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Introduction: Anemia may contribute significantly to the onset of Parkinson's disease (PD). Current research on the association between anemia and PD risk is inconclusive, and the relationships between anemia-related blood cell indices and PD incidence require further clarification. This study aims to investigate the relationships between anemia, blood cell indicators, and PD risk using a thorough prospective cohort study., Methods: We used data from the UK Biobank, a prospective cohort study of 502,649 participants, and ultimately, 365,982 participants were included in the analysis. Cox proportional hazards models were utilized to adjust for confounding factors, aiming to thoroughly explore the associations between anemia and blood cell indices with the risk of incident PD. The interaction between anemia and Polygenic Risk Score (PRS) for PD was also examined. Linear regression and mediation analyses assessed potential mechanisms driven by brain structures, including grey matter volume., Results: During a median follow-up of 14.24 years, 2513 participants were diagnosed with PD. Anemia considerably increased PD risk (hazard ratio [HR] 1.98, 95 % confidence interval [CI]: 1.81-2.18, P < 0.001) after adjustments. Those with high PRS for anemia had an 83 % higher PD incidence compared to low PRS participants. Sensitivity analyses confirmed result robustness. Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. Furthermore, mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD risk., Conclusion: In summary, we consider there to be a substantial correlation between anemia and increased PD risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Cyclophosphamide (CP) is an anticancer drug; however, clinical utilization of CP is limited, resulting from its considerable toxicities. This research was performed to explore the protective effects of Chlorogenic acid (CGA) on reproductive damage induced by CP in mice., Methods: Blood samples were collected for analysis of hormone content subsequently; semen samples were evaluated for quality, and testis samples were used for histopathological evaluation and analysis of oxidative stress biomarkers, protein and gene expression levels of steroid regulatory factors, and steroid synthase., Results: The results noted that CGA increased serum testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) activity; increased SOD, GPx, and GSH oxidative stress levels in testis tissue; and decreased MDA content in testis tissue. Testicular cells in the CGA treatment group gradually returned to normal morphology, and CYP11A1 and CYP17A1 levels increased after CGA treatment. The mRNA levels of CYP11A1, CYP17A1, StAR, 3β-HSD, and 17β-HSD were significantly raised in the CGA dose group. In the test dose range, CGA can improve sperm quality, quantitative abnormality, and serum T synthesis disorder caused by CP. This mechanism may be correlated with the inhibition of oxidative stress and antioxidation levels., Conclusions: Therefore, CGA has a protective impact on testicular injuries arising from CP in mice., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Integrating multi-stimuli response properties in one molecule is challenging. This study presents two 2D polymers, [(Bpydp)Ln(H 2 O)(BDC)]·NO 3 ·2H 2 O (Ln = Eu(1), Tb(2)), exhibiting rapid photo-responsiveness and the ability to detect specific small-molecule amines. In particular, complex 1 combines the functions of inkless printing, amine detection, anti-counterfeiting, and fluorescence recognition.

