Structural basis of exoribonuclease-mediated mRNA transcription termination.

Efficient termination is required for robust gene transcription. Eukaryotic organisms use a conserved exoribonuclease-mediated mechanism to terminate the mRNA transcription by RNA polymerase II (Pol II)1-5. Here we report two cryogenic electron microscopy structures of Saccharomyces cerevisiae Pol II pre-termination transcription complexes bound to the 5'-to-3' exoribonuclease Rat1 and its partner Rai1. Our structures show that Rat1 displaces the elongation factor Spt5 to dock at the Pol II stalk domain. Rat1 shields the RNA exit channel of Pol II, guides the nascent RNA towards its active centre and stacks three nucleotides at the 5' terminus of the nascent RNA. The structures further show that Rat1 rotates towards Pol II as it shortens RNA. Our results provide the structural mechanism for the Rat1-mediated termination of mRNA transcription by Pol II in yeast and the exoribonuclease-mediated termination of mRNA transcription in other eukaryotes.

LncRNA CHROMR/miR-27b-3p/MET axis promotes the proliferation, invasion, and contributes to rituximab resistance in diffuse large B-cell lymphoma.

Long non-coding RNAs (LncRNAs) could regulate chemoresistance through sponging microRNAs (miRNAs) and sequestering RNA binding proteins. However, the mechanism of lncRNAs in rituximab resistance in diffuse large B-cell lymphoma (DLBCL) is largely unknown. Here, we investigated the functions and molecular mechanisms of lncRNA CHROMR in DLBCL tumorigenesis and chemoresistance. LncRNA CHROMR is highly expressed in DLBCL tissues and cells. We examined the oncogenic functions of lncRNA CHROMR in DLBCL by a panel of gain-or-loss-of-function assays and in vitro experiments. LncRNA CHROMR suppression promotes CD20 transcription in DLBCL cells and inhibits rituximab resistance. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assay reveal that lncRNA CHROMR sponges with miR-27b-3p to regulate mesenchymal-epithelial transition factor (MET) levels and Akt signaling in DLBCL cells. Targeting the lncRNA CHROMR/miR-27b-3p/MET axis reduces DLBCL tumorigenesis. Altogether, these findings provide a new regulatory model, lncRNA CHROMR/miR-27b-3p/MET, which can serve as a potential therapeutic target for DLBCL.

Human CCR6+ Th Cells Show Both an Extended Stable Gradient of Th17 Activity and Imprinted Plasticity.

Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related Th cells (type 17 cells) and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The phenotypes and epigenomes of CCR6+ cells are stable across cell divisions under noninflammatory conditions. Nonetheless, activation in polarizing and nonpolarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the type 17 continuum to yield the unusual plasticity ascribed to type 17 cells.

Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis.

Glioma is the most common malignant tumor of the central nervous system, with EZH2 playing a crucial regulatory role. This study further explores the abnormal expression of EZH2 and its mechanisms in regulating glioma progression. Additionally, it was found that IHMT-337 can potentially be a therapeutic agent for glioma. The prognosis, expression, and localization of EZH2 were determined using bioinformatics, IHC staining, Western blot (WB) analysis, and immunofluorescence (IF) localization. The effects of EZH2 on cell function were assessed using CCK-8 assays, Transwell assays, and wound healing assays. Public databases and RT-qPCR were utilized to identify downstream targets. The mechanisms regulating these downstream targets were elucidated using MS-PCR and WB analysis. The efficacy of IHMT-337 was demonstrated through IC50 measurements, WB analysis, and RT-qPCR. The effects of IHMT-337 on glioma cells in vitro were evaluated using Transwell assays, EdU incorporation assays, and flow cytometry. The potential of IHMT-337 as a treatment for glioma was assessed using a blood-brain barrier (BBB) model and an orthotopic glioma model. Our research confirms significantly elevated EZH2 expression in gliomas, correlating with patient prognosis. EZH2 facilitates glioma proliferation, migration, and invasion alongside promoting SLC12A5 DNA methylation. By regulating SLC12A5 expression, EZH2 activates the WNK1-OSR1-NKCC1 pathway, enhancing its interaction with ERM to promote glioma migration. IHMT-337 targets EZH2 in vitro to inhibit WNK1 activation, thereby suppressing glioma cell migration. Additionally, it inhibits cell proliferation and arrests the cell cycle. IHMT-337 has the potential to cross the BBB and has successfully inhibited glioma progression in vivo. This study expands our understanding of the EZH2-SLC12A5 axis in gliomas, laying a new foundation for the clinical translation of IHMT-337 and offering new insights for precision glioma therapy.

