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1.
J Infect Dis ; 228(10): 1452-1455, 2023 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-37540090

RESUMO

BACKGROUND: Although fecal microbiota transplant has been used to prevent recurrent Clostridioides difficile infection (rCDI), documented pathogen transmissions highlight inherent safety risks of minimally processed stool. We describe manufacturing processes for fecal microbiota spores, live (VOWST; VOS, formerly SER-109), a microbiota-based oral therapeutic of Firmicutes spores. METHODS: Bacterial inactivation kill curves were obtained after ethanol exposure for 4 model organisms spiked into process intermediates. RESULTS: Bacterial log reduction factors ranged from 6.5 log10 to 7.4 log10 and lysis of spiked organisms occurred rapidly within 30 seconds. CONCLUSIONS: These experiments demonstrate substantial and rapid inactivation of representative organisms, supporting the potential benefit of VOS manufacturing processes to mitigate risk.


Assuntos
Clostridioides difficile , Infecções por Clostridium , Microbioma Gastrointestinal , Microbiota , Humanos , Fezes/microbiologia , Transplante de Microbiota Fecal , Infecções por Clostridium/prevenção & controle , Infecções por Clostridium/microbiologia , Recidiva
2.
Oncoimmunology ; 11(1): 2010905, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35481284

RESUMO

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRASG12V or EGFRL858R expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (Tregs), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Animais , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Citocinas/metabolismo , Receptores ErbB/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Microambiente Tumoral
3.
Sci Rep ; 11(1): 2097, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483550

RESUMO

Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson's disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson's gene, promotes lung tumorigenesis.


Assuntos
Adenocarcinoma/induzido quimicamente , Adenocarcinoma/genética , Carcinógenos/toxicidade , Predisposição Genética para Doença , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Doença de Parkinson/genética , Adenocarcinoma/patologia , Diferenciação Celular , Cocarcinogênese , Instabilidade Genômica , Humanos , Neoplasias Pulmonares/patologia , Fumar
5.
J Cosmet Dermatol ; 19(9): 2169-2173, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33439544

RESUMO

BACKGROUND: COVID-19 pandemic has affected the world from every aspect. Individuals are drained from social, financial, and emotional percussion of this pandemic. Psychosocial consequences are far greater than are being perceived. It is anticipated that once the pandemic is over the psycho-emotional turbulence would shake the whole populations of affected countries. AIMS AND OBJECTIVES: To review the psychological consequences of COVID-19 pandemic. METHODS: A literature search was conducted on major databases from January 2020 to April 2020 with the search terms of Covid-19, Corona virus, psychological, depression, anxiety, phobias, obsessive behaviors, paranoia, parental relationship, marital life and maternal and fetal bond. CONCLUSION: Patients with COVID-19 infection are more likely to suffer from a myriad of psychological consequences, and this infection may have profound effect on parenting, relationships, marital life, elderly, and maternal-fetal bond.


Assuntos
COVID-19/epidemiologia , COVID-19/psicologia , Pandemias , Estresse Psicológico/epidemiologia , Fatores Etários , Ansiedade/epidemiologia , Ansiedade/etiologia , Ansiedade/psicologia , COVID-19/complicações , COVID-19/transmissão , Depressão/epidemiologia , Depressão/etiologia , Depressão/psicologia , Feminino , Carga Global da Doença , Saúde Global , Pessoal de Saúde/psicologia , Pessoal de Saúde/estatística & dados numéricos , Humanos , Transmissão Vertical de Doenças Infecciosas , Masculino , Comportamento Materno/psicologia , Relações Materno-Fetais/psicologia , Comportamento Obsessivo/epidemiologia , Comportamento Obsessivo/etiologia , Comportamento Obsessivo/psicologia , Transtornos Paranoides/epidemiologia , Transtornos Paranoides/etiologia , Transtornos Paranoides/psicologia , Poder Familiar/psicologia , Transtornos Fóbicos/epidemiologia , Transtornos Fóbicos/etiologia , Transtornos Fóbicos/psicologia , Gravidez , Fatores de Risco , Estresse Psicológico/etiologia , Estresse Psicológico/psicologia
6.
Breast Cancer Res ; 21(1): 103, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488209

