MOTAI: A Novel Method for the Study of O-GalNAcylation and Complex O-Glycosylation in Cancer.

The Tn antigen, an immature truncated O-glycosylation, is a promising biomarker for cancer detection and diagnosis. However, reliable methods for analyzing O-GalNAcylation and complex O-glycosylation are lacking. Here, we develop a novel method, MOTAI, for the sequential analysis of O-glycosylation using different O-glycoproteases. MOTAI conjugates glycopeptides on a solid support and releases different types of O-glycosylation through sequential enzymatic digestion by O-glycoproteases, including OpeRATOR and IMPa. Because OpeRATOR has less activity on O-GalNAcylation, MOTAI enriches O-GalNAcylation for subsequent analysis. We demonstrate the effectiveness of MOTAI by analyzing fetuin O-glycosylation and Jurkat cell lines. We then apply MOTAI to analyze colorectal cancer and benign colorectal polyps. We identify 32 Tn/sTn-glycoproteins and 43 T/sT-glycoproteins that are significantly increased in tumor tissues. Gene Ontology analysis reveals that most of these proteins are ECM proteins involved in the adhesion process of the intercellular matrix. Additionally, the protein disulfide isomerase CRELD2 has a significant difference in Tn expression, and the abnormally glycosylated T345 and S349 O-glycosylation sites in cancer group samples may promote the secretion of CRELD2 and ultimately tumorigenesis through ECM reshaping. In summary, MOTAI provides a powerful new tool for the in-depth analysis of O-GalNAcylation and complex O-glycosylation. It also reveals the upregulation of Tn/sTn-glycoproteins in colorectal cancer, which may provide new insights into cancer biology and biomarker discovery.

Tuning the Mechanical Properties of 3D-printed Objects by Mixing Chain Transfer Agents in Norrish Type I Photoinitiated RAFT Polymerization.

Photoinduced 3D printing via photocontrolled reversible-deactivation radical polymerization (photoRDRP) techniques has emerged as a robust technique for creating polymeric materials. However, methods for precisely adjusting the mechanical properties of these materials remain limited. In this study, we present a facile approach for adjusting the mechanical properties of 3D-printed objects by adjusting the polymer dispersity within a Norrish type I photoinitiated reversible addition-fragmentation chain transfer (NTI-RAFT) polymerization-based 3D printing process. We investigated the effects of varying the concentrations and molar ratios of trithiocarbonate (BTPA) and xanthate (EXEP) on the mechanical properties of the printed materials. Our findings demonstrate that increased concentrations of RAFT agents or higher proportions of the more active BTPA lead to a decrease in Young's modulus and glass transition temperatures, along with an increase in elongation at break, which can be attributed to the enhanced homogeneity of the polymer network. Using a commercial LCD printer, the NTI-RAFT-based 3D printing system effectively produced materials with tailored mechanical properties, highlighting its potential for practical applications.

Sarcopenia is associated with short- and long-term mortality in patients with acute-on-chronic liver failure.

BACKGROUND: While sarcopenia is recognized as a predictor of mortality in cirrhosis, its influence on acute-on-chronic liver failure (ACLF) remains uncertain. Despite multiple studies examining the impact of sarcopenia on short-term mortality in patients with ACLF, the sample size of these studies was limited, and their outcomes were inconsistent. Therefore, this study aimed to explore the impact of sarcopenia on both short- and long-term mortality in patients with ACLF. METHODS: This retrospective cohort study included 414 patients with ACLF that were treated between January 2016 and September 2022. Sarcopenia was diagnosed based on the measurement of the skeletal muscle index at the third lumbar vertebra (L3-SMI). Subsequently, the patients were divided into sarcopenia and non-sarcopenia groups. We analysed the basic clinical data of the two groups. Multivariate Cox proportional analysis was used to analyse short-term (28 days) and long-term (1 year and overall) mortality rates. RESULTS: A total of 414 patients were included, with a mean age of 52.88 ± 13.41 years. Among them, 318 (76.8%) were male, and 239 (57.7%) had sarcopenia. A total of 280 (67.6%) patients died during the study period. Among them, 153 patients died within 28 days (37%) and 209 patients died within 1 year (50.5%). We found that the 28-day, 1-year and overall mortality rates in the sarcopenia group were significantly higher than those in the non-sarcopenia group (37% vs. 22.3%, P < 0.01; 50.5% vs. 34.9%, P < 0.01; and 67.6% vs. 53.1%, P < 0.01, respectively). Multivariate Cox regression analysis revealed that sarcopenia was significantly associated with increased mortality. The hazard ratios for sarcopenia were 2.05 (95% confidence interval [CI] 1.41-3.00, P < 0.01) for 28-day mortality, 1.81 (95% CI 1.29-2.54, P < 0.01) for 1-year mortality and 1.82 (95% CI 1.30-2.55, P < 0.01) for overall mortality. In addition, muscle density and international normalized ratio were associated with short- and long-term mortality. CONCLUSIONS: Sarcopenia is associated with both short- and long-term mortality in patients with ACLF. Therefore, regular monitoring for sarcopenia is important for these patients.