Balanced Solution versus Normal Saline in Predicted Severe Acute Pancreatitis: A Stepped Wedge Cluster Randomized Trial.

OBJECTIVE: To compare the effect of balanced multielectrolyte solutions(BMES) versus normal saline(NS) for intravenous fluid on chloride levels and clinical outcomes.in patients with predicted severe acute pancreatitis (pSAP). SUMMARY BACKGROUND DATA: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown. METHODS: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (APACHE II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase(Sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day3. Secondary endpoints included a composite of clinical and laboratory measures. RESULTS: Overall, 259 patients were enrolled from eleven sites to receive NS(n=147) or BMES(n=112). On trial day3, the mean chloride level was significantly lower in patients who received BMES(101.8 mmol/L(SD4.8) versus 105.8 mmol/L(SD5.9), difference -4.3 mmol/L [95%CI -5.6 to -3.0 mmol/L];P<0.001). For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome(19/112,17.0% versus 43/147,29.3%, P=0.024) and increased organ failure-free days (3.9 d(SD2.7) versus 3.5days(SD2.7), P<0.001) by trial day7. They also spent more time alive and out of ICU(26.4 d(SD5.2) versus 25.0days(SD6.4), P=0.009) and hospital(19.8 d(SD6.1) versus16.3days(SD7.2), P<0.001) by trial day30. CONCLUSIONS: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits(Trial registration number: ChiCTR2100044432).

A genome-wide association study uncovers a ZmRap2.7-ZCN9/ZCN10 module to regulate ABA signalling and seed vigour in maize.

Seed vigour, including rapid, uniform germination and robust seedling establishment under various field conditions, is becoming an increasingly essential agronomic trait for achieving high yield in crops. However, little is known about this important seed quality trait. In this study, we performed a genome-wide association study to identify a key transcription factor ZmRap2.7, which regulates seed vigour through transcriptionally repressing expressions of three ABA signalling genes ZmPYL3, ZmPP2C and ZmABI5 and two phosphatidylethanolamine-binding genes ZCN9 and ZCN10. In addition, ZCN9 and ZCN10 proteins could interact with ZmPYL3, ZmPP2C and ZmABI5 proteins, and loss-of-function of ZmRap2.7 and overexpression of ZCN9 and ZCN10 reduced ABA sensitivity and seed vigour, suggesting a complex regulatory network for regulation of ABA signalling mediated seed vigour. Finally, we showed that four SNPs in ZmRap2.7 coding region influenced its transcriptionally binding activity to the downstream gene promoters. Together with previously identified functional variants within and surrounding ZmRap2.7, we concluded that the distinct allelic variations of ZmRap2.7 were obtained independently during maize domestication and improvement, and responded separately for the diversities of seed vigour, flowering time and brace root development. These results provide novel genes, a new regulatory network and an evolutional mechanism for understanding the molecular mechanism of seed vigour.

Genotypic and phenotypic characteristics of sodium channel-associated epilepsy in Chinese population.

Variants in voltage-gated sodium channel (VGSC) genes are implicated in seizures, epilepsy, and neurodevelopmental disorders, constituting a significant aspect of hereditary epilepsy in the Chinese population. Through retrospective analysis utilizing next-generation sequencing (NGS), we examined the genotypes and phenotypes of VGSC-related epilepsy cases from a cohort of 691 epilepsy subjects. Our findings revealed that 5.1% of subjects harbored VGSC variants, specifically 22 with SCN1A, 9 with SCN2A, 1 with SCN8A, and 3 with SCN1B variants; no SCN3A variants were detected. Among these, 14 variants were previously reported, while 21 were newly identified. SCN1A variant carriers predominantly presented with Dravet Syndrome (DS) and Genetic Epilepsy with Febrile Seizures Plus (GEFS + ), featuring a heightened sensitivity to fever-induced seizures. Statistically significant disparities emerged between the SCN1A-DS and SCN1A-GEFS+ groups concerning seizure onset and genetic diagnosis age, incidence of status epilepticus, mental retardation, anti-seizure medication (ASM) responsiveness, and familial history. Notably, subjects with SCN1A variants affecting the protein's pore region experienced more frequent cluster seizures. All SCN2A variants were of de novo origin, and 88.9% of individuals with SCN2A variations exhibited cluster seizures. This research reveals a significant association between variations in VGSC-related genes and the clinical phenotype diversity of epilepsy subjects in China, emphasizing the pivotal role of NGS screening in establishing accurate disease diagnoses and guiding the selection of ASM.

