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1.
PLoS Biol ; 18(10): e3000850, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33017398

RESUMO

Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes-gender imbalance and splenic marginal zone B-cell lymphoma-emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer-deficient animals.


Assuntos
Linfócitos B/imunologia , Dosagem de Genes , Coração/embriologia , Homeostase , Intestinos/patologia , Infestações por Ácaros/imunologia , Receptores Notch/genética , Células-Tronco/patologia , Alelos , Animais , Sequência de Bases , Proliferação de Células , Cromatina/metabolismo , Sulfato de Dextrana , Ventrículos do Coração/embriologia , Ventrículos do Coração/patologia , Camundongos , Ácaros/fisiologia , Modelos Biológicos , Multimerização Proteica , Receptores Notch/metabolismo , Baço/imunologia , Esplenomegalia/imunologia , Esplenomegalia/parasitologia , Células-Tronco/metabolismo
2.
Ecotoxicol Environ Saf ; 264: 115487, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37729804

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted human-to-human via aerosols and air-borne droplets. Therefore, capturing and destroying viruses from indoor premises are essential to reduce the probability of human exposure and virus transmission. While the heating, ventilation, and air conditioning (HVAC) systems help in reducing the indoor viral load, a targeted approach is required to effectively remove SARS-CoV-2 from indoor air to address human exposure concerns. The present study demonstrates efficient trapping and destruction of SARS-CoV-2 via nano-enabled filter technology using the UV-A-stimulated photoelectrochemical oxidation (PECO) process. Aerosols containing SARS-CoV-2 were generated by nebulization inside an air-controlled test chamber where an air purifier (Air Mini+) was placed. The study demonstrated the efficient removal of SARS-CoV-2 (99.98 %) from the test chamber in less than two minutes and PECO-assisted destruction (over 99%) on the filtration media in 1 h. Furthermore, in a real-world scenario, the Molekule Air-Pro air purifier removed SARS-CoV-2 (a negative RT-qPCR result post-running the filter device) from the circulating air in a COVID-19 testing facility. Overall, the ability of two FDA-approved class II medical devices, Molekule Air-Mini+ and Air-Pro air purifiers, to remove and destroy SARS-CoV-2 in indoor settings was successfully demonstrated. The study indicates that as the "tripledemic" of COVID-19, influenza, and respiratory syncytial virus (RSV) overwhelm the healthcare facilities in the USA, the use of a portable air filtration device will help contain the spread of the viruses in close door facilities, such as in schools and daycare facilities.


Assuntos
Filtros de Ar , Poluição do Ar em Ambientes Fechados , COVID-19 , Humanos , SARS-CoV-2 , Teste para COVID-19 , Aerossóis e Gotículas Respiratórios , Poluição do Ar em Ambientes Fechados/prevenção & controle
3.
Blood ; 133(22): 2413-2426, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-30917956

RESUMO

Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from hematopoietic stem cells (HSCs) into mature effectors remain. The pseudokinase tribbles homolog 1 (Trib1) is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the granulocyte/macrophage progenitor (GMP). Using hematopoietic- and eosinophil-lineage-specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased CCAAT/enhancer binding protein α (C/EBPα) p42. Using an ex vivo differentiation assay, we found that interleukin 5 (IL-5) supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBPα. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at 2 distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.


Assuntos
Eosinófilos/metabolismo , Regulação da Expressão Gênica , Células Progenitoras de Granulócitos e Macrófagos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Mielopoese , Neutrófilos/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Eosinófilos/citologia , Células Progenitoras de Granulócitos e Macrófagos/citologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Transgênicos , Neutrófilos/citologia , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética
4.
Blood ; 128(18): 2229-2240, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27670423

