Environmental colloid behaviors of humic acid - Cadmium nanoparticles in aquatic environments.

Humic acid (HA), a principal constituent of natural organic matter (NOM), manifests ubiquitously across diverse ecosystems and can significantly influence the environmental behaviors of Cd(II) in aquatic systems. Previous studies on NOM-Cd(II) interactions have primarily focused on the immobilization of Cd(II) solids, but little is known about the colloidal stability of organically complexed Cd(II) particles in the environment. In this study, we investigated the formation of HA-Cd(II) colloids and quantified their aggregation, stability, and transport behaviors in a saturated porous media representative of typical subsurface conditions. Results from batch experiments indicated that the relative quantity of HA-Cd(II) colloids increased with increasing C/Cd molar ratio and that the carboxyl functional groups of HA dominated the stability of HA-Cd(II) colloids. The results of correlation analysis between particle size, critical aggregation concentration (CCC), and zeta potential indicated that both Derjaguin-Landau-Verwey-Overbeek (DLVO) and non-DLVO interactions contributed to the enhanced colloidal stability of HA-Cd(II) colloids. Column results further confirmed that the stable HA-Cd(II) colloid can transport fast in a saturated media composed of clean sand. Together, this study provides new knowledge of the colloidal behaviors of NOM-Cd(II) nanoparticles, which is important for better understanding the ultimate cycling of Cd(II) in aquatic systems.

Regulation of Hippo/YAP axis in colon cancer progression by the deubiquitinase JOSD1.

Colon cancer is a prevalent malignancy, while recent studies revealed the dys-regulation of Hippo signaling as the important driver for colon cancer progression. Several studies have indicated that post-translational modifications on YAP play crucial roles in both Hippo signaling activity and cancer progression. This raises a puzzling question about why YAP/TAZ, an auto-inhibitory pathway, is frequently over-activated in colon cancer, despite the suppressive cascade of Hippo signaling remaining operational. The protein stability of YAP is subject to a tiny balance between ubiquitination and deubiquitination processes. Through correlation analysis of DUBs (deubiquitinases) expression and Hippo target gene signature in colon cancer samples, we found JOSD1 as a critical deubiquitinase for Hippo signaling and colon cancer progression. JOSD1 could facilitate colon cancer progression and in colon cancer, inhibition of JOSD1 via shRNA has been demonstrated to impede tumorigenesis. Furthermore, molecular mechanism studies have elucidated that JOSD1 enhances the formation of the Hippo/YAP transcriptome by impeding K48-linked polyubiquitination on YAP. ChIP assays have shown that YAP binds to JOSD1's promoter region, promoting its gene transcription. These results suggest that JOSD1 is involved in both activating and being targeted by the Hippo signaling pathway in colon cancer. Consequently, a positive regulatory loop between JOSD1 and Hippo signaling has been identified, underscoring their interdependence during colon cancer progression. Thus, targeting JOSD1 may represent a promising therapeutic approach for managing colon cancer.

Controlled Spread of a Ag Layer from the Core to the Tip along the Branches of AuAg Nanostars for Improved SERS Detection of Okadaic Acid in Shellfish.

Plasmonic Au-Ag nanostars are excellent surface-enhanced Raman scattering (SERS) probes due to bimetallic coupling and the tip effect. However, the existing preparation methods of AuAg nanostars cannot achieve controlled growth of the Ag layer on the branches of nanostars and so cannot display their SERS to the maximum extent, thus limiting its sensitivity in biosensing. Herein, a novel strategy "PEI (polyethylenimine)-guided Ag deposition method" is proposed for synthesizing AuAg core-shell nanostars (AuAg@Ag NS) with a tunable distribution of the Ag layer from the core to the tip, which offers an avenue for investigating the correlation between SERS efficiency and the extent of spread of the Ag layer. It is found that AuAg@Ag NS with a Ag layer coated the whole branch has the strongest SERS performance because the coupling between the tips and Ag layer is maximized. Meanwhile, as a completely closed core-shell structure, AuAg@Ag NS can confine and anchor 4-ATP inside the Ag layer to avoid an unstable SERS signal. By connecting the aptamer, a reliable internal standard nanoprobe with a SERS enhancement factor (EF) up to 1.86 × 108 is prepared. Okada acid is detected through competitive adsorption of this SERS probes, and the detection limit is 36.6 pM. The results gain fundamental insights into tailoring the nanoparticle morphologies and preparation of internal standard nanoprobes and also provide a promising avenue for marine toxin detection in food safety.

