How different of the rhizospheric and endophytic microbial compositions in watermelons with different fruit shapes.

Fruit shape is an important character of watermelon. And the compositions of rhizospheric and endophytic microorganisms of watermelon with different fruit shape also remains unclear. To elucidate the biological mechanism of watermelon fruit shape formations, the rhizospheric and endophytic microbial community compositions between oval (OW) and circular watermelons (CW) were analyzed. The results showed that except of the rhizospheric bacterial richness (P < 0.05), the rhizospheric and endophytic microbial (bacterial and fungal) diversity were not statistically significant between OW and CW (P > 0.05). However, the endophytic microbial (bacterial and fungal) compositions were significantly different. Firstly, Bacillus, Rhodanobacter, Cupriavidus, Luteimonas, and Devosia were the unique soil dominant bacterial genera in rhizospheres of circular watermelon (CW); In contrast, Nocardioides, Ensifer, and Saccharomonospora were the special soil dominant bacterial genera in rhizospheres of oval watermelons (OW); Meanwhile, Cephalotrichum, Neocosmospora, Phialosimplex, and Papulaspora were the unique soil dominant fungal genera in rhizospheres of circular watermelon (CW); By contrast, Acremonium, Cladosporium, Cryptococcus_f__Tremellaceae, Sodiomyces, Microascus, Conocybe, Sporidiobolus, and Acremonium were the unique soil dominant fungal genera in rhizospheres of oval watermelons (OW). Additionally, Lechevalieria, Pseudorhodoferax, Pseudomonas, Massilia, Flavobacterium, Aeromicrobium, Stenotrophomonas, Pseudonocardia, Novosphingobium, Melittangium, and Herpetosiphon were the unique dominant endophytic bacterial genera in stems of CW; In contrast, Falsirhodobacter, Kocuria, and Kineosporia were the special dominant endophytic genera in stems of OW; Moreover, Lectera and Fusarium were the unique dominant endophytic fungal genera in stems of CW; By contrast, Cercospora only was the special dominant endophytic fungal genus in stems of OW. All above results suggested that watermelons with different fruit shapes exactly recruited various microorganisms in rhizospheres and stems. Meanwhile, the enrichments of the different rhizosphric and endophytic microorganisms could be speculated in relating to watermelon fruit shapes formation.

Microcystin-LR improves anti-tumor efficacy of oxaliplatin through induction of M1 macrophage polarization.

Tumor-associated macrophages within the tumor microenvironment play an immunosuppressive role by promoting tumor growth and immune evasion. Macrophages are highly plastic and can be stimulated to adopt an anti-tumor M1 phenotype. In this study, we used microcystin-LR (MC-LR), a cyclic heptapeptide produced by cyanobacteria, to induce in vitro macrophage innate immunity and transition into the anti-tumor M1 phenotype. MC-LR was also tested in vivo in a mouse model of colorectal cancer. An intraperitoneal injection of MC-LR increased the proportion of CD86⁺ M1 macrophages and triggered the maturation of CD11c⁺ dendritic cells within tumor tissues. MC-LR combined with the chemotherapeutic drug oxaliplatin significantly inhibited tumor growth in vivo. Flow cytometry analysis revealed increased infiltration of activated cytotoxic (CD8⁺, PD-1⁺) T-cells and anti-tumor cytokines (IFNγ and Granzyme B) in the tumor tissues of the combination therapy group, suggesting that this may be the primary mechanism behind the anti-tumor effect of the combination treatment. These findings indicate that MC-LR regulates the immune stimulation of macrophage polarization and dendritic cell maturation, effectively reversing tumor immunosuppression, activating an anti-tumor immune response, and enhancing tumor therapy.

Genomic prediction based on preselected single-nucleotide polymorphisms from genome-wide association study and imputed whole-genome sequence data annotation for growth traits in Duroc pigs.