Targeting VPS72 inhibits ACTL6A/MYC axis activity in HCC progression.

BACKGROUND AND AIMS: HCC is a highly heterogeneous disease that is caused largely by genomic copy number variations. Herein, the mechanistic and therapeutically targeted role of vacuolar protein sorting 72 homologue (VPS72), a novel copy number variation cis-driven gained gene identified by genome-wide copy number variation and transcriptome analyses in HCC, is not well understood. APPROACH AND RESULTS: First, overexpression of VPS72 enhanced the initiation and progression of HCC in vitro and in vivo . Mechanistically, VPS72 interacted with the oncoproteins MYC and actin-like 6A (ACTL6A) and promoted the formation of the ACTL6A/MYC complex. Furthermore, ACTL6A regulated VPS72 protein stability by weakening the interaction between tripartite motif containing 21 (TRIM21) and VPS72. Thus, the interaction between VPS72 and ACTL6A enhanced the affinity of MYC for its target gene promoters and promoted their transcription, thereby contributing to HCC progression, which was inhibited by adeno-associated virus serotype 8 (AAV8)-mediated short hairpin RNA (shRNA) against VPS72. CONCLUSIONS: This study reveals the molecular mechanism of ACTL6A/VPS72/MYC in HCC, providing a theoretical basis and therapeutic target for this malignancy.

Photocatalytic CO2 Reduction Using Ti3C2Xy (X = Oxo, OH, F, or Cl) MXene-ZrO2: Structure, Electron Transmission, and the Stability.

CO2 photoreduction using a semiconductor-based photocatalyst is a promising option for completing a new carbon-neutral cycle. The short lifetime of charges generated owing to light energy is one of the most critical problems in further improving the performance of semiconductor-based photocatalysts. This study shows the structure, electron transmission, and stability of Ti3C2Xy (X = oxo, OH, F, or Cl) MXene combined with a ZrO2 photocatalyst. Using H2 as a reductant, the photocatalytic CO formation rate increased by 6.6 times to 4.6 µmol h-1 gcat-1 using MXene (3.0 wt %)-ZrO2 compared to that using ZrO2, and the catalytic route was confirmed using 13CO2 to form 13CO. In clear contrast, using H2O (gas) as a reductant, CH4 was formed as the major product using Ti3C2Xy MXene (5.0 wt %)-ZrO2 at the rate of 3.9 µmol h-1 gcat-1. Using 13CO2 and H2O, 12CH4, 12C2H6, and 12C3H8 were formed besides H212CO, demonstrating that the C source was the partial decomposition and hydrogenation of Ti3C2Xy. Using the atomic force and high-resolution electron microscopies, 1.6 nm thick Ti3C2Xy MXene sheets were observed, suggesting ∼3 stacked layers that are consistent with the Ti-C and Ti···Ti interatomic distances of 0.218 and 0.301 nm, respectively, forming a [Ti6C] octahedral coordination, and the major component as the X ligand was suggested to be F and OH/oxo, with the temperature increasing by 116 K or higher owing to the absorbed light energy, all based on the extended X-ray absorption fine structure analysis.

Insect herbivory on woody broadleaf seedlings along a subtropical elevational gradient supports the resource concentration hypothesis.