Unveiling the synergetic benefits of the tunneling technique using stapler tractor in precise resection of lung segments: a retrospective cohort study.

Background: Tunneling technique has shown preliminary promise in lung segmentectomy which requires the use of staplers in specific procedures. However, the obstacle when staples pass is the most obvious factor hindering the implementation and development of this technique. This study investigated whether the obstacle of the technology could be addressed by using an innovative self-designed stapler tractor and analyzed the combined and respective advantages of them. Methods: The clinical data of patients with lung nodules located near anatomical sites with potential tunnel creation treated by segmentectomy were analyzed in this retrospective case-control study. The data were divided into four groups according to four distinct surgical strategies: In Group A, the tunneling technique was performed with a stapler tractor; in Group B, the tunneling technique was performed without a stapler tractor; in Group C, didn't perform the tunneling technique but using stapler tractor in a normal approach; and in Group D, neither performed the technique nor used the stapler tractor. The general linear data, operation times, intraoperative adverse events, postoperative recovery and complications were compared. Results: Compared with other groups, Group A exhibited the best surgical outcomes in comprehensive aspects. Separately, the tunnel groups (Group A&B) had better outcomes in the macro implementation of operation, including resection margin, the number of sampled intrapulmonary lymph nodes and resected subsegments, while the staple tractor groups (Group A&C) performed better on details of the procedure, including operation time, conversion to thoracotomy, and intraoperative bleeding (p < 0.05). Both of them were beneficial for shorter hospital stay, and the tunnel group was more advantageous. Conclusion: The tunneling technique is an advanced and beneficial surgical strategy for performing precise resection of lung segments while a stapler tractor can promote and facilitate it as a supplementary instrument. They show more combined benefits in effectively minimizing the occurrence of erroneous injuries and enhancing the operational efficacy.

Comparing developed and emerging nations' Economic development with environmental footprint for low-carbon competitiveness.

This study delves into the intricate relationship between economic growth and its ecological repercussions, employing a comprehensive assessment of ecological footprint across 131 nations. The time period considered for the research spans from 2009 to 2019. Utilizing the CS-ARDL methodology, the results indicate a correlation between reducing ecological footprint and bolstering private sector domestic credit. Additionally, a relationship between diminishing private sector domestic credit of banks and augmenting private sector domestic credit within the financial sector has been identified. In conjunction with other indicators of financial advancement, the significance of domestic lending to the private sector has been underscored. The study reveals a notable reduction in human population's adverse impact on the environment. However, increased levels of energy consumption, foreign direct investment and per capita GDP are associated with an improvement in global quality of life. Particularly noteworthy is the validation of the "pollution haven hypothesis" in the global economic context. The implications of this research are substantial; suggesting that global economic dynamics may support efforts towards environmental conservation. However, outcomes may vary across regions or countries, particularly regarding the emphasis placed by the financial sector on environmental preservation. This study comprehensively examines the complex nexus between economic progress and its ecological consequences, keeping in consideration factors such as financial growth, urbanization, energy consumption and Foreign Direct Investment (FDI).

Tuning the Mechanical Properties of 3D-printed Objects by Mixing Chain Transfer Agents in Radical Promoted Cationic RAFT Polymerization.

The utilization of (cationic) reversible addition-fragmentation chain transfer (RAFT) polymerization in photoinduced three-dimensional (3D) printing has emerged as a robust technique for fabricating a variety of stimuli-responsive materials. However, methods for precisely adjusting the mechanical properties of these materials remain limited, thereby constraining their broader applicability. In this study, a facile way is introduced to modulate the mechanical properties of 3D printed objects by mixing two chain transfer agents (CTAs) within a radical-promoted cationic RAFT (RPC-RAFT) polymerization-based 3D printing process. Through systematic investigations employing tensile testing and dynamic mechanical analysis (DMA), the influence of CTA concentration and molar ratio between two CTAs on the mechanical behavior of the printed objects are explored. These findings demonstrate that higher concentrations of CTAs or a greater molar ratio of the more active CTA within the mixed CTAs result in decreased Young's modulus and glass transition temperatures of the printed objects. Moreover, the tensile failure strain increased with the increasing CTA content, i.e., the samples became more ductile. This methodology broadens the toolbox available for tailoring the mechanical properties of 3D printed materials.

aChIP is an efficient and sensitive ChIP-seq technique for economically important plant organs.

