70 research outputs found
Gene therapy for B-cell lymphoma in a SCID mouse model using an immunoglobulin-regulated diphtheria toxin gene delivered by a novel adenovirus-polylysine conjugate
Parasite Mitogen-Activated Protein Kinases as Drug Discovery Targets to Treat Human Protozoan Pathogens
Protozoan pathogens are a highly diverse group of unicellular organisms, several of which are significant human pathogens. One group of protozoan pathogens includes obligate intracellular parasites such as agents of malaria, leishmaniasis, babesiosis, and toxoplasmosis. The other group includes extracellular pathogens such as agents of giardiasis and amebiasis. An unfortunate unifying theme for most human protozoan pathogens is that highly effective treatments for them are generally lacking. We will review targeting protozoan mitogen-activated protein kinases (MAPKs) as a novel drug discovery approach towards developing better therapies, focusing on Plasmodia, Leishmania, and Toxoplasma, about which the most is known
Efficient Foreign Gene Expression in Epstein-Barr Virus-Transformed Human B-Cells
Epstein-Barr virus (EBV) is a herpesvirus that transforms B-cells (B-LCL) and has undergone intense scrutiny owing to its association with Burkitt's lymphoma, nasopharyngeal carcinoma, and immunoblastic lymphomas. B-LCL have also proven useful in the study of human immunology. We describe a novel system for inducing efficient foreign gene expression in B-LCL using biotinylated adenovirus as an endosome-disrupting agent. Plasmid DNA is coupled to the exterior of viral particles by streptavidin-polylysine chimeric proteins. Up to 67% of B-LCL may be induced to express foreign genes in vitro in transient expression systems, and gene expression lasts for at least 17 days. We have expressed firefly luciferase, β-galactosidase (β-gal), chloramphenicol acetyltransferase, HIV gag, and env genes, as well as infectious HIV, and the EBV-specific BZLF gene in B-LCL with this system. In vivo delivery of a β-gal reporter gene to B-LCL was documented in a SCID mouse model. Potential applications include study of genetic regulation of EBV infection and transformation events, study of potential gene therapies for EBV-related B-cell tumors, and production of antigen-presenting cells for use in immunologic assays. Because of the high percentage of cells transformed and the length of foreign gene expression, the possibility of examining foreign gene expression in transient assays, without selection for clonal populations, exists
The Spitzer c2d Survey of Nearby Dense Cores: VI. The Protostars of Lynds Dark Nebula 1221
Observations of Lynds Dark Nebula 1221 from the Spitzer Space Telescope are
presented. These data show three candidate protostars towards L1221, only two
of which were previously known. The infrared observations also show signatures
of outflowing material, an interpretation which is also supported by radio
observations with the Very Large Array. In addition, molecular line maps from
the Five College Radio Astronomy Observatory are shown.
One-dimensional dust continuum modelling of two of these protostars, IRS1 and
IRS3, is described. These models show two distinctly different protostars
forming in very similar environments. IRS1 shows a higher luminosity and larger
inner radius of the envelope than IRS3. The disparity could be caused by a
difference in age or mass, orientation of outflow cavities, or the impact of a
binary in the IRS1 core.Comment: accepted for publication in Ap
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Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development
Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 50 end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development
The Time-resolved Atomic, Molecular and Optical Science Instrument at the Linac Coherent Light Source
The newly constructed Time-resolved atomic, Molecular and Optical science
instrument (TMO), is configured to take full advantage of both linear
accelerators at SLAC National Accelerator Laboratory, the copper accelerator
operating at a repetition rate of 120 Hz providing high per pulse energy, as
well as the superconducting accelerator operating at a repetition rate of about
1 MHz providing high average intensity. Both accelerators build a soft X-ray
free electron laser with the new variable gab undulator section. With this
flexible light sources, TMO supports many experimental techniques not
previously available at LCLS and will have two X-ray beam focus spots in line.
Thereby, TMO supports Atomic, Molecular and Optical (AMO), strong-field and
nonlinear science and will host a designated new dynamic reaction microscope
with a sub-micron X-ray focus spot. The flexible instrument design is optimized
for studying ultrafast electronic and molecular phenomena and can take full
advantage of the sub-femtosecond soft X-ray pulse generation program
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