Herskinddalsgaard4707

Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation-dependent transcription from chromatin templates in vitro. p300-mediated acetylation of NPM1 has been shown to further enhance its transcription activation potential. Acetylated and total NPM1 pools are increased in oral squamous cell carcinoma. However, the role of NPM1 or its acetylated form (AcNPM1) in transcriptional regulation in cells and oral tumorigenesis is not fully elucidated. Using ChIP-seq analyses, we provide the first genome-wide profile of AcNPM1 and show that AcNPM1 is enriched at transcriptional regulatory elements. AcNPM1 co-occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. In addition, using a high-throughput protein interaction profiling approach, we show that NPM1 interacts with RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. NPM1 histone chaperone activity also contributes to its transcription activation potential. Further, NPM1 depletion leads to decreased AcNPM1 occupancy and reduced expression of genes required for proliferative, migratory and invasive potential of oral cancer cells. NPM1 depletion also abrogates the growth of orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator during during RNA polymerase II-driven transcription and regulates the expression of genes that promote oral tumorigenesis.Long noncoding RNAs (lncRNAs) have been confirmed as important regulators during osteogenic differentiation. Previous research has disclosed that growth arrest-specific transcript 5 (GAS5) can promote osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs), but the underlying regulatory mechanism of GAS5 during the osteogenic differentiation of hBMSCs is unclear. Osteogenic differentiation was induced in hBMSCs by using osteogenic medium (OM). Gene expression was assessed by quantitative real-time PCR (RT-qPCR) or Western blot assays as needed. Alkaline phosphatase (ALP) activity, ALP staining, and alizarin red S (ARS) staining assays were performed to evaluate the impact of GAS5, microRNA 382-3p (miR-382-3p), and TATA box binding protein-associated factor 1 (TAF1) on osteogenic differentiation in vitro. The interaction among GAS5, miR-382-3p, and TAF1 was determined by RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays. Expression of GAS5 (transcript variant 2) was downregulated during the osteogenic differentiation of hBMSCs, and its overexpression retarded the osteogenic differentiation of hBMSCs. GAS5 inhibited miR-382-3p by targeting RNA-directed microRNA degradation (TDMD). miR-382-3p downregulation partially offset the promoted osteogenic differentiation of hBMSCs upon GAS5 silencing. TAF1 negatively modulated osteogenic differentiation, and it activated GAS5 transcription so as to form a positive GAS5-miR-382-3p-TAF1 feedback loop in hBMSCs. This research was the first to reveal that the GAS5-miR-382-3p-TAF1 feedback loop inhibited the osteogenic differentiation of hBMSCs, which provided new clues for exploring the mechanism of osteogenic differentiation and disclosed the potential of GAS5 as a promising target during osteogenic differentiation.In transcriptionally active genes, nucleosome positions in promoters are regulated by nucleosome-displacing factors (NDFs) and chromatin-remodeling enzymes. Depletion of NDFs or the RSC chromatin remodeler shrinks or abolishes the nucleosome-depleted regions (NDRs) in promoters, which can suppress gene activation and result in cryptic transcription. Despite their vital cellular functions, how the action of chromatin remodelers may be directly affected by site-specific binding factors like NDFs is poorly understood. Here, we demonstrate that two NDFs, Reb1 and Cbf1, can direct both Chd1 and RSC chromatin-remodeling enzymes in vitro, stimulating repositioning of the histone core away from their binding sites. CDK inhibition Interestingly, although the Pho4 transcription factor had a much weaker effect on nucleosome positioning, both NDFs and Pho4 were able to similarly redirect positioning of hexasomes. In chaperone-mediated nucleosome assembly assays, Reb1 but not Pho4 showed an ability to block deposition of the histone H3/H4 tetramer, but Reb1 did not block addition of the H2A/H2B dimer to hexasomes. Our in vitro results show that NDFs bias the action of remodelers to increase the length of the free DNA in the vicinity of their binding sites. These results suggest that NDFs could directly affect NDR architecture through chromatin remodelers.RASSF6, a member of the tumor suppressor Ras-association domain family (RASSF) proteins, regulates cell cycle arrest and apoptosis via p53 and plays a tumor suppressor role. We previously reported that RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. In this study, we demonstrated that RASSF6 has nuclear localization and nuclear export signals and that DNA damage triggers the nuclear accumulation of RASSF6. We found that RASSF6 directly binds to BAF53, the component of SWI/SNF complex. DNA damage induces CDK9-mediated phosphorylation of BAF53, which enhances the interaction with RASSF6 and increases the amount of RASSF6 in the nucleus. Subsequently, RASSF6 augments the interaction between BAF53 and BAF60a, another component of the SWI/SNF complex, and further promotes the interaction of BAF53 and BAF60a with p53. BAF53 silencing or BAF60a silencing attenuates RASSF6-mediated p53 target gene transcription and apoptosis. Thus, RASSF6 is involved in the regulation of DNA damage-induced complex formation, including BAF53, BAF60a, and p53.Although plasma, especially atmospheric plasma generated by corona discharge, has been proven to be effective in sterilization