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Background With the gradual deepening of the comprehensive reform of community health services, the prevention and control of single diseases for the entire population in the community is also constantly being optimized, However, there is still a lack of appropriate evaluation methods in the community to reflect its prevention and control effectiveness evaluation. Objective By analyzing and exploring the cost effect of the existing whole-population prevention and control measures of osteoporosis in Fenglin community, from 2016 to 2022, this paper answers the initial results and possible problems of the whole-population prevention and control of single disease in the community. Methods This study conducted a cost-effectiveness analysis on 4 293 community residents who received osteoporosis prevention and treatment in Fenglin community from 2016 to 2022. Divide the research object into three states based on bone density values: healthy, low bone mass, and osteoporosis, and construct a Markov model to analyze the influencing factors of different state transitions. And based on the predicted values of the Markov model combined with quality adjusted life years (QALY) , the increment of quality adjusted life years (QALY) is calculated. All costs invested in prevention and control work from 2016 to 2022 are counted, and the effectiveness of prevention and control is evaluated by the cost/quality adjusted life year increment ratio. Quality adjusted life years (QALY) are obtained by calculating the health utility value and expected life determined through literature search. Results The total cost of osteoporosis prevention and treatment in Fenglin community was 33 814 102.15 yuan. The total quality-adjusted life years of 4 293 community osteoporosis prevention and treatment population were 77 098.288 9 at the first diagnosis, the average per capita was 17.959, and the standard deviation was 9.34. At the second diagnosis, the total quality-adjusted life years were 79 616.936 1, the mean per capita was 18.546, the standard deviation was 9.342, and the difference between the two diagnoses was 2 518.647 2. The incremental cost-effectiveness ratio (ICER) is 2 132.907 0 yuan /QALY, and the incremental cost-effectiveness ratio (ICER) is less than 1 times (66 965.10 yuan) per capita GDP, indicating that the intervention scheme is fully cost-effective. Conclusion This study combined Markov model and quality-adjusted life years (QALY) to make a preliminary evaluation of the prevention and treatment effect of osteoporosis in Fenglin community. The results showed that the intervention program of osteoporosis prevention and treatment in Fenglin community was worth investing, and provided a certain basis for the accurate prevention and treatment decision of osteoporosis in the future.

Abstract Hepatocellular carcinoma (HCC) has high incidence and mortality rates worldwide. Damaged mitochondria are characterized by the overproduction of reactive oxygen species (ROS), which can promote cancer development. The prognostic value of the interplay between mitochondrial function and oxidative stress in HCC requires further investigation. Gene expression data of HCC samples were collected from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC). We screened prognostic oxidative stress mitochondria-related (OSMT) genes at the bulk transcriptome level. Based on multiple machine learning algorithms, we constructed a consensus oxidative stress mitochondria-related signature (OSMTS), which contained 26 genes. In addition, we identified six of these genes as having a suitable prognostic value for OSMTS to reduce the difficulty of clinical application. Univariate and multivariate analyses verified the OSMTS as an independent prognostic factor for overall survival (OS) in HCC patients. The OSMTS-related nomogram demonstrated to be a powerful tool for the clinical diagnosis of HCC. We observed differences in biological function and immune cell infiltration in the tumor microenvironment between the high- and low-risk groups. The highest expression of the OSMTS was detected in hepatocytes at the single-cell transcriptome level. Hepatocytes in the high- and low-risk groups differed significantly in terms of biological function and intercellular communication. Moreover, at the spatial transcriptome level, high expression of OSMTS was mainly in regions enriched in hepatocytes and B cells. Potential drugs targeting specific risk subgroups were identified. Our study revealed that the OSMTS can serve as a promising tool for prognosis prediction and precise intervention in HCC patients.