RESUMO

BACKGROUND: Solid tumors produce proteins that can induce the accumulation of bone marrow-derived cells in various tissues, and these cells can enhance metastatic tumor growth by several mechanisms. 4T1 murine mammary tumors are known to produce granulocyte colony-stimulating factor (G-CSF) and increase the numbers of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) in tissues such as the spleen and lungs of tumor-bearing mice. While surgical resection of primary tumors decreases MDSC levels in the spleen, the longevity and impact of MDSCs and other immune cells in the lungs after tumor resection have been less studied. METHODS: We used mass cytometry time of flight (CyTOF) and flow cytometry to quantify MDSCs in the spleen, peripheral blood, and lungs of mice bearing orthotopic murine mammary tumors. We also tested the effect of primary tumor resection and/or gemcitabine treatment on the levels of MDSCs, other immune suppressor and effector cells, and metastatic tumor cells in the lungs. RESULTS: We have found that, similar to mice with 4T1 tumors, mice bearing metastatic 4T07 tumors also exhibit accumulation of CD11b+Gr1+ MDSCs in the spleen and lungs, while tissues of mice with non-metastatic 67NR tumors do not contain MDSCs. Mice with orthotopically implanted 4T1 tumors have increased granulocytic (G-) MDSCs, monocytic (M-) MDSCs, macrophages, eosinophils, and NK cells in the lungs. Resection of primary 4T1 tumors decreases G-MDSCs, M-MDSCs, and macrophages in the lungs within 48 h, but significant numbers of functional immunosuppressive G-MDSCs persist in the lungs for 2 weeks after tumor resection, indicative of an environment that can promote metastatic tumor growth. The chemotherapeutic agent gemcitabine depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils in the lungs of 4T1 tumor-bearing mice, and we found that treating mice with gemcitabine after primary tumor resection decreases residual G-MDSCs in the lungs and decreases subsequent metastatic growth. CONCLUSIONS: Our data support the development of therapeutic strategies to target MDSCs and to monitor MDSC levels before and after primary tumor resection to enhance the effectiveness of immune-based therapies and improve the treatment of metastatic breast cancer in the clinic.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Experimentais/patologia , Mastectomia , Células Supressoras Mieloides/efeitos dos fármacos , Animais , Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , Linhagem Celular Tumoral , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Eosinófilos/patologia , Feminino , Células Matadoras Naturais/patologia , Neoplasias Pulmonares/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/imunologia , Gencitabina
7.
mBio ; 9(1)2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29487235

RESUMO

Listeria monocytogenes is a facultative intracellular bacterial pathogen that is frequently associated with food-borne infection. Of particular concern is the ability of L. monocytogenes to breach the blood-brain barrier, leading to life-threatening meningitis and encephalitis. The mechanisms used by bacterial pathogens to infect the brain are not fully understood. Here we show that L. monocytogenes is able to utilize vimentin for invasion of host cells. Vimentin is a type III intermediate filament protein within the cytosol but is also expressed on the host cell surface. We found that L. monocytogenes interaction with surface-localized vimentin promoted bacterial uptake. Furthermore, in the absence of vimentin, L. monocytogenes colonization of the brain was severely compromised in mice. The L. monocytogenes virulence factor InlF was found to bind vimentin and was necessary for optimal bacterial colonization of the brain. These studies reveal a novel receptor-ligand interaction that enhances infection of the brain by L. monocytogenes and highlights the importance of surface vimentin in host-pathogen interactions.IMPORTANCEListeria monocytogenes is an intracellular bacterial pathogen that is capable of invading numerous host cells during infection. L. monocytogenes can cross the blood-brain barrier, leading to life-threatening meningitis. Here we show that an L. monocytogenes surface protein, InlF, is necessary for optimal colonization of the brain in mice. Furthermore, in the absence of vimentin, a cytosolic intermediate filament protein that is also present on the surface of brain endothelial cells, colonization of the brain was significantly impaired. We further show that InlF binds vimentin to mediate invasion of host cells. This work identifies InlF as a bacterial surface protein with specific relevance for infection of the brain and underscores the significance of host cell surface vimentin interactions in microbial pathogenesis.