The use of whole-genome sequence (WGS) data is expected to improve genomic prediction (GP) power of complex traits because it may contain mutations that in strong linkage disequilibrium pattern with causal mutations. However, a few previous studies have shown no or small improvement in prediction accuracy using WGS data. Incorporating prior biological information into GP seems to be an attractive strategy that might improve prediction accuracy. In this study, a total of 6334 pigs were genotyped using 50K chips and subsequently imputed to the WGS level. This cohort includes two prior discovery populations that comprise 294 Landrace pigs and 186 Duroc pigs, as well as two validation populations that consist of 3770 American Duroc pigs and 2084 Canadian Duroc pigs. Then we used annotation information and genome-wide association study (GWAS) from the WGS data to make GP for six growth traits in two Duroc pig populations. Based on variant annotation, we partitioned different genomic classes, such as intron, intergenic, and untranslated regions, for imputed WGS data. Based on GWAS results of WGS data, we obtained trait-associated single-nucleotide polymorphisms (SNPs). We then applied the genomic feature best linear unbiased prediction (GFBLUP) and genomic best linear unbiased prediction (GBLUP) models to estimate the genomic estimated breeding values for growth traits with these different variant panels, including six genomic classes and trait-associated SNPs. Compared with 50K chip data, GBLUP with imputed WGS data had no increase in prediction accuracy. Using only annotations resulted in no increase in prediction accuracy compared to GBLUP with 50K, but adding annotation information into the GFBLUP model with imputed WGS data could improve the prediction accuracy with increases of 0.00%-2.82%. In conclusion, a GFBLUP model that incorporated prior biological information might increase the advantage of using imputed WGS data for GP.

Single-cell RNA sequencing highlights epithelial and microenvironmental heterogeneity in malignant progression of pancreatic ductal adenocarcinoma.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). Single-cell transcriptomics provides a unique perspective for dissecting the epithelial and microenvironmental heterogeneity that accompanies progression from benign IPMNs to invasive PDAC. Single-cell RNA sequencing was performed through droplet-based sequencing on 35 693 cells from three high-grade IPMNs and two IPMN-derived PDACs (all surgically resected). Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. For epithelial cells, we identified acinar-ductal cells and isthmus-pit cells enriched in IPMN lesions and profiled three types of PDAC-unique ductal cells. Notably, a proinflammatory immune component was distinctly observed in IPMNs, comprising CD4+ T cells, CD8+ T cells, and B cells, whereas M2 macrophages were significantly accumulated in PDAC. Through the analysis of cellular communication, the osteopontin gene (SPP1)-CD44 pathway between macrophages and epithelial cells were particularly strengthened in the PDAC group. Further prognostic analysis revealed that SPP1 is a biomarker of IPMN carcinogenesis for surveillance. This study demonstrates the ability to perform high-resolution profiling of single cellular transcriptomes during the progression of high-grade IPMNs to cancer. Notably, single-cell analysis provides an unparalleled insight into both epithelial and microenvironmental heterogeneity associated with early cancer pathogenesis and provides practical markers for surveillance and targets for cancer interception.

Metabolomics, Transcriptome and Single-Cell RNA Sequencing Analysis of the Metabolic Heterogeneity between Oral Cancer Stem Cells and Differentiated Cancer Cells.

Understanding the distinct metabolic characteristics of cancer stem cells (CSC) may allow us to better cope with the clinical challenges associated with them. In this study, OSCC cell lines (CAL27 and HSC3) and multicellular tumor spheroid (MCTS) models were used to generate CSC-like cells. Quasi-targeted metabolomics and RNA sequencing were used to explore altered metabolites and metabolism-related genes. Pathview was used to display the metabolites and transcriptome data in a KEGG pathway. The single-cell RNA sequencing data of six patients with oral cancer were analyzed to characterize in vivo CSC metabolism. The results showed that 19 metabolites (phosphoethanolamine, carbamoylphosphate, etc.) were upregulated and 109 metabolites (2-aminooctanoic acid, 7-ketocholesterol, etc.) were downregulated in both MCTS cells. Integration pathway analysis revealed altered activity in energy production (glycolysis, citric cycle, fatty acid oxidation), macromolecular synthesis (purine/pyrimidine metabolism, glycerophospholipids metabolism) and redox control (glutathione metabolism). Single-cell RNA sequencing analysis confirmed altered glycolysis, glutathione and glycerophospholipid metabolism in in vivo CSC. We concluded that CSCs are metabolically inactive compared with differentiated cancer cells. Thus, oral CSCs may resist current metabolic-related drugs. Our result may be helpful in developing better therapeutic strategies against CSC.

Supramolecular Peptide Amphiphile Nanospheres Reprogram Tumor-associated Macrophage to Reshape the Immune Microenvironment for Enhanced Breast Cancer Immunotherapy.