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is crucial for profiling histone modifications and transcription factor binding throughout the genome. However, its application in economically important plant organs (EIPOs) such as seeds, fruits and flowers is challenging due to their sturdy cell walls and complex constituents. Here we present advanced ChIP (aChIP), an optimized method that efficiently isolates chromatin from plant tissues while simultaneously removing cell walls and cellular constituents. aChIP precisely profiles histone modifications in all 14 tested EIPOs and identifies transcription factor and chromatin-modifying enzyme binding sites. In addition, aChIP enhances ChIP efficiency, revealing numerous novel modified sites compared with previous methods in vegetative tissues. aChIP reveals the histone modification landscape for rapeseed dry seeds, highlighting the intricate roles of chromatin dynamics during seed dormancy and germination. Altogether, aChIP is a powerful, efficient and sensitive approach for comprehensive chromatin profiling in virtually all plant tissues, especially in EIPOs.

[Retracted] MicroRNA­9 inhibits gastric cancer cell proliferation and migration by targeting neuropilin­1.

[This retracts the article DOI: 10.3892/etm.2019.7841.].

NAD+ deficiency primes defense metabolism via 1O2-escalated jasmonate biosynthesis in plants.

Nicotinamide adenine dinucleotide (NAD+) is a redox cofactor and signal central to cell metabolisms. Disrupting NAD homeostasis in plant alters growth and stress resistance, yet the underlying mechanisms remain largely unknown. Here, by combining genetics with multi-omics, we discover that NAD+ deficiency in qs-2 caused by mutation in NAD+ biosynthesis gene-Quinolinate Synthase retards growth but induces biosynthesis of defense compounds, notably aliphatic glucosinolates that confer insect resistance. The elevated defense in qs-2 is resulted from activated jasmonate biosynthesis, critically hydroperoxidation of α-linolenic acid by the 13-lipoxygenase (namely LOX2), which is escalated via the burst of chloroplastic ROS-singlet oxygen (1O2). The NAD+ deficiency-mediated JA induction and defense priming sequence in plants is recapitulated upon insect infestation, suggesting such defense mechanism operates in plant stress response. Hence, NAD homeostasis is a pivotal metabolic checkpoint that may be manipulated to navigate plant growth and defense metabolism for stress acclimation.

Epigenetic gene regulation in plants and its potential applications in crop improvement.

DNA methylation, also known as 5-methylcytosine, is an epigenetic modification that has crucial functions in plant growth, development and adaptation. The cellular DNA methylation level is tightly regulated by the combined action of DNA methyltransferases and demethylases. Protein complexes involved in the targeting and interpretation of DNA methylation have been identified, revealing intriguing roles of methyl-DNA binding proteins and molecular chaperones. Structural studies and in vitro reconstituted enzymatic systems have provided mechanistic insights into RNA-directed DNA methylation, the main pathway catalysing de novo methylation in plants. A better understanding of the regulatory mechanisms will enable locus-specific manipulation of the DNA methylation status. CRISPR-dCas9-based epigenome editing tools are being developed for this goal. Given that DNA methylation patterns can be stably transmitted through meiosis, and that large phenotypic variations can be contributed by epimutations, epigenome editing holds great promise in crop breeding by creating additional phenotypic variability on the same genetic material.

The Method of Lipemia Clearance Should be Based on the Characteristics and the Method of Testing in the Emergency Laboratory.