Assuntos
Encéfalo/parasitologia , Endocitose , Interações Hospedeiro-Patógeno , Listeria monocytogenes/fisiologia , Listeriose/parasitologia , Vimentina/metabolismo , Animais , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Listeriose/patologia , Camundongos , Ratos
8.
Mol Cancer ; 15(1): 67, 2016 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-27784305

RESUMO

Lung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking and exposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammation is the activation, expansion and infiltration of diverse immune cell types, including CD4+ T cells. Within this T cell subset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a fine balance to regulate appropriate adaptive immune responses.In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor foci development. Additionally, Th17 cells have been shown to be an integral component of the inflammatory milieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes. Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment, and that these two CD4+ T cell subsets play active roles in promoting lung cancer progression and metastasis.We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression, metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balance among Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognostic function and relationship to metastasis in lung cancer.


Assuntos
Neoplasias Pulmonares/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Animais , Progressão da Doença , Humanos , Camundongos , Metástase Neoplásica , Microambiente Tumoral
9.
Oncotarget ; 7(4): 3677-91, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26683227

RESUMO

SH2-containing-inositol-5'-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol-3-kinase pathway in hematopoietic cells and limits the development of leukemias and lymphomas. The potential role of SHIP in solid tumor development and metastasis remains unknown. While SHIP restricts the aberrant development of myeloid cells in C57BL/6 mice, there are conflicting reports regarding the effect of SHIP deletion in BALB/c mice with important consequences for determining the influence of SHIP in different model tumor systems. We generated SHIP-/- BALB/c mice and challenged them with syngeneic non-metastatic 67NR or metastatic 4T1 mammary tumors. We demonstrate that SHIP restricts the development, alternative-activation, and immunosuppressive function of myeloid cells in tumor-free and tumor-bearing BALB/c mice. Tumor-free SHIP-/- BALB/c mice exhibited pulmonary inflammation, myeloid hyperplasia, and M2-polarized macrophages and this phenotype was greatly exacerbated by 4T1, but not 67NR, tumors. 4T1-bearing SHIP-/- mice rapidly lost weight and died from necrohemorrhagic inflammatory pulmonary disease, characterized by massive infiltration of pulmonary macrophages and myeloid-derived suppressor cells that were more M2-polarized and immunosuppressive than wild-type cells. Importantly, while SHIP loss did not affect primary tumor growth, 4T1-bearing SHIP-/- mice had 7.5-fold more metastatic tumor cells in their lungs than wild-type mice, consistent with the influence of immunosuppressive myeloid cells on metastatic growth. Our findings identify the hematopoietic cell-restricted protein SHIP as an intriguing target to influence the development of solid tumor metastases, and support development of SHIP agonists to prevent the accumulation of immunosuppressive myeloid cells and tumor metastases in the lungs to improve treatment of metastatic breast cancer.


Assuntos
Neoplasias Pulmonares/prevenção & controle , Neoplasias Mamárias Experimentais/prevenção & controle , Monoéster Fosfórico Hidrolases/fisiologia , Pneumonia/prevenção & controle , Animais , Apoptose , Western Blotting , Proliferação de Células , Feminino , Humanos , Técnicas Imunoenzimáticas , Inositol Polifosfato 5-Fosfatases , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Macrófagos/metabolismo , Macrófagos/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/metabolismo , Células Mieloides/patologia , Pneumonia/genética , Pneumonia/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Metastasis Rev ; 33(4): 1025-41, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25359584

RESUMO

The metastasis of cancer is a complex and life-threatening process that is only partially understood. Immune suppressive cells are recognized as important contributors to tumour progression and may also promote the development and growth of tumour metastases. Specifically, regulatory T cells (Tregs) have been found to promote primary tumour progression, and emerging pre-clinical data suggests that Tregs may promote metastasis and metastatic tumour growth. While the precise role that Tregs play in metastatic progression is understudied, recent findings have indicated that by suppressing innate and adaptive anti-tumour immunity, Tregs may shield tumour cells from immune detection, and thereby allow tumour cells to survive, proliferate and acquire characteristics that facilitate dissemination. This review will highlight our current understanding of Tregs in metastasis, including an overview of pre-clinical findings and discussion of clinical data regarding Tregs and therapeutic outcome. Evolving strategies to directly ablate Tregs or to inhibit their function will also be discussed. Improving our understanding of how Tregs may influence tumour metastasis may lead to novel treatments for metastatic cancer.


