Short-term responses of soil enzyme activities and stoichiometry to litter input in Castanopsis carlesii and Cunninghamia lanceolata plantations.

Litter input triggers the secretion of soil extracellular enzymes and facilitates the release of carbon (C), nitrogen (N), and phosphorus (P) from decomposing litter. However, how soil extracellular enzyme activities were controlled by litter input with various substrates is not fully understood. We examined the activities and stoichiometry of five enzymes including ß-1,4-glucosidase, ß-D-cellobiosidase, ß-1,4-N-acetyl-glucosaminidase, leucine aminopeptidase and acidic phosphatase (AP) with and without litter input in 10-year-old Castanopsis carlesii and Cunninghamia lanceolata plantations monthly during April to August, in October, and in December 2021 by using an in situ microcosm experiment. The results showed that: 1) There was no significant effect of short-term litter input on soil enzyme activity, stoichiometry, and vector properties in C. carlesii plantation. In contrast, short-term litter input significantly increased the AP activity by 1.7% in May and decreased the enzymatic C/N ratio by 3.8% in August, and decreased enzymatic C/P and N/P ratios by 11.7% and 10.3%, respectively, in October in C. lanceolata plantation. Meanwhile, litter input increased the soil enzymatic vector angle to 53.8° in October in C. lanceolata plantations, suggesting a significant P limitation for soil microorganisms. 2) Results from partial least squares regression analyses showed that soil dissolved organic matter and microbial biomass C and N were the primary factors in explaining the responses of soil enzymatic activity to short-term litter input in both plantations. Overall, input of low-quality (high C/N) litter stimulates the secretion of soil extracellular enzymes and accelerates litter decomposition. There is a P limitation for soil microorganisms in the study area.

Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on 2 selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. SIGNIFICANCE: PDAC is a notoriously difficult-to-treat malignancy, and our limited understanding of causal protein markers hampers progress in developing effective early detection strategies and treatments. Our study identifies novel causal proteins using genetic instruments and subsequently functionally validates selected novel proteins. This dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions.

Adipose-derived stem cells enriched with therapeutic mRNA TGF-ß3 and IL-10 synergistically promote scar-less wound healing in preclinical models.

Skin wound healing often leads to scar formation, presenting physical and psychological challenges for patients. Advancements in messenger RNA (mRNA) modifications offer a potential solution for pulsatile cytokine delivery to create a favorable wound-healing microenvironment, thereby preventing cutaneous fibrosis. This study aimed to investigate the effectiveness of human adipose-derived stem cells (hADSCs) enriched with N 1-methylpseudouridine (m1ψ) modified transforming growth factor-ß3 (TGF-ß3) and interleukin-10 (IL-10) mRNA in promoting scar-free healing in preclinical models. The results demonstrated that the modified mRNA (modRNA)-loaded hADSCs efficiently and temporarily secreted TGF-ß3 and IL-10 proteins. In a dorsal injury model, hADSCs loaded with modRNA TGF-ß3 and IL-10 exhibited multidimensional therapeutic effects, including improved collagen deposition, extracellular matrix organization, and neovascularization. In vitro experiments confirmed the ability of these cells to markedly inhibit the proliferation and migration of keloid fibroblasts, and reverse the myofibroblast phenotype. Finally, collagen degradation mediated by matrix metalloproteinase upregulation was observed in an ex vivo keloid explant culture model. In conclusion, the synergistic effects of the modRNA TGF-ß3, IL-10, and hADSCs hold promise for establishing a scar-free wound-healing microenvironment, representing a robust foundation for the management of wounds in populations susceptible to scar formation.

Mothers' Perceived Co-Parenting and Preschooler's Problem Behaviors: The Mediating Role of Maternal Parenting Stress and the Moderating Role of Family Resilience.

