Experimental chemotherapy of radiation injury with synthetic lysophospholipid analogs in mice

Synthetic lysophospholipids represent a variety of analogs of the naturally occurring 2-lysophosphatidylcholine. Some of these compounds showed significant therapeutic effects on the survival of mice following radiation injury when administered after various doses of whole-body X irradiation. Such therapeutic effects were discernible even when the treatment was given 6 hr after irradiation, and both intravenous and oral application were effective. Intravenous application of 2 X 25 mg/kg lysophospholipid after whole-body X irradiation around the LD50 resulted in significantly higher numbers of surviving animals. The mode of action remains speculative.     

Reconciling Carbon-cycle Concepts, Terminology, and Methods

Recent projections of climatic change have focused a great deal of scientific and public attention on patterns of carbon (C) cycling as well as its controls, particularly the factors that determine whether an ecosystem is a net source or sink of atmospheric carbon dioxide (CO₂). Net ecosystem production (NEP), a central concept in C-cycling research, has been used by scientists to represent two different concepts. We propose that NEP be restricted to just one of its two original definitions—the imbalance between gross primary production (GPP) and ecosystem respiration (ER). We further propose that a new term—net ecosystem carbon balance (NECB)—be applied to the net rate of C accumulation in (or loss from [negative sign]) ecosystems. Net ecosystem carbon balance differs from NEP when C fluxes other than C fixation and respiration occur, or when inorganic C enters or leaves in dissolved form. These fluxes include the leaching loss or lateral transfer of C from the ecosystem; the emission of volatile organic C, methane, and carbon monoxide; and the release of soot and CO₂ from fire. Carbon fluxes in addition to NEP are particularly important determinants of NECB over long time scales. However, even over short time scales, they are important in ecosystems such as streams, estuaries, wetlands, and cities. Recent technological advances have led to a diversity of approaches to the measurement of C fluxes at different temporal and spatial scales. These approaches frequently capture different components of NEP or NECB and can therefore be compared across scales only by carefully specifying the fluxes included in the measurements. By explicitly identifying the fluxes that comprise NECB and other components of the C cycle, such as net ecosystem exchange (NEE) and net biome production (NBP), we can provide a less ambiguous framework for understanding and communicating recent changes in the global C cycle.     

Pan-Arctic modelling of net ecosystem exchange of CO2

Net ecosystem exchange (NEE) of C varies greatly among Arctic ecosystems. Here, we show that approximately 75 per cent of this variation can be accounted for in a single regression model that predicts NEE as a function of leaf area index (LAI), air temperature and photosynthetically active radiation (PAR). The model was developed in concert with a survey of the light response of NEE in Arctic and subarctic tundras in Alaska, Greenland, Svalbard and Sweden. Model parametrizations based on data collected in one part of the Arctic can be used to predict NEE in other parts of the Arctic with accuracy similar to that of predictions based on data collected in the same site where NEE is predicted. The principal requirement for the dataset is that it should contain a sufficiently wide range of measurements of NEE at both high and low values of LAI, air temperature and PAR, to properly constrain the estimates of model parameters. Canopy N content can also be substituted for leaf area in predicting NEE, with equal or greater accuracy, but substitution of soil temperature for air temperature does not improve predictions. Overall, the results suggest a remarkable convergence in regulation of NEE in diverse ecosystem types throughout the Arctic.     

A Framework to Assess Biogeochemical Response to Ecosystem Disturbance Using Nutrient Partitioning Ratios

