Drug Discovery and Development for Kinetoplastid Diseases

We review the disease, biology and biochemistry of kinetoplastids, as well as the new drugs and drug candidates that have entered the clinic in the last decade. We also describe examples of the pre-clinical exploration of small molecules against various protein targets, (e.g., cysteine proteases, the proteasome and tubulin), as well as cutting-edge molecular and computational strategies, and technologies being brought to bear to discover and develop new anti-trypanosomal drugs. For comprehensive descriptions of the disease, biology and drug therapies prior to 2011, the reader is encouraged to review the chapter by P. M. Woster that appeared in 2010 in the seventh edition of Burger’s Medicinal Chemistry, Drug Discovery, and Development, with the title Antiprotozoal/Antiparasitic Agents

Combination of Mass Cytometry and Imaging Analysis Reveals Origin, Location, and Functional Repopulation of Liver Myeloid Cells in Mice

BACKGROUND & AIMS: Resident macrophages are derived from yolk sac precursors and seed the liver during embryogenesis. Native cells may be replaced by bone marrow precursors during extensive injuries, irradiation, and infections. We investigated the liver populations of myeloid immune cells and their location, as well as the dynamics of phagocyte repopulation after full depletion. The effects on liver function due to the substitution of original phagocytes by bone marrow-derived surrogates were also examined. METHODS: We collected and analyzed liver tissues from C57BL/6 (control), LysM-EGFP, B6 ACTb-EGFP, CCR2-/-, CD11c-EYFP, CD11c-EYFP-DTR, germ-free mice, CX3CR1gfp/gfp, CX3CR1gpf/wt, and CX3CR1-DTR-EYFP. Liver nonparenchymal cells were immunophenotyped using mass cytometry and gene expression analyses. Kupffer and dendritic cells were depleted from mice by administration of clodronate, and their location and phenotype were examined using intravital microscopy and time-of-flight mass cytometry. Mice were given acetaminophen gavage or intravenous injections of fluorescently labeled Escherichia coli, blood samples were collected and analyzed, and liver function was evaluated. We assessed cytokine profiles of liver tissues using a multiplexed array. RESULTS: Using mass cytometry and gene expression analyses, we identified 2 populations of hepatic macrophages and 2 populations of monocytes. We also identified 4 populations of dendritic cells and 1 population of basophils. After selective depletion of liver phagocytes, intravascular myeloid precursors began to differentiate into macrophages and dendritic cells; dendritic cells migrated out of sinusoids, after a delay, via the chemokine CX3CL1. The cell distribution returned to normal in 2 weeks, but the repopulated livers were unable to fully respond to drug-induced injury or clear bacteria for at least 1 month. This defect was associated with increased levels of inflammatory cytokines, and dexamethasone accelerated the repopulation of liver phagocytes. CONCLUSIONS: In studies of hepatic phagocyte depletion in mice, we found that myeloid precursors can differentiate into liver macrophages and dendritic cells, which each localize to distinct tissue compartments. During replenishment, macrophages acquire the ability to respond appropriately to hepatic injury and to remove bacteria from the blood stream.status: publishe

Encapsulated Brucella ovis Lacking a Putative ATP-Binding Cassette Transporter (ΔabcBA) Protects against Wild Type Brucella ovis in Rams.

