Iron(II) Complexes of Di­methyl­tri­aza­cyclo­phane

Treatment of the ortho-tri­aza­cyclo­phane 1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-triene [(C6H5)3(NH)(NCH3)2, L1] with Fe[N(SiMe3)2]2 yields the dimeric iron(II) complex bis­(μ-1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-trien-7-ido)bis­[(μ-1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-trien-7-ido)iron(II)], [Fe(C20H18N3)4] or Fe2(L1)4 (9). Dissolution of 9 in tetra­hydro­furan (THF) results in solvation by two THF ligands and the formation of a simpler monoiron complex, namely bis­(μ-1,4-di­methyl­tribenzo[b,e,h][1,4,7]tri­aza­cyclo­nona-2,5,8-trien-7-ido-κN7)bis­(tetra­hydro­furan-κO)iron(II), [Fe(C20H18N3)2(C4H8O)2] or (L1)2Fe(THF)2 (10). The reaction is reversible and 10 reverts in vacuo to diiron complex 9. In the structures of both 9 and 10, the monoanionic tri­aza­cyclo­phane ligand L1− is observed in only the less-symmetric saddle conformation. No bowl-shaped crown conformers are observed in the solid state, thus preventing chelating κ3-coordination to the metal as had been proposed earlier based on density functional theory (DFT) calculations. Instead, the L1− ligands are bound in either a η2-chelating fashion through the amide and one amine donor (for one of the four ligands of 9), or solely through their amide N atoms in an even simpler monodentate η1-coordination mode. Density functional calculations on dimer 9 revealed nearly full cationic charges on each Fe atom and no bonding inter­action between the two metal centers, consistent with the relatively long FeFe distance of 2.912 (1) Å observed in the solid state

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia

SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia

The production of noncanonical mRNA transcripts is associated with cell transformation. Driven by our previous findings on the sensitivity of T cell acute lymphoblastic leukemia (T-ALL) cells to SF3B1 inhibitors, we identified that SF3B1 inhibition blocks T-ALL growth in vivo with no notable associated toxicity. We also revealed protein stabilization of the U2 complex component SF3B1 via deubiquitination. Our studies showed that SF3B1 inhibition perturbs exon skipping, leading to nonsense-mediated decay and diminished levels of DNA damage response-related transcripts, such as the serine/threonine kinase CHEK2, and impaired DNA damage response. We also identified that SF3B1 inhibition leads to a general decrease in R-loop formation. We further demonstrate that clinically used SF3B1 inhibitors synergize with CHEK2 inhibitors and chemotherapeutic drugs to block leukemia growth. Our study provides the proof of principle for posttranslational regulation of splicing components and associated roles and therapeutic implications for the U2 complex in T cell leukemia

Image_2_Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.eps

BackgroundRespiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.MethodsNasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared.FindingsIncreased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for InterpretationIncreased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.</p

Image_1_Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.eps

BackgroundRespiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.MethodsNasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared.FindingsIncreased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for InterpretationIncreased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.</p

DataSheet_4_Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.xlsx

BackgroundRespiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.MethodsNasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared.FindingsIncreased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for InterpretationIncreased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.</p

DataSheet_1_Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.xlsx

BackgroundRespiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.MethodsNasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared.FindingsIncreased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for InterpretationIncreased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.</p

DataSheet_2_Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.xlsx

BackgroundRespiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.MethodsNasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared.FindingsIncreased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for InterpretationIncreased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.</p

DataSheet_6_Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.xlsx

BackgroundRespiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.MethodsNasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared.FindingsIncreased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for InterpretationIncreased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.</p

Table_1_Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.pdf

BackgroundRespiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes.MethodsNasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared.FindingsIncreased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for InterpretationIncreased expression of cilia-related genes in clinically indistinguishable infants with critical RSV may differentiate between infants who will require prolonged hospitalization and infants who will recover quickly. Validation of these findings in a larger cohort is needed to determine whether a cilia-related gene signature can predict duration of illness in infants with critical bronchiolitis. The ability to identify which infants with critical RSV bronchiolitis may require prolonged hospitalization using non-invasive nasal samples would provide invaluable prognostic information to parents and medical providers.</p