Tumor immunotherapy has become a research hotspot in cancer treatment, with macrophages playing a crucial role in tumor development. However, the tumor microenvironment restricts macrophage functionality, limiting their therapeutic potential. Therefore, modulating macrophage function and polarization is essential for enhancing tumor immunotherapy outcomes. Here, a supramolecular peptide amphiphile drug-delivery system (SPADS) is utilized to reprogram macrophages and reshape the tumor immune microenvironment (TIM) for immune-based therapies. The approach involved designing highly specific SPADS that selectively targets surface receptors of M2-type macrophages (M2-Mφ). These targeted peptides induced M2-Mφ repolarization into M1-type macrophages by dual inhibition of endoplasmic reticulum and oxidative stresses, resulting in improved macrophagic antitumor activity and immunoregulatory function. Additionally, TIM reshaping disrupted the immune evasion mechanisms employed by tumor cells, leading to increased infiltration, and activation of immune cells. Furthermore, the synergistic effect of macrophage reshaping and anti-PD-1 antibody (aPD-1) therapy significantly improved the immune system's ability to recognize and eliminate tumor cells, thereby enhancing tumor immunotherapy efficacy. SPADS utilization also induced lung metastasis suppression. Overall, this study demonstrates the potential of SPADS to drive macrophage reprogramming and reshape TIM, providing new insights, and directions for developing more effective immunotherapeutic approaches in cancer treatment.

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia.

Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV-sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV-susceptible and DA-resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA-resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL-1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.

qGLF5 from Oryza rufipogon Griff. improves kernel shape, plant architecture, and yield in rice.

KEY MESSAGE: A novel QTL qGLF5 from Oryza rufipogon Griff. improves yield per plant and plant architecture in rice. Kernel size and plant architecture are critical agronomic traits that are key targets for improving crop yield. From the single-segment substitution lines of Oryza rufipogon Griff. in the indica cultivar Huajingxian74 (HJX74) background, we identified a novel quantitative trait locus (QTL), named qGLF5, which improves kernel shape, plant architecture, and yield per plant in rice. Compared with the control HJX74, the plant height, panicles per plant, panicle length, primary branches per panicle, secondary branches per panicle, and kernels per plant of the near-isogenic line-qGLF5 (NIL-qGLF5) are significantly increased. NIL-qGLF5 has long and narrow kernels by regulating cell number, cell length and width in the spikelet hulls. Yield per plant of NIL-qGLF5 is increased by 35.02% compared with that of HJX74. In addition, qGLF5 significantly improves yield per plant and plant architecture of NIL-gw5 and NIL-GW7. These results indicate that qGLF5 might be beneficial for improving plant architecture and kernel yield in rice breeding by molecular design.

qGL3.4 controls kernel size and plant architecture in rice.

Kernel size and plant architecture play important roles in kernel yield in rice. Cloning and functional study of genes related to kernel size and plant architecture are of great significance for breeding high-yield rice. Using the single-segment substitution lines which developed with Oryza barthii as a donor parent and an elite indica cultivar Huajingxian74 (HJX74) as a recipient parent, we identified a novel QTL (quantitative trait locus), named qGL3.4, which controls kernel size and plant architecture. Compared with HJX74, the kernel length, kernel width, 1000-kernel weight, panicle length, kernels per plant, primary branches, yield per plant, and plant height of near isogenic line-qGL3.4 (NIL-qGL3.4) are increased, whereas the panicles per plant and secondary branches per panicle of NIL-qGL3.4 are comparable to those of HJX74. qGL3.4 was narrowed to a 239.18 kb interval on chromosome 3. Cell analysis showed that NIL-qGL3.4 controlled kernel size by regulating cell growth. qGL3.4 controls kernel size at least in part through regulating the transcription levels of EXPANSINS, GS3, GL3.1, PGL1, GL7, OsSPL13 and GS5. These results indicate that qGL3.4 might be beneficial for improving kernel yield and plant architecture in rice breeding.

GS6.1 controls kernel size and plant architecture in rice.

