Crocetin Enhances Temozolomide Efficacy in Glioblastoma Therapy Through Multiple Pathway Suppression.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that is difficult to remove surgically. Research suggests that substances from saffron, namely crocetin and crocin, could be effective natural treatments, showing abilities to kill cancer cells. METHODS: Our study focused on evaluating the effects of crocetin on glioma using the U87 cell line. We specifically investigated how crocetin affects the survival, growth, and spread of glioma cells, exploring its impact at concentrations ranging from 75-150 µM. The study also included experiments combining crocetin with the chemotherapy drug Temozolomide (TMZ) to assess potential synergistic effects. RESULTS: Crocetin significantly reduced the viability, proliferation, and migration of glioma cells. It achieved these effects by decreasing the levels of Matrix Metallopeptidase 9 (MMP-9) and Ras homolog family member A (RhoA), proteins that are critical for cancer progression. Additionally, crocetin inhibited the formation of cellular structures necessary for tumor growth. It blocked multiple points of the Ak Strain Transforming (AKT) signaling pathway, which is vital for cancer cell survival. This treatment led to increased cell death and disrupted the cell cycle in the glioma cells. When used in combination with TMZ, crocetin not only enhanced the reduction of cancer cell growth but also promoted cell death and reduced cell replication. This combination therapy further decreased levels of high mobility group box 1 (HMGB1) and Receptor for Advanced Glycation End-products (RAGE), proteins linked to inflammation and tumor progression. It selectively inhibited certain pathways involved in the cellular stress response without affecting others. CONCLUSION: Our results underscore the potential of crocetin as a treatment for glioma. It targets various mechanisms involved in tumor growth and spread, offering multiple avenues for therapy. Further studies are essential to fully understand and utilize crocetin's benefits in treating glioma.

Training students to serve as standardized patients in an objective structured clinical examination is feasible: A mixed-methods study.

AIM: This study aimed to evaluate examinees' perceptions of the performance of student standardized patients (SPs) and to explore student SPs' experiences. BACKGROUND: Objective structured clinical examination (OSCE) is a standard approach to the task of evaluating students' clinical competency that relies on SPs. However, professional SPs are characterized by high costs and insufficient availability. Training students to serve as SPs can help address this lack of OSCE resources. However, only preliminary evidence regarding this process and its feasibility has been reported. DESIGN: We used a concurrent mixed-method study design that included quantitative surveys and qualitative group interviews. METHODS: Our sample consisted of two-year Bachelor of Nursing program students and trained student SPs who were recruited in May 2021. We used a 5-item performance evaluation tool to assess the SPs' performance. The reliability of this evaluation tool was indicated by a Cronbach's α coefficient of.95. Descriptive statistics were used to assess the examinees' satisfaction with the student SPs' performance using SPSS 28.0 software. We used a semi-structured interview guide during a group interview; the interview was transcribed verbatim and analyzed via thematic analysis with the assistance of Microsoft Word software. RESULTS: Eighty-two nursing school students responded to the survey and 10 student SPs were included in a group interview. Nursing school students rated SPs' performance favorably. The mean score assigned to the SPs on the performance scale was 4.41 out of 5. The student SPs described the challenges and benefits that they experienced regarding their role. The challenges they described included 1) staying true to my role, 2) overcoming a physically overwhelming role and 3) facing the threat of insecurity. However, the corresponding benefits included 1) gaining rewards, 2) advancing nursing competency and 3) experiencing a sense of accomplishment. CONCLUSION: After undergoing training, the SPs performed well. They experienced a variety of challenges and obtained certain benefits. In health care education, recruiting students to serve as SPs is feasible.

Genetic association of diabetic retinopathy with long noncoding RNA CDKN2B-AS1 gene polymorphism.

