Trace mineral imbalances have been suggested as having a causative or contributory role in chronic wasting disease (CWD), a prion disease of several North American cervid species. To begin exploring ...relationships between tissue mineral concentrations and CWD in natural systems, we measured liver tissue concentrations of copper, manganese, and molybdenum in samples from 447 apparently healthy, adult (≥2 yr old) mule deer (Odocoileus hemionus) culled or vehicle killed from free-ranging populations in north-central Colorado, United States, where CWD occurs naturally; we also measured copper concentrations in brain-stem (medulla oblongata at the obex) tissue from 181 of these deer. Analyses revealed a wide range of concentrations of all three minerals among sampled deer (copper: 5.6–331 ppm in liver, 1.5–31.9 ppm in obex; manganese: 0.1–21.4 ppm in liver; molybdenum: 0.5–4.0 ppm in liver). Bayesian multiple regression analysis revealed a negative association between obex copper (−0.097; 95% credible interval −0.192 to −0.006) and the probability of sampled deer also being infected with CWD, as well as a positive association between liver manganese (0.158; 95% credible interval 0.066 to 0.253) and probability of infection. We could not discern whether the tendencies toward lower brain-stem copper concentrations or higher systemic manganese concentrations in infected deer preceded prion infection or rather were the result of infection and its subsequent effects, although the distribution of trace mineral concentrations in infected deer seemed more suggestive of the latter.
A novel class of 3,5,6-trisubstituted naphthostyril analogues was designed and synthesized to study the structure–activity relationship for inhibition of cyclin-dependent kinase 2 (CDK2). These ...compounds, particularly molecules with side-chain modifications providing additional hydrogen bonding capability, were demonstrated to be potent CDK2 inhibitors with cellular activities consistent with CDK2 inhibition. These molecules inhibited tumor cell proliferation and G1-S and G2-M cell-cycle progression in vitro. The X-ray crystal structure of a 2-aminoethyleneamine derivative bound to CDK2, refined to 2.5A resolution, is presented.
A novel class of 3,5,6-trisubstituted naphthostyril analogues was designed and synthesized to study the structure–activity relationship for inhibition of cyclin-dependent kinase 2 (CDK2). These compounds, particularly molecules with side-chain modifications providing additional hydrogen bonding capability, were demonstrated to be potent CDK2 inhibitors with cellular activities consistent with CDK2 inhibition.
Murine collagen-induced arthritis (CIA) is characterized by pannus formation, cell infiltration, and cartilage erosion, and shares histologic and immunologic features with rheumatoid arthritis. ...Numerous cytokines are reportedly associated with RA and/or CIA; however, their mechanistic role is not clear. To determine the role of IL-12 in CIA, DBA/1 LacJ mice were administered 3 x 10(8) plaque-forming units of mIL-12 i.p. in a nonreplicating adenoviral vector (AdIL-12) on day 25 following primary type II collagen immunization. Our studies demonstrated that systemic transient overexpression of IL-12 accelerated disease progression and augmented the arthritis severity relative to mice expressing a replication-deficient, E1-deleted Ad5 construct. A likely mechanism for this increase in pathology was the increase in the expression of cytokines and chemokines known to play a proinflammatory role in disease. In particular, levels of murine IFN-gamma were significantly increased in mice overexpressing AdIL-12 relative to the replication-deficient, E1-deleted Ad5 construct. Interestingly, the C-X-C chemokine murine macrophage inflammatory protein-2, as well as the C-C chemokines murine monocyte chemoattractant protein-1 and murine macrophage inflammatory protein-1alpha were up-regulated by AdIL-12 relative to controls. In an additional set of studies, neutralization of endogenous IL-12 in CIA mice was shown to delay disease onset and attenuate disease severity. IFN-gamma levels in the mice receiving anti-IL-12 were significantly decreased in joint homogenates. These studies demonstrate that IL-12 is an important cytokine involved in controlling the production of chemokines/cytokines leading to the evolution of experimental arthritis.
Chronic hyperglycemia is thought to be important in the development of diabetic neovascularization but the mechanisms involved remain poorly understood. Interleukin-8 (IL-8) is a leukocyte chemokine ...and activating agent with angiogenic properties that is present in diabetic vitreous and may play a role in diabetic vasculopathy. We studied IL-8 and monocyte chemotactic protein-1 (MCP-1) production by human retinal pigment epithelial (hRPE) cells exposed to glycated human serum albumin (GHSA). Enzyme-linked immunoassay GHSA (500 micrograms/mL)-treated hRPE cells secreted levels of IL-8 and MCP-1 detectable within 4 h and reached 26.0 +/- 1.3 and 42.2 0.4 ng/10(6) cells/mL after 24 h, respectively. Induction of IL-8 and MCP-1 by GHSA at concentrations ranging from 62.5 to 3,000 micrograms/mL exhibited dose-dependent kinetics. The GHSA-induced chemokine secretion by hRPE was almost completely inhibited by actinomycin D and cycloheximide, suggesting that de novo mRNA and protein synthesis are necessary for the GHSA-induced IL-8 and MCP-1 production. Northern blot analysis of GHSA-induced hRPE IL-8 and MCP-1 mRNA expression corresponded to the time- and dose-dependent increases measured by enzyme-linked immunosorbent assay. High concentrations of glucose (20 mM; 360 mg/dl) increased GHSA-induced hRPE IL-8 and MCP-1 secretion, whereas added insulin (0.5 ng/mL) inhibited IL-8 but not MCP-1 protein secretion and mRNA expression. GHSA also induced hRPE to secrete GRO-alpha, RANTES, and NAP-2 chemokines. GHSA induction of hRPE chemokines further suggests a role for the hRPE in leukocyte infiltration, vascular injury, and neovascularization.
''Succinctly laying out the problems and prospects for the Middle East in the new century, Freedman's book will be widely read in classrooms across the country.''--Glenn E. Robinson, Naval ...Postgraduate School This collection analyzes the impact of the three major developments of the latter part of the 20th century on the future of the Middle East in the 21st century: the Arab-Israeli peace process, the 1979 Islamic revolution in Iran, and the Iraqi invasion of Kuwait.
Unravelling patterns and mechanisms of biogeographical transitions is crucial if we are to understand compositional gradients at large spatial extents, but no studies have thus far examined ...breakpoints in community composition of freshwater plants across continents. Using a dataset of almost 500 observations of lake plant community composition from six continents, we examined, for the first time, if such breakpoints in geographical space exist for freshwater plants and how well a suite of ecological factors (including climatic and local environmental variables) can explain transitions in community composition from the subtropics to the poles. Our combination of multivariate regression tree (MRT) analysis and k-means partitioning suggests that the most abrupt breakpoint exists between temperate to boreal regions on the one hand and freshwater plant communities harbouring mainly subtropical or Mediterranean assemblages on the other. The spatially structured variation in current climatic conditions is the most likely candidate for controlling these latitudinal patterns, although one cannot rule out joint effects of eco-evolutionary constraints in the harsher high-latitude environments and post-glacial migration lags after Pleistocene Ice Ages. Overall, our study supports the foundations of global regionalisation for freshwater plants and anticipates further biogeographical research on freshwater plant communities once datasets have been harmonised for conducting large-scale spatial analyses.
Frankenstein vagy a modern Prométheusz Göncz, Árpád (translator); Lukács, József (electronic version made by); Szabó, Attila (proofreader) ... Web Resource
Provider: - Institution: - Data provided by Europeana Collections- Subject date: 19. sz.- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 ...Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
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