[Clinical Characteristics and Prognosis of Patients with Acute Leukemia Complicated with Mucormycosis after Chemotherapy].

OBJECTIVE: To analyze the characteristics and prognosis of patients with mucormycosis after chemotherapy for acute leukemia, and to strengthen understanding of the disease. METHODS: 7 cases of acute leukemia (AL) patients diagnosed with mucormycosis by metagenomic next generation sequencing (mNGS) after chemotherapy at the First Affiliated Hospital of Bengbu Medical College from October 2021 to June 2022 were collected, and their clinical data, including clinical characteristics, diagnosis, treatment, and prognosis, were retrospectively analyzed. RESULTS: Among the 7 patients with AL complicated with mucormycosis, there were 3 males and 4 females, with a median age of 52(20-59) years. There were 6 cases of acute myeloid leukemia (AML) and 1 case of acute lymphocytic leukemia (ALL). Extrapulmonary involvement in 4 cases, including 1 case suspected of central nervous system involvement. The median time for the occurrence of mucor infection was 16(6-69) days after chemotherapy and 19(14-154) days after agranulocytosis. The main clinical manifestations of mucormycosis were fever (7/7), cough (3/7), chest pain (3/7) and dyspnea (1/7). The most common chest CT imaging findings were nodules, patchy or mass consolidation (6/7). All patients were treated with posaconazole or voriconazole prophylaxis during neutropenia phase. 5 patients died within 8 months, and the median time from diagnosis to death was 1 month. CONCLUSION: Although prophylactic antifungal therapy is adopted, patients with acute leukemia still have a risk of mucor infection during the neutropenia phase. Fever is the main manifestation in the early stage of mucor infection. The use of intravenous antifungal drugs alone is ineffective and there is a high mortality rate in acute leukemia patients with mucormycosis.

SSM-Net: Semi-supervised multi-task network for joint lesion segmentation and classification from pancreatic EUS images.

Pancreatic cancer does not show specific symptoms, which makes the diagnosis of early stages difficult with established image-based screening methods and therefore has the worst prognosis among all cancers. Although endoscopic ultrasonography (EUS) has a key role in diagnostic algorithms for pancreatic diseases, B-mode imaging of the pancreas can be affected by confounders such as chronic pancreatitis, which can make both pancreatic lesion segmentation and classification laborious and highly specialized. To address these challenges, this work proposes a semi-supervised multi-task network (SSM-Net) to leverage unlabeled and labeled EUS images for joint pancreatic lesion classification and segmentation. Specifically, we first devise a saliency-aware representation learning module (SRLM) on a large number of unlabeled images to train a feature extraction encoder network for labeled images by computing a contrastive loss with a semantic saliency map, which is obtained by our spectral residual module (SRM). Moreover, for labeled EUS images, we devise channel attention blocks (CABs) to refine the features extracted from the pre-trained encoder on unlabeled images for segmenting lesions, and then devise a merged global attention module (MGAM) and a feature similarity loss (FSL) for obtaining a lesion classification result. We collect a large-scale EUS-based pancreas image dataset (LS-EUSPI) consisting of 9,555 pathologically proven labeled EUS images (499 patients from four categories) and 15,500 unlabeled EUS images. Experimental results on the LS-EUSPI dataset and a public thyroid gland lesion dataset show that our SSM-Net clearly outperforms state-of-the-art methods.

Jujubae Fructus extract prolongs lifespan and improves stress tolerance in Caenorhabditis elegans dependent on DAF-16/SOD-3.