Assuntos
Neoplasias/imunologia , Prognóstico , Linfócitos T Reguladores/imunologia , Humanos , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/terapia , Linfócitos T Reguladores/patologia
11.
J Immunol ; 192(1): 512-22, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24285836

RESUMO

Myeloid-derived suppressor cells (MDSCs) are emerging as potential promoters of metastatic tumor growth, and there is interest in targeting immature MDSCs by inducing their differentiation into more mature myeloid cells. We used all-trans retinoic acid (ATRA) to differentiate MDSCs in mice bearing metastatic 4T1 or 4TO7 murine mammary tumors, and assessed the immune-suppressive mechanisms and potencies of different myeloid cell subpopulations. Metastatic mammary tumors induced the accumulation of distinct populations of immature CD11b(+)Gr1(+)F4/80(-)Ly6C(mid)Ly6G(+) MDSCs ("Gr1(+) cells") and mature CD11b(+)Gr1(-)F4/80(+) cells ("F4/80(+) cells") in metastatic target organs. ATRA triggered the differentiation of Gr1(+) cells into F4/80(+) cells in the lungs and, unexpectedly, enhanced pulmonary metastatic tumor growth. We found that F4/80(+)Ly6C(-)Ly6G(-) mature macrophages (Ms) were up to 30-fold more potent immune suppressors than Gr1(+) cells on a per-cell basis, which we postulate may contribute to the increased metastatic growth observed with ATRA treatment. F4/80(+) cells and Gr1(+) cells used different reactive oxygen species (ROS)-mediated mechanisms of immunosuppression ex vivo, with F4/80(+) cells producing higher levels of ROS, which is consistent with their superior immunosuppressive abilities. These data highlight the potent immunosuppressive functions of Ms, reveal that Ms can suppress T cell responses via ROS production, and suggest that ROS inhibitors may be useful in promoting antitumor immune responses. Our findings also caution against using ATRA to modulate myeloid cell differentiation and function to treat breast cancer metastases in the lung, and support the development of therapeutic strategies to enhance antitumor immunity by targeting myeloid cells as a collective group.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Macrófagos/imunologia , Células Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunofenotipagem , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Transgênicos , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Células Mieloides/patologia , Metástase Neoplásica , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tretinoína/farmacologia
12.
Immunity ; 37(5): 930-46, 2012 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-23123061

RESUMO

Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues, which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with the generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens.


Assuntos
Antígeno Carcinoembrionário/imunologia , Imunidade nas Mucosas/imunologia , Intestinos/imunologia , Linfócitos T/imunologia , Motivos de Aminoácidos/genética , Motivos de Aminoácidos/imunologia , Animais , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/metabolismo , Citoplasma/genética , Citoplasma/imunologia , Citoplasma/metabolismo , Homeostase , Imunidade nas Mucosas/genética , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Mucosa Intestinal/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Ativação Linfocitária , Metagenoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Isoformas de Proteínas , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T/metabolismo , Tirosina/genética , Tirosina/imunologia , Tirosina/metabolismo
13.
FEMS Microbiol Lett ; 322(1): 41-50, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21658105

RESUMO

The percentage of bacterial infections refractory to standard antibiotic treatments is steadily increasing. Among the most problematic hospital and community-acquired pathogens are methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA). One novel strategy proposed for treating infections of multidrug-resistant bacteria is the activation of latent toxins of toxin-antitoxin (TA) protein complexes residing within bacteria; however, the prevalence and identity of TA systems in clinical isolates of MRSA and PA has not been defined. We isolated DNA from 78 MRSA and 42 PA clinical isolates and used PCR to probe for the presence of various TA loci. Our results showed that the genes for homologs of the mazEF TA system in MRSA and the relBE and higBA TA systems in PA were present in 100% of the respective strains. Additionally, reverse transcriptase PCR analysis revealed that these transcripts are produced in the clinical isolates. These results indicate that TA genes are prevalent and transcribed within MRSA and PA and suggest that activation of the toxin proteins could be an effective antibacterial strategy for these pathogens.