PREMISE: Theories of plant-herbivore interactions hold that seedlings are more vulnerable to herbivory in warmer and more stable climates at lower elevations. Hypotheses of plant apparency, resource concentration, and resource availability have been proposed to explain variability in leaf herbivory. However, seasonal differences in the effects of these hypotheses on leaf herbivory on seedlings remain unclear. METHODS: We evaluated the three herbivory hypotheses by comparing the percentage and frequency of leaf herbivory in understory broadleaf seedlings in a subtropical forest in May (spring) and October (autumn) along an elevational gradient (290-1370 m a.s.l.). In total, we measured 2890 leaves across 696 seedlings belonging to 95 species and used beta regressions to test the effects of plant apparency (e.g., leaf area, seedling height), resource concentration (e.g., plant species diversity), and resource availability (e.g., canopy openness, soil available N and P) on leaf herbivory. RESULTS: Seedlings exhibited unimodal patterns of leaf herbivory along elevation, with drivers of leaf herbivory varying by the month. Variation in the frequency of leaf herbivory was best explained by the resource concentration hypothesis (e.g., plant species diversity) in both months, and herbivory was lower on seedlings in sites with higher plant diversity. Plant apparency hypothesis (e.g., leaf area, seedling height) was weakly supported only in spring, and the evidence for resource availability hypothesis (e.g., canopy openness, soil nutrients) was mixed. CONCLUSIONS: This study supports the resource concentration hypothesis and reveals the importance of seasonal difference on understanding leaf herbivory patterns and the drivers of plant diversity in subtropical forests.

Genome-wide expression quantitative trait locus analysis reveals silk-preferential gene regulatory network in maize.

Silk of maize (Zea mays L.) contains diverse metabolites with complicated structures and functions, making it a great challenge to explore the mechanisms of metabolic regulation. Genome-wide identification of silk-preferential genes and investigation of their expression regulation provide an opportunity to reveal the regulatory networks of metabolism. Here, we applied the expression quantitative trait locus (eQTL) mapping on a maize natural population to explore the regulation of gene expression in unpollinated silk of maize. We obtained 3,985 silk-preferential genes that were specifically or preferentially expressed in silk using our population. Silk-preferential genes showed more obvious expression variations compared with broadly expressed genes that were ubiquitously expressed in most tissues. We found that trans-eQTL regulation played a more important role for silk-preferential genes compared to the broadly expressed genes. The relationship between 38 transcription factors and 85 target genes, including silk-preferential genes, were detected. Finally, we constructed a transcriptional regulatory network around the silk-preferential gene Bx10, which was proposed to be associated with response to abiotic stress and biotic stress. Taken together, this study deepened our understanding of transcriptome variation in maize silk and the expression regulation of silk-preferential genes, enhancing the investigation of regulatory networks on metabolic pathways.

LDLa containing C-type lectin mediates phagocytosis of V.anguillarum and regulates immune effector genes in shrimp.

C-type lectins (CTLs) function as pattern recognition receptors (PRRs) by recognizing invading microorganisms, thereby triggering downstream immune events against infected pathogens. In this study, a novel CTL containing a low-density lipoprotein receptor class A (LDLa) domain was obtained from Litopenaeus vannamei, designed as LvLDLalec. Stimulation by the bacterial pathogen Vibrio anguillarum (V. anguillarum) resulted in remarkable up-regulation of LvLDLalec, as well as release of LvLDLalec into hemolymph. The rLvLDLalec protein possessed broad-spectrum bacterial binding and agglutinating activities, as well as hemocyte attachment ability. Importantly, LvLDLalec facilitated the bacterial clearance in shrimp hemolymph and protected shrimp from bacterial infection. Further studies revealed that LvLDLalec promoted hemocytes phagocytosis against V. anguillarum and lysosomes were involved in the process. Meanwhile, LvLDLalec participated in humoral immunity through activating and inducing nuclear translocation of Dorsal to regulate phagocytosis-related genes and antimicrobial peptides (AMPs) genes, thereby accelerated the removal of invading pathogens in vivo and improved the survival rate of L. vannamei. These results unveil that LvLDLalec serves as a PRR participate in cellular and humoral immunity exerting opsonin activity to play vital roles in the immune regulatory system of L. vannamei.

Study of multifunctional anti-AD ligands: design, synthesis, X-ray crystal structure and biological evaluation of diosmetin derivatives.