Jujubae Fructus, the fruit of Ziziphus jujuba Mill has been used as one of the medicine food homology species for thousands of years in China. Studies have shown that the active ingredients of Jujubae Fructus have a variety of biological effects, but its role in the aging process still lacks knowledge. Here, we investigated the effect of Jujubae Fructus extract (JE) on Caenorhabditis elegans lifespan and its potential mechanism. The lifespan of C. elegans treated with JE was signifificantly increased in a dose-dependent manner. In addition, JE treatment prolonged the reproductive period and increased normal activity during aging in C. elegans. Similarly, JE supplementation also enhanced the resistance to heat and oxidative stress in C. elegans. Furthermore, the mutant worms' lifespan assays demonstrated that JE requires daf-16 to prolong lifespan. DAF-16::GFP analysis of TJ356 showed that JE treatment translocates DAF-16::GFP to nucleus in transgenic worms. By analyzing the downstream of daf-16, we identify that JE may regulate sod3 downstream of daf-16. Mutant worms' lifespan and transgenic reporter gene expression assays revealed that increasing SOD-3 expression was critical for extending longevity in C. elegans with JE therapy. Collectively, these data indicate that JE may have an important role in C. elegans longevity that is dependent on DAF-16 and SOD-3.

The diversification of the shoot branching system: A quantitative and comparative perspective in meristem determinacy.

Reiterative shoot branching largely defines important yield components of crops and is essentially controlled by programs that direct the initiation, dormancy release, and differentiation of meristems in the axils of leaves. Here, we focus on meristem determinacy, defining the number of reiterations that shape the shoot architectures and exhibit enormous diversity in a wide range of species. The meristem determinacy per se is hierarchically complex and context-dependent for the successively emerged meristems, representing a crucial mechanism in shaping the complexity of the shoot branching. In addition, we have highlighted that two key components of axillary meristem developmental programs may have been co-opted in controlling flower/ear number of an axillary inflorescence in legumes/maize, hinting at the diversification of axillary-meristem-patterning programs in different lineages. This begs the question how axillary meristem patterning programs may have diversified during plant evolution and hence helped shape the rich variation in shoot branching systems.

Ultra-Fast Selenol-Yne Click (SYC) Reaction Enables Poly(selenoacetal) Covalent Adaptable Network Formation.

The emergence of covalent adaptable networks (CANs) based on dynamic covalent bonds (DCBs) presents a promising avenue for achieving resource recovery and utilization. In this study, we discovered a novel dynamic covalent bond called selenacetal, which is obtained through a double click reaction between selenol and activated alkynes. Density functional theory (DFT) calculations demonstrated that the ΔG for the formation of selenoacetals ranges from 12 to 18 kJ mol-1, suggesting its potential for dynamic reversibility. Dynamic exchange experiments involving small molecules and polymers provide substantial evidence supporting the dynamic exchange properties of selenoacetals. By utilizing this highly efficient click reaction, we successfully synthesized dynamic materials based on selenoacetal with remarkable reprocessing capabilities without any catalysts. These materials exhibit chemical recycling under alkaline conditions, wherein selenoacetal (SA) can decompose into active enone selenide (ES) and diselenides. Reintroducing selenol initiates a renewed reaction with the enone selenide, facilitating material recycling and yielding a newly developed dynamic material exhibiting both photo- and thermal responsiveness. The results underscore the potential of selenoacetal polymers in terms of recyclability and selective degradation, making them a valuable addition to conventional covalent adaptable networks.

Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances.

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.

Ba2Ga2F6(IO3)(PO4): the first fluoride-containing iodate-phosphate with a 1D [Ga2F6(IO3)(PO4)]4- helix chain.

Herein, the first F-containing iodate-phosphate, namely Ba2Ga2F6(IO3)(PO4), was prepared via a hydrothermal reaction, in which HPF6 (70 wt% solution in water) was used as the source of both fluoride and phosphate anions for the first time. Ba2Ga2F6(IO3)(PO4) features an unprecedented 1D [Ga2F6(IO3)(PO4)]4- helix chain, composed of a 1D Ga(1)(IO3)O4F chain via the bridging of 0D Ga(2)(PO4)F5. The UV-Vis spectrum shows that Ba2Ga2F6(IO3)(PO4) has a wide bandgap with a short-UV absorption edge (4.35 eV; 253 nm). Birefringence measurement under a polarizing microscope shows that Ba2Ga2F6(IO3)(PO4) displays a moderate birefringence of 0.072@550 nm, which is consistent with the value (0.070@550 nm) obtained by DFT calculations, indicating that Ba2Ga2F6(IO3)(PO4) has potential applications as a short-UV birefringent material. This study highlights the crucial role played by the incorporation of specific functional groups into compounds, shedding light on their contribution to promising inorganic functional materials.

