Type I Interferon Sensitizes Lymphocytes to Apoptosis and Reduces Resistance to Listeria Infection

Infection with Listeria monocytogenes causes lymphocyte apoptosis that is mediated by the actions of the pore-forming virulence factor listeriolysin O (LLO). Previous work showed that activated lymphocytes were highly sensitive to LLO-induced apoptosis, whereas resting lymphocytes were less susceptible. We now show that mice deficient in the type I interferon (IFN) receptor were more resistant to Listeria infection and had less apoptotic lesions than wild-type counterparts. Furthermore, treatment of resting splenic lymphocytes with recombinant IFN-αA enhanced their susceptibility to LLO-induced apoptosis. Together, these data suggest that type I IFN signaling is detrimental to handling of a bacterial pathogen and may enhance the susceptibility of lymphocytes undergoing apoptosis in response to bacterial pore-forming toxins

Lymphocytes are detrimental during the early innate immune response against Listeria monocytogenes

Mice deficient in lymphocytes are more resistant than normal mice to Listeria monocytogenes infection during the early innate immune response. This paradox remains unresolved: lymphocytes are required for sterilizing immunity, but their presence during the early stage of the infection is not an asset and may even be detrimental. We found that lymphocyte-deficient mice, which showed limited apoptosis in infected organs, were resistant during the first four days of infection but became susceptible when engrafted with lymphocytes. Engraftment with lymphocytes from type I interferon receptor–deficient (IFN-αβR−/−) mice, which had reduced apoptosis, did not confer increased susceptibility to infection, even when the phagocytes were IFN-αβR+/+. The attenuation of innate immunity was due, in part, to the production of the antiinflammatory cytokine interleukin 10 by phagocytic cells after the apoptotic phase of the infection. Thus, immunodeficient mice were more resistant relative to normal mice because the latter went through a stage of lymphocyte apoptosis that was detrimental to the innate immune response. This is an example of a bacterial pathogen creating a cascade of events that leads to a permissive infective niche early during infection

Recombinant Listeria monocytogenes expressing a cell wall-associated listeriolysin O is weakly virulent but immunogenic

Listeriolysin O (LLO) is an essential virulence factor for the gram-positive bacterium Listeria monocytogenes. Our goal was to determine if altering the topology of LLO would alter the virulence and toxicity of L. monocytogenes in vivo. A recombinant strain was generated that expressed a surface-associated LLO (sLLO) variant secreted at 40-fold-lower levels than the wild type. In culture, the sLLO strain grew in macrophages, translocated to the cytosol, and induced cell death. However, the sLLO strain showed decreased infectivity, reduced lymphocyte apoptosis, and decreased virulence despite a normal in vitro phenotype. Thus, the topology of LLO in L. monocytogenes was a factor in the pathogenesis of the infection and points to a role of LLO secretion during in vivo infection. The sLLO strain was cleared by severe combined immunodeficient (SCID) mice. Despite the attenuation of virulence, the sLLO strain was immunogenic and capable of eliciting protec-tive T-cell responses. Listeria monocytogenes is a gram-positive facultative intra-cellular pathogen extensively used to understand host-patho-gen interactions (44, 51, 53). It expresses the highly conserved pore-forming toxin listeriolysin O (LLO), a member of a large family of cholesterol-dependent cytolysins found in many im

Estudio teórico de un riogenerador para la generación de energía eléctrica en el sector Sausicucho – Distrito de Cachachi

La presente investigación tuvo como objetivo realizar un estudio teórico para generar energía eléctrica a partir del potencial hidráulico en un riogenerador para el Sector Sausicucho – Distrito de Cachachi. La investigación fue de tipo aplicada, descriptivo, diseño pre experimental. La población a los sectores rurales con potencial de fuente hidráulica, sin conexión al SEIN y como muestra al Sector Poblado Sausicucho con fuente hidráulica del rio Sausicucho. El generador eléctrico seleccionado fue de característica monofásico con una potencia nominal de 48.40 KVA con un voltaje de 220V y velocidad de rotación de 1800 RPM, con reductor de 100.98 RPM. Asimismo, se comparó los datos de operación del riogenerador con los de las turbinas Pelton y Michell – Banki, dónde se necesita una altura geodésica de 0m y 18 palas con un riogenerador, 16m y 21 cucharas con turbina Pelton y 22m y 1 inyector con turbina Michell – Banki. El presente proyecto tiene un beneficio útil de 41897.10 US$/año, con una inversión de 28605.20 US$ y un retorno de inversión de 8 meses. Desde el criterio financiero el proyecto es viable con una TIR del 146% y un VAN de 290067.47 US$ en 15 años con una tasa de interés del 10%

2014-2015 Master Class - Boris Slutsky (Piano)

https://spiral.lynn.edu/conservatory_masterclasses/1035/thumbnail.jp

Reorganización de lo centros de capacitación de la Asociación Fe y Alegría tomo VI Centros de Capacitación de Mecánica General.

Se representa básicamente los Diseños propuestos para la solución de la problemática encontrada en los centros de Capacitación de esta Especialidad, por lo tanto se divide en dos áreas de estudio una referente al Plan y Programas de Estudio y otra al área Administrativa

A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors

Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety, pharmacokinetics, and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments. Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): PartA = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W

The pancreas anatomy conditions the origin and properties of resident macrophages

We examine the features, origin, turnover, and gene expression of pancreatic macrophages under steady state. The data distinguish macrophages within distinct intrapancreatic microenvironments and suggest how macrophage phenotype is imprinted by the local milieu. Macrophages in islets of Langerhans and in the interacinar stroma are distinct in origin and phenotypic properties. In islets, macrophages are the only myeloid cells: they derive from definitive hematopoiesis, exchange to a minimum with blood cells, have a low level of self-replication, and depend on CSF-1. They express Il1b and Tnfa transcripts, indicating classical activation, M1, under steady state. The interacinar stroma contains two macrophage subsets. One is derived from primitive hematopoiesis, with no interchange by blood cells and alternative, M2, activation profile, whereas the second is derived from definitive hematopoiesis and exchanges with circulating myeloid cells but also shows an alternative activation profile. Complete replacement of islet and stromal macrophages by donor stem cells occurred after lethal irradiation with identical profiles as observed under steady state. The extraordinary plasticity of macrophages within the pancreatic organ and the distinct features imprinted by their anatomical localization sets the base for examining these cells in pathological conditions