Purpose: To evaluate the associations of single-nucleotide polymorphisms (SNPs) in the high-temperature requirement protease A 1 ( HTRA1) gene with myopia., Methods: 25 SNPs in HTRA1 were selected, including 23 haplotype-tagging SNPs, SNP rs2142308 from a previous genome-wide association study (GWAS) of myopia and rs11200638, a SNP strongly associated with age-related macular degeneration (AMD). All SNPs were genotyped in a Hong Kong Chinese cohort of 533 myopia subjects (including 175 high myopia, 189 moderate myopia and 189 mild myopia) and 280 non-myopic controls. The association of individual SNPs were evaluated in overall myopia and different subgroups of myopia using logistic regression., Results: A tagging SNP, rs11200647, was significantly associated with myopia (p=2.17×10 -4 , OR=0.67). Nominal associations were detected for the AMD-associated SNP rs11200638 (p=0.0042, OR=1.37) and tagging SNPs rs12266322 (p=0.0048, OR=0.59) and rs17103569 (p=0.047, OR=1.34). The association of rs11200647 with myopia remained significant after adjusting for rs11200638, rs12266322 and rs17103569. In sub-group analysis, two tagging SNPs, rs11200647 (p=2.24×10 -4 , OR=0.58) and rs12266322 (p=8.31×10 -4 , OR=0.39), showed significant association with moderate myopia. In haplotype association analysis, haplotypes AT (p=1.00×10 -4 , OR=1.77) and haplotype GT (p=0.0019, OR=0.64), defined by rs11200647 and rs66884382, were significantly associated with myopia., Conclusions: This study provided new evidence to support HTRA1 as an associated gene for myopia, especially moderate myopia. The findings suggested that myopia and AMD may have shared genetic components., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Resveratrol (RSVL) is a plant-derived polyhydroxyphenolic compound with excellent anticancer properties, alone or in combination with other chemotherapeutic drugs. However, the anticancer mechanism of RSVL is diverse and high concentrations are often required for RSVL to exert its anticancer effect, which would also adversely affect normal cells., Purpose: The main objective of this study is to investigate the molecular mechanism of how non-cytotoxic concentrations of RSVL enhance the anticancer effect of cisplatin involving a newly identified RSVL-binding protein., Methods: Cell viability of cell lines from three cancer types exposed to RSVL and/or cisplatin was measured by NBB staining assay. RSVL-binding proteins were identified using RSVL-bound CNBr-activated Sepharose 4B beads coupled with LC-MS/MS, and the binding between RSVL and novel RSVL-binding protein was further confirmed with an in vitro pull-down assay. The expression of proteins was examined by immunoblot analysis, and the activity of methyltransferase was evaluated by in vitro methylation assay. The methylation level of H3R17 in the gene promoter was investigated using ChIP-qPCR. Bioinformatics analysis was conducted to identify pathway enrichment of genes, predict drug sensitivity, and analyze the survival of cancer patients., Results: Low doses of RSVL might promote cancer cell growth whereas high doses of RSVL showed cytotoxic effects on normal cells. When co-treated with a lower cisplatin dose, non-cytotoxic RSVL levels showed synergistic anticancer effects. Here, coactivator-associated arginine methyltransferase 1 (CARM1) was identified as a novel RSVL-binding protein, and we showed that the upregulation of CARM1 increased the sensitivity of cancer cells to RSVL. Interestingly, we found that CARM1 was essential in the RSVL-induced sensitivity of cisplatin. Further molecular mechanistic studies revealed that RSVL could stabilize CARM1 protein, resulting in the upregulation and increased methyltransferase activity of CARM1. Additionally, we showed that the methylation levels of H3R17 in the promoter of p21, a downstream gene of CARM1 involving cell cycle arrest, were significantly increased after RSVL treatment. Finally, data from our bioinformatics analysis suggested that CARM1 could be utilized as a potential biomarker for chemotherapeutic drug sensitivity and prognosis in cancers., Conclusions: This study identified CARM1 as a RSVL-binding protein for the first time and elucidated the potential roles of CARM1 in enhancing the efficacy of cisplatin by low doses of RSVL, which could have important clinical implications., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Mycophenolate mofetil (MMF) has been used to treat interstitial lung disease (ILD), but mycophenolate (MPA) pharmacokinetics was not reported for this use. This ancillary study of the EVER-ILD protocol aimed at describing the pharmacokinetic variability of MPA using population modelling in ILD., Methods: Concentrations of MPA were measured during