SRSF2 plays a dual role, functioning both as a transcriptional regulator and a key player in alternative splicing. The absence of Srsf2 in MyoD + progenitors resulted in perinatal mortality in mice, accompanied by severe skeletal muscle defects. SRSF2 deficiency disrupts the directional migration of MyoD progenitors, causing them to disperse into both muscle and non-muscle regions. Single-cell RNA-sequencing analysis revealed significant alterations in Srsf2-deficient myoblasts, including a reduction in extracellular matrix components, diminished expression of genes involved in ameboid-type cell migration and cytoskeleton organization, mitosis irregularities, and premature differentiation. Notably, one of the targets regulated by Srsf2 is the serine/threonine kinase Aurka. Knockdown of Aurka led to reduced cell proliferation, disrupted cytoskeleton, and impaired differentiation, reflecting the effects seen with Srsf2 knockdown. Crucially, the introduction of exogenous Aurka in Srsf2-knockdown cells markedly alleviated the differentiation defects caused by Srsf2 knockdown. Furthermore, our research unveiled the role of Srsf2 in controlling alternative splicing within genes associated with human skeletal muscle diseases, such as BIN1, DMPK, FHL1, and LDB3. Specifically, the precise knockdown of the Bin1 exon17-containing variant, which is excluded following Srsf2 depletion, profoundly disrupted C2C12 cell differentiation. In summary, our study offers valuable insights into the role of SRSF2 in governing MyoD progenitors to specific muscle regions, thereby controlling their differentiation through the regulation of targeted genes and alternative splicing during skeletal muscle development.

Summary: Pancreatic cancer is highly lethal with limited effective treatments. This study explores the therapeutic effects of eupalinolide B (EB) from Eupatorium lindleyanum DC on pancreatic cancer cells. Through cellular functional assays, we observed that EB effectively inhibits cell viability, proliferation, migration, and invasion. In a xenograft mouse model, EB treatment resulted in reduced pancreatic cancer tumor growth and decreased expression of Ki-67. Mechanistically, EB induces apoptosis, elevates reactive oxygen species (ROS) levels, and disrupts copper homeostasis. RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA) identified copper ion binding pathways and potential involvement in cuproptosis. Furthermore, EB enhances the cytotoxic effects of elesclomol (ES), increasing ROS levels in a copper-dependent manner and exhibiting synergistic cytotoxicity. These findings suggest that EB, either alone or in combination with ES, represents a promising strategy for targeting metal ion dysregulation and inducing potential cuproptosis in pancreatic cancer, offering a potential improvement in therapeutic outcomes.

Deoxynivalenol (DON), commonly known as vomitoxin, is a mycotoxin produced by fungi and is frequently found as a contaminant in various cereal-based food worldwide. While the harmful effects of DON have been extensively studied in different tissues, its specific impact on the proliferation of skeletal muscle cells remains unclear. In this study, we utilized murine C2C12 myoblasts as a model to explore the influence of DON on their proliferation. Our observations indicated that DON exhibits dose-dependent toxicity, significantly inhibiting the proliferation of C2C12 cells. Through the application of RNA-seq analysis combined with gene set enrichment analysis, we identified a noteworthy downregulation of genes linked to the extracellular matrix (ECM) and condensed chromosome. Concurrently with the reduced expression of ECM genes, immunostaining analysis revealed notable changes in the distribution of fibronectin, a vital ECM component, condensing into clusters and punctate formations. Remarkably, the exposure to DON induced the formation of multipolar spindles, leading to the disruption of the normal cell cycle. This, in turn, activated the p53-p21 signaling pathway and ultimately resulted in apoptosis. These findings contribute significant insights into the mechanisms through which DON induces toxicity within skeletal muscle cells.

Abstract Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).