MAIN CONCLUSION: A novel QTL GS6.1 increases yield per plant by controlling kernel size, plant architecture, and kernel filling in rice. Kernel size and plant architecture are critical agronomic traits that greatly influence kernel yield in rice. Using the single-segment substitution lines (SSSLs) with an indica cultivar Huajingxian74 as a recipient parent and American Jasmine as a donor parent, we identified a novel quantitative trait locus (QTL), named GS6.1. Near isogenic line-GS6.1 (NIL-GS6.1) produces long and narrow kernels by regulating cell length and width in the spikelet hulls, thus increasing the 1000-kernel weight. Compared with the control, the plant height, panicles per plant, panicle length, kernels per plant, secondary branches per panicle, and yield per plant of NIL-GS6.1 are increased. In addition, GS6.1 regulates the kernel filling rate. GS6.1 controls kernel size by modulating the transcription levels of part of EXPANSINs, kernel filling-related genes, and kernel size-related genes. These results indicate that GS6.1 might be beneficial for improving kernel yield and plant architecture in rice breeding by molecular design.

Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.

ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade.

Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy.

Remote cardiac rehabilitation program during the COVID-19 pandemic for patients with stable coronary artery disease after percutaneous coronary intervention: a prospective cohort study.

OBJECTIVE: The coronavirus disease-19 (COVID-19) pandemic restricts rapid implementation of in-person delivery of cardiac rehabilitation (CR) at the center for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI), thus enabling a cohort comparison of in-person vs. remote CR program. This study aims to investigate outcomes of exercise capacity, health-related quality of life (HRQL), mental health, and family burden of stable CAD patients undergoing PCI in low-to-moderate risk after different delivery models of CR program. METHODS: The study included a cohort of stable CAD patients undergoing PCI who had experienced two naturally occurring modes of CR program after hospital discharge at two time periods, January 2019 to December 2019 (in-person CR program) and May 2020 to May 2021 (remote CR program). The exercise capacity was assessed by means of 6-min walk test (6MWT), maximal oxygen uptake (VO2max) and the respiratory anaerobic threshold (VO2AT) before discharge, at the end of the 8-week and 12-week in-person or remote CR program after discharge. RESULTS: No adverse events occurred during the CR period. CAD patients had a longer distance walked in 6 min with a higher VO2max after 8-week and 12-week CR program whether in-person or remote model (p < 0.05). The distance walked in 6 min was longer and the maximal oxygen uptake (VO2max) was higher at the end of the 12-week in-person or remote CR program than 8-week in-person or remote CR program (p < 0.05). The respiratory anaerobic threshold (VO2AT) of CAD patients was decreased after 8-week CR program whether in-person or remote model (p < 0.05). CAD patients receiving remote CR program exhibited higher HRQL scores in domains of vitality (p = 0.048), role emotional (p = 0.039), mental health (p = 0.014), and the summary score of the mental composite (p = 0.048) compared to in-person CR program after 8 weeks. The anxiety and depression scores of CAD patients undergoing PCI were decreased after 8-week CR program whether in-person or remote model (p < 0.05). The CAD patients receiving remote delivery showed lower anxiety and depression scores compared to those receiving in-person delivery at the end of the 8-week CR program (p < 0.05). It was found that the family burden scores of CAD patients undergoing PCI were reduced after 8-week and 12-week CR program whether in-person or remote model (p < 0.05). The CAD patients receiving remote CR program showed lower family burden scores than those receiving in-person CR program after whether 8 weeks or 12 weeks (p < 0.05). CONCLUSION: These data indicate that a properly designed and monitored remote delivery represents a feasible and safe model for low-to-moderate-risk, stable CAD patients undergoing PCI inaccessible to in-person CR during the COVID-19 pandemic.

Loss of Mettl3 enhances liver tumorigenesis by inducing hepatocyte dedifferentiation and hyperproliferation.

While a few works have shown that Mettl3 plays oncogenic roles in hepatocellular carcinoma (HCC), its function in early HCC tumorigenesis remains unclear. In Mettl3flox/flox; Alb-Cre knockout mice, Mettl3 loss leads to aberrant hepatocyte homeostasis and liver damage. Importantly, Mettl3 deletion dramatically accelerates liver tumorigenesis in various HCC mouse models. Depletion of Mettl3 in adult Mettl3flox/flox mice through TBG-Cre administration also enhances liver tumor development, while overexpression of Mettl3 inhibits hepatocarcinogenesis. Mechanistically, aggravated tumorigenesis upon Mettl3 deletion is a consequence of hepatocyte dedifferentiation and hyperproliferation via m6A-mediated modulation on Hnf4α and cell cycle genes. In contrast, by using Mettl3flox/flox; Ubc-Cre mice, depletion of Mettl3 in established HCC ameliorates tumor progression. Additionally, Mettl3 is overexpressed in HCC tumors compared with adjacent non-tumor tissues. The present findings define a tumor-suppressive role of Mettl3 in liver tumorigenesis, indicating its potentially opposite stage-dependent functions in HCC initiation versus progression.