Introduction: Problem behaviors in preschoolers signals social adjustment challenges. This study investigates the mediating role of parenting stress in the relationship between co-parenting and these behaviors, and examines how family resilience impacts this dynamic. Methods: A detailed survey was conducted with 1279 mothers of 3-6-year-olds in Shanghai, China, focusing on co-parenting, family resilience, parenting stress, and children's behaviors. We employed SPSS 26 for initial tests and the Hayes PROCESS macro in SPSS 23.0 for advanced analysis, using bootstrap methods to assess mediation and moderation effects. Results: The analysis revealed that maternal parenting stress mediates the relationship between co-parenting and children's problem behaviors. Specifically, unsupportive co-parenting or low levels of supportive co-parenting heightened maternal stress, which in turn increased children's problem behaviors. Family resilience was found to moderate this relationship, buffering the impact of unsupportive co-parenting on maternal stress. High family resilience levels were associated with lower parenting stress, regardless of co-parenting quality. Conclusion: These findings highlight the importance of enhancing family resilience and supportive co-parenting to mitigate parenting stress and reduce problem behaviors in children. It has practical implications for developing family-centred interventions and policies to strengthen family resilience and co-parenting skills.

Application of machine learning in prediction of Pb2+ adsorption of biochar prepared by tube furnace and fluidized bed.

Data mining by machine learning (ML) has recently come into application in heavy metals purification from wastewater, especially in exploring lead removal by biochar that prepared using tube furnace (TF-C) and fluidized bed (FB-C) pyrolysis methods. In this study, six ML models including Random Forest Regression (RFR), Gradient Boosting Regression (GBR), Support Vector Regression (SVR), Kernel Ridge Regression (KRR), Extreme Gradient Boosting (XGB), and Light Gradient Boosting Machine (LGBM) were employed to predict lead adsorption based on a dataset of 1012 adsorption experiments, comprising 422 TF-C groups from our experiments and 590 FB-C groups from literatures. The XGB model showed superior accuracy and predictive performance for adsorption, achieving R2 values for TF-C (0.992) and FB-C (0.981), respectively. Contrasting inferior results were observed in other models, including RF (0.962 and 0.961), GBR (0.987 and 0.975), SVR (0.839 and 0.763), KRR (0.817 and 0.881), and LGBM (0.975 and 0.868). Additionally, a hybrid dataset combining both biochars in Pb adsorption also indicated high accuracy (0.972) as obtained from XGB model. The investigation revealed that the influence of char characteristics and adsorption conditions on Pb adsorption differs between the two biochar. Specific char characteristics, particularly nitrogen content, significantly influence lead adsorption in both biochar. Interestingly, the influence of pyrolysis temperature (PT) on lead adsorption is found to be greater for TF-C than for FB-C. Consequently, careful consideration of PT is crucial when preparing TF-C biochar. These findings offer practical guidance for optimizing biochar preparation conditions during heavy metal removal from wastewater.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular disease.

Fixed-dose combination (FDC) therapy, also known as polypill therapy, targets risk factors for atherosclerotic cardiovascular disease (ASCVD) and has been proposed as a strategy to reduce global ASCVD burden. Here we conducted a systematic search for relevant studies from 2016-2022 to assess the effects of FDC therapy for prevention of ASCVD. The studies selected include randomized trials evaluating FDC therapy with at least one blood pressure-lowering drug and one lipid-lowering drug. The study data were independently extracted, the quality of evidence was appraised by multiple reviewers and effect estimates were pooled using a fixed-effect meta-analysis when statistical heterogeneity was low to moderate. The main outcomes of the analysis were all-cause mortality, fatal and nonfatal ASCVD events, adverse events, systolic blood pressure, low-density lipoprotein cholesterol and adherence. Among 26 trials (n = 27,317 participants, 43.2% female and mean age range 52.9-76.0), FDC therapy was associated with lower low-density lipoprotein cholesterol and systolic blood pressure, with higher rates of adherence and adverse events in both primary and mixed secondary prevention populations. For studies with a mostly primary prevention population, FDC therapy was associated with lower risk of all-cause mortality by 11% (5.6% versus 6.3%; relative risk (risk ratio) of 0.89; 95% confidence interval 0.78 to 1.00; I2 = 0%; four trials and 16,278 participants) and risk of fatal and nonfatal ASCVD events by 29% (6.1% versus 8.4%; relative risk (risk ratio) of 0.71; 95% confidence interval 0.63 to 0.79; I2 = 0%; five trials and 15,503 participants). One adequately powered trial in an exclusively secondary prevention population showed that FDC therapy reduced the risk of major adverse cardiovascular events by 24%. These findings support adoption and implementation of polypills to lower risk for all-cause mortality and ASCVD.