Exploration into the Mechanism of Yiyi Baijiang Decoction Attenuating Chronic Pelvic Inflammation Based on Network Pharmacology and Experimental Verification.

Patients with chronic pelvic inflammation (CPI) experience irregular menstrual, ectopic pregnancy, and infertility. Yiyi Baijiang Decoction attenuates CPI in patients with uncovered mechanisms. CPI therapeutic targets intersected with those of Yiyi Baijiang Decoction, followed by importing into STRING to obtain protein-target interaction. "Drug-component-disease-target" interaction was constructed by Cytoscape. mRNA and protein levels were detected by real-time quantitative PCR (RT-qPCR) and western blot. Yiyi Baijiang Decoction contained 199 active ingredients. There were 1071 drug targets for Yiyi Baijiang Decoction and 1622 therapeutic targets for CPI. The GO functional enrichment analysis revealed 3445 biological processes, and the KEGG pathway enrichment analysis screened 67 signal pathways. Decreased ALB, increased protein kinase B (AKT1), interleukin (IL)-6, vascular endothelial growth factor A (VEGFA), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K/AKT)-extracellular-regulated protein kinases (ERK)1/2 activation in CPI mice were abolished by Yiyi Baijiang Decoction. Yiyi Baijiang Decoction attenuates CPI by inactivating PI3K/AKT and ERK1/2 and regulating ALB, VEGFA, AKT1, and IL-6.

Greatly Enhanced Thermoelectric Performance of Flexible Cu2-xS Composite Film on Nylon by Se Doping.

In this work, flexible Cu2-xS films on nylon membranes are prepared by combining a simple hydrothermal synthesis and vacuum filtration followed by hot pressing. The films consist of Cu2S and Cu1.96S two phases with grain sizes from nano to submicron. Doping Se on the S site not only increases the Cu1.96S content in the Cu2-xS to increase carrier concentration but also modifies electronic structure, thereby greatly improves the electrical properties of the Cu2-xS. Specifically, an optimal composite film with a nominal composition of Cu2-xS0.98Se0.02 exhibits a high power factor of ~150.1 µW m-1 K-2 at 300 K, which increases by ~138% compared to that of the pristine Cu2-xS film. Meanwhile, the composite film shows outstanding flexibility (~97.2% of the original electrical conductivity is maintained after 1500 bending cycles with a bending radius of 4 mm). A four-leg flexible thermoelectric (TE) generator assembled with the optimal film generates a maximum power of 329.6 nW (corresponding power density of 1.70 W m-2) at a temperature difference of 31.1 K. This work provides a simple route to the preparation of high TE performance Cu2-xS-based films.

A Reinterpretation of paracolpium in radical hysterectomy: new insights into its surgical implication.

OBJECTIVE: To reinterpret the surgical anatomy of paracolpium in radical hysterectomy and to explore its implications for the surgery. SETTING: The term "paracolpium," first defined by Fothergill in 1907, is essential in radical hysterectomy. However, several challenges remain unresolved. These include: (1) inconsistent terminology in relation to its defined attributes; (2) the lack of consensus on anatomical landmarks; (3) unclear associations with the cardinal and sacral ligaments; and (4) the critical implications and requirements of paracolpium resection in radical hysterectomy practices. PARTICIPANTS: A patient in her 60s diagnosed with stage IB2 cervical cancer was enrolled in a clinical trial and assigned to the laparoscopic surgery group. A step-by-step, narrated video demonstration. INTERVENTIONS: During the procedure, post-excision of the uterosacral, cardinal, and vesicovaginal ligaments, we identified a ligament-like structure situated between the middle third of the vagina and the pelvic wall. We have termed this structure the "paracolpium ligament." A detailed anatomical description was performed, outlining its crucial attachments.