BACKGROUND: This study aimed to compare the lipemia removal efficiency of highspeed centrifugation, lipid scavengers, and dilution for biochemical analytes. METHODS: We collected 30 cases of lipemic plasma in an emergency laboratory and divided them into 4 aliquots. Lipemia was removed by highspeed centrifugation, lipid scavenger, dilution, and ultracentrifugation, then analytes were measured by an AU5800 analyzer. Taking ultracentrifugation as reference, the efficiencies of the other three methods were evaluated based on the deviation. RESULTS: When highspeed centrifugation was used for lipemia removal, DBIL (18.62%), and Magnesium (6.09%) could not satisfy the criterion. When lipid scavengers were applied to remove lipemia, CRP (-86.70%), TP (-8.29%), CKMB (-44.85%), DBIL (37.96%), Glu (4.20%) and phosphate (14.32%) were not suggested as lipid scavengers. For dilution, nearly half of the analytes could satisfy the criterion, including AMY (2.41%), CRP (5.54%), ALT (2.85%), GGTL (-1.73%), ALP (-0.04%), Glu (-0.84%), LDH (0.06%), CK (0.68%), BUN (3.80%), CREA (-1.54%), UA (5.42%), and magnesium (0.43%). CONCLUSIONS: Neither of the methods for lipid removal could satisfy all emergency department tests for lipid removal. This finding suggests that removing lipemia in the clinical laboratory should be based on the characteristics and the method of testing.

Harnessing transcription factor-driven ROS for synergistic multimodal lung cancer treatment.

Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond.

Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis.

Background: Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. Methods: A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. Results: A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. Conclusions: In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.

Simultaneous mutations in ITPK4 and MRP5 genes result in a low phytic acid level without compromising salt tolerance in Arabidopsis.

Generation of crops with low phytic acid (myo-inositol-1,2,3,4,5,6-hexakisphosphate (InsP6)) is an important breeding direction, but such plants often display less desirable agronomic traits. In this study, through ethyl methanesulfonate-mediated mutagenesis, we found that inositol 1,3,4-trisphosphate 5/6-kinase 4 (ITPK4), which is essential for producing InsP6, is a critical regulator of salt tolerance in Arabidopsis. Loss of function of ITPK4 gene leads to reduced root elongation under salt stress, which is primarily because of decreased root meristem length and reduced meristematic cell number. The itpk4 mutation also results in increased root hair density and increased accumulation of reactive oxygen species during salt exposure. RNA sequencing assay reveals that several auxin-responsive genes are down-regulated in the itpk4-1 mutant compared to the wild-type. Consistently, the itpk4-1 mutant exhibits a reduced auxin level in the root tip and displays compromised gravity response, indicating that ITPK4 is involved in the regulation of the auxin signaling pathway. Through suppressor screening, it was found that mutation of Multidrug Resistance Protein 5 (MRP5)5 gene, which encodes an ATP-binding cassette (ABC) transporter required for transporting InsP6 from the cytoplasm into the vacuole, fully rescues the salt hypersensitivity of the itpk4-1 mutant, but in the itpk4-1 mrp5 double mutant, InsP6 remains at a very low level. These results imply that InsP6 homeostasis rather than its overall amount is beneficial for stress tolerance in plants. Collectively, this study uncovers a pair of gene mutations that confer low InsP6 content without impacting stress tolerance, which offers a new strategy for creating "low-phytate" crops.

Research on the optimal ratio of improved electrolytic manganese residue substrate about Pennisetum sinese Roxb growth effects.

Electrolytic manganese slag (EMR) is a solid waste generated in the manganese hydrometallurgy process. It not only takes up significant land space but also contains Mn2+, which can lead to environmental contamination. There is a need for research on the treatment and utilization of EMR. Improved EMR substrate for Pennisetum sinese Roxb growth was determined in pot planting experiments. The study tested the effects of leaching solution, microorganisms, leaf cell structures, and growth data. Results indicated a substrate of 45% EMR, 40% phosphogypsum, 5% Hericium erinaceus fungi residue, 5% quicklime, and 5% dolomite sand significantly increased the available phosphorus content (135.54 ± 2.88 µg·g-1) by 17.95 times, compared to pure soil, and enhanced the relative abundance of dominant bacteria. After 240 days, the plant height (147.00 ± 0.52 cm), number of tillers (6), and aerial dry weight (144.00 ± 15.99g) of Pennisetum sinese Roxb increased by 5.81%, 200%, and 32.58%, respectively. Analyses of leaves and leaching solution revealed that the highest leaf Mn content (46.84 ± 2.91 µg·g-1) being 3.38 times higher than in pure soil, and the leaching solution Mn content (0.66 ± 0.13 µg·g-1) was lowest. Our study suggested P. sinese Roxb grown in an improved EMR substrate could be a feasible option for solidification treatment and resource utilization of EMR.