Background Currently, there is a lack of clinical competence evaluation tools applicable of general practitioners (GPs) practicing in rural settings in China, resulting in the lack of researches on the clinical competence evaluation of GPs in rural. Objective To explore reliability and validity of an evaluation index system for consultation competency of rural GPs developed previously, and provide an evaluation tool with high reliability and validity for scientific and objective assessment of consultation competence of GPs in rural settings. Methods Based on the evaluation system for consultation competency of rural GPs, a corresponding questionnaire was designed, and points were assigned to each option on a 5-point Likert scale. From September to December 2022, GPs or assistant general practitioners (AGPs) who were working in rural township health centers in Guangxi Province were recruited as the research subjects by using the purposive sampling and stratified sampling methods, the questionnaire was distributed through a national web-based survey platform-"WJX" to them. Cronbach's α coefficient, split-half coefficient, critical ratio (CR) and correlation coefficients were calculated based on questionnaire data. Confirmative factor analysis was employed to fit questionnaire data and assumed model, and calculate three categories of indicators, including preliminary fit criteria (PFC), overall model fit (OMF), and fit of internal structural model (FISM), to verify the degree of fit and structural validity of the measured data. Results A total of 600 questionnaires were distributed and 366 were validly collected, with an effective recovery rate of 61.0%, 86.1% were registered as GPs and 13.9% as AGPs, who came from five cities, including Nanning, Guilin, Wuzhou, Baise, and Guigang, and 204 township health centers in Guangxi Province. Cronbach'α coefficient for the whole questionnaire or for every section was higher than 0.700, and Guttman Split-Half coefficient was 0.931. The initial first-order model met the PFC well; except for goodness of fit index (GFI), adjusted goodness of fit index (AGFI), and normed fit index (NFI), other indicators related to the OMF reached for the best levels in the modified first-order model. Apart from R2 for 9 observable variables less than 0.5, the FISM for the modified first-order model showed good effects. The initial second-order model indicated as similar effects on the PFC as the initial first-order model; the modified second-order model shared similar OMF with the modified first-order model; the modified second-order model was inferior to the modified first-order model in terms of the FISM. Eventually, questionnaire data fitted the modified first-order model better. Conclusion The evaluation index system for consultation competency of rural GPs shows high reliability and validity, which can be used for research and practical work on the evaluation of consultation competence evaluation of GPs in rural settings.

Background: Tracheoesophageal fistula (TEF) remains a rare but significant clinical challenge, mainly due to the absence of established, effective treatment approaches. The current focus of therapeutic strategy is mainly on fistula closure. However, this approach often misses important factors, such as accelerating fistula contraction and fostering healing processes, which significantly increases the risk of disease recurrence. Methods: In order to investigate if Mesenchymal Stem Cells (MSCs) can enhance fistula repair, developed a TEF model in beagles. Dynamic changes in fistula diameter were monitored by endoscopy. Concurrently, we created a model of LPS-induced macrophage to replicate the inflammatory milieu typical in TEF. In addition, the effect of MSC supernatant on inflammation mitigation was evaluated. Furthermore, we looked at the role of TLR4/NF-κB pathway plays in the healing process. Results: Our research revealed that the local administration of MSCs significantly accelerated the fistula's healing process. This was demonstrated by a decline in TEF apoptosis and decrease in the production of pro-inflammatory cytokines. Furthermore, in vivo experiments demonstrated that the MSC supernatant was effective in suppressing pro-inflammatory cytokine expression and alleviating apoptosis in LPS-induced macrophages. These therapeutic effects were mainly caused by the suppression of TLR4/NF-κB pathway. Conclusion: According to this study, MSCs can significantly improve TEF recovery. They achieve this via modulating apoptosis and inflammatory responses, mainly by selectively inhibiting the TLR4/NF-κB pathway.