AIM: We attempted to test the influences of cyclin dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene polymorphisms on the susceptibility to Diabetic retinopathy (DR). METHODS: Five single-nucleotide polymorphisms (SNPs) of the CDKN2B-AS1 gene, rs564398, rs1333048, rs1537373, rs2151280, and rs8181047 were examined in 280 DR cases and 455 DR-free diabetic controls. RESULTS: Among these loci tested, we demonstrated that diabetic carriers of at least one polymorphic allele (G) of rs2151280 (AG and GG; AOR, 1.613; 95% CI, 1.040-2.501; p = 0.033) are more susceptible to proliferative DR but not non-proliferative DR. This genetic association with the risk of developing proliferative DR was further strengthened in homozygotes for the polymorphic allele (G) of rs2151280 (GG; AOR, 2.194; 95% CI, 1.117-4.308; p = 0.023). We detected a significant association of the polymorphic allele (G) of rs2151280 with proliferative DR patients (OR, 1.503; 95% CI, 1.112-2.033; p = 0.008) but not with the entire DR or non-proliferative DR group. Moreover, as compared to those who do not possess the polymorphic allele of rs2151280 (AA), DR patients carrying at least one polymorphic allele of rs2151280 (AG + GG) exhibited a lower glomerular filtration rate and HDL cholesterol level, revealing a promotive role of rs2151280 in renal and cardiovascular complications of diabetes. CONCLUSION: Taken together, our findings implicate an impact of CDKN2B-AS1 gene polymorphisms on the progression of DR.

Molecular insights into MpAGO1 and its regulatory miRNA, miR11707, in the high-temperature acclimation of Marchantia polymorpha.

As a model plant for bryophytes, Marchantia polymorpha offers insights into the role of RNA silencing in aiding early land plants navigate the challenges posed by high-temperature environments. Genomic analysis revealed unique ARGONAUTE1 ortholog gene (MpAGO1) in M. polymorpha that is regulated by two species-specific microRNAs (miRNAs), miR11707.1 and miR11707.2. Comparative studies of small RNA profiles from M. polymorpha cellular and MpAGO1 immunoprecipitation (MpAGO1-IP) profiles at various temperatures, along with analyses of Arabidopsis AGO1 (AtAGO1), revealed that MpAGO1 has a low-selectivity for a diverse range of small RNA species than AtAGO1. Protein structural comparisons revealed no discernible differences in the MID domains of MpAGO1 and AtAGO1, suggesting the complexity of miRNA species specificity and necessitating further exploration. Small RNA profiling and size exclusion chromatography have pinpointed a subset of M. polymorpha miRNAs, notably miR11707, that remain in free form within the cell at 22°C but are loaded into MpAGO1 at 28°C to engage in RNA silencing. Investigations into the mir11707 gene editing (mir11707ge) mutants provided evidence of the regulation of miR11707 in MpAGO1. Notably, while MpAGO1 mRNA expression decreases at 28°C, the stability of the MpAGO1 protein and its associated miRNAs is essential for enhancing the RISC activity, revealing the importance of RNA silencing in enabling M. polymorpha to survive thermal stress. This study advances our understanding of RNA silencing in bryophytes and provides groundbreaking insights into the evolutionary resilience of land plants to climatic adversities.

Cell-Electrode Models for Impedance Analysis of Epithelial and Endothelial Monolayers Cultured on Microelectrodes.

Electric cell-substrate impedance sensing has been used to measure transepithelial and transendothelial impedances of cultured cell layers and extract cell parameters such as junctional resistance, cell-substrate separation, and membrane capacitance. Previously, a three-path cell-electrode model comprising two transcellular pathways and one paracellular pathway was developed for the impedance analysis of MDCK cells. By ignoring the resistances of the lateral intercellular spaces, we develop a simplified three-path model for the impedance analysis of epithelial cells and solve the model equations in a closed form. The calculated impedance values obtained from this simplified cell-electrode model at frequencies ranging from 31.25 Hz to 100 kHz agree well with the experimental data obtained from MDCK and OVCA429 cells. We also describe how the change in each model-fitting parameter influences the electrical impedance spectra of MDCK cell layers. By assuming that the junctional resistance is much smaller than the specific impedance through the lateral cell membrane, the simplified three-path model reduces to a two-path model, which can be used for the impedance analysis of endothelial cells and other disk-shaped cells with low junctional resistances. The measured impedance spectra of HUVEC and HaCaT cell monolayers nearly coincide with the impedance data calculated from the two-path model.

Targeting the CDK7-MDK axis to suppresses irinotecan resistance in colorectal cancer.

AIMS: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer. MAIN METHODS: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan. KEY FINDINGS: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan. SIGNIFICANCE: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.

Viscolin-mediated antiapoptotic and neuroprotective effects in cortical neurons exposed to oxygen-glucose deprivation and rats subjected to transient focal cerebral ischemia.