and food preservation, its disinfection mechanism on chilled pork is poorly understood. In this research, the bactericidal and preservation effect of corona discharge plasma (CDP) was investigated. The maximum bactericidal effect was found after 20 kV 4 kHz CDP treatment, with 2.77 log (colony-forming unit [CFU]/g), 2.41 log (CFU/g), and 1.36 log (CFU/g) reduction for Pantoea agglomerans, Serratia liquefaciens, and Kurthia zopfii, respectively, after 10 min of exposure. The efficiency of microbial inactivation was attributed to the increase of ozone, hydrogen peroxide and morphological changes. It was observed that the microbial level and total volatile binding nitrogen value of CDP-treated chilled pork samples were suppressed during storage, whereas the increase of thiobarbituric acid reactive substances value and the changes of color were still worthy of attention. The aim of this study was to explore the effect of pulsed CDP on the inactivation of spoilage microorganism inoculated on the surface of fresh pork. The prospect of this technology in meat preservation industry was also investigated.Studies have shown that ferroptosis, an iron-dependent regulated cell death, is related to prognosis and chemotherapy, but the role of ferroptosis in pancreatic adenocarcinoma (PAAD) is still unclear. We aimed at constructing a ferroptosis-related gene (FRGs) model to predict the PAAD patients' overall survival (OS) and at exploring their values in chemotherapy. We downloaded the mRNA-sequencing data and corresponding clinical data of patients with PAAD from The Cancer Genome Atlas. Lasso-penalized Cox regression analysis was utilized to construct a prognostic risk model, including spermidine/spermine N1-acetyltransferase 1 (SAT1), SAT2, TFRC, SLC39A8, MAP1LC3A, ALOX15, and PROM2. Receiver operating characteristic curves were used to evaluate the prognostic model. International Cancer Genome Consortium cohorts were used to validate this model. Then, we used Genomics of Drug Sensitivity in Cancer and Gene Expression Omnibus databases to analyze the correlation between FRGs and drug sensitivity. Notably, SAT1 showed significant influence in cisplatin and gemcitabine resistance. Finally, in vitro experiments demonstrated that the combination of gemcitabine and cisplatin could induce ferroptosis in AsPC1 cells, probably through elevated SAT1 expression. Taken together, Our 7-gene signature has significant values in predicting the PAAD patients' OS, and it may help inform the clinical treatment of PAAD.Campylobacteriosis is one of the most common bacteria causing human gastroenteritis. Poultry is a major reservoir of Campylobacter spp. as well as the main source of transmission. Due to the increased occurrence of campylobacteriosis, poultry slaughterhouses are under pressure to deliver carcasses with low contamination. However, a few studies have been carried out to evaluate Campylobacter contamination of broiler carcasses in Brazilian slaughter lines. Therefore, in this study, we aimed at detecting and quantifying the thermotolerant Campylobacter spp. at different stages of the poultry slaughtering process. The samples were collected from 12 points in three slaughterhouses in southern Brazil, at an interval of 12 months, and were tested for Campylobacter spp. by conventional microbiological technique, the most probable number, and real-time PCR. A total of 432 samples were analyzed. The majority of strains belonged to Campylobacter jejuni (92%), and the flock positivity among the three techniques was similar in most cases. Campylobacter was detected in all slaughtering stages. Although contamination has remained similar (p > 0.05) throughout almost all the slaughter process, evisceration seemed to be an important source of contamination. Our results reinforce the idea that the final carcass quality after the slaughtering process is directly influenced by the level of contamination of the broiler flocks on arrival at the processing plant.Aim To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration-time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80-1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR 0.78; 90% CI 0.69-0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80-1.25. Conclusion Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.The field of prebiotic chemistry has demonstrated that complex organic chemical systems that exhibit various life-like properties can be produced abiotically in the laboratory. Understanding these chemical systems is important for astrobiology and life detection since we do not know the extent to which prebiotic chemistry might exist or have existed on other worlds. Nor do we know what signatures are diagnostic of an extant or "failed" prebiotic system. On Earth, biology has suppressed most abiotic organic chemistry and overprints geologic records of prebiotic chemistry; therefore, it is difficult to validate whether chemical signatures from future planetary missions are remnant or extant prebiotic systems. The "biosignature threshold" between whether a chemical signature is more likely to be produced by abiotic versus biotic chemistry on a given world could vary significantly, depending on the particular environment, and could change over time, especially if life were to emerge and diversify on that world. To interpret organic signatures detected during a planetary mission, we advocate for (1) gaining a more complete understanding of prebiotic/abiotic chemical possibilities in diverse planetary environments and (2) involving experimental prebiotic samples as analogues when generating comparison libraries for "life-detection" mission instruments.