Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule

The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.     

Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients

Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene-deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.     

Productivity is a poor predictor of plant species richness

For more than 30 years, the relationship between net primary productivity and species richness has generated intense debate in ecology about the processes regulating local diversity. The original view, which is still widely accepted, holds that the relationship is hump-shaped, with richness first rising and then declining with increasing productivity. Although recent meta-analyses questioned the generality of hump-shaped patterns, these syntheses have been criticized for failing to account for methodological differences among studies. We addressed such concerns by conducting standardized sampling in 48 herbaceous-dominated plant communities on five continents. We found no clear relationship between productivity and fine-scale (meters(-2)) richness within sites, within regions, or across the globe. Ecologists should focus on fresh, mechanistic approaches to understanding the multivariate links between productivity and richness.     

Rapid bottom melting widespread near Antarctic Ice Sheet grounding lines

As continental ice from Antarctica reaches the grounding line and begins to float, its underside melts into the ocean. Results obtained with satellite radar interferometry reveal that bottom melt rates experienced by large outlet glaciers near their grounding lines are far higher than generally assumed. The melting rate is positively correlated with thermal forcing, increasing by 1 meter per year for each 0.1 degrees C rise in ocean temperature. Where deep water has direct access to grounding lines, glaciers and ice shelves are vulnerable to ongoing increases in ocean temperature.     

Bermuda's Southern Aeolianite Reef Tract

The outer reef on the explored southeast margin of the Bermuda platform is a submerged dune ridge thinly veneered with encrusting organisms. Aeolianites were deposited on what appears to be an older truncated surface, the reef-front terrace, now submerged to a depth of about 18 meters. Underwater examination reveals relict features of probable solutional origin that honeycomb the aeolinite and that have undergone only minor modification by erosion since the last eustatic rise of the sea. Submarine planation, even in this marginal area of reef growth, is a relatively slow process.     

Is neutral genetic diversity related to quantitative variation in semen traits in bulls?

Conservation decisions based on neutral genetic diversity have been observed to promote retention of useful quantitative variation in biological populations. An experiment was undertaken to determine the association between microsatellite marker polymorphisms and phenotypic variation in semen production and cryosurvival traits in bulls. Thirty-five ejaculates were collected from ten bulls of two breeds and evaluated before and after cryopreservation for several semen traits. The bulls were also genotyped using a set of sixteen bovine-specific microsatellite marker loci. Fixation indices (F_ST), heterozygosity and Nei's genetic distance measures were computed from allele frequency data for each of the bulls. Molecular and phenotypic data were used to compute tri-distance matrices for the ten bulls and correlated using Mantel's test in GenAIEx 6.5. The study revealed extensive heterogeneity in semen traits, heterozygosity and F_ST values among the bulls. Large pairwise phenotypic and genetic distances were also observed. Correlation between pairwise genetic distances and phenotypic distances was significant and highly positive for sperm viability (r = .61, p < .001) and moderately positive for sperm motility (r = .40–42, p < .05) variables. For sperm morphology, ejaculate volume and sperm concentration, correlation with genetic distances was positive, low and not significantly different from zero (p > .05). A tendency for a triangular-shaped relationship between genetic and phenotypic distances for post-thaw motility and viability traits was also observed. Accordingly, association with neutral genetic diversity was absent for semen production traits and moderate to highly positive for sperm cryosurvival traits. Given these findings, conservation decisions based on neutral genetic diversity may capture variation in some adaptive traits, but not others.     

