Widespread occurrence of AP in amyloidotic tissues. An immunohistochemical observation

Plasma (P)-component of amyloid (AP or SAP), while not an integral part of the amyloid fibril, has been considered to be intimately associated with virtually every different type of amyloid. In the present study, we evaluated the distribution of AP in the organs frequently involved in two forms of human systemic amyloidosis (AA and AF) and in mouse AA amyloidosis, by use of immunohistochemistry with anti-AP. Although the amyloid deposits generally showed moderate reactions with anti-AP, they were not always clearly distinguished from the surrounding non-amyloid tissue elements which often stained as well. The basement membrane often showed even stronger reaction to anti-AP than the adjacent amyloid deposits, and liver sections demonstrated such a high overall reaction to anti-AP that the anti-AP reaction on the amyloid deposits was often obscurred. The present results suggest that the binding between AP and the amyloid fibril may not be monospecific, that AP by this technique occurs rather widely throughout the body, and therefore that anti-AP may not be considered as specific a marker for amyloid deposits in immunohistochemical and perhaps other studies as well.     

Hierarchy of cytotoxic T cell clones. II. Intraclonal triggering of lysis by hapten-specific CTL

Cells from clones of anti-hapten murine cytotoxic T lymphocytes (CTL) can act as both target and effector cells, but will not lyse members of the same clone. The effect of haptenation on the cytolytic activity of anti-fluorescein (FL) and anti-trinitrophenol (TNP) CTL clones was examined. Treatment of anti-FL clones with fluorescein isothiocyanate or anti-TNP clones with trinitrobenzene sulphonic acid induces these clones to kill in an antigen-independent fashion. Targets killed by the haptenated CTL included syngeneic and allogeneic B lymphocyte blast cells, P815, YAC-1 and in one case human GM 4072 tumor cells. The importance of CD8 and T cell receptor (TCR) occupancy is demonstrated by the ability to block autotriggering by antibody directed against Ly 2 and the TCR. The results demonstrate that effects other than antigen recognition of the target play a role in the final outcome of effector-target cell interactions and provide a mechanism which could lead to autodestruction and immunosuppression particularly in some types of viral infection.     

Interactions Among Fuel Management,Species Composition,Bark Beetles,and Climate Change and the Potential Effects on Forests of the Lake Tahoe Basin

Climate-driven increases in wildfires, drought conditions, and insect outbreaks are critical threats to forest carbon stores. In particular, bark beetles are important disturbance agents although their long-term interactions with future climate change are poorly understood. Droughts and the associated moisture deficit contribute to the onset of bark beetle outbreaks although outbreak extent and severity is dependent upon the density of host trees, wildfire, and forest management. Our objective was to estimate the effects of climate change and bark beetle outbreaks on ecosystem carbon dynamics over the next century in a western US forest. Specifically, we hypothesized that (a) bark beetle outbreaks under climate change would reduce net ecosystem carbon balance (NECB) and increase uncertainty and (b) these effects could be ameliorated by fuels management. We also examined the specific tree species dynamics—competition and release—that determined NECB response to bark beetle outbreaks. Our study area was the Lake Tahoe Basin (LTB), CA and NV, USA, an area of diverse forest types encompassing steep elevation and climatic gradients and representative of mixed-conifer forests throughout the western United States. We simulated climate change, bark beetles, wildfire, and fuels management using a landscape-scale stochastic model of disturbance and succession. We simulated the period 2010–2100 using downscaled climate projections. Recurring droughts generated conditions conducive to large-scale outbreaks; the resulting large and sustained outbreaks significantly increased the probability of LTB forests becoming C sources over decadal time scales, with slower-than-anticipated landscape-scale recovery. Tree species composition was substantially altered with a reduction in functional redundancy and productivity. Results indicate heightened uncertainty due to the synergistic influences of climate change and interacting disturbances. Our results further indicate that current fuel management practices will not be effective at reducing landscape-scale outbreak mortality. Our results provide critical insights into the interaction of drivers (bark beetles, wildfire, fuel management) that increase the risk of C loss and shifting community composition if bark beetle outbreaks become more frequent.     

A High-Content Small Molecule Screen Identifies Sensitivity of Glioblastoma Stem Cells to Inhibition of Polo-Like Kinase 1

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF^−/−, or p53^−/−), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value.     

Territorial behaviour in southern impala rams (Aepyceros melampus Lichtenstein)

The role of territoriality was investigated by studying 25 impala rams at a reserve in the Waterberg region of South Africa (23°45′S, 28°23′E). Mean territorial tenure was 67.25 days (range 23–99), with a mean territory size of 21.0 ± 11.27 ha, compared with home ranges of 34.1 ± 9.03 ha for territorial rams and 58.8 ± 33.35 ha for bachelor rams, using the fixed kernel method. Territory boundaries remained constant, whilst the area surrounding important features such as water holes, appears to be neutral in terms of territoriality. The rut, as evidenced from peaks in chasing and roaring, lasted for 2 months from 10 April to 10 June 2001, with intensified behaviour including matings observed from 16 May to 4 June 2001. Territorial rams chase and roar more than bachelors. Flehmen and display behaviours are performed by all rams, whilst fights and other reproductive behaviours are generally rare. Bachelors browse more than territorial rams. Only bachelors spar and allogroom, and orally groom themselves more than territorial rams.