RESUMO

Activating NOTCH1 mutations are frequent in human T-cell acute lymphoblastic leukemia (T-ALL) and Notch inhibitors (γ-secretase inhibitors [GSIs]) have produced responses in patients with relapsed, refractory disease. However, sustained responses, although reported, are uncommon, suggesting that other pathways can substitute for Notch in T-ALL. To address this possibility, we first generated KrasG12D transgenic mice with T-cell-specific expression of the pan-Notch inhibitor, dominant-negative Mastermind (DNMAML). These mice developed leukemia, but instead of accessing alternative oncogenic pathways, the tumor cells acquired Notch1 mutations and subsequently deleted DNMAML, reinforcing the notion that activated Notch1 is particularly transforming within the context of T-cell progenitors. We next took a candidate approach to identify oncogenic pathways downstream of Notch, focusing on Myc and Akt, which are Notch targets in T-cell progenitors. KrasG12D mice transduced with Myc developed T-ALLs that were GSI-insensitive and lacked Notch1 mutations. In contrast, KrasG12D mice transduced with myristoylated AKT developed GSI-sensitive T-ALLs that acquired Notch1 mutations. Thus, Myc can substitute for Notch1 in leukemogenesis, whereas Akt cannot. These findings in primary tumors extend recent work using human T-ALL cell lines and xenografts and suggest that the Notch/Myc signaling axis is of predominant importance in understanding both the selective pressure for Notch mutations in T-ALL and response and resistance of T-ALL to Notch pathway inhibitors.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptor Notch1/genética , Animais , Western Blotting , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Camundongos Transgênicos , Mutação , Reação em Cadeia da Polimerase em Tempo Real
5.
Biochem Soc Trans ; 43(5): 1112-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26517933

RESUMO

The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue-specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types.


Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Hematopoese/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia Mieloide/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Doença Aguda , Animais , Regulação Leucêmica da Expressão Gênica , Humanos , Modelos Genéticos , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética
6.
Blood ; 121(25): 5015-24, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23670180

RESUMO

Hematopoiesis is a tightly regulated process resulting in the production of blood cells. Self-renewal and differentiation of hematopoietic stem cells (HSCs) are key processes in hematopoietic development. Disruption of these steps can lead to altered cell distribution and disease. To investigate the role of the nuclear factor-κB subunit RelA/p65 in the regulation of HSCs in vivo, we generated mice lacking RelA/p65 in the hematopoietic compartment. Using this model system, we show that loss of p65 severely impairs HSC function and occurs in conjunction with increased hematopoietic stem and progenitor cell cycling, extramedullary hematopoiesis, and differentiation defects. Gene array studies of phenotypic HSCs indicate the up-regulation of genes normally expressed in lineage restricted cells, as well as the down-regulation of genes involved in HSC maintenance and homeostasis. We hypothesize that changes in gene expression in p65-deficient cells lead to decreased self-renewal and differentiation efficiency of hematopoietic stem and progenitor cells. These studies demonstrate that p65 is an important regulator of hematopoiesis through the transcription of genes involved in HSC fate.


Assuntos
Regulação da Expressão Gênica/fisiologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Fator de Transcrição RelA/metabolismo , Animais , Diferenciação Celular/fisiologia , Feminino , Citometria de Fluxo , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição RelA/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-36673732

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resulting COVID-19 (coronavirus disease 2019) pandemic have required mass diagnostic testing, often taking place in testing sites within hospitals, clinics, or at satellite locations. To establish the potential of SARS-CoV-2 aerosol transmission and to identify junctures during testing that result in increased viral exposure, aerosol and surface samples were examined for the presence of SARS-CoV-2 RNA from locations within Nebraska Medicine COVID-19 testing and vaccine clinics. Aerosols containing SARS-CoV-2 RNA detected within clinics suggest viral shedding from infected individuals. SARS-CoV-2 RNA detection in aerosol samples was shown to correlate with clinic operation and patient infection, as well as with community infection findings. Additionally, SARS-CoV-2 RNA was detected in surface samples collected from clinics. The presence of SARS-CoV-2 RNA in aerosols in these clinics supports the continued use of respiratory protection and sanitization practices for healthcare workers, and other workers with public facing occupations.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/epidemiologia , Teste para COVID-19 , RNA Viral , Aerossóis e Gotículas Respiratórios
8.
J Exp Med ; 217(5)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32150623

RESUMO

In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.