The RALF2-FERONIA-MYB63 module orchestrates growth and defense in tomato roots.

Plant secreted peptides RAPID ALKALINISATION FACTORs (RALFs), which act through the receptor FERONIA (FER), play important roles in plant growth. However, it remains unclear whether and how RALF-FER contributes to the trade-off of plant growth-defense. Here, we used a variety of techniques such as CRISPR/Cas9, protein-protein interaction and transcriptional regulation methods to investigate the role of RALF2 and its receptor FER in regulating lignin deposition, root growth, and defense against Fusarium oxysporum f. sp. lycopersici (Fol) in tomato (Solanum lycopersicum). The ralf2 and fer mutants show reduced primary root length, elevated lignin accumulation, and enhanced resistance against Fol than the wild-type. FER interacts with and phosphorylates MYB63 to promote its degradation. MYB63 serves as an activator of lignin deposition by regulating the transcription of dirigent protein gene DIR19. Mutation of DIR19 suppresses lignin accumulation, and reverses the short root phenotype and Fol resistance in ralf2 or fer mutant. Collectively, our results demonstrate that the RALF2-FER-MYB63 module fine-tunes root growth and resistance against Fol through regulating the deposition of lignin in tomato roots. The study sheds new light on how plants maintain the growth-defense balance via RALF-FER.

A survey of 701 cases of tinea faciei in Hangzhou, southeastern China, from 2018 to 2023.

BACKGROUND: Tinea faciei, a specific dermatophytosis that affects the glabrous skin of the face, not only causes physical discomfort but also leads to greater psychological distress. Tinea faciei is a public health concern. OBJECTIVES: To analyse the epidemiological characteristics, responsible dermatophyte species and clinical features of tinea faciei in Hangzhou. METHODS: Data were obtained from the Laboratory Information System of the Mycology Laboratory and Medical Information System at a hospital in Hangzhou. Isolates were identified based on their macroscopic appearance and microscopic morphology. RESULTS: Tinea faciei was diagnosed in 701 patients, involving 359 males and 342 females, aged between 2 months and 97 years. In total, 499 isolates (71.18%) were identified as Trichophyton rubrum. Anthropophilic isolates were identified in 297 (82.73%) males and 207 (60.53%) females (p < .01). Among patients with anthropophilic dermatophytes infection, 447 (88.69%) were adults. Zoophilic dermatophytes were isolated in 57 (15.88%) males and 130 (38.01%) females (p < .01), among whom 108 (57.75%) were children. CONCLUSIONS: Anthropophilic dermatophytes, especially T. rubrum, were the predominant cause of tinea faciei, while zoophilic dermatophytes were the most prevalent in children. Compared with men, women may be more susceptible to zoophilic dermatophytes.

Natural Variation in the Promoter of GmSPL9d Affects Branch Number in Soybean.

The branch number is a crucial factor that influences density tolerance and is closely associated with the yield of soybean. However, its molecular regulation mechanisms remain poorly understood. This study cloned a candidate gene GmSPL9d for regulating the soybean branch number based on the rice OsSPL14 homologous gene. Meanwhile, the genetic diversity of the GmSPL9d was analyzed using 3599 resequencing data and identified 55 SNP/InDel variations, which were categorized into seven haplotypes. Evolutionary analysis classified these haplotypes into two groups: GmSPL9d H-I and GmSPL9d H-II. Soybean varieties carrying the GmSPL9d H-II haplotype exhibited a significantly lower branch number compared with those carrying the GmSPL9d H-I haplotype. Association analysis between the variation sites and branch number phenotypes revealed a significant correlation between the promoter variations and the branch number. Promoter activity assays demonstrated that the GmSPL9d H-II promoter displayed significantly higher activity than the GmSPL9d H-I promoter. Transgenic experiments confirmed that the plants that carried the GmSPL9d H-II promoter exhibited a significantly lower branch number compared with those that carried the GmSPL9d H-I promoter. These findings indicate that the variation in the GmSPL9d promoter affected its transcription level, leading to differences in the soybean branch number. This study provides valuable molecular targets for improving the soybean plant structure.

Immune cell signatures and causal association with irritable bowel syndrome: A mendelian randomization study.