Effect of mindfulness-based stress reduction in patients with acute myocardial infarction after successful primary percutaneous coronary intervention: a retrospective study.

OBJECTIVE: This study aimed to examine the effects of mindfulness-based stress reduction (MBSR) in patients with acute myocardial infarction (AMI) after primary percutaneous coronary intervention (PPCI). METHODS: A retrospective study was conducted with data collected from AMI patients who underwent successful PPCI. The study included 61 cases that received 8-week MBSR intervention (MBSR group) and 61 cases that received weekly health education (control group) over the same period. Outcome measures, including hemodynamic parameters, psychosocial characteristics [Hospital Anxiety and Depression Scale (HADS), Perceived Stress Scale (PSS), Perceived Social Support Scale (PSSS)], health-related quality of life [HRQoL, 7-item Seattle Angina Questionnaire (SAQ-7)], and major adverse cardiovascular events (MACE), were assessed at baseline (T1), post-intervention (T2), 1 month after the post-intervention (T3) and 3 months after the post-intervention (T4). RESULTS: Compared to the control group, the MBSR group showed improvements in blood pressure, specifically in systolic blood pressure (SBP) at T4, and diastolic blood pressure (DBP) at T3 and T4, and mean arterial blood pressure (MABP) at T3 and T4. Additionally, the MBSR group had lower scores of anxiety and perceived stress (HADS, PSS) and higher scores of perceived social support (PSSS) after the intervention. Furthermore, the MBSR group had higher scores on the SAQ-7 at all measurement points. The control group had a significantly higher total MACE rate compared to the MBSR group (26.23% vs. 9.84%). CONCLUSIONS: This study provides support for the potential benefits of MBSR as an adjunctive treatment for AMI patients undergoing PPCI.

NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and hypovascular tumor microenvironment. Nucleolar and spindle associated protein 1 (NUSAP1) is a microtubule-associated protein that is known to be involved in cancer biology. Our study aimed to investigate the role of NUSAP1 in glycolytic metabolism and metastasis in PDAC. Expression and prognostic value of NUSAP1 in PDAC and common gastrointestinal tumors was evaluated. The function of NUSAP1 in PDAC progression was clarified by single-cell RNA-seq and further experiments in vitro, xenograft mouse model, spontaneous PDAC mice model and human tissue microarray. The downstream genes and signaling pathways regulated by NUSAP1 were explored by RNA-Seq. And the regulation of NUSAP1 on Lactate dehydrogenase A (LDHA)-mediated glycolysis and its underlying mechanism was further clarified by CHIP-seq. NUSAP1 was an independent unfavorable predictor of PDAC prognosis that playing a critical role in metastasis of PDAC by regulating LDHA-mediated glycolysis. Mechanically, NUSAP1 could bind to c-Myc and HIF-1α that forming a transcription regulatory complex localized to LDHA promoter region and enhanced its expression. Intriguingly, lactate upregulated NUSAP1 expression by inhibiting NUSAP1 protein degradation through lysine lactylated (Kla) modification, thus forming a NUSAP1-LDHA-glycolysis-lactate feedforward loop. The NUSAP1-LDHA-glycolysis-lactate feedforward loop is one of the underlying mechanisms to explain the metastasis and glycolytic metabolic potential in PDAC, which also provides a novel insights to understand the Warburg effect in cancer. Targeting NUSAP1 would be an attractive paradigm for PDAC treatment.

Characterization of Silver Nanoparticles Synthesized by the Aqueous Extract of Zanthoxylum nitidum and Its Herbicidal Activity against Bidens pilosa L.

Phytosynthesis of silver nanoparticles (Ag NPs) has been progressively acquiring attractiveness. In this study, the root of Zanthoxylum nitidum was used to synthesize Ag NPs, and its pre-emergence herbicidal activity was tested. The synthesized Ag NPs by the aqueous extract from Z. nitidum were characterized by visual inspection, ultraviolet-visible spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), transmission electron microscopy (TEM), and energy dispersive X-ray spectroscopy (EDX). The plant-mediated synthesis was completed within 180 min and the Ag NPs exhibited a characteristic peak at around 445 nm. The results of the DLS measurement showed that the average hydrodynamic diameter was 96 nm with a polydispersity index (PDI) of 0.232. XRD results indicated the crystalline nature of the phytogenic Ag NPs. A TEM analysis revealed that the nanoparticles were spherical with an average particle size of 17 nm. An EDX spectrum confirmed the presence of an elemental silver signal. Furthermore, the Ag NPs exhibited a herbicidal potential against the seed germination and seedling growth of Bidens Pilosa L. The present work indicates that Ag NPs synthesized by plant extract could have potential for the development of a new nanoherbicide for weed prevention and control.