Submitted by Nuzia Santos ([email protected]) on 2016-04-05T16:46:49Z No. of bitstreams: 1 Encapsulated Brucella(...) Transporte.pdf: 3817674 bytes, checksum: fc75361cde3ac21b6b485230614c7a04 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2016-04-05T16:56:00Z (GMT) No. of bitstreams: 1 Encapsulated Brucella(...) Transporte.pdf: 3817674 bytes, checksum: fc75361cde3ac21b6b485230614c7a04 (MD5)Made available in DSpace on 2016-04-05T16:56:01Z (GMT). No. of bitstreams: 1 Encapsulated Brucella(...) Transporte.pdf: 3817674 bytes, checksum: fc75361cde3ac21b6b485230614c7a04 (MD5) Previous issue date: 2015Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Patologia Geral. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Patologia Geral. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Patologia Geral. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Patologia Geral. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilUniversidade Estadual do Maranhão. Departamento de Patologia. São Luís, MA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, BrasilEmpresa Brasileira de Agropecuária. Juiz de Fora, MG, BrasilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Patologia Geral. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Escola de Veterinária. Departamento de Clínica e Cirurgia Veterinárias. Belo Horizonte, MG, BrasilThis study aimed to evaluate protection induced by the vaccine candidate B. ovis ΔabcBA against experimental challenge with wild type B. ovis in rams. Rams were subcutaneously immunized with B. ovis ΔabcBA encapsulated with sterile alginate or with the non encapsulated vaccine strain. Serum, urine, and semen samples were collected during two months after immunization. The rams were then challenged with wild type B. ovis (ATCC25840), and the results were compared to non immunized and experimentally challenged rams. Immunization, particularly with encapsulated B. ovis ΔabcBA, prevented infection, secretion of wild type B. ovis in the semen and urine, shedding of neutrophils in the semen, and the development of clinical changes, gross and microscopic lesions induced by the wild type B. ovis reference strain. Collectively, our data indicates that the B. ovis ΔabcBA strain is an exceptionally good vaccine strain for preventing brucellosis caused by B. ovis infection in rams

The LHCb upgrade I

International audienceThe LHCb upgrade represents a major change of the experiment. The detectors have been almost completely renewed to allow running at an instantaneous luminosity five times larger than that of the previous running periods. Readout of all detectors into an all-software trigger is central to the new design, facilitating the reconstruction of events at the maximum LHC interaction rate, and their selection in real time. The experiment's tracking system has been completely upgraded with a new pixel vertex detector, a silicon tracker upstream of the dipole magnet and three scintillating fibre tracking stations downstream of the magnet. The whole photon detection system of the RICH detectors has been renewed and the readout electronics of the calorimeter and muon systems have been fully overhauled. The first stage of the all-software trigger is implemented on a GPU farm. The output of the trigger provides a combination of totally reconstructed physics objects, such as tracks and vertices, ready for final analysis, and of entire events which need further offline reprocessing. This scheme required a complete revision of the computing model and rewriting of the experiment's software

The LHCb upgrade I

International audienceThe LHCb upgrade represents a major change of the experiment. The detectors have been almost completely renewed to allow running at an instantaneous luminosity five times larger than that of the previous running periods. Readout of all detectors into an all-software trigger is central to the new design, facilitating the reconstruction of events at the maximum LHC interaction rate, and their selection in real time. The experiment's tracking system has been completely upgraded with a new pixel vertex detector, a silicon tracker upstream of the dipole magnet and three scintillating fibre tracking stations downstream of the magnet. The whole photon detection system of the RICH detectors has been renewed and the readout electronics of the calorimeter and muon systems have been fully overhauled. The first stage of the all-software trigger is implemented on a GPU farm. The output of the trigger provides a combination of totally reconstructed physics objects, such as tracks and vertices, ready for final analysis, and of entire events which need further offline reprocessing. This scheme required a complete revision of the computing model and rewriting of the experiment's software

The LHCb upgrade I

International audienceThe LHCb upgrade represents a major change of the experiment. The detectors have been almost completely renewed to allow running at an instantaneous luminosity five times larger than that of the previous running periods. Readout of all detectors into an all-software trigger is central to the new design, facilitating the reconstruction of events at the maximum LHC interaction rate, and their selection in real time. The experiment's tracking system has been completely upgraded with a new pixel vertex detector, a silicon tracker upstream of the dipole magnet and three scintillating fibre tracking stations downstream of the magnet. The whole photon detection system of the RICH detectors has been renewed and the readout electronics of the calorimeter and muon systems have been fully overhauled. The first stage of the all-software trigger is implemented on a GPU farm. The output of the trigger provides a combination of totally reconstructed physics objects, such as tracks and vertices, ready for final analysis, and of entire events which need further offline reprocessing. This scheme required a complete revision of the computing model and rewriting of the experiment's software