the prescriptions, the common syndromes of CSVD were speculated to be Qi deficiency with blood stasis, liver-kidney Yin deficiency, intermingled phlegm and stasis, and wind-phlegm obstructing the collaterals. Association rule analysis identified 39 strong association rules, with Astragali Radix→Chuanxiong Rhizoma having the highest support and Paeoniae Radix Rubra + Persicae Semen→Chuanxiong Rhizoma having the highest confidence. CSVD is a syndrome characterized by deficiency in nature and excess in superficiality, with Qi deficiency and essence depletion as the fundamental aspects, and turbid phlegm and blood stasis as the manifestations. The treatment principles should focus on tonifying Qi, activating blood, and nourishing the liver and kidney, as well as resolving phlegm, dispelling stasis, subsiding wind, unblocking the collaterals, pacifying liver, and subduing Yang.
Connections between the formulations of physics and geometry have been evident throughout history, from classical mechanics to general relativity. Independently, quantum mechanics has been established in flat space. In this study, we investigate the geometric-like coupling of a test particle and its quantized form in a gravitational field. The main text consists of three parts: the characterization of the particle and its operator form is pointwise established. Minimal coupling with the electromagnetic potential is analyzed as a reference via an infinitesimal transform. Subsequently, the geometric coupling from the geodesic strain and its associated phase transform of the initial parallel test particle is formally studied. Within the gravitational field equation, the phase transform is specified via metric tensors in general. The linearized field condition is analyzed explicitly to show the local analogy between the four-potential in gauge-like and geometric-like couplings. From the isomorphism and function maps, the amplitude and phase in the operator form are translated to the quantum form and the Schrödinger-like equation is obtained. The representation of local equivalence and the phase transform condition is formulated. Examples of the phase shift and potential well, as well as the geometric Aharonov-Bohm effect, are studied for potential applications. Finally, the geometric-like and gauge-like couplings are summarized based on the concept of pointwise characterization and associated matrix transformation.
Congenital biliary dilatation (CBD) in children remains a disease of enigmatic origin. Prevailing theories focusing on anomalous pancreaticobiliary ductal union (APBDU) fail to explain the critical anatomical hallmark of Type Ia CBD: the coexistence of a distal stenotic segment (DSS) and a proximal dilated segment (PDS). We aimed to define region-specific molecular landscapes to bridge this fundamental gap. We conducted label-free proteomic and histomorphometric analyses on distinct surgical specimens-cystic duct (CD: as the least-affected internal reference), DSS, and PDS-from pediatric CBD patients (n = 5 proteomics; n = 12 validation). Key findings were rigorously validated using multiplex immunofluorescence, immunohistochemistry, and functional enrichment. Proteomic profiling established DSS and PDS as biologically distinct pathological entities. While both segments shared severe epithelial dysfunction and mechanosensory ciliary loss, a profound molecular dichotomy emerged in smooth muscle remodeling. The DSS was characterized by robust ferroptosis-associated fibrosis (TFR1/α-SMA co-localization) and β-amyloid-associated neural degeneration. Conversely, the PDS exhibited marked muscular atrophy and wall tension failure (CALD1 upregulation). This regional proteomic atlas reveals a pronounced spatial dichotomy, calling into question the adequacy of traditional uniform disease models. These findings suggest that ferroptosis may contribute to distal stenosis and highlight potential therapeutic targets to mitigate fibrosis and improve long-term surgical outcomes.
Sharp Raman bands near 1450 and 1530 cm-1 observed under 633 nm excitation have previously been attributed to localized vibrational modes of zigzag and armchair graphene edges. Here, we employ an isotope-resolved Raman spectroscopy approach to investigate the origin of these features. Monolayer 13C graphene was synthesized and transferred alongside 12C graphene reference samples, enabling a direct comparison of isotope-dependent Raman signatures under identical processing conditions. Despite clear isotope-induced shifts of the intrinsic graphene modes, the peaks near 1450 and 1530 cm-1 exhibit no isotope-dependent frequency shift, demonstrating that they do not originate from graphene lattice vibrations. Instead, their excitation-wavelength dependence and spectral characteristics are consistent with Raman enhancement of adsorbed molecular species under resonant conditions. These results establish isotope labeling as a robust experimental strategy for distinguishing intrinsic graphene vibrational modes from extrinsic Raman signals and provide a revised interpretation of Raman features previously attributed to graphene edge phonons.