Predicting likelihood of in vivo chemotherapy response in canine lymphoma using ex vivo drug sensitivity and immunophenotyping data in a machine learning model

We report a precision medicine platform that evaluates the probability of chemotherapy drug efficacy for canine lymphoma by combining ex vivo chemosensitivity and immunophenotyping assays with computational modelling. We isolated live cancer cells from fresh fine needle aspirates of affected lymph nodes and collected post‐treatment clinical responses in 261 canine lymphoma patients scheduled to receive at least 1 of 5 common chemotherapy agents (doxorubicin, vincristine, cyclophosphamide, lomustine and rabacfosadine). We used flow cytometry analysis for immunophenotyping and ex vivo chemosensitivity testing. For each drug, 70% of treated patients were randomly selected to train a random forest model to predict the probability of positive Veterinary Cooperative Oncology Group (VCOG) clinical response based on input variables including antigen expression profiles and treatment sensitivity readouts for each patient's cancer cells. The remaining 30% of patients were used to test model performance. Most models showed a test set ROC‐AUC > 0.65, and all models had overall ROC‐AUC > 0.95. Predicted response scores significantly distinguished (P < .001) positive responses from negative responses in B‐cell and T‐cell disease and newly diagnosed and relapsed patients. Patient groups with predicted response scores >50% showed a statistically significant reduction (log‐rank P < .05) in time to complete response when compared to the groups with scores <50%. The computational models developed in this study enabled the conversion of ex vivo cell‐based chemosensitivity assay results into a predicted probability of in vivo therapeutic efficacy, which may help improve treatment outcomes of individual canine lymphoma patients by providing predictive estimates of positive treatment response.     

Application of systems-simulation in the Venezuelan cattle industry

This paper shows how systems-simulation can be applied to answer agricultural development type questions. A computer simulation model of the Venezuelan cattle industry is presented, some of the validation efforts are discussed, and results from a number of computer runs are shown in order to illustrate how alternative programmes might affect the transition of the traditional cattle population to a more modern and productive population. Different programmes are shown to accomplish some objectives better than others. No optimisation over all possible development objectives was attempted, as this would depend upon the relative weights attached to the objectives by the decision-makers.It has been the authors' experience that modelling of biological and economic processes provides an important link between observations about the real world (raw data) and decision-makers in an information system designed to provide useful information. The building and operation of the computer model of the Venezuelan cattle population illustrates how a systems-simulation approach can be used in policy formulation.     

Heavy‐metal displacement in chelate‐treated soil with sludge during phytoremediation

Heavy metals (HMs) in domestic sewage sludge, applied to land, contaminate soils. Phytoremediation is the use of plants to clean‐up toxic HMs from soil. Chelating agents are added to soil to solubilize the metals for enhanced uptake. Yet no studies report the displacement of HMs in soil with sludge following solubilization with chelates. The objective of this work was to determine the uptake or leaching of HMs due to a chelate added to a soil from a sludge farm that had received sludge for 25 y. The soil was placed in long columns (105 cm long; ?? 39 cm) in a greenhouse. Columns either had a plant (hybrid poplar; Populus deltoides Marsh. × P. nigra L.) or no plant. After the poplar seedlings had grown for 144 d, the tetrasodium salt of the chelating agent EDTA was irrigated onto the surface of the soil at a rate of 1 g per kg of soil. Drainage water, soil, and plants were analyzed for three toxic HMs (Cd, Ni, Pb) and four essential HMs (Cu, Fe, Mn, Zn). At harvest, extractable and total concentrations of each HM in the soil with EDTA were similar to those in soil without EDTA. The chelate did not affect the concentrations of HMs in the roots or leaves. With or without plants, EDTA mobilized all seven HMs and increased their concentrations in drainage water. Lower concentrations of Cd, Cu, Fe, Ni, and Zn in leachate from columns with EDTA and plants compared to columns with EDTA and no plants showed that poplars can reduce groundwater contamination by intercepting these HMs in the soil. But the poplar plants did not reduce Pb and Mn in the leachate from columns with EDTA. Concentrations of Cd and Pb in the leachate mobilized by EDTA remained above drinking‐water standards with or without plants. The results showed that a chelate (EDTA) should not be added to a soil at a sludge farm to enhance phytoremediation. The chelate mobilized HMs that leached to drainage water and contaminated it.