Neoantigen identification: Technological advances and challenges.

Neoantigens have emerged as promising targets for cutting-edge immunotherapies, such as cancer vaccines and adoptive cell therapy. These neoantigens are unique to tumors and arise exclusively from somatic mutations or non-genomic aberrations in tumor proteins. They encompass a wide range of alterations, including genomic mutations, post-transcriptomic variants, and viral oncoproteins. With the advancements in technology, the identification of immunogenic neoantigens has seen rapid progress, raising new opportunities for enhancing their clinical significance. Prediction of neoantigens necessitates the acquisition of high-quality samples and sequencing data, followed by mutation calling. Subsequently, the pipeline involves integrating various tools that can predict the expression, processing, binding, and recognition potential of neoantigens. However, the continuous improvement of computational tools is constrained by the availability of datasets which contain validated immunogenic neoantigens. This review article aims to provide a comprehensive summary of the current knowledge as well as limitations in neoantigen prediction and validation. Additionally, it delves into the origin and biological role of neoantigens, offering a deeper understanding of their significance in the field of cancer immunotherapy. This article thus seeks to contribute to the ongoing efforts to harness neoantigens as powerful weapons in the fight against cancer.

Transcriptomic and physiological analyses reveal different grape varieties response to high temperature stress.

High temperatures affect grape yield and quality. Grapes can develop thermotolerance under extreme temperature stress. However, little is known about the changes in transcription that occur because of high-temperature stress. The heat resistance indices and transcriptome data of five grape cultivars, 'Xinyu' (XY), 'Miguang' (MG), 'Summer Black' (XH), 'Beihong' (BH), and 'Flame seedless' (FL), were compared in this study to evaluate the similarities and differences between the regulatory genes and to understand the mechanisms of heat stress resistance differences. High temperatures caused varying degrees of damage in five grape cultivars, with substantial changes observed in gene expression patterns and enriched pathway responses between natural environmental conditions (35 °C ± 2 °C) and extreme high temperature stress (40 °C ± 2 °C). Genes belonging to the HSPs, HSFs, WRKYs, MYBs, and NACs transcription factor families, and those involved in auxin (IAA) signaling, abscisic acid (ABA) signaling, starch and sucrose pathways, and protein processing in the endoplasmic reticulum pathway, were found to be differentially regulated and may play important roles in the response of grape plants to high-temperature stress. In conclusion, the comparison of transcriptional changes among the five grape cultivars revealed a significant variability in the activation of key pathways that influence grape response to high temperatures. This enhances our understanding of the molecular mechanisms underlying grape response to high-temperature stress.

Safety of an inactivated COVID-19 vaccine (CoronaVac) in children aged 7-14 years in Taizhou, China.

Our study aimed to evaluate the safety of CoronaVac, an inactivated vaccine made by Sinovac, in children aged 7-14. We conducted a parent-administered online survey to monitor adverse reactions after vaccinating children in Taizhou, China, from February 15, 2021, to January 19, 2022. 767 parents completed the survey after receiving a questionnaire via WeChat. Overall, 15.3 % (117/767) of children experienced adverse effects after the first dose, and 12.2 % (88/724) after the second. Muscle pain was the most common adverse reaction post-first dose (10.0 %), while localized pain or itching at the injection site was most common after the second dose (7.6 %). In conclusion, the vaccine has a low incidence of side effects. The mild to moderate, transient, and common nature of these effects further boosts parents' confidence in vaccinating their children.

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. METHODS: We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. RESULTS: The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. CONCLUSIONS/INTERPRETATION: Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. DATA AVAILABILITY: RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

The Facial Artery Perforator Flap for Reconstruction of Facial Defects: Surgical Pearls and Clinical Series.