OBJECTIVE: Previously, we have successfully purified and synthesized viscolin, an agent derived from Viscum coloratum extract, which has shown significant potential in the treatment of stroke. Our study aimed to evaluate the neuroprotective effects of viscolin. METHODS: We first assessed the cytotoxicity of viscolin on primary neuronal cultures and determined its antioxidant and radical scavenging properties. Subsequently, we identified the optimal dose-response of viscolin in protecting against glutamate-induced neurotoxicity. RESULTS: Our results demonstrated that viscolin at a concentration of 10 µM effectively reduced neuronal cell death up to 6 hours after glutamate-induced neurotoxicity. Additionally, we investigated the therapeutic window of opportunity and the potential of viscolin in preventing necrotic and apoptotic damage in cultured neurons exposed to oxygen glucose deprivation-induced neurotoxicity. Our findings showed that viscolin treatment significantly reduced DNA breakage, prevented the release of cytochrome c from mitochondria to cytosol, increased the expression of anti-apoptotic protein Bcl-2, decreased the expression of pro-apoptotic protein Bax, and reduced the number of TUNEL-positive cells. Additionally, our in vivo investigation demonstrated a reduction in brain infarction following middle cerebral artery occlusion. CONCLUSION: Viscolin has potential utility as a therapeutic agent in the treatment of stroke.

Substrate diversity of NSUN enzymes and links of 5-methylcytosine to mRNA translation and turnover.

Maps of the RNA modification 5-methylcytosine (m5C) often diverge markedly not only because of differences in detection methods, data depand analysis pipelines but also biological factors. We re-analysed bisulfite RNA sequencing datasets from five human cell lines and seven tissues using a coherent m5C site calling pipeline. With the resulting union list of 6,393 m5C sites, we studied site distribution, enzymology, interaction with RNA-binding proteins and molecular function. We confirmed tRNA:m5C methyltransferases NSUN2 and NSUN6 as the main mRNA m5C "writers," but further showed that the rRNA:m5C methyltransferase NSUN5 can also modify mRNA. Each enzyme recognises mRNA features that strongly resemble their canonical substrates. By analysing proximity between mRNA m5C sites and footprints of RNA-binding proteins, we identified new candidates for functional interactions, including the RNA helicases DDX3X, involved in mRNA translation, and UPF1, an mRNA decay factor. We found that lack of NSUN2 in HeLa cells affected both steady-state levels of, and UPF1-binding to, target mRNAs. Our studies emphasise the emerging diversity of m5C writers and readers and their effect on mRNA function.

Generation of a biliary tract cancer cell line atlas reveals molecular subtypes and therapeutic targets.

Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.

A 20 year experience in the management of non-tubal ectopic pregnancies in a tertiary hospital - a retrospective review.

BACKGROUND: Non-tubal ectopic pregnancies account for < 10% of all ectopic pregnancies. Due to its rarity and wide variation in clinical practice, there is no guideline or consensus for its management. We reported our 20-year experience in the management of non-tubal ectopic pregnancies in a tertiary hospital. METHODS: This is a retrospective review of all women admitted for non-tubal ectopic pregnancies from January 2003 to December 2022 in a tertiary hospital. Women with non-tubal ectopic pregnancies diagnosed by ultrasound or operation were included for analysis. RESULTS: Within the study period, 180 women were diagnosed to have non-tubal ectopic pregnancies at a mean gestation of 6.8 weeks. 16.7% (30/180) were conceived via assisted reproduction. Medical treatment was the first-line management option for 81 women, of which 75 (92.1%) women received intralesional methotrexate administered under transvaginal ultrasound guidance. The success rate of intralesional methotrexate ranges from 76.5% to 92.3%. Intralesional methotrexate was successful even in cases with a positive fetal pulsation or with high human chorionic gonadotrophin levels up to 252605U/L. Twenty seven women were managed expectantly and 40 underwent surgery. Nine (11.1%), two (6.1%), and one (2.3%) women required surgery due to massive or recurrent bleeding following medical, expectant, or surgical treatment. Hysterotomy and uterine artery embolization were necessary to control bleeding in one Caesarean scar and one cervical pregnancy. CONCLUSIONS: Intralesional methotrexate is more effective than systemic methotrexate and should be considered as first line medical treatment for non-tubal ectopic pregnancies. It has a high success rate in the management of unruptured non-tubal ectopic pregnancies even in the presence of fetal pulsations or high human chorionic gonadotrophin levels, but patients may require a prolonged period of monitoring. Close surveillance and readily available surgery were required due to the risk of heavy post-procedural intra-abdominal bleeding.