Investigating the Impact of the Community of Inquiry Presence on Online Learning Satisfaction: A Chinese College Student Perspective.

Purpose: This study investigated how teaching, social, and cognitive presence within the community of inquiry (CoI) framework impacts Chinese college students' online learning satisfaction through self-regulated learning and emotional states. Methods: A total of 2608 Chinese college students from 112 universities completed a 38-item Likert scale survey measuring teaching, social and cognitive presence, self-regulated learning, emotional states, and online learning satisfaction after COVID-19 restrictions were lifted on December 7, 2022. The study examined the influence of teaching, social, and cognitive presence on online learning satisfaction, mediated by self-regulated learning and moderated by emotional states using SmartPLS. It also analyzed demographic differences using multi-group analysis in the model. Results: The results indicated a significant positive relationship between a) self-regulated learning and online learning satisfaction, b) teaching presence, cognitive presence, and self-regulated learning, but no relationship between social presence and self-regulated learning. Additionally, self-regulated learning partially mediated the relationship between teaching and cognitive presence and online learning satisfaction. In contrast, self-regulated learning did not mediate the association between social presence and online learning satisfaction. Positive emotional states moderated the relationship between self-regulated learning and online learning satisfaction. Implications: The study advances the knowledge of these factors influencing online learners' satisfaction, which can help create efficient programs and regulations for students, teachers, and policymakers.

Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole-Exome Sequencing.

OBJECTIVE: Previous studies have underlined the genetic susceptibility in the pathogenesis of palindromic rheumatism (PR), but the known PR loci only partially explain the disease's genetic background. We aimed to genetically identify PR by whole-exome sequencing (WES). METHODS: This multicenter prospective study was conducted in 10 Chinese specialized rheumatology centers between September 2015 and January 2020. WES was performed in 185 patients with PR and in 272 healthy controls. PR patients were divided into PR subgroups who were negative for anti-citrullinated protein antibody (ACPA-) and positive for ACPA (ACPA+) according to ACPA titer (cutoff value 20 IU/liter). We conducted whole-exome association analysis for the WES data. We used HLA imputation to type HLA genes. In addition, we used the polygenic risk score to measure the genetic correlations between PR and rheumatoid arthritis (RA) and the genetic correlations between ACPA- PR and ACPA+ PR. RESULTS: Among 185 patients with PR enrolled in our study, 50 patients (27.02%) were ACPA+ and 135 PR patients (72.98%) were ACPA-. We identified 8 novel loci (in the ACPA- PR group: ZNF503, RPS6KL1, HOMER3, HLA-DRA; in the ACPA+ PR group: RPS6KL1, TNPO2, WASH2P, FANK1) and 3 HLA alleles (in the ACPA- PR group: HLA-DRB1*0803 and HLA-DQB1; in the ACPA+ PR group: HLA-DPA1*0401) that were associated with PR and that surpassed genome-wide significance (P < 5 × 10-8 ). Furthermore, polygenic risk score analysis showed that PR and RA were not similar (R2 < 0.025), whereas ACPA+ PR and ACPA- PR showed a moderate genetic correlation (0.38 < R2 < 0.8). CONCLUSION: This study demonstrated the distinct genetic background between ACPA- and ACPA+ PR patients. Additionally, our findings strengthened that PR and RA were not genetically similar.

RNA helicase DHX15 exemplifies a unique dependency in acute leukemia.

RNA-binding proteins (RBP) have emerged as essential regulators that control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. The implications of essential RBP during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBP identifies RNA helicase DHX15, which facilitates the disassembly of the spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during the transition from doublenegative to double-positive cells (CD4-CD8- to CD4+CD8+). Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate that it has prominent anti-T-ALL efficacy. Collectively, our data highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach, i.e., splicing perturbation by targeting spliceosome disassembly, may achieve considerable anti-tumor efficacy.