Acute inhalation toxicology and proposed emergency exposure limits of nitrogen trifluoride,

Acute exposures of rats, mice, dogs and monkeys to nitrogen trifluoride have been carried out and median lethal concentrations were determined for rats and mice. Confirmative evidence was obtained that the immediate effects of acute exposure are caused by extensive methemoglobin formation and resulting anoxia. Dogs surviving exposure to 9600 ppm for 60 min exhibit a Heinz body anemia with red blood cell count, hemoglobin and hematocrit decreasing 33% to minimum values by the end of the second week postexposure. Recovery of hematologic values to preexposure levels is attained in 40 days. In dogs, the anemia caused by a dose level of 120,000 ppm-min is severe enough to invalidate that dose as an emergency exposure limit (EEL). At 30,000 ppm-min, however, no detectable anemia occurs, and no other toxic effects are discernible. The results of experiments conducted at subacute levels justify recommending an upward revision of the EEL to 30,000 ppm-min from the proposed National Academy of Science, National Research Council value of 3000 ppm-min.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33816/1/0000072.pd

Performance of a cryogenic test facility for 4 K interferometer delay line investigations

The next generation of space-borne instruments for far infrared astronomical spectroscopy will utilize large diameter, cryogenically cooled telescopes in order to achieve unprecedented sensitivities. Low background, ground-based cryogenic facilities are required for the cryogenic testing of materials, components and subsystems. The University of Lethbridge Test Facility Cryostat (TFC) is a large volume, closed cycle, 4 K cryogenic facility, developed for this purpose. This paper discusses the design and performance of the facility and associated metrology instrumentation, both internal and external to the TFC. Additionally, an apparatus for measuring the thermal and mechanical properties of carbon-fiber-reinforced polymers is presented

Keratin 12 missense mutation induces the unfolded protein response and apoptosis in meesmann epithelial corneal dystrophy

Meesmann epithelial corneal dystrophy (MECD) is a rare autosomal dominant disorder caused by dominant-negative mutations within the KRT3 or KRT12 genes, which encode the cytoskeletal protein keratins K3 and K12, respectively. To investigate the pathomechanism of this disease, we generated and phenotypically characterized a novel knock-in humanized mouse model carrying the severe, MECD-associated, K12-Leu132Pro mutation. Although no overt changes in corneal opacity were detected by slit-lamp examination, the corneas of homozygous mutant mice exhibited histological and ultrastructural epithelial cell fragility phenotypes. An altered keratin expression profile was observed in the cornea of mutant mice, confirmed by western blot, RNA-seq and quantitative real-time polymerase chain reaction. Mass spectrometry (MS) and immunohistochemistry demonstrated a similarly altered keratin profile in corneal tissue from a K12-Leu132Pro MECD patient. The K12-Leu132Pro mutation results in cytoplasmic keratin aggregates. RNA-seq analysis revealed increased chaperone gene expression, and apoptotic unfolded protein response (UPR) markers, CHOP and Caspase 12, were also increased in the MECD mice. Corneal epithelial cell apoptosis was increased 17-fold in the mutant cornea, compared with the wild-type (P < 0.001). This elevation of UPR marker expression was also observed in the human MECD cornea. This is the first reporting of a mouse model for MECD that recapitulates the human disease and is a valuable resource in understanding the pathomechanism of the disease. Although the most severe phenotype is observed in the homozygous mice, this model will still provide a test-bed for therapies not only for corneal dystrophies but also for other keratinopathies caused by similar mutations

Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1

Background: The cellular and molecular mechanisms of tumour response following chemotherapy are largely unknown. We found that low dose anti-tumour agents up-regulate early growth response 1 (EGR1) expression. EGR1 is a member of the immediate-early gene group of transcription factors which modulate transcription of multiple genes involved in cell proliferation, differentiation, and development. It has been reported that EGR1 act as either tumour promoting factor or suppressor. We therefore examined the expression and function of EGR1 in osteosarcoma. Methods: We investigated the expression of EGR1 in human osteosarcoma cell lines and biopsy specimens. We next examined the expression of EGR1 following anti-tumour agents treatment. To examine the function of EGR1 in osteosarcoma, we assessed the tumour growth and invasion in vitro and in vivo. Results: Real-time PCR revealed that EGR1 was down-regulated both in osteosarcoma cell lines and osteosarcoma patients’ biopsy specimens. In addition, EGR1 was up-regulated both in osteosarcoma patient’ specimens and osteosarcoma cell lines following anti-tumour agent treatment. Although forced expression of EGR1 did not prevent osteosarcoma growth, forced expression of EGR1 prevented osteosarcoma cell invasion in vitro. In addition, forced expression of EGR1 promoted downregulation of urokinase plasminogen activator, urokinase receptor, and urokinase plasminogen activity. Xenograft mice models showed that forced expression of EGR1 prevents osteosarcoma cell migration into blood vessels. Conclusions: These findings suggest that although chemotherapy could not prevent osteosarcoma growth in chemotherapy-resistant patients, it did prevent osteosarcoma cell invasion by down-regulation of urokinase plasminogen activity via up-regulation of EGR1 during chemotherapy periods