Polypharmacy among adults with asthma in the United States, 2005-2020.

BACKGROUND: Asthma is a chronic disease that often requires medication for control. Polypharmacy remains a major issue to medication adherence; however, its evidence among patients with asthma is limited. OBJECTIVES: To evaluate the prevalence and determinants of polypharmacy and its associations with asthma control among adults with asthma in the United States. METHODS: Data from the 2005-2020 National Health and Nutrition Examination Survey (NHANES) were used to estimate the weighted prevalence of polypharmacy. Selected variables, including demographics, comorbidities, prescription medications, and asthma-related adverse events, were extracted from the NHANES. Multivariable logistic regression was conducted to identify factors associated with polypharmacy. Another two sets of multivariable logistic regression models were employed to further assess the association between polypharmacy and asthma-related adverse events: one for asthma attacks and the other for asthma-related emergency room visits. RESULTS: From 2005 to 2020, polypharmacy prevalence was 34.3% and 14.1% among adults with and without asthma, respectively. Characteristics, including older age (P<0.01), non-Hispanic blacks (P<0.01), health insurance coverage (P<0.01), number of healthcare visits (P<0.01), and multiple comorbidities (P<0.01) were associated with polypharmacy. Polypharmacy was associated with increased risks of having asthma attacks (OR, 1.38; 95% CI, 1.08-1.76) and asthma-related emergency room visits (OR, 1.46; 95% CI, 1.09-1.94) among adults with asthma. Among patients taking at least one asthma medication, risks of asthma attacks and asthma-related ER visits did not differ between those with and without polypharmacy. CONCLUSION: Approximately one in three adults with asthma experienced polypharmacy in the United States. Disparities existed in several characteristics, highlighting the necessity for appropriate care and policies among vulnerable populations. Further validation on the impact of polypharmacy on asthma control is required.

Optimizing immunofluorescence with high-dynamic-range imaging to enhance PD-L1 expression evaluation for 3D pathology assessment from NSCLC tumor tissue.

Assessing programmed death ligand 1 (PD-L1) expression through immunohistochemistry (IHC) is the golden standard in predicting immunotherapy response of non-small cell lung cancer (NSCLC). However, observation of heterogeneous PD-L1 distribution in tumor space is a challenge using IHC only. Meanwhile, immunofluorescence (IF) could support both planar and three-dimensional (3D) histological analyses by combining tissue optical clearing with confocal microscopy. We optimized clinical tissue preparation for the IF assay focusing on staining, imaging, and post-processing to achieve quality identical to traditional IHC assay. To overcome limited dynamic range of the fluorescence microscope's detection system, we incorporated a high dynamic range (HDR) algorithm to restore the post imaging IF expression pattern and further 3D IF images. Following HDR processing, a noticeable improvement in the accuracy of diagnosis (85.7%) was achieved using IF images by pathologists. Moreover, 3D IF images revealed a 25% change in tumor proportion score for PD-L1 expression at various depths within tumors. We have established an optimal and reproducible process for PD-L1 IF images in NSCLC, yielding high quality data comparable to traditional IHC assays. The ability to discern accurate spatial PD-L1 distribution through 3D pathology analysis could provide more precise evaluation and prediction for immunotherapy targeting advanced NSCLC.

The Clinical Impact of Different Types of Preoperative Biliary Intervention on Postoperative Biliary Tract Infection of Patients Undergoing Pancreaticoduodenectomy.

Background: For patients with obstructive jaundice and who are indicated for pancreaticoduodenectomy (PD) or biliary intervention, either endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography and drainage (PTCD) may be indicated preoperatively. However, the possibility of procedure-related postoperative biliary tract infection (BTI) should be a concern. We tried to evaluate the impact of ERCP and PTCD on postoperative BTI. Methods: Patients diagnosed from June 2013 to March 2022 with periampullary lesions and with PD indicated were enrolled in this cohort. Patients without intraoperative bile culture and non-neoplastic lesions were excluded. Clinical information, including demographic and laboratory data, pathologic diagnosis, results of microbiologic tests, and relevant infectious outcomes, was extracted from medical records for analysis. Results: One-hundred-and-sixty-four patients from the cohort (164/689) underwent preoperative biliary intervention, either ERCP (n = 125) or PTCD (n = 39). The positive yield of intraoperative biliary culture was significantly higher in patients who underwent ERCP than in PTCD (90.4% vs. 41.0%, p < 0.001). Although there was no significance, a trend of higher postoperative BTI (13.8% vs. 2.7%) and BTI-related septic shock (5 vs. 0, 4.0% vs. 0%) in the ERCP group was noticed. While the risk factors for postoperative BTI have not been confirmed, a trend suggesting a higher incidence of BTI associated with ERCP procedures was observed, with a borderline p-value (p = 0.05, regarding ERCP biopsy). Conclusions: ERCP in patients undergoing PD increases the positive yield of intraoperative biliary culture. PTCD may be the favorable option if preoperative biliary intervention is indicated.