The development of anti-AD drugs has attracted much attention as the number of AD patients is increasing year by year. Five diosmetin derivatives (1-5) were designed and synthesized by introducing carbamate groups. The crystal structure of 1 was analyzed by X-ray diffraction, which showed a large conjugated coplanar structure and might be favorable for the insertion into the Aß folding. Meanwhile, in vitro experiments were carried out to investigate the anticholinesterase activity, metal chelating property, antioxidant activity, and anti-Aß aggregation ability of 1-5. The results showed that 1-5 had good cholinesterase inhibitory activities. Compound 4 showed the highest inhibitory activities against butyrylcholinesterase (IC50 = 0.0760 µM). Further kinetic experiments and molecular docking studies showed that 4 could bind well to butyrylcholinesterase. The molecular dynamics simulations also signified that compared with diosmetin, 4 could reduce the flexibility of the butyrylcholinesterase protein skeleton to a greater extent, and thus had a better inhibitory effect. In addition, 1-5 could selectively chelate copper ions and all of them had good antioxidant activity as well as anti-Aß aggregation ability. Among them, 4 had the strongest activity to inhibit Cu2+-induced Aß aggregation (51.09%) and had low cytotoxicity. In addition, in vivo ROS activity assay (Caenorhabditis elegans) showed that 4 had the ability to scavenge ROS. Besides, the in vivo Aß aggregation assay showed that 4 could reduce Aß aggregation. In conclusion, 4 has the potential to be developed into a multifunctional anti-AD drug.

Endometrioid carcinomas with sex cord-like formations and hyalinization: spontaneous pregnancy after conservative treatment.

Endometrioid carcinoma with sex cord-like formations and hyalinization of the uterine corpus, or corded and hyalinized endometrioid adenocarcinoma (CHEC), is a rare morphological variant of endometrioid carcinoma, for which there is limited literature and few cases reports. Most researchers tend to consider CHEC as a low-grade cancer with a favorable prognosis. Full-staging surgery is the primary choice for this disease, and no case of CHEC has been previously reported to be treated conservatively. Here, we present the following case to explore the possibility of fertility-preserving treatment for young women with CHEC. A 23-year-old nulliparous patient diagnosed with presumed stage IA CHEC received fertility-sparing treatment at the Obstetrics and Gynecology Hospital of Fudan University and got a complete response (CR) after 10 months of conservative treatment. The patient subsequently became pregnant spontaneously, successfully conceived, and gave birth to a healthy male neonate without any sign of recurrence during 37 months follow-up after CR. The patient's postpartum follow-up is continuing. Presently, CHEC is not included in the fertility-sparing field of any available guidelines. This case indicates that fertility-sparing treatment may be an option for highly selected patients with CHEC. Continuous follow-up remains mandatory to observe long-term outcomes.

Multiple mediation of the association between childhood emotional abuse and adult obesity by anxiety and bulimia - a sample from bariatric surgery candidates and healthy controls.

Bulimia, which means a person has episodes of eating a very large amount of food (bingeing) during which the person feels a loss of control over their eating, is the most primitive reason for being overweight and obese. The extended literature has indicated that childhood emotional abuse has a close relationship with adverse mood states, bulimia, and obesity. To comprehensively understand the potential links among these factors, we evaluated a multiple mediation model in which anxiety/depression and bulimia were mediators between childhood emotional abuse and body mass index (BMI). A set of self-report questionnaires, including the Childhood Trauma Questionnaire (CTQ), Beck Anxiety Inventory, Beck Depression Inventory (BDI), and Eating Disorder Inventory (EDI), was sent out. Clinical data from 37 obese patients (age: 29.65 ± 5.35, body mass index (BMI): 37.59 ± 6.34) and 37 demographically well-matched healthy people with normal body weight (age: 31.35 ± 10.84, BMI: 22.16 ± 3.69) were included in the investigation. We first performed an independent t-test to compare all scales or subscale scores between the two groups. Then, we conducted Pearson correlation analysis to test every two variables' pairwise correlation. Finally, multiple mediation analysis was performed with BMI as the outcome variable, and childhood emotional abuse as the predictive variable. Pairs of anxiety, bulimia, and depression, bulimia were selected as the mediating variables in different multiple mediation models separately. The results show that the obese group reported higher childhood emotional abuse (t = 2.157, p = 0.034), worse mood state (anxiety: t = 5.466, p < 0.001; depression: t = 2.220, p = 0.030), and higher bulimia (t = 3.400, p = 0.001) than the healthy control group. Positive correlations were found in every pairwise combination of BMI, childhood emotional abuse, anxiety, and bulimia. Multiple mediation analyses indicate that childhood emotional abuse is positively linked to BMI (ß = 1.312, 95% CI = 0.482-2.141). The model using anxiety and bulimia as the multiple mediating variables is attested to play roles in the relationship between childhood emotional abuse and obesity (indirect effect = 0.739, 95% CI = 0.261-1.608, 56.33% of the total effect). These findings confirm that childhood emotional abuse contributes to adulthood obesity through the multiple mediating effects of anxiety and bulimia. The present study adds another potential model to facilitate our understanding of the eating psychopathology of obesity.