BACKGROUND: Based on the knowledge of facial vascularity, facial artery perforator flaps could be used as potent tools for facial defect reconstruction. However, lack of experience and misconception of this technique limits the broad application in the clinical background. Here, we discussed surgical techniques based on our previous experience with facial artery perforator (FAP)-based facial defect reconstruction. METHODS: A retrospective review of 12 patients undergoing facial defect reconstruction using an FAP flap was performed, including 8 defects in the mid-facial part and 4 defects in the nasal area generally resulted from basal cell carcinoma (8 patients), squamous cell carcinoma (3 patients), and actinic keratosis (one patient). RESULTS: All patients received one-stage FAP flap reconstruction. The overall follow-up period was 6 to 12 months. All reconstructions were successful with satisfactory patient-reported outcome and no local recurrence. No significant complications were observed in most cases, except for one instance of partial flap loss. CONCLUSIONS: Overall, taking advantage of FAP flaps will contribute to a good functional and esthetic outcome of facial defect reconstructions.

Long non-coding RNA ACTA2-AS1 suppresses metastasis of papillary thyroid cancer via regulation of miR-4428/KLF9 axis.

BACKGROUND: Metastasis is the primary cause of recurrence and death in patients with papillary thyroid carcinoma (PTC). LncRNA ACTA2-AS1, a long non-coding RNA, acts as a tumor suppressor in multiple types of human malignancies, while the role of ACTA2-AS1 in PTC metastasis remains unclear. METHODS: The ACTA2-AS1 expression in PTC tissues was analyzed. The sponged roles of ACTA2-AS1 via miR-4428/KLF9 axis were identified using starBase tool. The function of ACTA2-AS1 in PTC was performed with in vitro and in vivo experiments. The correlation between DNA methylation and mRNA expressions of these gene in the TCGA dataset was explored. RESULTS: ACTA2-AS1 expression was downregulated in PTC tissues without metastasis and further decreased in PTC tissues with lymph node metastasis compared with that in normal tissues. Functionally, the overexpression of ACTA2-AS1 inhibited the growth, proliferation, and invasion of PTC cells, whereas its depletion exerted opposite effect. In vivo, ACTA2-AS1 expression inhibited PTC metastasis. Furthermore, ACTA2-AS1 acted as a competing endogenous RNA for miR-4428, thereby positively regulating the expression of miR-4428 target gene, KLF9. Finally, miR-4428 overexpression enhanced invasive potential of PTC cells and significantly weakened the effects of ACTA2-AS1 on promotion and inhibition of KLF9 expression as well as invasive ability of PTC cells, respectively. In the TCGA dataset, the methylation level of ACTA2-AS1 was significantly correlated with its mRNA expression (r = 0.21, p = 2.1 × e-6). CONCLUSIONS: Our findings demonstrate that ACTA2-AS1 functions as a tumor suppressor in PTC progression at least partly by regulating the miR-4428-dependent expression of KLF9.

Trade-off in the partitioning of recent photosynthate carbon under global change.

There may be trade-offs in the allocation patterns of recent photosynthetic carbon (RPC) allocation in response to environmental changes, with a greater proportion of RPC being directed towards compartments experiencing limited resource availability. Alternatively, the allocation of RPC could shift from sources to sinks as plants processing excess photosynthates. It prompts the question: Does the pattern of RPC allocation vary under global changes? If so, is this variation driven by optimal or by residual C allocation strategies? We conducted a meta-analysis by complicating 273 pairwise observations from 55 articles with 13 C or 14 C pulse or continuous labeling to assess the partitioning of RPC in biomass (leaf, stem, shoot, and root), soil pools (soil organic C, rhizosphere, and microbial biomass C) and CO2 fluxes under elevated CO2 (eCO2 ), warming, drought and nitrogen (N) addition. We propose that the increased allocation of RPC to belowground under sufficient CO2 results from the excretion of excess photosynthates. Warming led to a significant reduction in the percentage of RPC allocated to shoots, alongside an increase in roots allocation, although this was not statistically significant. This pattern is due to the reduced water availability resulting from warming. In conditions of drought, there was a notable increase in the partitioning of RPC to stems (+7.25%) and roots (+36.38%), indicative of a greater investment of RPC in roots for accessing water from deeper soil. Additionally, N addition led to a heightened allocation of RPC in leaves (+10.18%) and shoots (+5.78%), while reducing its partitioning in soil organic C (-8.92%). Contrary to the residual C partitioning observed under eCO2 , the alterations in RPC partitioning in response to warming, drought, and N supplementation are more comprehensively explained through the lens of optimal partitioning theory, showing a trade-off in the partitioning of RPC under global change.

Business decision-making of power generators in competitive electricity market.

