Triggered star formation surrounding Wolf-Rayet star HD 211853

The environment surrounding Wolf-Rayet star HD 211853 is studied in molecular emission, infrared emission, as well as radio and HI emission. The molecular ring consists of well-separated cores, which have a volume density of 10$^{3}$ cm$^{-3}$ and kinematic temperature $\sim$20 K. Most of the cores are under gravitational collapse due to external pressure from the surrounding ionized gas. From SED modeling towards the young stellar objects (YSOs), sequential star formation is revealed on a large scale in space spreading from the Wolf-Rayet star to the molecular ring. A small scale sequential star formation is revealed towards core A, which harbors a very young star cluster. Triggered star formations is thus suggested. The presence of PDR, the fragmentation of the molecular ring, the collapse of the cores, the large scale sequential star formation indicate the "Collect and Collapse" process functions in this region. The star forming activities in core A seem to be affected by the "Radiation-Driven Implosion" (RDI) process

Small-Molecule Targeting of RNA Polymerase I Activates a Conserved Transcription Elongation Checkpoint

Summary Inhibition of RNA polymerase I (Pol I) is a promising strategy for modern cancer therapy. BMH-21 is a first-in-class small molecule that inhibits Pol I transcription and induces degradation of the enzyme, but how this exceptional response is enforced is not known. Here, we define key elements requisite for the response. We show that Pol I preinitiation factors and polymerase subunits (e.g., RPA135) are required for BMH-21-mediated degradation of RPA194. We further find that Pol I inhibition and induced degradation by BMH-21 are conserved in yeast. Genetic analyses demonstrate that mutations that induce transcription elongation defects in Pol I result in hypersensitivity to BMH-21. Using a fully reconstituted Pol I transcription assay, we show that BMH-21 directly impairs transcription elongation by Pol I, resulting in long-lived polymerase pausing. These studies define a conserved regulatory checkpoint that monitors Pol I transcription and is activated by therapeutic intervention.Peer reviewe

Widespread genetic heterogeneity of human ribosomal RNA genes

Polymorphism drives survival under stress and provides adaptability. Genetic polymorphism of ribosomal RNA (rRNA) genes derives from internal repeat variation of this multicopy gene, and from interindividual variation. A considerable amount of rRNA sequence heterogeneity has been proposed but has been challenging to estimate given the scarcity of accurate reference sequences. We identified four rDNA copies on chromosome 21 (GRCh38) with 99% similarity to recently introduced reference sequence KY962518.1. We customized a GATK bioinformatics pipeline using the four rDNA loci, spanning a total 145 kb, for variant calling and used high-coverage whole-genome sequencing (WGS) data from the 1000 Genomes Project to analyze variants in 2504 individuals from 26 populations. We identified a total of 3791 variant positions. The variants positioned nonrandomly on the rRNA gene. Invariant regions included the promoter, early 5 ' ETS, most of 18S, 5.8S, ITS1, and large areas of the intragenic spacer. A total of 470 variant positions were observed on 28S rRNA. The majority of the 28S rRNA variants were located on highly flexible human-expanded rRNA helical folds ES7L and ES27L, suggesting that these represent positions of diversity and are potentially under continuous evolution. Several variants were validated based on RNA-seq analyses. Population analyses showed remarkable ancestry-linked genetic variance and the presence of both high penetrance and frequent variants in the 5 ' ETS, ITS2, and 28S regions segregating according to the continental populations. These findings provide a genetic view of rRNA gene array heterogeneity and raise the need to functionally assess how the 28S rRNA variants affect ribosome functions.Peer reviewe

Hyaluronan Does Not Affect Bupivacaine's Inhibitory Action on Voltage-Gated Potassium Channel Activities in Bovine Articular Chondrocytes