Assuntos
Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Doença Crônica , Humanos , Imunidade , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Fenótipo , Ligação Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Transcrição Gênica , Carga Viral
9.
Mol Cancer Ther ; 7(2): 391-7, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18245668

RESUMO

Chronic myelogenous leukemia is a malignant disease of the hematopoietic stem cell compartment, which is characterized by expression of the BCR-ABL fusion protein. Expression of BCR-ABL allows myeloid cells to grow in the absence of the growth factors interleukin-3 and granulocyte-macrophage colony-stimulating factor. The tyrosine kinase activity of BCR-ABL constitutively activates signaling pathways associated with Ras and its downstream effectors and with the Jak/STAT pathway. Additionally, we reported previously that BCR-ABL activates the transcription factor nuclear factor-kappaB (NF-kappaB) in a manner dependent on Ras and that inhibition of NF-kappaB by expression of a modified form of IkappaBalpha blocked BCR-ABL-driven tumor growth in a xenograft model. Here, we show that a highly specific inhibitor of IkappaB kinase beta, a key upstream regulator of the NF-kappaB pathway, induces growth suppression and death in cells expressing wild-type, Imatinib-resistant, or the T315I Imatinib/Dasatinib-resistant forms of BCR-ABL. Cell cycle variables were not affected by this compound. These data indicate that blockage of BCR-ABL-induced NF-kappaB activation via IkappaB kinase beta inhibition represents a potential new approach for treatment of Imatinib- or Dasatinib-resistant forms of chronic myelogenous leukemia.


Assuntos
Genes abl , Quinase I-kappa B/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Antineoplásicos/farmacologia , Benzamidas , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dasatinibe , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Quinase I-kappa B/metabolismo , Quinase I-kappa B/fisiologia , Mesilato de Imatinib , Fosforilação/efeitos dos fármacos , Transfecção , Células Tumorais Cultivadas
10.
PLoS One ; 11(5): e0155408, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27191957

RESUMO

Trib2 is highly expressed in human T cell acute lymphoblastic leukemia (T-ALL) and is a direct transcriptional target of the oncogenic drivers Notch and TAL1. In human TAL1-driven T-ALL cell lines, Trib2 is proposed to function as an important survival factor, but there is limited information about the role of Trib2 in primary T-ALL. In this study, we investigated the role of Trib2 in the initiation and maintenance of Notch-dependent T-ALL. Trib2 had no effect on the growth and survival of murine T-ALL cell lines in vitro when expression was blocked by shRNAs. To test the function of Trib2 on leukemogenesis in vivo, we generated Trib2 knockout mice. Mice were born at the expected Mendelian frequencies without gross developmental anomalies. Adult mice did not develop pathology or shortened survival, and hematopoiesis, including T cell development, was unperturbed. Using a retroviral model of Notch-induced T-ALL, deletion of Trib2 unexpectedly decreased the latency and increased the penetrance of T-ALL development in vivo. Immunoblotting of primary murine T-ALL cells showed that the absence of Trib2 increased C/EBPα expression, a known regulator of cell proliferation, and did not alter AKT or ERK phosphorylation. Although Trib2 was suggested to be highly expressed in T-ALL, transcriptomic analysis of two independent T-ALL cohorts showed that low Trib2 expression correlated with the TLX1-expressing cortical mature T-ALL subtype, whereas high Trib2 expression correlated with the LYL1-expressing early immature T-ALL subtype. These data indicate that Trib2 has a complex role in the pathogenesis of Notch-driven T-ALL, which may vary between different T-ALL subtypes.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores Notch/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Expressão Gênica , Marcação de Genes , Loci Gênicos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Penetrância , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais
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