an 8-h course for 27 ILD patients treated with 1000 mg MMF b.i.d. Absorption, distribution and elimination of MPA were described using population compartment models with first-order transfer and elimination rate constants, while accounting for both absorption peaks using gamma absorption models., Results: The pharmacokinetics of MPA was best described using a two-compartment model and two gamma absorption models, model performances of this model were still similar to those of a one gamma absorption model. This pharmacokinetics seemed to be notably influenced by body weight, renal function and inflammatory status. The distribubtion value area under the concentration curve between two administrations of MMF was AUC 12  = 52.5 mg.h/L in median (interquartile range: 42.2-58.0 mg.h/L)., Conclusion: This is the first study reporting MPA pharmacokinetics in ILD. This pharmacokinetics appears to be similar to other indications and should be further investigated in future studies., (© 2024 The Author(s). Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Purpose: This study aimed to report a newly developed, high-fidelity synthetic simulator to simulate excision and primary anastomotic (EPA) bulbar urethroplasty and its clinical use for new practitioners in shortening the learning curve., Material and Methods: The bulbar urethral anastomosis simulator consists of several standardized components created according to the actual size of the male patient. Interns, novice residents, and fellows inexperienced with urethral reconstruction ( n  = 10, 5, 5) from different medical centres were invited to participate in the training programme. Two reconstructive urology experts monitored each practice. Following the training, three kinds of validity testing were used to assess the simulator: face, content, and construct. In the intern group, the task performance in the first five training sessions and the last five training ones were compared using a self-control approach. In the resident and fellow group, the real surgical data, including estimated blood loss, operative duration, and 6-month post-operative success rate of trainees after training, are plotted, which are compared with that of reconstructive urology experts ( n  = 5) included retrospectively to study the effectiveness of the simulator in shortening the learning curve., Results: The overall mean satisfaction rate for the simulators was inspiring and evaluated by experts. In the intern group, significant improvement can be achieved through 10 training sessions ( p  < 0.05). In clinical practice, the intraoperative indicators and surgical success rate of both the training groups showed the tendency to close or even better than those in the expert group. In terms of the learning curve, training groups performed better compared with experts in the early stages of their careers., Conclusions: In conclusion, this synthetic training simulator for bulbar urethral anastomosis is novel, effective, and convenient for beginners of different groups. The training course can bridge the gap between preclinical use and actual surgery via this simulator., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 The Author(s). BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified., Methods: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test., Results: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits., Conclusions: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders., (© 2024. The Author(s).)

Anther dehiscence is a crucial event in plant reproduction, tightly regulated and dependent on the lignification of the anther endothecium. In this study, we investigated the rapid lignification process that ensures timely anther dehiscence in Arabidopsis. Our findings reveal that endothecium lignification can be divided into two distinct phases. During Phase I, lignin precursors are synthesized without polymerization, while Phase II involves simultaneous synthesis of lignin precursors and polymerization. The transcription factors MYB26, NST1/2, and ARF17 specifically regulate the pathway responsible for the synthesis and polymerization of lignin monomers in Phase II. MYB26-NST1/2 is the key regulatory pathway responsible for endothecium lignification, while ARF17 facilitates this process by interacting with MYB26. Interestingly, our results demonstrate that the lignification of the endothecium, which occurs within approximately 26 h, is much faster than that of the vascular tissue. These findings provide valuable insights into the regulation mechanism of rapid lignification in the endothecium, which enables timely anther dehiscence and successful pollen release during plant reproduction., (© 2024 Institute of Botany, Chinese Academy of Sciences.)