Assuntos
Antitoxinas/genética , Toxinas Bacterianas/genética , Staphylococcus aureus Resistente à Meticilina/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/genética , Infecções Estafilocócicas/microbiologia , Transcrição Gênica , Antitoxinas/metabolismo , Toxinas Bacterianas/metabolismo , Humanos , Staphylococcus aureus Resistente à Meticilina/classificação , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/metabolismo , Dados de Sequência Molecular , Filogenia , Pseudomonas aeruginosa/classificação , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/metabolismo
14.
Microbiology (Reading) ; 157(Pt 2): 387-397, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21030436

RESUMO

The axe-txe operon encodes a toxin-antitoxin (TA) pair, Axe-Txe, that was initially identified on the multidrug-resistance plasmid pRUM in Enterococcus faecium. In Escherichia coli, expression of the Txe toxin is known to inhibit cell growth, and co-expression of the antitoxin, Axe, counteracts the toxic effect of Txe. Here, we report the nucleotide sequence of pS177, a 39 kb multidrug-resistant plasmid isolated from vancomycin-resistant Ent. faecium, which harbours the axe-txe operon and the vanA gene cluster. RT-PCR analysis revealed that the axe-txe transcript is produced by strain S177 as well as by other vancomycin-resistant enteroccoci. Moreover, we determine the mechanism by which the Txe protein exerts its toxic activity. Txe inhibits protein synthesis in E. coli without affecting DNA or RNA synthesis, and inhibits protein synthesis in a cell-free system. Using in vivo primer extension analysis, we demonstrate that Txe preferentially cleaves single-stranded mRNA at the first base after an AUG start codon. We conclude that Txe is an endoribonuclease which cleaves mRNA and inhibits protein synthesis.


Assuntos
Proteínas de Bactérias/metabolismo , Endorribonucleases/metabolismo , Enterococcus faecium/enzimologia , Plasmídeos/genética , RNA Mensageiro/metabolismo , Proteínas de Bactérias/genética , DNA Bacteriano/genética , Endorribonucleases/genética , Enterococcus faecium/genética , Óperon , Biossíntese de Proteínas , RNA Bacteriano/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
15.
Arch Neurol ; 60(6): 884-8, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12810495

RESUMO

BACKGROUND: Alzheimer disease (AD) is characterized by memory and visuospatial deficits with relative sparing of personality. Mutations in 3 genes (presenilin 1 and 2 and amyloid precursor protein) are associated with presenile AD. Presenilin 1 gene mutations have not been described in African Americans. METHODS: We studied an African American family with autosomal dominant rapidly progressive dementia and psychosis occurring early in the fifth decade of life. We performed neurologic evaluations, psychometrics, and neuroimaging. We sequenced the amyloid precursor protein gene, presenilin 1 and 2, and tau in affected and unaffected family members. One patient underwent a brain biopsy and subsequent autopsy. RESULTS: Personality change, auditory and visual hallucinations, delusions, memory impairment, word-finding difficulties, and subsequent rigidity, dystonia, myoclonus, and mutism developed in 2 brothers. Neuropsychometric testing in one was consistent with frontotemporal dementia or atypical AD. Neuroimaging studies showed diffuse cortical involvement. A clinical diagnosis of familial non-Alzheimer dementia was made. However, results of temporal lobe biopsy in one revealed amyloid neuritic plaques, and autopsy results confirmed the diagnosis of AD. Gene sequencing revealed a presenilin 1 point mutation (M139V) cosegregating with the disease. A tau polymorphism in exon 7 (A178T) was found in an affected brother and unaffected relatives. CONCLUSIONS: We report the first documented presenilin mutation in African American patients presenting with early personality change, psychosis, and memory loss with preserved praxis. The M139V mutation can present differently between kindreds, with some features suggestive of a frontal lobe syndrome. The M139V mutation can lead to atypical AD, and genetic background may have a role in determining the phenotype of genetically defined AD.


Assuntos
Doença de Alzheimer/genética , Proteínas de Membrana/genética , Mutação Puntual/genética , Adulto , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/genética , População Negra , Encéfalo/patologia , Feminino , Genes Dominantes/genética , Alucinações/etiologia , Humanos , Masculino , Transtornos da Memória/etiologia , Pessoa de Meia-Idade , Exame Neurológico , Testes Neuropsicológicos , Transtornos da Personalidade/etiologia , Fenótipo , Placa Amiloide/patologia , Presenilina-1 , Presenilina-2 , Proteínas tau/química , Proteínas tau/genética
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