Kettering University

About: Kettering University is a education organization based out in Flint, Michigan, United States. It is known for research contribution in the topics: Cancer & RNA. The organization has 6842 authors who have published 7689 publications receiving 337503 citations. The organization is also known as: GMI Engineering & Management Institute & General Motors Institute.

The DExH protein NPH-II is a processive and directional motor for unwinding RNA.

Abstract: All aspects of cellular RNA metabolism and processing involve DExH/D proteins, which are a family of enzymes that unwind or manipulate RNA in an ATP-dependent fashion1 DExH/D proteins are also essential for the replication of many viruses, and therefore provide targets for the development of therapeutics2 All DExH/D proteins characterized to date hydrolyse nucleoside triphosphates and, in most cases, this activity is stimulated by the addition of RNA or DNA1 Several members of the family unwind RNA duplexes in an NTP-dependent fashion in vitro1,3; therefore it has been proposed that DExH/D proteins couple NTP hydrolysis to RNA conformational change in complex macromolecular assemblies4 Despite the central role of DExH/D proteins, their mechanism of RNA helicase activity remains unknown Here we show that the DExH protein NPH-II unwinds RNA duplexes in a processive, unidirectional fashion with a step size of roughly one-half helix turn We show that there is a quantitative connection between ATP utilization and helicase processivity, thereby providing direct evidence that DExH/D proteins can function as molecular motors on RNA

Essential Role for Neutrophils but not Alveolar Macrophages at Early Time Points following Aspergillus fumigatus Infection

Abstract: Alveolar macrophages and neutrophils mediate innate immune defense against the opportunistic fungal pathogen Aspergillus fumigatus and are believed to be essential for host survival following inhalation of fungal spores (conidia). Although alveolar macrophages are postulated to kill inhaled conidia and neutrophils are believed to act against hyphae, the relative contribution of alveolar macrophages and neutrophils to early defense against A. fumigatus remain incompletely defined. To more precisely characterize the contributions of alveolar macrophages and neutrophils in antifungal host defense, we selectively depleted each cell population at different times following pulmonary challenge with conidia. Mice depleted of alveolar macrophages prior to pulmonary A. fumigatus infection recruited neutrophils normally and restricted hyphal tissue invasion. In contrast, neutrophil depletion prior to or within 3 h after infection was associated with high mortality. Neutrophil depletion at later time points, however, was associated with nearly normal survival rates. Our studies suggest that neutrophils, but not alveolar macrophages, provide essential anticonidial defense and that a brief period of influx into the respiratory tree is sufficient to prevent conidial germination and invasive disease.

Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies.

Abstract: Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti–CTLA-4 and anti–PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti–CTLA-4 plus anti–PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti–PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti–PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.