Inflammation is one of the key injury factors for spinal cord injury (SCI). Exosomes (Exos) derived from M2 macrophages have been shown to inhibit inflammation and be beneficial in SCI animal models. However, lacking targetability restricts their application prospects. Considering that chemokine receptors increase dramatically after SCI, viral macrophage inflammatory protein II (vMIP-II) is a broad-spectrum chemokine receptor binding peptide, and lysosomal associated membrane protein 2b (Lamp2b) is the key membrane component of Exos, we speculated that vMIP-II-Lamp2b gene-modified M2 macrophage-derived Exos (vMIP-II-Lamp2b-M2-Exo) not only have anti-inflammatory properties, but also can target the injured area by vMIP-II. In this study, using a murine contusive SCI model, we revealed that vMIP-II-Lamp2b-M2-Exo could target the chemokine receptors which highly expressed in the injured spinal cords, inhibit some key chemokine receptor signaling pathways (such as MAPK and Akt), further inhibit proinflammatory factors (such as IL-1β, IL-6, IL-17, IL-18, TNF-α, and iNOS), and promote anti-inflammatory factors (such as IL-4 and Arg1) productions, and the transformation of microglia/macrophages from M1 into M2. Moreover, the improved histological and functional recoveries were also found. Collectively, our results suggest that vMIP-II-Lamp2b-M2-Exo may provide neuroprotection by targeting the injured spinal cord, inhibiting some chemokine signals, reducing proinflammatory factor production and modulating microglia/macrophage polarization., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 μM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg -1 ·d -1 , i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07-1.30, P < 0.001), and triglyceride-glucose index (TyG, OR = 0.56, 95% CI 0.36-0.83, P = 0.005) as independent factors for CAA. Therefore, we constructed a CAA prediction nomogram without haemorrhagic imaging markers. The nomogram yielded an area under the curve (AUC) of 0.811 (95% CI 0.764-0.865) in the training set and 0.830 (95% CI 0.718-0.887) in the test set, indicating an ability to identify high-risk CAA patients. These results show that CSVD patients can be phenotyped using novel inflammatory and insulin resistance indices, potentially allowing identification of high-risk CAA patients without haemorrhagic imaging markers., (© 2024. The Author(s).)

Background: Oxidative stress is a crucial factor contributing to the occurrence and development of secondary damage in spinal cord injuries (SCI), ultimately impacting the recovery process. α-lipoic acid (ALA) exhibits potent antioxidant properties, effectively reducing secondary damage and providing neuroprotective benefits. However, the precise mechanism by which ALA plays its antioxidant role remains unknown., Methods: We established a model of moderate spinal cord contusion in rats. Experimental rats were randomly divided into 3 distinct groups: the sham group, the model control group (SCI&#95;Veh), and the ALA treatment group (SCI&#95;ALA). The sham group rats were exposed only to the SC without contusion injury. Rats belonging to SCI&#95;Veh group were not administered any treatment after SCI. Rats of SCI&#95;ALA group were intraperitoneally injected with the corresponding volume of ALA according to body weight for three consecutive days after the surgery. Subsequently, three days after SCI, spinal cord samples were obtained from three groups of rats: the sham group, model control group, and administration group. Thereafter, total RNA was extracted from the samples and the expression of three sets of differential genes was analyzed by transcriptome sequencing technology. Real-time PCR was used to verify the sequencing results. The impact of ALA on oxidative stress in rats following SCI was assessed by measuring their total antioxidant capacity and hydrogen peroxide (H 2 O 2 ) content. The effects of ALA on rat recovery following SCI was investigated through Beattie and Bresnahan (BBB) score and footprint analysis., Results: The findings from the transcriptome sequencing analysis revealed that the model control group had 2975 genes with altered expression levels when compared to the ALA treatment group. Among these genes, 1583 were found to be upregulated while 1392 were down-regulated. Gene ontology (GO) displayed significant enrichment in terms of functionality, specifically in oxidative phosphorylation, oxidoreductase activity, and signaling receptor activity. The Kyoto encyclopedia of genes and genomes (KEGG) pathway was enriched in oxidative phosphorylation, glutathione metabolism and cell cycle. ALA was found to have multiple benefits for rats after SCI, including increasing their antioxidant capacity and reducing H 2 O 2 levels. Additionally, it was effective in improving motor function (such as 7 days after SCI, the BBB score for SCI&#95;ALA was 8.400 ± 0.937 compared to 7.050 ± 1.141 for SCI&#95;Veh) and promoting histological recovery after SCI (The results of HE demonstrated that the percentage of damage area in was 44.002 ± 6.680 in the SCI&#95;ALA and 57.215 ± 3.964 in the SCI&#95;Veh at the center of injury.). The sequence data from this study has been deposited into Sequence Read Archive (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242507)., Conclusion: Overall, the findings of this study confirmed the beneficial effects of ALA on recovery in SCI rats through transcriptome sequencing, behavioral, as well histology analyses.