This paper assesses seasonal and spatial mismatch between irrigation water demands and water supply in the Kaleshwaram Lift Irrigation Scheme (KLIS) command area, India where inflows dependent on the monsoon seasons, high evapotranspiration, timing of canal-release, and planting schemes have a combined effect on irrigation reliability. Based on multi-year occurrences data, which covers climate-data between 2000 and 2023, groundwater-observations data between 2015 and 2023, reservoir and canal-operation data between 2019 and 2023, and crops/land-use data between 2022 and 2023, the study generates a monthly water-balance framework, here variables specific periods were used according to the verified data availability. Digital Elevation Model (DEM)-based Geographic Information System (GIS) preprocessing was combined with the results of CROPWAT and Soil and Water Assessment Tool (SWAT) to estimate the reference evapotranspiration (ET 0), crop evapotranspiration (ET c), effective rainfall, runoff, recharge, and soil-moisture change. The available supply was estimated by using an addition of canal release, reservoir- operation values, ground water contribution, and contribution of return-flow. These findings indicate that irrigation takes up the largest portion of the annual water needs with about 98.4% of total yearly needs i.e. 1650 Mm3 of the total 1677 Mm3. The gross supply available was around 730 Mm3 which could only satisfy about 43.5% of the overall demand leaving behind an annual unfulfilled demand of around 947 Mm3, which would cater to almost 56.5% of the aggregate demand. The greatest demand was at April-May where it was approximately 197-212 Mm3/month, or 11.8-12.7% annual demand during this period. None of the months had over supply and highest monthly loss was in the months of March-May corresponding to a range of approximately 102-127 Mm3 monthly which only constituted about 10.8-13.4% of the annual loss in that year. The seasonal interpretation shows that the periods of water-stress are peak three months pre-monsoon and Rabi (spring) and Kharif (autumn) depend heavily on storage of the reservoir, efficient rainfall distribution, and timing of the canals. The results prove that annual supply volumes cannot be considered the only factors of KLIS performance, monthly alignment of crop-water demand and monsoon recharge with the performance of the storage and the canal delivery plays a vital role. The research offers application evidence on how to better reservoir rule curves, canal-sort, conjunctive ground water utilization, crop-arrangement and deficit-irrigation techniques in monsoon-based command regions that are semi-arid.
This study aimed to elucidate the mechanism for enhancing efficacy through processing of Ziziphi Spinosae Semen(ZSS) by integrating in vitro intestinal microbiota transformation and in vivo pharmacokinetic studies to clarify the differences in metabolic transformation characteristics between raw and processed ZSS. High-performance liquid chromatography was employed to analyze the metabolic rates of the two major components, spinosin and jujuboside A, in raw ZSS and fried Ziziphi Spinosae Semen(FZSS) mediated by the intestinal microbiota. High-throughput 16S rRNA sequencing was used to investigate the regulatory effects of ZSS and FZSS on the intestinal microbiota in rats with insomnia. A UPLC-Q-TOF-MS/MS method was developed and validated for the quantification of spinosin and jujuboside A in rat plasma and subsequently applied to a comparative pharmacokinetic study of ZSS and FZSS in a rat model of insomnia induced by DL-4-chlorophenylalanine(PCPA). The results showed that the metabolic rates of spinosin and jujuboside A mediated by the intestinal microbiota were significantly accelerated in the FZSS group compared to the ZSS group. Relative to the non-medicated control group, both ZSS and FZSS groups significantly increased the relative abundance of beneficial bacteria, such as Firmicutes and Lactobacillus, while decreasing the relative abundance of harmful bacteria, such as Proteobacteria and Clostridium. The maximum plasma concentration(C_(max)) of spinosin in the FZSS group was 20.01 ng·mL~(-1), which was significantly lower than that in the ZSS group(45.41 ng·mL~(-1)). Similarly, the C_(max) of jujuboside A was significantly lower in the FZSS group(12.32 ng·mL~(-1)) compared to the ZSS group(16.31 ng·mL~(-1)). The clearance rate of spinosin and jujuboside A was significantly faster in the FZSS group(38 058.83,28 141.27 L·h~(-1)·kg~(-1), respectively) than in the ZSS group. Stir-frying process increased the content of amino acids in FZSS, promoted the growth of Lactobacillus and Bifidobacterium, accelerated the decomposition rate of spinosin and jujuboside A in the intestine, and consequently reduced their plasma concentration in rats. Building upon our previous research, the stir-frying process accelerated the intestinal decomposition of spinosin and jujuboside A, promoted the production of their secondary metabolites, and enhanced the sedative and hypnotic effects. This study elucidates the metabolic characteristics of spinosin and jujuboside A in ZSS and FZSS from both in vivo and in vitro metabolic perspectives, preliminarily revealing the significant impact of processing on the bioavailability of these components. These findings provide a reference for elucidating the processing mechanism underlying "enhancing efficacy through processing" of ZSS.
The rhizome is the traditional medicinal part of Paris, renowned for its definite efficacy and significant medicinal value. Studies have indicated that beyond the rhizome, non-medicinal parts of Paris also contain abundant active compounds and have traditional folk applications in certain southeast Asian countries. In recent years, with the expansion of cultivation areas, the annual yield of Paris rhizomes has kept increasing. Consequently, the yield of its non-medicinal parts, which regenerate annually, has also grown significantly. However, due to the lack of effective utilization, these parts are often discarded as waste, resulting in substantial resource wastage. This paper systematically reviews the chemical constituents and pharmacological activities of non-medicinal parts, including stems, leaves, fruit peels, seeds, and fibrous roots, of Paris plants. It analyzes their potential application value and proposes feasible resource utilization strategies, aiming to provide theoretical support and practical references for the efficient development and comprehensive utilization of Paris resources.