Disturbances affect almost all terrestrial ecosystems, but it has been difficult to identify general principles regarding these influences. To improve our understanding of the long-term consequences of disturbance on terrestrial ecosystems, we present a conceptual framework that analyzes disturbances by their biogeochemical impacts. We posit that the ratio of soil and plant nutrient stocks in mature ecosystems represents a characteristic site property. Focusing on nitrogen (N), we hypothesize that this partitioning ratio (soil N: plant N) will undergo a predictable trajectory after disturbance. We investigate the nature of this partitioning ratio with three approaches: (1) nutrient stock data from forested ecosystems in North America, (2) a process-based ecosystem model, and (3) conceptual shifts in site nutrient availability with altered disturbance frequency. Partitioning ratios could be applied to a variety of ecosystems and successional states, allowing for improved temporal scaling of disturbance events. The generally short-term empirical evidence for recovery trajectories of nutrient stocks and partitioning ratios suggests two areas for future research. First, we need to recognize and quantify how disturbance effects can be accreting or depleting, depending on whether their net effect is to increase or decrease ecosystem nutrient stocks. Second, we need to test how altered disturbance frequencies from the present state may be constructive or destructive in their effects on biogeochemical cycling and nutrient availability. Long-term studies, with repeated sampling of soils and vegetation, will be essential in further developing this framework of biogeochemical response to disturbance.     

Epigenetic inactivation of the Ras-association domain family 1 (RASSF1A) gene and its function in human carcinogenesis

The Ras GTPases are a superfamily of molecular switches that regulate cellular proliferation and apoptosis in response to extra-cellular signals. The regulation of these pathways depends on the interaction of the GTPases with specific effectors. Recently, we have cloned and characterized a novel gene encoding a putative Ras effector: the Ras-association domain family 1 (RASSF1) gene. The RASSF1 gene is located in the chromosomal segment of 3p21.3. The high allelic loss in a variety of cancers suggested a crucial role of this region in tumorigenesis. At least two forms of RASSF1 are present in normal human cells. The RASSF1A isoform is highly epigenetically inactivated in lung, breast, ovarian, kidney, prostate, thyroid and several other carcinomas. Re-expression of RASSF1A reduced the growth of human cancer cells supporting a role for RASSF1 as a tumor suppressor gene. RASSF1A inactivation and K-ras activation are mutually exclusive events in the development of certain carcinomas. This observation could further pinpoint the function of RASSF1A as a negative effector of Ras in a pro-apoptotic signaling pathway. In malignant mesothelioma and gastric cancer RASSF1A methylation is associated with virus infection of SV40 and EBV, respectively, and suggests a causal relationship between viral infection and progressive RASSF1A methylation in carcinogenesis. Furthermore, a significant correlation between RASSF1A methylation and impaired lung cancer patient survival was reported, and RASSF1A silencing was correlated with several parameters of poor prognosis and advanced tumor stage (e.g. poor differentiation, aggressiveness, and invasion). Thus, RASSF1A methylation could serve as a useful marker for the prognosis of cancer patients and could become important in early detection of cancer.     

Frequent intra-tumoural heterogeneity of promoter hypermethylation in malignant melanoma

To investigate intra-tumoural coexistence and heterogeneity of aberrant promoter hypermethylation of different tumour suppressor genes in melanoma, we analyzed the intra-tumoural distribution of promoter methylation of RASSF1A, p16, DAPK, MGMT, and Rb in 339 assays of 34 tumours (15 melanoma primaries, 19 metastases) by methylation-specific PCR, correlation to histopathology and RASSF1A expression. We detected promoter hypermethylation of at least one gene in 74% of tumours (30%, 52%, 33%, 20%, and 40% for RASSF1A, p16, DAPK, MGMT and Rb, respectively). 70% of the cases exhibited an inhomogeneous methylation pattern (17%, 45%, 33%, 20%, and 40% for RASSF1A, p16, DAPK, MGMT and Rb, respectively). Samples from the core of the tumours represented the methylation state of the whole tumours more accurately than the periphery. Local intra-tumoural correlation was found between the promoter hypermethylation state of p16 and Rb or p16 and DAPK, or epitheloid tumour cell type and RASSF1A or p16 methylation. Mitosis rate and sex was correlated with methylation of RASSF1A. Histological results confirmed that promoter hypermethylation of RASSF1A led to aberrant expression patterns. We conclude that intra-tumoural inhomogeneity of promoter hypermethylation is frequent in melanoma and this supports the hypothesis of clonal instability during progression of melanomas. In prognosis studies, missing the intra-tumoural sample representativeness may result in a reduction of the sensitivities or specificities.     