Remediating soil contaminated with polycyclic aromatic hydrocarbons (PAHs) presents a significant environmental challenge due to their toxic and carcinogenic properties. Traditional PAHs remediation methods-chemical, thermal, and bioremediation-along with conventional soil-washing agents like surfactants and cyclodextrins face challenges of cost, ecological harm, and inefficiency. Here we show an effective and environmentally friendly calixarene derivative for PAHs removal through soil washing. Thiacalix[4]arene tetrasulfonate (TCAS) has a unique molecular structure of a sulfonate group and a sulfur atom, which enhances its solubility and facilitates selective binding with PAHs. It forms host-guest complexes with PAHs through π-π stacking, OH-π interactions, hydrogen bonding, van der Waals forces, and electrostatic interactions. These interactions enable partial encapsulation of PAH molecules, aiding their desorption from the soil matrix. Our results show that a 0.7% solution of TCAS can extract approximately 50% of PAHs from contaminated soil while preserving soil nutrients and minimizing adverse environmental effects. This research unveils the pioneering application of TCAS in removing PAHs from contaminated soil, marking a transformative advancement in resource-efficient and sustainable soil remediation strategies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Triple-negative breast cancer (TNBC) has negative expressions of ER, PR and HER2. Due to the insensitivity to both endocrine therapy and HER2-targeted therapy, the main treatment method for TNBC is cytotoxic chemotherapy. However, the curative effect of chemotherapy is limited because of the existence of acquired or intrinsic multidrug resistance. MicroRNAs (miRNAs) are frequently dysregulated in malignant tumors and involved in tumor occurrence and progression. Interestingly, growing studies show that miRNAs are involved in chemoresistance in TNBC. Thus, targeting dysregulated miRNAs could be a plausible way for better treatment of TNBC. Here, we present the updated knowledge of miRNAs associated with chemoresistance in TNBC, which may be helpful for the early diagnosis, prognosis and treatment of this life-threatening disease.

The traditional lecture-based learning (LBL) method is facing great challenges due to its low efficiency and single proceeding form. We designed a PRI-E learning mode that combined and modified problem-based, case-based, and evidence-based learning with a step-by-step approach. We evaluated the practical learning outcomes of using the PRI-E mode by comparing it with traditional lecture-based learning in oral and maxillofacial oncology education. "PRI-E" consists of the first letters of the English words Passion, Research, Innovation, and Education, and it means "the best Education". This prospective randomized controlled trial included 40 participants. We evenly divided the participants into the PRI-E (n = 20) and LBL group (n = 20) based on the entrance test scores. The same staff group designed and then taught the learning content with different group measures. The evaluation included the final test scores and questionnaire assessments. Without affecting the examination results, the PRI-E teaching method was more satisfactory and popular with participants in terms of ability development and classroom participation. Enacting the PRI-E teaching method required more time, but this did not affect its popularity among the participants. Compared with the LBL learning mode, the PRI-E learning mode was more organized and efficient in oral and maxillofacial oncology education without affecting academic performance. This model has a high degree of satisfaction, which is conducive to training students' comprehensive ability., (© 2024. The Author(s).)