Objective: The purpose of this study is to analyze the inherent relationship between the score values and the biomechanical characteristics of the forward kicking motion, we aim to identify the fundamental variables influencing the score values of the forward kicking motion and establish the key biomechanical factors that effectively trigger scoring in the forward kicking motion.Methods: The DaeDo electronic scoring system was used with the Vicon optical motion capture system and the Kistler 3D force platform to obtain kinematic and kinetic variables of the front roundhouse kick motion. Linear bivariate correlation analysis and principal component analysis were used to analyze the associations between kinematic, kinetic variables, and scoring values, and summarize key biomechanical factors for effectively scoring.Results: The peak ankle plantar flexion angle and knee extension torque of the kicking leg showed a significant negative correlation with scoring values (r < 0, p < 0.05), while other variables showed no statistical significance. The peak knee flexion angle and hip extension angular velocity of the supporting leg showed a significant positive correlation with scoring values (r > 0, p < 0.01), while the peak ankle plantar flexion torque showed a significant negative correlation with scoring values (r < 0, p < 0.05), and other variables showed no statistically significant correlation. The absolute values of eigenvectors of the first and second principal components, which included hip angular velocity, ankle angle, knee torque, and hip torque, were relatively large, indicating their strong influence on effective scoring triggering.Conclusion: Maintaining ankle dorsiflexion and a larger knee flexion angle in the kicking leg is favorable for triggering scoring. Higher knee flexion angle and hip extension angular velocity in the supporting leg are also advantageous for triggering scoring. “Body posture” and “Strength” are key factors that effectively trigger scoring.

Abstract RNA splicing dysregulation and the involvement of specific splicing factors are emerging as common factors in both obesity and metabolic disorders. The study provides compelling evidence that the absence of the splicing factor SRSF1 in mature adipocytes results in whitening of brown adipocyte tissue (BAT) and impaired thermogenesis, along with the inhibition of white adipose tissue browning in mice. Combining single‐nucleus RNA sequencing with transmission electron microscopy, it is observed that the transformation of BAT cell types is associated with dysfunctional mitochondria, and SRSF1 deficiency leads to degenerated and fragmented mitochondria within BAT. The results demonstrate that SRSF1 effectively binds to constitutive exon 6 of Ndufs3 pre‐mRNA and promotes its inclusion. Conversely, the deficiency of SRSF1 results in impaired splicing of Ndufs3, leading to reduced levels of functional proteins that are essential for mitochondrial complex I assembly and activity. Consequently, this deficiency disrupts mitochondrial integrity, ultimately compromising the thermogenic capacity of BAT. These findings illuminate a novel role for SRSF1 in influencing mitochondrial function and BAT thermogenesis through its regulation of Ndufs3 splicing within BAT.

ERCC2 plays a pivotal role in DNA damage repair, however, its specific function in cancer remains elusive. In this study, we made a significant breakthrough by discovering a substantial upregulation of ERCC2 expression in glioblastoma (GBM) tumor tissue. Moreover, elevated levels of ERCC2 expression were closely associated with poor prognosis. Further investigation into the effects of ERCC2 on GBM revealed that suppressing its expression significantly inhibited malignant growth and migration of GBM cells, while overexpression of ERCC2 promoted tumor cell growth. Through mechanistic studies, we elucidated that inhibiting ERCC2 led to cell cycle arrest in the G0/G1 phase by blocking the CDK2/CDK4/CDK6/Cyclin D1/Cyclin D3 pathway. Notably, we also discovered a direct link between ERCC2 and CDK4, a critical protein in cell cycle regulation. Additionally, we explored the potential of TRAIL, a low-toxicity death ligand cytokine with anticancer properties. Despite the typical resistance of GBM cells to TRAIL, tumor cells undergoing cell cycle arrest exhibited significantly enhanced sensitivity to TRAIL. Therefore, we devised a combination strategy, employing TRAIL with the nanoparticle DMC-siERCC2, which effectively suppressed the GBM cell proliferation and induced apoptosis. In summary, our study suggests that targeting ERCC2 holds promise as a therapeutic approach to GBM treatment.

