A species' response to spatial climatic variation does not predict its response to climate change.

The dominant paradigm for assessing ecological responses to climate change assumes that future states of individuals and populations can be predicted by current, species-wide performance variation across spatial climatic gradients. However, if the fates of ecological systems are better predicted by past responses to in situ climatic variation through time, this current analytical paradigm may be severely misleading. Empirically testing whether spatial or temporal climate responses better predict how species respond to climate change has been elusive, largely due to restrictive data requirements. Here, we leverage a newly collected network of ponderosa pine tree-ring time series to test whether statistically inferred responses to spatial versus temporal climatic variation better predict how trees have responded to recent climate change. When compared to observed tree growth responses to climate change since 1980, predictions derived from spatial climatic variation were wrong in both magnitude and direction. This was not the case for predictions derived from climatic variation through time, which were able to replicate observed responses well. Future climate scenarios through the end of the 21st century exacerbated these disparities. These results suggest that the currently dominant paradigm of forecasting the ecological impacts of climate change based on spatial climatic variation may be severely misleading over decadal to centennial timescales.

Seasonal drought in North America's sagebrush biome structures dynamic mesic resources for sage-grouse.

The North American semi-arid sagebrush, Artemisia spp., biome exhibits considerable climatic complexity driving dynamic spatiotemporal shifts in primary productivity. Greater and Gunnison sage-grouse, Centrocercus urophasianus and C. minimus, are adapted to patterns of resource intermittence and rely on stable adult survival supplemented by occasional recruitment pulses when climatic conditions are favorable. Predictions of intensifying water scarcity raise concerns over new demographic bottlenecks impacting sage-grouse populations in drought-sensitive landscapes. We estimate biome-wide mesic resource productivity from 1984 to 2016 using remote sensing to identify patterns of food availability influencing selective pressures on sage-grouse. We linked productivity to abiotic factors to examine effects of seasonal drought across time, space, and land tenure, with findings partitioned along gradients of ecosystem water balance within Great Basin, Rocky Mountains and Great Plains regions. Precipitation was the driver of mesic resource abundance explaining ≥70% of variance in drought-limited vegetative productivity. Spatiotemporal shifts in mesic abundance were apparent given biome-wide climatic trends that reduced precipitation below three-quarters of normal in 20% of years. Drought sensitivity structured grouse populations wherein landscapes with the greatest uncertainty in mesic abundance and distribution supported the fewest grouse. Privately owned lands encompassed 40% of sage-grouse range, but contained a disproportional 68% of mesic resources. Regional drought sensitivity identified herein acted as ecological minimums to influence differences in landscape carrying capacity across sage-grouse range. Our model depictions likely reflect a new normal in water scarcity that could compound impacts of demographic bottlenecks in Great Basin and Great Plains. We conclude that long-term population maintenance depends on a diversity of drought resistant mesic resources that offset climate driven variability in vegetative productivity. We recommend a holistic public-private lands approach to mesic restoration to offset a deepening risk of water scarcity.

Assessment of occupational and public exposure to trichloramine in Swiss indoor swimming pools: a proposal for an occupational exposure limit.

OBJECTIVES: The presence of trichloramine in the air in different indoor swimming pools has been studied in several countries. In almost all studies, the results show a possible health impact due to trichloramine among pool attendants. The main objectives of our study were to evaluate, for the first time in Switzerland, occupational and public trichloramine exposure in a representative panel of indoor pools and to propose an occupational exposure limit for trichloramine. METHODS: Measurements were done in 30 indoor swimming pools located in three regions of Switzerland: Jura, Neuchâtel, and Fribourg. All investigations were performed during the 2007-2008 winter season in order to assure closed windows and standard ventilation conditions. Trichloramine air samplings were performed at 130 cm above the floor around the pool. Analyses of free chlorine and bounded chlorine were performed on-site, and water samples were immediately sent to the laboratory for analysis of trihalomethanes, urea, and dissolved organic carbon. A health questionnaire was distributed to all the participants. RESULTS: Our results indicate that in all the studied facilities except one, the trichloramine concentrations were below the French reference value of 0.5 mg m(-3), and only three were equal to or slightly over 0.3 mg m(-3). Overall, our results point out a very low and consistent range of trichloramine concentrations (mean concentration of trichloramine: 0.114 ± 0.043 mg m(-3)). A total of 184 questionnaires were filled out by pool workers. Of the study population, 66% were men (n = 117), 21% were smokers (9 women and 29 men), and only 7% (n = 13) were ex-smokers. The control group was composed of 71 persons (38 men and 33 women); 22% (n = 15) were smokers and 24% (n = 16) ex-smokers. CONCLUSIONS: Our results demonstrate an increasing risk of irritative symptoms up to a level of 0.2-0.3 mg m(-3) of trichloramine. The health data in our study, as well as the review of the literature, strongly suggest fixing the trichloramine occupational exposure limit at 0.3 mg m(-3). Severe technical standards (on flocculation, filters, water flow, and ventilation systems) and regulations on water quality (free and combined chlorine, urea, and amount of fresh water) contribute to reducing trichloramine formation and, consequently, occupational and public trichloramine exposure. In addition, to ensure good public hygiene (showering before swimming), correct and regular public awareness campaigns should be undertaken.