This study aimed to investigate the association between irritable bowel syndrome (IBS) and Parkinson's disease (PD) utilizing prospective cohort study and Mendelian randomization. The dataset contained a substantial cohort of 426,911 participants from the UK Biobank, discussing the association between IBS and PD with Cox proportional hazards models and case-control analysis while adjusting for covariates such as age, gender, ethnicity and education level. In univariate Cox regression model, the risk of PD was reduced in IBS patients (HR: 0.774, 95%CI: 0.625-0.956, P = 0.017), but the statistical significance diminished in the three models after adjusting for other variables. In a few subgroup analyses, IBS patients are less likely to develop into PD, and patients diagnosed with IBS after 2000 also had a lower risk (HR: 0.633, 95%CI: 0.403-0.994, P = 0.047) of subsequently developing PD. In addition, we matched five healthy control participants based on gender and age at the end of the study for each IBS patient diagnosed during the follow-up period, and logistic regression results (OR:1.239, 95%CI: 0.896-1.680, P = 0.181) showed that IBS was not associated with the risk of PD. Mendelian randomization did not find significant evidence of the causal relationship between IBS and Parkinson's disease (OR: 0.801, 95%CI: 0.570-1.278, P = 0.204). Overall, we suggest that IBS status is not associated with the risk of developing PD, and that these findings provide valuable insights into the clinical management and resource allocation of patients with IBS., (© 2024. The Author(s).)

Treatment of 27- O -acetylwithaferin A ( 2 ) with the non-nucleophilic base, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), afforded 5β,6β-epoxy-4β-hydroxy-1-oxo-witha-2(3),23(24),25(27)-trienolide ( 3 ) and 4 , a homodimer of withaferin A resulting from a Diels-Alder [4 + 2] type cycloaddition of the intermediate α,β-dimethylene-δ-lactone ( 9 ). Structures of 3 and 4 were elucidated using HRMS and 1D and 2D NMR spectroscopic data. The structure of 4 was also confirmed by single crystal X-ray crystallographic analysis of its bis -4- O - p -nitrobenzoate ( 8 ). Formation of withaferin A homodimer ( 4 ) as the major product suggests regio- and stereoselectivity of the Diels-Alder [4 + 2] cycloaddition reaction of 9 . Acetylation of 2 - 4 afforded their acetyl derivatives 5 - 7 , respectively. Compounds 2 - 4 and 6 - 8 were evaluated for their cytotoxic activities against four prostate cancer (PC) cell lines (LNCaP, 22Rv1, DU-145, and PC-3) and normal human foreskin fibroblast (HFF) cells. Significantly, 4 exhibited improved activity compared to the other compounds for most of the tested cell lines.

Polyketides with the isochroman-3-one pharmacophore are rare among fungal natural products as their biosynthesis requires an unorthodox S-type aromatic ring cyclization. Genome mining uncovered a conserved gene cluster in select leotiomycetous fungi that encodes the biosynthesis of cytosporones, including isochroman-3-one congeners. Combinatorial biosynthesis in total biosynthetic and biocatalytic formats in Saccharomyces cerevisiae and in vitro reconstitution of key reactions with purified enzymes revealed how cytosporone structural and bioactivity diversity is generated. The S-type acyl dihydroxyphenylacetic acid (ADA) core of cytosporones is assembled by a collaborating polyketide synthase pair. Thioesterase domain-catalyzed transesterification releases ADA esters, some of which are known Nur77 modulators. Alternatively, hydrolytic release allows C6 hydroxylation by a flavin-dependent monooxygenase, yielding a trihydroxybenzene moiety. Reduction of the C9 carbonyl by a short chain dehydrogenase/reductase initiates isochroman-3-one formation, affording cytosporones with cytotoxic and antimicrobial activity. Enoyl di- or trihydroxyphenylacetic acids are generated as shunt products, while isocroman-3,4-diones are formed by autoxidation. The cytosporone pathway offers novel polyketide biosynthetic enzymes for combinatorial synthetic biology to advance the production of "unnatural" natural products for drug discovery.