Abstract Objectives Monetizing health has sparked controversy and has implications for pricing strategies of emerging health technologies. Medical insurance payers typically set up thresholds for quality-adjusted life years (QALY) gains based on health productivity and budget affordability, but they rarely consider patient willingness-to-pay (WTP). Our study aims to compare Chinese payer threshold and patient WTP toward QALY gain of advanced non-small cell lung cancer (NSCLC) and to inform a potential inclusion of patient WTP under more complex decision-making scenarios. Methods A regression model was constructed with cost as the independent variable and QALY as the dependent variable, where the regression coefficients reflect mean opportunity cost, and by transforming these coefficients, the payer threshold can be obtained. Patient WTP was elicited through a contingent valuation method survey. The robustness of the findings was examined through sensitivity analyses of model parameters and patient heterogeneity. Results The payer mean threshold in the base-case was estimated at 150,962 yuan (1.86 times per capita GDP, 95% CI 144,041–159,204). The two scenarios analysis generated by different utility inputs yielded thresholds of 112,324 yuan (1.39 times per capita GDP) and 111,824 yuan (1.38 times per capita GDP), respectively. The survey included 85 patients, with a mean WTP of 148,443 yuan (1.83 times per capita GDP, 95% CI 120,994–175,893) and median value was 106,667 yuan (1.32 times the GDP per capita). Due to the substantial degree of dispersion, the median was more representative. The payer threshold was found to have a high probability (98.5%) of falling within the range of 1–2 times per capita GDP, while the robustness of patient WTP was relatively weak. Conclusions In China, a country with a copayment system, payer threshold was higher than patient WTP, indicating that medical insurance holds significant decision-making authority, thus temporarily negating the need to consider patient WTP.

Hyperuricemia, a major worldwide burden on public hygiene, is closely connected with dietary habits. However, few studies have evaluated the association of dietary diversity with hyperuricemia. To preliminarily reveal the status of a diversified diet in preventing hyperuricemia based on a neighborhood-based, massive-scale cohort in China, a total of 43,493 participants aged 20–74 years old, with no history of hyperuricemia at baseline, were enrolled in the research from April 2016 to December 2019. The Dietary Diversity Score (DDS) was utilized to evaluate the dietary variety and split the participants into the low-, medium-, and high-DDS groups. Information on participants was connected to regional health information systems that acquired data on hyperuricemia instances up to 28 February 2023. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox proportional hazards models. Restricted cubic splines (RCS) were implemented to analyze dose–response correlation. A total of 1460 individuals with newly diagnosed hyperuricemia were observed over a median follow-up period of 5.59 years. Compared to the low-DDS group, HRs for the medium- and high-DDS groups were 0.87 (95% CI 0.76–0.99) and 0.80 (95% CI 0.70–0.91) in the fully adjusted model, respectively. The risk of hyperuricemia incidence was reduced by 5% for each 1 unit of DDS increase. A linear correlation of DDS with hyperuricemia emerged and further revealed that the intake of 8–10 broad categories of food could decrease the incidence of hyperuricemia. Our results validate the dietary principle of “food diversification” recommended in guidelines. Conclusions should be applied with caution considering the paucity of related evidence in additional nations.

Prevalent neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and stroke are increasingly becoming a global burden as society ages. It is well-known that degeneration and loss of neurons are the fundamental underlying processes, but there are still no effective therapies for these neurological diseases. In recent years, plenty of studies have focused on the pharmacology and feasibility of natural products as new strategies for the development of drugs that target neurological disorders. Antrodia camphorata has become one of the most promising candidates, and the crude extracts and some active metabolites of it have been reported to play various pharmacological activities to alleviate neurological symptoms at cellular and molecular levels. This review highlights the current evidence of Antrodia camphorata against neurological disorders, including safety evaluation, metabolism, blood-brain barrier penetration, neuroprotective activities, and the potential on regulating the gut-microbiome-brain axis. Furthermore, potential strategies to resolve problematic issues identified in previous studies are also discussed. We aim to provide an overview for the ongoing development and utilization of Antrodia camphorata in cerebral neuropathology.