The waste solid resource utilization was achieved.The growth and ecological restoration value of Pennisetum sinese Roxb in an improved EMR substrate was found.An optimal ratio of improved EMR substrate was proposed.

DNA methylation and whole-genome transcription analysis in CD4+ T cells from systemic lupus erythematosus patients with or without renal damage.

BACKGROUND: Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus (SLE) patients and is associated with increased mortality. DNA methylation, one of the most important epigenetic modifications, has been reported as a key player in the pathogenesis of SLE. Hence, our article aimed to explore DNA methylation in CD4+ T cells from LNs to identify additional potential biomarkers and pathogenic genes involved in the progression of LN. METHODS: Our study enrolled 46 SLE patients with or without kidney injury and 23 healthy controls from 2019 to 2022. CD4+ T cells were sorted for DNA methylation genotyping and RNA-seq. Through bioinformatics analysis, we identified the significant differentially methylated CpG positions (DMPs) only in the LN group and validated them by Bisulfite PCR. Integration analysis was used to screen for differentially methylated and expressed genes that might be involved in the progression of LN, and the results were analyzed via cell experiments and flow cytometry. RESULTS: We identified 243 hypomethylated sites and 778 hypermethylated sites only in the LN cohort. Three of these DMPs, cg08332381, cg03297029, and cg16797344, were validated by Bisulfite PCR and could be potential biomarkers for LN. Integrated analysis revealed that the expression of BCL2L14 and IFI27 was regulated by DNA methylation, which was validated by azacytidine (5-aza) treatment. The overexpression of BCL2L14 in CD4+ T cells might induce renal fibrosis and inflammation by regulating the differentiation and function of Tfh cells. CONCLUSION: Our study identified novel aberrant DMPs in CD4+ T cells only in LN patients and DNA methylation-regulated genes that could be potential LN biomarkers. BCL2L14 is likely involved in the progression of LN and might be a treatment target.

Cas12a-mediated gene targeting by sequential transformation strategy in Arabidopsis thaliana.

Gene targeting (GT) allows precise manipulation of genome sequences, such as knock-ins and sequence substitutions, but GT in seed plants remains a challenging task. Engineered sequence-specific nucleases (SSNs) are known to facilitate GT via homology-directed repair (HDR) in organisms. Here, we demonstrate that Cas12a and a temperature-tolerant Cas12a variant (ttCas12a) can efficiently establish precise and heritable GT at two loci in Arabidopsis thaliana (Arabidopsis) through a sequential transformation strategy. As a result, ttCas12a showed higher GT efficiency than unmodified Cas12a. In addition, the efficiency of transcriptional and translational enhancers for GT via sequential transformation strategy was also investigated. These enhancers and their combinations were expected to show an increase in GT efficiency in the sequential transformation strategy, similar to previous reports of all-in-one strategies, but only a maximum twofold increase was observed. These results indicate that the frequency of double strand breaks (DSBs) at the target site is one of the most important factors determining the efficiency of genetic GT in plants. On the other hand, a higher frequency of DSBs does not always lead to higher efficiency of GT, suggesting that some additional factors are required for GT via HDR. Therefore, the increase in DSB can no longer be expected to improve GT efficiency, and a new strategy needs to be established in the future. This research opens up a wide range of applications for precise and heritable GT technology in plants.

Escitalopram moderately outperforms citalopram towards anti-neuroinflammation and neuroprotection in 6-hydroxydopamine-induced mouse model of Parkinson's disease.