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes ( CD38 , GPNMB , RAB29 , TMEM175 , TTC19 ) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Background: Gastrointestinal motility disorders tend to develop after pancreaticoduodenectomy (PD). The objectives of this study were: (1) to investigate the impact of needleless transcutaneous neuromodulation (TN) on the postoperative recuperation following pancreaticoduodenectomy (PD), and (2) to explore the underlying mechanisms by which TN facilitates the recovery of gastrointestinal function after PD., Methods: A total of 41 patients scheduled for PD were randomized into two groups: the TN group ( n  = 21) and the Sham-TN group ( n  = 20). TN was performed at acupoints ST-36 and PC-6 twice daily for 1 h from the postoperative day 1 (POD1) to day 7. Sham-TN was performed at non-acupoints. Subsequent assessments incorporated both heart rate variation and dynamic electrogastrography to quantify alterations in vagal activity (HF) and gastric pacing activity., Results: 1)TN significantly decreased the duration of the first passage of flatus ( p  < 0.001) and defecation ( p  < 0.01) as well as the time required to resume diet ( p  < 0.001) when compared to sham-TN;2)Compared with sham-TN, TN increased the proportion of regular gastric pacing activity ( p  < 0.01);3) From POD1 to POD7, there was a discernible augmentation in HF induced by TN stimulation( p  < 0.01);4) TN significantly decreased serum IL-6 levels from POD1 to POD7 ( p  < 0.001);5) TN was an independent predictor of shortened hospital stay(β = - 0.349, p  = 0.035)., Conclusion: Needleless TN accelerates the recovery of gastrointestinal function and reduces the risk of delayed gastric emptying in patients after PD by enhancing vagal activity and controlling the inflammatory response.

Background: Ischemic stroke is a disease in which cerebral blood flow is blocked due to various reasons, leading to ischemia, hypoxia, softening, and even necrosis of brain tissues. The level of cortisol is related to the occurrence and progression of ischemic stroke. However, the mechanism governing their interrelationship is still unclear. The main objective of this study was to identify and understand the molecular mechanism between cortisol and IS., Methods: The common cortisol-related biological processes were screened by mutual verification of two data sets and the cortisol-related hub biomarkers were identified. Modular analysis of protein interaction networks was performed, and the differential pathway analysis of individual genes was conducted by GSVA and GSEA. Drug and transcription factor regulatory networks of hub genes were excavated, and the diagnostic potential of hub genes was analyzed followed by the construction of a diagnostic model., Results: By screening the two data sets by GSVA, three biological processes with common differences were obtained. After variation analysis, four cortisol-related hub biomarkers (CYP1B1, CDKN2B, MEN1, and USP8) were selected. Through the modular analysis of the protein-protein interaction network and double verification of GSVA and GSEA, a series of potential molecular mechanisms of hub genes were discovered followed by a series of drug regulatory networks and transcription factor regulatory networks. The hub biomarkers were found to have a high diagnostic value by ROC; thus, a diagnostic model with high diagnostic efficiency was constructed. The diagnostic value was mutually confirmed in the two data sets., Conclusion: Four cortisol-related hub biomarkers are identified in this study, which provides new ideas for the key changes of cortisol during the occurrence of IS., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe -/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 μg/mL) time-dependently increased Par3L expression. In Apoe -/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: SRPK1 is a splicing-related protein that plays an important role in the development and function of the human brain. This article presents evidence that SRPK1 has distinct spatiotemporal expression patterns enriched in processes related to neurodevelopmental disorders across development., Material and Method: We used the BrainSpan growing mammalian brain transcriptome to evaluate the distribution of SRPK1 throughout the entire brain. RNA-sequencing data were gathered from 524 tissue samples recovered from 41 postmortem brains of physiologically normal individuals spanning early developing fetus (8 postconception weeks, PCW) to later life (40 years of age). Using the Allen Human Brain Atlas (AHBA) dataset, we analyzed the spatial gene expression of 15 adult human brains. Using Toppgene, we identified genes that exhibit significant coexpression with SRPK1., Results: We found evidence that analyzing the spatiotemporal gene expression profile and identifying coexpressed genes reveals that SRPK1 expression is involved in various neurodevelopmental and somatic events throughout the lifetime., Conclusion: Our findings highlight the importance of detailed maps of gene expression in the human brain for improved human-to-human translation and illustrate differences in SRPK1 expression across anatomical areas and developmental stages in healthy human brain tissue., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)