Objectives. The objective of this paper is to determine if hyaluronan affects bupivacaine's anesthetic function. Methods. Whole cell patch clamp recordings were performed on bovine articular chondrocytes cultured in 60 mm dishes. The chondrocytes were treated with phosphate-buffered saline (control group), 7.5 mg/mL hyaluronan (Orthovisc), 0.25% bupivacaine, or a mixture of 7.5 mg/mL hyaluronan and 0.25% bupivacaine. Outward currents were elicited by step depolarization from −90 mV to 150 mV with 5 mV increments and holding for 200 ms. Results. The amplitude of outward currents elicited at 150 mV was 607.1 ± 135.4 pA (mean ± standard error) in the chondrocytes treated with phosphate buffered saline, 550.0 ± 194.9 pA in the chondrocytes treated with hyaluronan, 18.4 ± 8.3 pA in the chondrocytes treated with bupivacaine, and 12.8 ± 2.6 pA in the chondrocytes treated with a mixture of hyaluronan and bupivacaine. Conclusion. Hyaluronan does not affect bupivacaine's inhibitory action on the potassium channel activities in bovine articular chondrocytes. This finding suggests that intra-articular injection of a mixture of hyaluronan and bupivacaine may not affect the anesthetic effects of bupivacaine

Mesenchymal stromal cells and vascular morphogenesis: gene expression profiles and promoting pathways

Objective: Hematopoietic cells and mesenchymal stromal cells are closely related to endothelial cells in theembryological cell differentiation lineages. To study the pathobiology of vascular immunology and microenvironmentin vascular morphogenesis, we analyzed the genetic factors known to be involved in vascular anomalies in humansand mice in the expression data from the Immunological Genome Project (ImmGen).Methods: We mined the Pictures of Standard Syndromes of Undiagnosed Malformations and NCBI OnlineMendelian Inheritance in Man databases to construct a gene list related to vasculature. We studied the expressionsignatures of these genes in the ImmGen database. Hierarchical clustering analyses were performed using Partek®Genomics Suite 6.6. Next, the acquired clusters were separately investigated within Ingenuity Pathway Analysis(IPA). Based on these results we performed a Principal Component Analysis (PCA) with pericyte samples from aseparate database to investigate the relation with pericytes.Results: Our database queries resulted in a gene list of 438 genes related to vasculature, of which 384 could bestudied within the ImmGen data set. Through hierarchical clustering we identified five distinct clusters of whichone was specific for expression in mesenchymal cell lines. Next, using IPA we found various pathways related topericyte functions. A subsequent PCA with pericyte samples showed a close resemblance to specific stromal cells ofmesenchymal origin indicating shared expression profiles for vascular genes between pericytes and these cell types.These results indicate that the processes of Epithelial-Mesenchymal-Transition and or Endothelial-MesenchymalTransition underly the interaction between epithelial/endothelial cells and mesenchymal stromal cells in vascularmorphogenesis.Conclusion: In this data analysis study, we performed data fusion from various sources that may aid futuremechanistic and therapeutic studies in study design and cell type selection as well as provide a potential strategyto find therapeutic targets based on the specific pathological molecular mechanisms related to vascular anomalies

Mesenchymal stromal cells and vascular morphogenesis: gene expression profiles and promoting pathways

Objective: Hematopoietic cells and mesenchymal stromal cells are closely related to endothelial cells in theembryological cell differentiation lineages. To study the pathobiology of vascular immunology and microenvironmentin vascular morphogenesis, we analyzed the genetic factors known to be involved in vascular anomalies in humansand mice in the expression data from the Immunological Genome Project (ImmGen).Methods: We mined the Pictures of Standard Syndromes of Undiagnosed Malformations and NCBI OnlineMendelian Inheritance in Man databases to construct a gene list related to vasculature. We studied the expressionsignatures of these genes in the ImmGen database. Hierarchical clustering analyses were performed using Partek®Genomics Suite 6.6. Next, the acquired clusters were separately investigated within Ingenuity Pathway Analysis(IPA). Based on these results we performed a Principal Component Analysis (PCA) with pericyte samples from aseparate database to investigate the relation with pericytes.Results: Our database queries resulted in a gene list of 438 genes related to vasculature, of which 384 could bestudied within the ImmGen data set. Through hierarchical clustering we identified five distinct clusters of whichone was specific for expression in mesenchymal cell lines. Next, using IPA we found various pathways related topericyte functions. A subsequent PCA with pericyte samples showed a close resemblance to specific stromal cells ofmesenchymal origin indicating shared expression profiles for vascular genes between pericytes and these cell types.These results indicate that the processes of Epithelial-Mesenchymal-Transition and or Endothelial-MesenchymalTransition underly the interaction between epithelial/endothelial cells and mesenchymal stromal cells in vascularmorphogenesis.Conclusion: In this data analysis study, we performed data fusion from various sources that may aid futuremechanistic and therapeutic studies in study design and cell type selection as well as provide a potential strategyto find therapeutic targets based on the specific pathological molecular mechanisms related to vascular anomalies

