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EXTREMELY LOW DOSES OF X-RADIATION CAN INDUCE ADAPTIVE RESPONSES IN MOUSE PROSTATE
The pKZ1 mouse chromosomal inversion assay is the only assay that has detected modulation of a mutagenic endpoint after single whole body X-irradiation with doses lower than 1 mGy. A non-linear dose response for chromosomal inversion has been observed in spleen and prostate between 0.001 mGy and 10 mGy, with doses between 0.005-0.01 mGy causing an increase in inversions and doses between 1ā10 mGy causing a reduction below spontaneous inversion frequency. An adaptive response is a decreased biological effect induced by a low radiation dose. Adaptive responses contradict the linear-no-threshold model of risk estimation. We demonstrated that very low (0.001 mGy, 0.01 mGy, 1 mGy and 10 mGy) doses of X-radiation induced a chromosomal inversion adaptive response as measured by a reduction in the frequency of subsequent high dose (1000 mGy) induced inversions in prostate. These are the lowest X-radiation doses reported to induce an adaptive response for any endpoint. Adaptive response experiments were also performed where the high dose was administered four hours prior to a low dose of 0.01 mGy or 10 mGy. In both cases an adaptive response was observed. Identification of the modifying factors involved in the adaptive response may provide candidates for radioprotection
Association Between Objectively Measured Physical Activity and Cognitive Function in Older AdultsāThe Reasons for Geographic and Racial Differences in Stroke Study
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116310/1/jgs13829_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/116310/2/jgs13829.pd
The protoāoncogene function of Mdm2 in bone
Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2Tg) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblastāspecific Mdm2 overexpressing (Mdm2TgOb) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected ageārelated bone loss in mice, providing a role for the protoāoncogenic activity of Mdm2 in bone health of adult animals
Volume 35, AMT-1 Cruise Report and Preliminary Results
This report documents the scientific activities on board the Royal Research Ship (RRS) 'James Clark Ross' during the irst Atlantic Meridional Transect (AMT-1), 21 September to 24 October 1995. The ship sailed from Grimsby (England) for Montevideo (Uruguay) and then continued on to Stanley (Falkland Islands). The primary objective of the AMT program is to investigate basic biological processes in the open Atlantic Ocean over very broad spatial scales. For AMT-1, the meridional range covered was approximately 50 deg N to 50 deg S or nearly 8,000 nmi. The measurements to be taken during the AMT cruises are fundamental for the calibration, validation, and continuing understanding of remotely sensed observations of biological oceanography. They are also important for understanding plankton community structure over latitudinal scales and the role of the world ocean in global carbon cycles. During AMT-1 a variety of instruments were used to map the physical, chemical, and biological structure of the upper 200 m of the water column. Ocean color measurements were made using state-of-the-art sensors, whose calibration was traceable to the highest international standards. New advances in fluorometry were used to measure photosynthetic activity, which was then used to further interpret primary productivity. A unique set of samples and data were collected for the planktonic assemblages that vary throughout the range of the transect. These data will yield new interpretations on community composition and their role in carbon cycling. While the various provinces of the Atlantic Ocean were being crossed, the partial pressure of CO2 was related to biological productivity. This comparison revealed the areas of drawdown of atmospheric CO2 and how these areas relate to the surrounding biological productivity. These data, plus the measurements of light attenuation and phytoplankton optical properties, will be used as a primary input for basin-scale biological productivity models to help develop ecosystem dynamics models which will be important for improving the forecasting abilities of modelers. The AMT program is also attempting to meet the needs of international agencies in their implementation of Sensor Intercomparison and Merger for Biological and Interdisciplinary Ocean Studies (SIMBIOS), a program to develop a methodology and operational capability to combine data products from the various ocean color satellite missions
Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness
Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the Ī±2-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness. DOI: http://dx.doi.org/10.7554/eLife.04499.00
Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype
The Lnk adapter protein negatively regulates the signaling of thrombopoietin (TPO), the main megakaryocyte (MK) growth factor. Lnk-deficient (-/-) mice have increased TPO signaling and increased MK number. Interestingly, several mouse models exist in which increased MK number leads to a high bone mass phenotype. Here we report the bone phenotype of these mice. MicroCT and static histomorphometric analyses at 20 weeks showed the distal femur of Lnk-/- mice to have significantly higher bone volume fraction and trabecular number compared to wild-type (WT) mice. Notably, despite a significant increase in the number of osteoclasts (OC), and decreased bone formation rate in Lnk-/- mice compared to WT mice, Lnk-/- mice demonstrated a 2.5-fold greater BV/TV suggesting impaired OC function in vivo. Additionally, Lnk-/- mouse femurs exhibited non-significant increases in mid-shaft cross-sectional area, yet increased periosteal BFR compared to WT femurs was observed. Lnk-/- femurs also had non-significant increases in polar moment of inertia and decreased cortical bone area and thickness, resulting in reduced bone stiffness, modulus, and strength compared to WT femurs. Of note, Lnk is expressed by OC lineage cells and when Lnk-/- OC progenitors are cultured in the presence of TPO, significantly more OC are observed than in WT cultures. Lnk is also expressed in osteoblast (OB) cells and in vitro reduced alkaline phosphatase activity was observed in Lnk-/- cultures. These data suggest that both direct effects on OB and OC as well as indirect effects of MK in regulating OB contributes to the observed high bone mass. J. Cell. Biochem. 118: 2231-2240, 2017
Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-assigned Steatosis Grades of Liver Biopsies from Adults with Nonalcoholic Steatohepatitis
Background & Aims
We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference.
Methods
We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed.
Results
At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%Ā±3.7%, 18.1%Ā±4.3%, and 30.1%Ā±8.1%. PDFF classified steatosis grade 0ā1 vs 2ā3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91ā0.98), and grade 0ā2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93ā0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2ā3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%Ā±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%Ā±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%Ā±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71ā0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63ā0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity.
Conclusions
Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference
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