Objective To construct a scientific and systematic competency evaluation tool for master of nursing specialists (MNS) and to provide a reference for the training, assessment and competency evaluation of MNS.Methods A first draft of the indicators for assessing MNS core competencies was developed on the basis of published research and group discussions. Between June and December 2020, the indicators were revised using two rounds of the Delphi expert consultation method, with questionnaires completed by 16 experts from five provinces in China.Results The valid retrieval rate of the two questionnaires was 100.00%, and the coefficient of expert authority was 0.931. The Kendall’s concordance coefficients of the two rounds of questionnaires were 0.136 (p

To investigate the distribution, contamination status, and antibiotic resistance of Listeria monocytogenes in four types of retail poultry meat, including chicken, duck, goose, and pigeon, sold in Jiading District, Shanghai, a total of 236 retail poultry meat samples were collected, and L. monocytogenes isolates were obtained for identification and antibiotic susceptibility testing against 14 common antibiotics. Forty-one L. monocytogenes isolates were detected from the 236 retail poultry meat samples, with detection rates of 24.47%, 19.44%, 14.75%, and 4.44% in chicken, goose, duck, and pigeon meat, respectively. Among refrigerated, frozen, and room temperature samples, refrigerated poultry had the highest detection rate at 25.40%, while frozen poultry had the lowest at 13.33%. The detection rate of L. monocytogenes in chicken meat differed significantly between the storage temperatures, while no significant differences were found for other poultry types. No significant differences in detection rates were observed between different retail locations or packaging methods. Isolates exhibited complete resistance to cefoxitin (FOX) and increasing resistance over time to tetracycline (TET) and clindamycin (CLI), while low levels of resistance were found for penicillin (PEN), oxacillin (OXA), and erythromycin (ERY). Resistance to ERY and TET suggests the potential for multidrug resistance. Significant differences in antibiotic resistance profiles were observed among L. monocytogenes from the various poultry types. In summary, contamination status and antibiotic resistance profiles differed among retail chicken, duck, goose, and pigeon meat sold and the resistance rate of strains continues to increase in Jiading District, Shanghai. Targeted control measures should be implemented to reduce the emergence of resistant strains, as retail conditions had minimal impact on L. monocytogenes prevalence in poultry meat.

IntroductionCadmium (Cd) is a highly toxic heavy metal which contaminates agricultural soils and is easily absorbed by plants. Brassica rapa L. is one of the most popular vegetables in China and is known to accumulate Cd in its roots and aerial tissues.MethodsA highly Cd-resistant bacterium (‘CD2’) was isolated and identified. Its ability to immobilize Cd(II) in medium was studied. Strain CD2 were added into Cd-polluted soil to ameliorate Cd accumulation in B. rapa. The underlying mechanisms of ‘CD2’ to reduce Cd accumulation in B. rapa. were analyzed by transcriptomics.Results and discussionStrain CD2 was classified as belonging to the genus Stenotrophomonas. Strain CD2 was found to be able to remove 0.1 mmol/L Cd(II) after 36 h by intracellular sequestration and by producing biofilm, exopolysaccharide, and H2S. When applied to Cd-contaminated soil, ‘CD2’ significantly increased the content of nonbioavailable Cd by 212.70%. Furthermore, ‘CD2’-inoculated B. rapa exhibited a 51.16% decrease in the Cd content of roots and a 55.56% decrease in the Cd content of aerial tissues. Transcriptome analysis identified 424 differentially expressed genes (DEGs) in the roots and 501 DEGs in the aerial tissues of uninoculated Cd-exposed plants. By comparison, 1107 DEGs were identified in the roots and 1721 DEGs were identified in the aerial tissues of ‘CD2’-inoculated Cd-exposed plants. In both treatment groups, genes related to vacuolar sequestration were upregulated, resulting in inhibited Cd transport. In addition, both catalase and glutathione transferase were induced in uninoculated plants, while the oxidative stress-related genes CPK and RBOH belonged to ‘plant-pathogen interactions’ were upregulated in ‘CD2’-inoculated plants. Moreover, inoculation with ‘CD2’ resulted in the enrichment of phenylpropane metabolism; cutin, suberine, and wax biosynthesis; and the AP2, Dof, WOX, Trihelix, B3, EIL, and M-type_MADS transcription factors; as well as the downregulation of zinc transporters and blue copper proteins. All of these changes likely contributed to the reduced Cd accumulation in ‘CD2’-inoculated B. rapa. The results of this study suggest that Stenotrophomonas sp. CD2 may prove to be a useful inoculant to prevent Cd accumulation in B. rapa.