Marker genes identify three somatic cell types in the fetal mouse ovary

The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries during embryogenesis is critical for their function and the health of the individual in later life. Although the adult ovary has been investigated in great detail, we are only starting to understand the cellular and molecular biology of early ovarian development. Here we show that the adult stem cell marker Lgr5 is expressed in the cortical region of the fetal ovary and this expression is mutually exclusive to FOXL2. Strikingly, a third somatic cell population can be identified, marked by the expression of NR2F2, which is expressed in LGR5- and FOXL2 double-negative ovarian somatic cells. Together, these three marker genes label distinct ovarian somatic cell types. Using lineage tracing in mice, we show that Lgr5-positive cells give rise to adult cortical granulosa cells, which form the follicles of the definitive reserve. Moreover, LGR5 is required for correct timing of germ cell differentiation as evidenced by a delay of entry into meiosis in Lgr5 loss-of-function mutants, demonstrating a key role for LGR5 in the differentiation of pre-granulosa cells, which ensure the differentiation of oogonia, the formation of the definitive follicle reserve, and long-term female fertility.     

Depleted 15N in hydrolysable-N of arctic soils and its implication for mycorrhizal fungi–plant interaction

Uptake of nitrogen (N) via root-mycorrhizal associations accounts for a significant portion of total N supply to many vascular plants. Using stable isotope ratios (δ¹⁵N) and the mass balance among N pools of plants, fungal tissues, and soils, a number of efforts have been made in recent years to quantify the flux of N from mycorrhizal fungi to host plants. Current estimates of this flux for arctic tundra ecosystems rely on the untested assumption that the δ¹⁵N of labile organic N taken up by the fungi is approximately the same as the δ¹⁵N of bulk soil. We report here hydrolysable amino acids are more depleted in ¹⁵N relative to hydrolysable ammonium and amino sugars in arctic tundra soils near Toolik Lake, Alaska, USA. We demonstrate, using a case study, that recognizing the depletion in ¹⁵N for hydrolysable amino acids (δ¹⁵N = ?5.6‰ on average) would alter recent estimates of N flux between mycorrhizal fungi and host plants in an arctic tundra ecosystem.     

Incident radiation and the allocation of nitrogen within Arctic plant canopies: implications for predicting gross primary productivity

Arctic vegetation is characterized by high spatial variability in plant functional type (PFT) composition and gross primary productivity (P). Despite this variability, the two main drivers of P in sub‐Arctic tundra are leaf area index (L_T) and total foliar nitrogen (N_T). L_T and N_T have been shown to be tightly coupled across PFTs in sub‐Arctic tundra vegetation, which simplifies up‐scaling by allowing quantification of the main drivers of P from remotely sensed L_T. Our objective was to test the L_T–N_T relationship across multiple Arctic latitudes and to assess L_T as a predictor of P for the pan‐Arctic. Including PFT‐specific parameters in models of L_T–N_T coupling provided only incremental improvements in model fit, but significant improvements were gained from including site‐specific parameters. The degree of curvature in the L_T–N_T relationship, controlled by a fitted canopy nitrogen extinction co‐efficient, was negatively related to average levels of diffuse radiation at a site. This is consistent with theoretical predictions of more uniform vertical canopy N distributions under diffuse light conditions. Higher latitude sites had higher average leaf N content by mass (N_M), and we show for the first time that L_T–N_T coupling is achieved across latitudes via canopy‐scale trade‐offs between N_M and leaf mass per unit leaf area (L_M). Site‐specific parameters provided small but significant improvements in models of P based on L_T and moss cover. Our results suggest that differences in L_T–N_T coupling between sites could be used to improve pan‐Arctic models of P and we provide unique evidence that prevailing radiation conditions can significantly affect N allocation over regional scales.