Cervical Septum Incision Adversely Impacts Clinical Outcomes in Women with Complete Uterine Septum and Duplicated Cervix.

STUDY OBJECTIVE: To investigate the reproductive outcomes of women with complete septate uterus and duplicated cervix who either did or did not receive cervical septum incision during hysteroscopic transcervical incision of the uterine septum. DESIGN: Retrospective study approved by the hospital ethics committee. SETTING: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. PATIENTS: Women with complete septate uterus and duplicated cervix who underwent hysteroscopic transcervical incision of the uterine septum in Obstetrics and Gynecology Hospital of Fudan University between January 2008 and December 2020 (n = 105). INTERVENTIONS: Hysteroscopic incision of the septum. MEASUREMENTS AND MAIN RESULTS: Included patients were grouped according to whether or not cervical septum incision was performed. Reproductive outcomes including gravidity, abortion rate, preterm birth rate, full-term birth rate, premature rupture of membranes, and cervical incompetence were assessed. In the no incision group, the abortion rate (7.4%) was significantly lower than that of the incision group (27.6%, p = .01); the preterm birth rate (4.6%) was significantly lower than that of the incision group (36.8%); and the full-term birth rate (95.5%) exceeded that of the incision group (63.2%, p <.01). Incidence of premature rupture of membranes and cervical incompetence during pregnancy was higher in the incision group (15.8% and 10.5%, p <.01 and p = .03). CONCLUSION: Significantly improved reproductive outcomes were observed among patients with complete septate uterus and duplicated cervix whose cervical septum was preserved during the hysteroscopic transcervical incision of the uterine septum procedure.

miR-373-3p promotes aerobic glycolysis in colon cancer cells by targeting MFN2.

MicroRNAs (miRNAs) are implicated in the development of cancers and may serve as potential targets for therapy. However, the functions and underlying mechanisms of miRNAs in cancers are not well understood. This work aims to study the role of miR-373-3p in colon cancer cells. We find that the expression of miR-373-3p mimics promotes and the miR-373-3p inhibitor suppresses aerobic glycolysis and proliferation of colon cancer cells. Mechanistically, miR-373-3p inhibits the expression of MFN2, a gene that is known to suppress glycolysis, which leads to the activation of glycolysis and eventually the proliferation of cells. In a nude mouse tumor model, the expression of miR-373-3p in colon cancer cells promotes tumor growth by enhancing lactate formation, which is inhibited by the co-expression of MFN2 in the cells. Administration of the miR-373-3p antagomir blunts in vivo tumor growth by decreasing lactate production. In addition, in human colon cancers, the expression levels of miR-373-3p are increased, while those of MFN2 mRNA are decreased, and the increase of miR-373-3p is associated with the decrease of MFN2 mRNA. Our results reveal a previously unknown function and underlying mechanism of miR-373-3p in the regulation of glycolysis and proliferation in cancer cells and underscore the potential of targeting miR-373-3p for colon cancer treatment.

MiR-375 impairs breast cancer cell stemness by targeting the KLF5/G6PD signaling axis.