Summary: Flavonoids are a class of secondary metabolites widely distributed in plants. Regiospecific modification by methylation and glycosylation determines flavonoid diversity. A rare flavone glycoside, diosmin (luteolin-4′-methoxyl-7-O-glucosyl-rhamnoside), occurs in Chrysanthemum indicum. How Chrysanthemum plants evolve new biosynthetic capacities remains elusive. Here, we assemble a 3.11-Gb high-quality C. indicum genome with a contig N50 value of 4.39 Mb and annotate 50,606 protein-coding genes. One (CiCOMT10) of the tandemly repeated O-methyltransferase genes undergoes neofunctionalization, preferentially transferring the methyl group to the 4′-hydroxyl group of luteolin with ortho-substituents to form diosmetin. In addition, CiUGT11 (UGT88B3) specifically glucosylates 7-OH group of diosmetin. Next, we construct a one-pot cascade biocatalyst system by combining CiCOMT10, CiUGT11, and our previously identified rhamnosyltransferase, effectively producing diosmin with over 80% conversion from luteolin. This study clarifies the role of transferases in flavonoid diversity and provides important gene elements essential for producing rare flavone.

Abstract Background Castleman’s disease (CD) is a rare disease that has clinical and pathological similarities to lymphoma and is characterized by a high frequency of associated immunological dysfunction. ImmunoglobulinG4-related disease (IgG4-RD) is a collection of systemic disorders that affect numerous organs and are also referred to as IgG4-associated sclerosing diseases. CD and IgG4-RD are difficult to separate because they may manifest similar commin clinical features. Case presentation This case describes a 53-year-old female who, during routine medical check-up, exhibited a progressive increase in serum globulin levels and a simultaneous worsening of anemia symptoms, raising concern for a clonal plasma cell disease such as myeloma. However, bone marrow punctures did not reveal any abnormal plasma cells. Also, serum and urine immunofixation electrophoresis demonstrated no abnormal monoclonal protein bands. In addition, several laboratory findings excluded chronic liver disease, chronic infections caused by bacteria or viruses. Later, we found elevated serum IgG4 levels (10,700 mg/L), and identified multiple enlarged lymph nodes throughout the patient’s body. Axillary lymph node aspiration revealed no abnormal lymphocytes, ruling out the possibility of lymphoma. Pathological morphology of the axillary lymph revealed a large number of plasma cells in the lymphatic follicles. In addition, there was a reduction in lymphatic follicle size and apoptosis of the germinal centres. Immunohistochemistry revealed IgG4+/IgG + in > 40% of cells, and more than 100 IgG4 + cells per high powered field (HPF) of specimen. As of now, finding strongly suggested IgG4-RD. This patient was treated with glucocorticoids and various immunosuppressive drugs, such as prednisone, cyclosporine, methotrexate, cyclophosphamide, mycophenolate mofetil, azathioprine and hydroxychloroquine. Unfortunately, the patient did not recover. Ultimately, idiopathic multicentric Castleman disease (iMCD) was diagnosed in relation to the patient’s clinical presentation and laboratory tests, and after combination chemotherapy (VCD: Bortezomib, Cyclophosphamide and Dexamethasone), durable remission was achieved without serious adverse effects. During the follow-up period of one year and ten months, the patient remained stable. Conclusion The diagnosis of Castleman must be distinguished from other disorders such as IgG4-RD, malignant lymphoma, reactive hyperplasia of various lymph nodes (mostly caused by viral infections), plasmacytoma, advanced HIV and rheumatic diseases. Besides observing systemic symptoms, laboratory tests such as immunoglobulin levels, complement levels, interleukin levels, and C-reactive protein levels should also be performed in order to determine a diagnosis.