This paper presents a theoretical framework for the business decision-making process of the power generators as price takers when considering the participation of energy storage. The framework assesses rational valuation, optimal sales strategies, and hedging options for power plants with and without a gross sales constraint. The valuation and optimal sales strategy problems are analyzed using a risk-neutral pricing approach, dynamic programming principles, and the trinomial tree model suitable for the regime switching model. The formulation of a price risk hedging scheme flexible and widely used over-the-counter electricity derivative, the electricity contract for difference, as a tool for hedging electricity spot price risk. The minimum variance hedge ratio and its corresponding hedging efficiency formula are derived. In the section of numerical simulations, we first use the EM algorithm to calibrate the electricity spot model based on electricity spot price data of Nord Pool. Numerical simulations are then conducted on the operational decision-making of power generators under three different forms of energy storage. The results of the simulations provide a basis for power generators to evaluate the real-time value of power plants, to select optimal real-time power sales, and to determine the optimal timing of power plant transfer and storage methods.

Comparison of Batroxobin Versus the Combination of Batroxobin and Intratympanic Dexamethasone Injection in the Treatment of Sudden Sensorineural Hearing Loss.

Introduction: Sudden sensorineural hearing loss (SSNHL) manifests as an abrupt decline in hearing by at least 30 dB within a 3 day period. Intratympanic dexamethasone injection (ITDI) has gained recognition as a potential treatment for SSNHL. This study aims to investigate the efficacy of combining batroxobin with ITDI (Bat and ITDI) in treating SSNHL patients and its influence on peripheral blood inflammatory indicators. Methods: SSNHL patients were retrospectively categorized into the control group (treated with Bat) and the observation group (treated with Bat and ITDI). The study involved analyzing clinical baseline data, evaluating clinical efficacy, and comparing the total effective rates among SSNHL patients with different audiometric curve types in the observation group. Routine blood tests were performed on peripheral blood samples to calculate the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and to determine C-reactive protein (CRP) levels. Adverse reactions and complications were closely monitored. Results: Following treatment, both groups displayed improvements in hearing, with the observation group exhibiting a significantly higher total effective rate (75.90%) than the control group (59.78%). For patients with 3 distinct types of sudden hearing loss (high-frequency, flat-frequency, total deafness), Bat and ITDI treatment demonstrated increased total effective rate for patients with different sudden hearing loss types (high-frequency, flat-frequency, and total deafness). Both groups experienced reduced peripheral blood CRP levels and the NLR/PLR values, with the observation group demonstrating lower values. Additionally, across the 4 audio metric subtypes, the levels of peripheral blood CRP, NLR, and PLR decreased in SSNHL patients, and the observation group had a lower incidence of adverse reactions compared to the control group. Conclusions: Bat and ITDI emerge as notably more effective for SSNHL patients, displaying potential for reducing peripheral blood inflammatory indicator levels and mitigating the incidence of adverse reactions or complications, thereby enhancing safety.

Identification of blood metabolites associated with risk of Alzheimer's disease by integrating genomics and metabolomics data.

Specific metabolites have been reported to be potentially associated with Alzheimer's disease (AD) risk. However, the comprehensive understanding of roles of metabolite biomarkers in AD etiology remains elusive. We performed a large AD metabolome-wide association study (MWAS) by developing blood metabolite genetic prediction models. We evaluated associations between genetically predicted levels of metabolites and AD risk in 39,106 clinically diagnosed AD cases, 46,828 proxy AD and related dementia (proxy-ADD) cases, and 401,577 controls. We further conducted analyses to determine microbiome features associated with the detected metabolites and characterize associations between predicted microbiome feature levels and AD risk. We identified fourteen metabolites showing an association with AD risk. Five microbiome features were further identified to be potentially related to associations of five of the metabolites. Our study provides new insights into the etiology of AD that involves blood metabolites and gut microbiome, which warrants further investigation.

Associations between genetically predicted plasma protein levels and Alzheimer's disease risk: a study using genetic prediction models.

BACKGROUND: Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets. METHODS: We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent. RESULTS: We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment. CONCLUSIONS: Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.

Optimization of Flavonoid Extraction from Eucommia ulmoides pollen using Respond Surface Methodology and its biological activities.