Identification of an E3 ligase that targets the catalytic subunit of RNA Polymerase I upon transcription stress

Publisher Copyright: © 2022 The AuthorsRNA Polymerase I (Pol I) synthesizes rRNA, which is the first and rate-limiting step in ribosome biogenesis. Factors governing the stability of the polymerase complex are not known. Previous studies characterizing Pol I inhibitor BMH-21 revealed a transcriptional stress-dependent pathway for degradation of the largest subunit of Pol I, RPA194. To identify the E3 ligase(s) involved, we conducted a cell-based RNAi screen for ubiquitin pathway genes. We establish Skp–Cullin–F-box protein complex F-box protein FBXL14 as an E3 ligase for RPA194. We show that FBXL14 binds to RPA194 and mediates RPA194 ubiquitination and degradation in cancer cells treated with BMH-21. Mutation analysis in yeast identified lysines 1150, 1153, and 1156 on Rpa190 relevant for the protein degradation. These results reveal the regulated turnover of Pol I, showing that the stability of the catalytic subunit is controlled by the F-box protein FBXL14 in response to transcription stress.Peer reviewe

Expression of AS3MT alters transcriptional profiles in human urothelial cells exposed to arsenite

Inorganic arsenic (iAs) is an environmental toxicant and human carcinogen. The enzymatic methylation of iAs that is catalyzed by arsenic (+3 oxidation state)-methyltransferase (AS3MT) generates reactive methylated intermediates that contribute to the toxic and carcinogenic effects of iAs. We have shown that clonal human urothelial cells (UROtsa/F35) that express rat AS3MT and methylate iAs are more susceptible to acute toxicity of arsenite (iAsIII) than parental UROtsa cells that do not express AS3MT and do not methylate iAs. The current work examines transcriptional changes associated with AS3MT expression and identifies specific categories of genes expressed in UROtsa and UROtsa/F35 cells in response to a 24-h exposure to 1 or 50 μM iAsIII. Here, the expression of 21,073 genes was assessed using Agilent Human 1A(V2) arrays. Venn analysis showed marked concentration-dependent differences between gene expression patterns in UROtsa and UROTsa/F35 cells exposed to iAsIII. Among 134 genes altered by exposure to subtoxic 1 μM iAsIII, only 14 were shared by both cell lines. Exposure to cytotoxic 50 μM iAsIII uniquely altered 1389 genes in UROtsa/F35 and 649 genes in UROtsa cells; 5033 altered genes were associated with the chemical alone. In UROtsa, but not UROtsa/F35 cells exposure to 1 μM iAsIII altered expression of genes associated with cell adhesion. In contrast, expression of genes involved in cell cycle regulation was significantly altered in UROtsa/F35 cells at this exposure level. At 50 μM iAsIII, pathways regulating cell cycle, cell death, transcription, and metabolism were affected in both cell lines. However, only Urotsa/F35 cells showed numerous G-protein and kinase pathway alterations as well as alterations in pathways involved in cell growth and differentiation. These data link the AS3MT-catalyzed methylation of iAs to specific genomic responses in human cells exposed to iAsIII. Further analysis of these responses will help to characterize the role of AS3MT-catalyzed methylation in modulation of iAsIII toxicity