BACKGROUND: The mucosal barrier's immune-brain interactions, pivotal for neural development and function, are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome (IBS). Prior studies linking immune inflammation with IBS have been inconsistent. To further elucidate this relationship, we conducted a Mendelian randomization (MR) analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS. Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets. AIM: To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS. We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies. METHODS: We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS. By utilizing genetic data from public databases, we examined the causal associations between 731 immune cell markers, encompassing median fluorescence intensity, relative cell abundance, absolute cell count, and morphological parameters, with IBS susceptibility. Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy. RESULTS: Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes. However, our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes (P < 0.05). Nine immune phenotypes demonstrated a protective effect against IBS [inverse variance weighting (IVW) < 0.05, odd ratio (OR) < 1], while 21 others were associated with an increased risk of IBS onset (IVW ≥ 0.05, OR ≥ 1). CONCLUSION: Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS, providing valuable insights into the pathophysiology of the condition. These results pave the way for the development of more precise biomarkers and targeted therapies for IBS. Furthermore, this research enriches our comprehension of immune cell roles in IBS pathogenesis, offering a foundation for more effective, personalized treatment approaches. These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.

NMDA receptor within nucleus accumbens shell regulates propofol self-administration through D1R/ERK/CREB signalling pathway.

Addictive properties of propofol have been demonstrated in both humans and animals. The nucleus accumbens (NAc) shell (NAsh) in the brain, along with the interactions between N-methyl-D-aspartate receptor (NMDAR) and the dopamine D1 receptor (D1R), as well as their downstream ERK/CREB signalling pathway in the NAc, are integral in regulating reward-seeking behaviour. Nevertheless, it remains unclear whether NMDARs and the NMDAR-D1R/ERK/CREB signalling pathway in the NAsh are involved in mediating propofol addiction. To investigate it, we conducted experiments with adult male Sprague-Dawley rats to establish a model of propofol self-administration behaviour. Subsequently, we microinjected D-AP5 (a competitive antagonist of NMDARs, 1.0-4.0 µg/0.3 µL/site) or vehicle into bilateral NAsh in rats that had previously self-administered propofol to examine the impact of NMDARs within the NAsh on propofol self-administration behaviour. Additionally, we examined the protein expressions of NR2A and NR2B subunits, and the D1R/ERK/CREB signalling pathways within the NAc. The results revealed that propofol administration behaviour was enhanced by D-AP5 pretreatment in NAsh, accompanied by elevated expressions of phosphorylation of NR2A (Tyr1246) and NR2B (Tyr1472) subunits. There were statistically significant increases in the expressions of D1Rs, as well as in the phosphorylated ERK1/2 (p-ERK1/2) and CREB (p-CREB). This evidence substantiates a pivotal role of NMDARs in the NAsh, with a particular emphasis on the NR2A and NR2B subunits, in mediating propofol self-administration behaviour. Furthermore, it suggests that this central reward processing mechanism may operate through the NMDAR-D1R/ERK/CREB signal transduction pathway.

Largely Enhanced Thermoelectric Performance of Flexible Ag2Se Film by Cationic Doping and Dual-Phase Engineering.

Recent studies have shown that silver selenide is a promising thermoelectric material at room temperature. Herein, flexible films with a nominal composition of (Ag1-xCux)2Se are prepared by a simple and efficient one-pot method combined with vacuum-assisted filtration and hot pressing. The thermoelectric properties of the films are regulated by both cationic doping and a dual-phase strategy via a wet chemical method. As the x increases, not only Cu is doped into the Ag2Se, but different new phases (CuAgSe and/or CuSe2) also appear. The (Ag1-xCux)2Se film with x = 0.02 composed of Cu-doped Ag2Se and CuAgSe shows a high PF of ∼2540 µW m-1 K-2 (ZT ∼ 0.90) and outstanding flexibility at room temperature. The high thermoelectric properties of the film are due to the effect of Cu doping and the CuAgSe phase, including the increase in electrical conductivity caused by doping, the enhanced phonon scattering at the Ag2Se/CuAgSe interface, and the interaction between the energy filtering effect and the doping effect. In addition to the high output performance (PDmax = 28.08 W m-2, ΔT = 32.2 K), the flexible device assembled with the (Ag0.98Cu0.02)2Se film also has potential applications as a temperature sensor.

PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. METHODS: This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. RESULTS: Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). CONCLUSIONS: Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.