Abstract Background Intellectual disability (ID) is characterized by an IQ

Abstract Background Magnetic resonance-guided adaptive radiotherapy (MRgART) treatment sessions at MR-Linac are time-consuming and changes in organs at risk volumes can impact the treatment dosimetry. This study aims to evaluate the feasibility to control bladder filling during the rectum MRgART online session and its effectiveness on plan dosimetry. Methods A total of 109 online adaptive sessions of 24 rectum cancer patients treated at Unity 1.5 T MR-Linac with a short course radiotherapy (25 Gy, 5 Gy × 5) for whom the adaptive plan was optimized and recalculated online based on the daily magnetic resonance imaging (MRI) were analysed. Patients were fitted with a bladder catheter to control bladder filling; the bladder is emptied and then partially filled with a known amount of saline at the beginning and end of the online session. A first MRI ( $${\mathrm{MRI}}_{\mathrm{i}}$$ MRI i ) acquired at the beginning of the session was used for plan adaptation and the second ( $${\mathrm{MRI}}_{\mathrm{f}}$$ MRI f ) was acquired while approving the adapted plan and rigidly registered with the first to ensure the appropriateness of the isodoses on the ongoing delivery treatment. For each fraction, the time interval between the two MRIs and potential bladder changes were assessed with independent metrics, and the impact on the plan dosimetry was evaluated by comparing target and organs at risk dose volume histogram cut-off points of the plan adapted on $${\mathrm{MRI}}_{\mathrm{i}}$$ MRI i and recalculated on $${\mathrm{MRI}}_{\mathrm{f}}$$ MRI f . Results Median bladder volume variations, DSC, and HD of 8.17%, 0.922, and 2.92 mm were registered within a median time of 38 min between $${\mathrm{MRI}}_{\mathrm{i}}$$ MRI i and $${\mathrm{MRI}}_{\mathrm{f}}$$ MRI f ; dosimetric differences 0.05. Conclusion The use of a bladder filling control procedure can help ensure the dosimetric accuracy of the online adapted treatment delivered.

Prior research suggests that humans rationally integrate semantic expectations and the likelihood of noise corruptions in robust language comprehension. For such inferences to be maximally useful in normal communication, people should be sensitive to the fine-grained statistical structure of likely errors that vary across contexts, but this has not yet been shown. Here we hypothesize that a rational language user should represent fine-grained patterns of potential mistakes. To test this hypothesis, we employ a novel free-form text editing task, where participants are asked to edit sentences with subject-verb agreement errors, among stimuli with various type of other errors. We build a Bayesian cognitive model to infer the parameters of the model of errors, based on the observed frequency of the type of edits and judgments of plausibility of sentences without agreement errors in an independent norming study. Results suggest that the full Bayesian model explains the editing choice data better than alternative models that attribute the variance in human behaviors to either prior or context-insensitive error likelihood. Furthermore, the estimated likelihood parameters show a pattern in the distribution of errors qualitatively similar to that reported in empirical research of language production, suggesting that humans' intuitive theory of errors may be rational as to represent language-wise statistical structure of errors in the environment. These results provide quantitative evidence that humans closely track prior statistics over linguistic forms and deploy a context-sensitive model of errors in reasoning about the cause of problem from erroneous input.