Citalopram and escitalopram are structurally close-related antidepressants and both forms are widely used in the world. We aimed to comparatively evaluate the anti-neuroinflammatory and neuroprotective effects of escitalopram and citalopram in Parkinson's disease (PD) mouse model. Mice were randomly divided into six groups and received 6-hydroxydopamine (6-OHDA) or vehicle administration. The mice were then treated with escitalopram, citalopram or saline for consecutive 7 days. Behaviors, neuroinflammation, neurotransmitters, and neurotoxicity were assessed. Results showed that citalopram but not escitalopram worsened body weight loss and increased freezing time in the PD mice. Both drugs had no impact on the anxiety-like behaviors but ameliorated the depressive-like behaviors as in elevated plus maze and sucrose splash tests. Escitalopram but not citalopram ameliorated motor discoordination in the PD mice as in rotarod test. In accordance, escitalopram but not citalopram attenuated the 6-OHDA-induced nigrostriatal dopaminergic loss. Further mechanistic investigations showed that both drugs mitigated activations of microglia and astrocytes and/or levels of pro-inflammatory cytokines in the PD mice, but escitalopram showed appreciably better effects in the substantia nigra. Neurotransmitter examination in the prefrontal cortex suggested that the two drugs had comparable effects on the disturbed neurotransmitters in the PD mice, but citalopram was prone to disrupt certain normal homeostasis. In conclusion, escitalopram is moderately superior than citalopram to suppress neuroinflammation and to protect against dopaminergic neuronal death and motor discoordination in the 6-OHDA-induced PD mice. Our findings imply that escitalopram shall be prescribed with priority over citalopram to treat PD patients with depression as escitalopram may meanwhile provide greater additional benefits to the patients.

Influence of TPMT and NUDT15 Genetic Polymorphisms on Mercaptopurine Pharmacokinetics in Healthy Volunteers.

Aims: This study aimed to investigate the impact of genetic polymorphisms of thiopurine methyltransferase (TPMT) and NUDT15 on pharmacokinetics profile of mercaptopurine in healthy adults in China. Methods: Blood samples were obtained from 45 healthy adult volunteers who were administered azathioprine. Genomic DNA was extracted and sequenced for TPMT and NUDT15. The plasma concentrations of 6-mercaptopurine (6-MP) were determined by ultra-performance liquid chromatography-tandem mass spectrometry. Finally, pharmacokinetic parameters were calculated based on the time-concentration curve. Results: Among the 45 healthy adult volunteers enrolled in the study, two TPMT allelic variants and three NUDT15 allelic variants were detected. In total, six genotypes were identified, including TPMT*1/*1&NUDT15*1/*1, TPMT*1/*1&NUDT15*1/*2, TPMT*1/*1&NUDT15*1/*9, TPMT*1/*1&NUDT15*2/*5, TPMT*1/*6&NUDT15*1/*2, and TPMT*1/*3&NUDT15*1/*2. The results indicated that Area Under Curve (AUC) of 6-MP in volunteers with TPMT*1/*3&NUDT15*1/*2 and TPMT*1/*6&NUDT15*1/*2 were 1.57-1.62-fold higher than in individuals carrying the wild type (TPMT*1/*1&NUDT15*1/*1). Compared with wild type, the half-life (T1/2) of TPMT*1/*6&NUDT15*1/*2 was extended by 1.98 times, whereas T1/2 of TPMT*1/*3&NUDT15*1/*2 decreased by 67%. The maximum concentration (Cmax) of TPMT*1/*3&NUDT15*1/*2 increased significantly by 2.15-fold, whereas the corresponding clearance (CL/F) decreased significantly by 58.75%. Conclusion: The findings of this study corroborate the notion that various genotypes of TPMT and NUDT15 can impact the pharmacokinetics of mercaptopurine, potentially offering foundational insights for personalized mercaptopurine therapy.

A Facile Approach to Construct Novel Polyesters as Soft Midblock for Thermoplastic Elastomers.

The development of innovative synthetic strategies to create functional polycaprolactones is highly demanded for advanced material applications. In this contribution, we reported a facile synthetic strategy to prepare a class of CL-based monomers (R-TO) derived from epoxides. They readily polymerize via well-controlled ring-opening polymerization (ROP) to afford a series of polyesters P(R-TO) with high molecular weight (Mn up to 350 kDa). Sequential addition copolymerization of MTO and L-lactide (L-LA) allowed to access of a series of ABA triblock copolymers with composition-dependent mechanical properties. Notably, P(L-LA)100-b-P(MTO)500-b-P(L-LA)100 containing the amorphous P(MTO) segment as a soft midblock and crystalline P(L-LA) domain as hard end block behaved as an excellent thermoplastic elastomer (TPE) with high elongation at break (1438±204 %), tensile strength (23.5±1.7 MPa), and outstanding elastic recovery (>88 %).