Flavonoids, known for their abundance in Eucommia ulmoides pollen, possess diverse biological functions, including antioxidants, antibacterial agents, and anti-tumor properties. This study aims to establish effective parameters for flavonoid extraction from Eucommia ulmoides pollen using a microwave-assisted method, characterize the flavonoid composition of the extracted material, and explore its biological activities. Building upon the initial results from single-factor experiments, response surface methodology was employed to optimize the extraction parameters. The inhibitory effect of human breast cancer cells (MCF-7) was evaluated by CCK assay and Live/dead staining. Simultaneously, the extract's scavenging ability against DPPH free radicals and its antibacterial properties against Escherichia coli and Staphylococcus aureus were investigated. The results demonstrated that the flavonoid yield reached 3.28 g per 100 g of pollen, closely aligning with the predicted value. The IC50 for flavonoid-mediated DPPH radical scavenging was 0.04 mg/mL. The extract exhibited a robust inhibitory effect on both Escherichia coli and Staphylococcus aureus. Concurrently, the extract displayed a significant inhibitory effect on the growth and proliferation of MCF-7 cells in a dose-dependent and time-dependent manner. In addition, six kinds of flavonoids have been identified by UPLC-TOF-MS/MS technology, providing further support to the study on the anti-oxidation and anti-tumor mechanism of Eucommia ulmoides pollen extracts.

Elucidating the role of blood metabolites on pancreatic cancer risk using two-sample Mendelian randomization analysis.

Pancreatic ductal adenocarcinoma (PDAC) is an uncommon but highly fatal malignancy. Identifying causal metabolite biomarkers offers an opportunity to facilitate effective risk assessment strategies for PDAC. In this study, we performed a two-sample Mendelian randomization (MR) study to characterize the potential causal effects of metabolites in plasma on PDAC risk. Genetic instruments were determined for a total of 506 metabolites from one set of comprehensive genome-wide association studies (GWAS) involving 913 individuals of European ancestry from the INTERVAL/EPIC-Norfolk cohorts. Another set of genetic instruments was developed for 483 metabolites from an independent GWAS conducted with 8299 individuals of European ancestry from the Canadian Longitudinal Study on Aging (CLSA) cohort. We analyzed GWAS data of the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), comprising 8275 PDAC cases and 6723 controls of European ancestry. The association of metabolites with PDAC risk was assessed using the inverse-variance weighted (IVW) method, and complemented with sensitivity analyses of MR-Egger and MR-PRESSO tests. Potential side effects of targeting the identified metabolites for PDAC intervention were further evaluated by a phenome-wide MR (Phe-MR) analysis. Forty-four unique metabolites were identified to be significantly associated with PDAC risk, of which four top-ranking metabolites (X: 12798, X: 11787, X: 11308 and X: 19141) showed replication evidence when using instruments developed from both two cohorts. Our results highlight novel blood metabolites related to PDAC risk, which may help prioritize metabolic features for PDAC mechanistic research and further evaluation of their potential role in PDAC risk assessment.

Pectin based hydrogel with covalent coupled doxorubicin and limonin loading for lung tumor therapy.

Self-healing hydrogels have shown great application potential in drug delivery for anti-tumor therapy and tissue engineering. In this research, Doxorubicin (DOX) was coupled onto the oxidized pectin (pec-Ald) to prepare DOX grafted pec-AD and used to fabricate self-healing hydrogel for lung cancer therapy combined with novel herbal medicine extract limonin targeting lung cancer cells. The hydrogel was prepared with P(NIPAM195-co-AH54) cross-linking and the hydrazone bond cross-linked hydrogel showed good mechanical property and self-healing behavior. With pectin composition, the hydrogel was still biodegradable catalyzed by enzyme and in vivo. The hydrogel formed fast fit for injectable application and the hydrogel itself showed moderate lung cancer inhibition activity. With limonin loading, the hydrogel showed synergistic lung cancer therapy with the tumor growth greatly inhibited. The covalent coupling of DOX and loaded limonin in the hydrogel decreased in vivo toxicity and the hydrogel degraded on time. With biodegradability and improved lung cancer therapy efficiency, this DOX grafted self-healing hydrogel could find great potential application in cancer therapy in near future.