A mouse Fcgamma-Fcepsilon protein that inhibits mast cells through activation of FcgammaRIIB, SH2 domain-containing inositol phosphatase 1, and SH2 domain-containing protein tyrosine phosphatases.

BACKGROUND: A human Fcgamma-Fcepsilon fusion protein (GE2) designed to inhibit FcepsilonRI signaling by coaggregating FcepsilonRI with the inhibitory receptor FcgammaRIIB has been shown to inhibit mast cell activation and block cutaneous anaphylaxis. A critical issue remained as to whether the mechanism of GE2 inhibition is competition for IgE binding or inhibitory signaling through FcgammaRIIB. OBJECTIVE: Our aim was to define the in vitro and in vivo mechanism of action of a mouse homolog of GE2 (mGE) and to assess the potential of human GE2 (hGE2) for therapeutic administration. METHODS: The in vitro activity of mGE on mediator release and signaling pathways was characterized in IgE-sensitized bone marrow-derived mast cells (BMMCs). The in vivo activity of mGE was examined in mouse passive cutaneous and passive systemic anaphylaxis models, and the therapeutic activity of hGE2 was evaluated in Ascaris suum-sensitized cynomolgus monkeys. RESULTS: mGE inhibited release of histamine and cytokines by BMMCs from wild-type mice but not by BMMCs from FcgammaRIIB-deficient mice. In mice mGE blocked IgE-dependent anaphylaxis mediated by mast cells with sustained efficacy. In BMMCs mGE decreased spleen tyrosine kinase and extracellular signal-regulated kinases 1/2 phosphorylation and induced FcgammaRIIB phosphorylation and the subsequent recruitment of SH2 domain-containing inositol polyphosphate 5' phosphatase (SHIP) 1 and SH2 domain-containing protein tyrosine phosphatase (SHP) 1/2 phosphatases. When administered therapeutically, hGE2 protected sensitized monkeys from local anaphylaxis for 3 weeks. CONCLUSION: mGE-mediated inhibition of mast cell activation is associated with inhibitory signaling through FcgammaRIIB that results from activation of SHIP-1 and SHP-1/2 phosphatases.

Novel antibody hinge regions for efficient production of CH2 domain-deleted antibodies.

HuCC49 deltaCH2 is a heavy chain constant domain 2 domain-deleted antibody under development as a radioimmunotherapeutic for treating carcinomas overexpressing the TAG-72 tumor antigen. Mammalian cell culture biosynthesis of HuCC49 deltaCH2 produces two isoforms (form A and form B) in an approximate 1:1 ratio, and consequently separation and purification of the desired form A isoform adversely impact process and yield. A protein engineering strategy was used to develop a panel of hinge-engineered HuCC49 deltaCH2 antibodies to identify hinge sequences to optimize production of the form A isoform. We found that adding a single proline residue at Kabat position 243, immediately adjacent to the carboxyl end of the core middle hinge CPPC domain, resulted in an increase from 39 to 51% form A isoform relative to the parent HuCC49 deltaCH2 antibody. Insertion of the amino acids proline-alanine-proline (PAP) at positions 243-245 enhanced production of the form A isoform to 72%. Insertion of a cysteine-rich 15-amino acid IgG3 hinge motif (CPEPKSCDTPPPCPR) in both of these mutant antibodies resulted in secretion of predominantly form A isoform with little or no detectable form B. Yields exceeding 98% of the form A isoform have been realized. Preliminary peptide mapping and mass spectrometry analysis suggest that at least two, and as many as five, inter-heavy chain disulfide linkages may be present.