Treatment pattern among patients with relapsed/refractory multiple myeloma (RRMM) who had received pomalidomide-based regimens in Taiwan.

BACKGROUND/PURPOSE: The treatment landscape of relapsed/refractory multiple myeloma (RRMM) is rapidly evolving in Taiwan. The present study aimed to assess the treatment patterns among RRMM patients in Taiwan. METHODS: This retrospective, chart review-based, non-interventional study collected data on RRMM patients (≥20 years old) receiving pomalidomide-based treatment between January 2017 and December 2020 across five sites in Taiwan. RESULTS: Median age of the study population was 65.6 years. Approximately 75% patients received a doublet regimen and 25% were on a triplet regimen. Disease progression was the most common cause for switching to pomalidomide-based treatments in doublet (71.2%) and triplet (58.3%) groups. Patients in doublet and triplet groups (>80%) received 4 mg pomalidomide as a starting dose. Overall response rate (ORR: 31.5% and 45.8%) and median progression-free survival (PFS: 4.7 and 6.8 months) were reported in the doublet and triplet regimen. Doublet regimen was discontinued mainly due to disease progression or death (78.1%); however, triplet regimen patients mainly terminated their treatment due to reimbursement limitations (29.2%). Healthcare resource utilization (HRU) was comparable between doublet and triplet groups. CONCLUSION: In Taiwan, half of RRMM patients received pomalidomide-based triplet regimens. Triplet regimens showed a trend towards better outcomes with longer PFS and higher response rates compared to doublets. Notably, the duration of triplet use is influenced by reimbursement limitations. This study provides insight into RRMM treatment patterns in Taiwan and the findings suggest that triplet regimens may be a better alternative than doublet regimens.

Oxytocin treatment rescues irritability-like behavior in Cc2d1a conditional knockout mice.

Irritability, a state of excessive reactivity to negative emotional stimuli, is common in individuals with autism spectrum disorder (ASD). Although it has a significant negative impact of patients' disease severity and quality of life, the neural mechanisms underlying irritability in ASD remain largely unclear. We have previously demonstrated that male mice lacking the Coiled-coil and C2 domain containing 1a (Cc2d1a) in forebrain excitatory neurons recapitulate numerous ASD-like behavioral phenotypes, including impaired social behaviors and pronounced repetitive behaviors. Here, using the bottle-brush test (BBT) to trigger and evaluate aggressive and defensive responses, we show that Cc2d1a deletion increases irritability-like behavior in male but not female mice, which is correlated with reduced number of oxytocin (OXT)-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Intranasal OXT administration or chemogenetic activation of OXT neurons in the PVN rescues irritability-like behavior in Cc2d1a conditional knockout (cKO) mice. Administration of a selective melanocortin receptor 4 agonist, RO27-3225, which potentiates endogenous OXT release, also alleviates irritability-like behavior in Cc2d1a cKO mice, an effect blocked by a specific OXT receptor antagonist, L-368,899. We additionally identify a projection connecting the posterior ventral segment of the medial amygdala (MeApv) and ventromedial nucleus of the ventromedial hypothalamus (VMHvl) for governing irritability-like behavior during the BBT. Chemogenetic suppression of the MeApv-VMHvl pathway alleviates irritability-like behavior in Cc2d1a cKO mice. Together, our study uncovers dysregulation of OXT system in irritability-like behavior in Cc2d1a cKO mice during the BBT and provide translatable insights into the development of OXT-based therapeutics for clinical interventions.

From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development.

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC50 values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-ß-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE's main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs.

Effect of increased soil available phosphorus from vermicompost application on the bioavailability, chemical form, and bioaccessibility of heavy metals.