Recurrence of breast cancer may be due to the presence of breast cancer stem cells (BCSC). Abnormal tumor cell growth is closely associated with increased reactive oxygen species (ROS) and disruption of redox homeostasis, and BCSCs exhibit low levels of ROS. The detailed mechanism between the low levels of ROS in BCSCs and their maintenance of stemness characteristics has not been reported. A growing number of studies have shown that tumor development is often accompanied by metabolic reprogramming, which is an important hallmark of tumor cells. As the first rate-limiting enzyme of pentose phosphate pathway (PPP), the expression of G6PD is precisely regulated in tumor cells, and there is a certain correlation between PPP and BCSCs. MiR-375 has been shown to inhibit stem cell-like properties in breast cancer, but the exact mechanism is not clear. Here, KLF5, as a transcription factor, was identified to bind to the promoter of G6PD to promote its expression, whereas miR-375 inhibited the expression of KLF5 by binding to the 3'UTR region of KLF5 mRNA and thus reduced the expression of G6PD expression, inhibits PPP to reduce NADPH, and increases ROS levels in breast cancer cells, thereby weakening breast cancer cell stemness. Our study reveals the specific mechanism by which miR-375 targets the KLF5/G6PD signaling axis to diminish the stemness of breast cancer cells, providing a therapeutic strategy against BCSCs.

Zinc finger Protein207 orchestrates glioma migration through regulation of epithelial-mesenchymal transition.

BACKGROUND: Glioma represents the predominant primary malignant brain tumor. For several years, molecular profiling has been instrumental in the management and therapeutic stratification of glioma, providing a deeper understanding of its biological complexity. Accumulating evidence unveils the putative involvement of zinc finger proteins (ZNFs) in cancer. This study aimed to elucidate the role and significance of ZNF207 in glioma. METHODS: Utilizing online data such as The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), the Genotype-Tissue Expression (GTEx) project, the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and the Human Protein Atlas (HPA) databases, in conjunction with bioinformatics methodologies including GO, KEGG, GSEA, CIBERSORT immune cell infiltration estimation, and protein-protein interaction (PPI) analysis, enabled a comprehensive exploration of ZNF207's involvement in gliomagenesis. Immunohistochemistry and RT-PCR techniques were employed to validate the expression level of ZNF207 in glioma samples. Subsequently, the biological effects of ZNF207 on glioma cells were explored through in vitro assays. RESULTS: Our results demonstrate elevated expression of ZNF207 in gliomas, correlating with unfavorable patient outcomes. Stratification analyses were used to delineate the prognostic efficacy of ZNF207 in glioma with different clinicopathological characteristics. Immunocorrelation analysis revealed a significant association between ZNF207 expression and the infiltration levels of T helper cells, macrophages, and natural killer (NK) cells. Utilizing ZNF207 expression and clinical features, we constructed an OS prediction model and displayed well discrimination with a C-index of 0.861. Moreover, the strategic silencing of ZNF207 attenuated glioma cell advancement, evidenced by diminished cellular proliferation, weakened cell tumorigenesis, augmented apoptotic activity, and curtailed migratory capacity alongside the inhibition of the epithelial-mesenchymal transition (EMT) pathway. CONCLUSIONS: ZNF207 may identify as a prospective biomarker and therapeutic candidate for glioma prevention, providing valuable insights into understanding glioma pathogenesis and treatment strategies.

Hydroxylated hierarchical flower-like COF for solid-phase extraction of adrenergic receptor agonists in milk.

A new detection platform based on a hydroxylated covalent organic framework (COF) integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was constructed and used for detecting adrenergic receptor agonists (ARAs) residues in milk. The hydroxylated COF was prepared by polymerization of tris(4-aminophenyl)amine and 1,3,5-tris(4-formyl-3-hydroxyphenyl)benzene and applied to solid-phase extraction (SPE) of ARAs. This hydroxylated COF was featured with hierarchical flower-like morphology, easy preparation, and copious active adsorption sites. The adsorption model fittings and molecular simulation were applied to explore the potential adsorption mechanism. This detection platform was suitable for detecting four α2- and five ß2-ARAs residues in milk. The linear ranges of the ARAs were from 0.25 to 50 µg·kg-1; the intra-day and the inter-day repeatability were in the range 2.9-7.9% and 2.0-10.1%, respectively. This work demonstrates this hydroxylated COF has great potential as SPE cartridge packing, and provides a new way to determine ARAs residues in milk.