Phosphorus (P) plays an important role in immobilizing heavy metals (HMs), thereby preventing their accumulation, especially in edible parts of crops. In this study, vermicompost (VM) and chemical fertilizers (CFs) were used as soil amendments to increase the available P concentration in soil contaminated with cadmium (Cd) and nickel (Ni), with the aim of reducing their bioavailability, uptake, and bioaccessibility. Using CF and VM as soil amendments substantially increased the available P and exchangeable potassium concentrations in the soil. Furthermore, VM addition led to an increase in OM content and in exchangeable calcium and magnesium, resulting in the improved growth of lettuce. It also reduced the uptake of Cd and Ni in the two lettuce cultivars tested in the study. However, CF addition boosted the accumulation of Cd and Ni by increasing the soil acidity. CF addition, and especially VM addition, altered the chemical forms of Cd and Ni from active to inactive. Overall, the results of this study underscore the positive impact of using VM as a soil amendment on lettuce growth and the prevention of HM accumulation in edible parts of lettuce. VM addition led to decreased bioavailability, uptake, and bioaccessibility of HMs in soil, which could improve food safety and reduce potential risks associated with HM contamination.

Effects of cutting tool geometry on material removal of a gradient nanograined CoCrNi medium entropy alloy.

CoCrNi medium-entropy alloys (MEAs) have attracted extensive attention and research because of their superior mechanical properties, such as higher ductility, strength, and toughness. This study uses molecular dynamics (MD) simulations to investigate the cutting behavior of a gradient nanograined (GNG) CoCrNi MEA. Moreover, it explores the influence of relative tool sharpness and rake angle on the cutting process. The results show that an increase in the average grain size of the GNG samples leads to a decrease in the average resultant cutting force, as predicted by the Hall-Petch relationship. The deformation behavior shows that grain boundaries are crucial in inhibiting the propagation of strain and stress. As the average grain size of the GNG sample increases, the range of shear strain distribution and average von Mises stress decreases. Moreover, the cutting chips become thinner and longer. The subsurface damage is limited to a shallow layer at the surface. Since thermal energy is generated in the high grain boundary density, the temperature of the contact zone between the substrate and the cutting tool increases as the GNG size decreases. The cutting chips removed from the GNG CoCrNi MEA substrates will transform into a mixed structure of face-centered cubic and hexagonally close-packed phases. The sliding and twisting of grain boundaries and the merging of grains are essential mechanisms for polycrystalline deformation. Regarding the cutting parameters, the average resultant force, the material accumulation, and the chip volume increase significantly with the increase in cutting depth. In contrast to sharp tools, which mainly use shear deformation, blunt tools remove material by plowing, and the cutting force increases with the increase in cutting-edge radius and negative rake angle.

Differentiation in theta and gamma activation in weight-shifting learning between people with parkinson's disease of different anxiety severities.

Anxiety and postural control deficits may be related in people with Parkinson's disease (PwPD). However, the association between anxiety levels and weight-shifting control remains ambiguous. This study investigated whether 1) weight-shifting control differed between PwPD with and without anxiety, and 2) the learning effect of weight-shifting differed between the two populations. Additionally, we evaluated cortical activities to investigate neural mechanisms underlying weight-shifting control. Twenty-eight PwPD (14 anxiety, 14 nonanxiety) participated in a 5-day weight-shifting study by coupling the bearing weight of their more-affected leg to a sinusoidal target at 0.25 Hz. We tested the weight-shifting control on day 1 (pretest), day 3 (posttest), and day 5 (retention test) with a learning session on day 3. The error and jerk of weight-shifting trajectory and the theta and gamma powers of electroencephalography in prefrontal, frontal, sensorimotor and parietal-occipital areas were measured. At the pretest, the anxiety group showed larger error and smaller jerk of weight-shifting with greater prefrontal theta, frontal gamma, and sensorimotor gamma powers than the nonanxiety group. Anxiety intensity was correlated positively with weight-shifting error and theta power but negatively with weight-shifting jerk. Reduced weight-shifting error with increased theta power after weight-shifting learning was observed in the nonanxiety group. However, the anxiety group showed decreased gamma power after weight-shifting learning without behavior change. Our findings suggest differential weight-shifting control and associated cortical activation between PwPD with and without anxiety. In addition, anxiety would deteriorate weight-shifting control and hinder weight-shifting learning benefits in PwPD, leading to less weight-shifting accuracy and correction.