Artificial selection reveals heritable variation for developmental instability

Fluctuating (nondirectional) asymmetry (FA) of bilaterally paired structures on a symmetrical organism is commonly used to assay the developmental instability (DI) caused by environmental or genetic factors. Although evidence for natural selection to reduce FA has been reported, evidence that FA (and by extension DI) is heritable is weak. We report the use of artificial selection to demonstrate heritable variation in the fluctuating asymmetry of interlandmark distances within the wing in an outbred population of Drosophila melanogaster. Our estimates for the heritability of FA range from 0% to 1% and result in estimates for the heritability of DI as large as 20%, comparable to values typical for life-history traits. These values indicate the existence of evolutionarily relevant genetic variation for DI and the effectiveness of selection for reduced FA suggests that natural selection has not fixed all the genetic variants that would improve developmental stability in these populations.     

Measurement and meaning in biology

Measurement--the assignment of numbers to attributes of the natural world--is central to all scientific inference. Measurement theory concerns the relationship between measurements and reality; its goal is ensuring that inferences about measurements reflect the underlying reality we intend to represent. The key principle of measurement theory is that theoretical context, the rationale for collecting measurements, is essential to defining appropriate measurements and interpreting their values. Theoretical context determines the scale type of measurements and which transformations of those measurements can be made without compromising their meaningfulness. Despite this central role, measurement theory is almost unknown in biology, and its principles are frequently violated. In this review, we present the basic ideas of measurement theory and show how it applies to theoretical as well as empirical work. We then consider examples of empirical and theoretical evolutionary studies whose meaningfulness have been compromised by violations of measurement-theoretic principles. Common errors include not paying attention to theoretical context, inappropriate transformations of data, and inadequate reporting of units, effect sizes, or estimation error. The frequency of such violations reveals the importance of raising awareness of measurement theory among biologists.     

Comparisons of watershed sulfur budgets in southeast Canada and northeast US: new approaches and implications

Most of eastern North America receives elevated levels of atmospheric deposition of sulfur (S) that result from anthropogenic SO₂ emissions from fossil fuel combustion. Atmospheric S deposition has acidified sensitive terrestrial and aquatic ecosystems in this region; however, deposition has been declining since the 1970s, resulting in some recovery in previously acidified aquatic ecosystems. Accurate watershed S mass balances help to evaluate the extent to which atmospheric S deposition is retained within ecosystems, and whether internal cycling sources and biogeochemical processes may be affecting the rate of recovery from decreasing S atmospheric loads. This study evaluated S mass balances for 15 sites with watersheds in southeastern Canada and northeastern US for the period 1985 to 2002. These 15 sites included nine in Canada (Turkey Lakes, ON; Harp Lake, ON; Plastic Lake, ON; Hermine, QC; Lake Laflamme, QC; Lake Clair, QC; Lake Tirasse, QC; Mersey, NS; Moosepit, NS) and six in the US (Arbutus Lake, NY; Biscuit Brook, NY; Sleepers River, VT; Hubbard Brook Experimental Forest, NH; Cone Pond, NH; Bear Brook Watershed, ME). Annual S wet deposition inputs were derived from measured bulk or wet-only deposition and stream export was obtained by combining drainage water fluxes with SO₄ ^2? concentrations. Dry deposition has the greatest uncertainty of any of the mass flux calculations necessary to develop accurate watershed balances, and here we developed a new method to calculate this quantity. We utilized historical information from both the US National Emissions Inventory and the US (CASTNET) and the Canadian (CAPMoN) dry deposition networks to develop a formulation that predicted SO₂ concentrations as a function of SO₂ emissions, latitude and longitude. The SO₂ concentrations were used to predict dry deposition using relationships between concentrations and deposition flux derived from the CASTNET or CAPMoN networks. For the year 2002, we compared the SO₂ concentrations and deposition predictions with the predictions of two continental-scale air quality models, the Community Multiscale Air Quality (CMAQ) model and A Unified Regional Air-quality Modeling System (AURAMS) that utilize complete inventories of emissions and chemical budgets. The results of this comparison indicated that the predictive relationship provides an accurate representation of SO₂ concentrations and S deposition for the region that is generally consistent with these models, and thus provides confidence that our approach could be used to develop accurate watershed S budgets for these 15 sites. Most watersheds showed large net losses of SO₄ ^2? on an annual basis, and the watershed mass balances were grouped into five categories based on the relative value of mean annual net losses or net gains. The net annual fluxes of SO₄ ^2? showed a strong relationship with hydrology; the largest net annual negative fluxes were associated with years of greatest precipitation amount and highest discharge. The important role of catchment hydrology on S budgets suggests implications for future predicted climate change as it affects patterns of precipitation and drought. The sensitivity of S budgets is likely to be greatest in watersheds with the greatest wetland area, which are particularly sensitive to drying and wetting cycles. A small number of the watersheds in this analysis were shown to have substantial S sources from mineral weathering, but most showed evidence of an internal source of SO₄ ^2?, which is likely from the mineralization of organic S stored from decades of increased S deposition. Mobilization of this internal S appears to contribute about 1?C6 kg S ha^?1 year^?1 to stream fluxes at these sites and is affecting the rate and extent of recovery from acidification as S deposition rates have declined in recent years. This internal S source should be considered when developing critical deposition loads that will promote ecosystem recovery from acidification and the depletion of nutrient cations in the northeastern US and southeastern Canada.     

Synthesis and in vitro evaluation of derivatives of the β₁-adrenergic receptor antagonist HX-CH 44

Isopropyl- and fluoroisopropyl-amino derivatives of the β(1)-adrenergic receptor antagonist 2-[4-[3-(tert-butyl-amino)-2-hydroxypropoxy]phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone ((±)HX-CH 44) were synthesized, including a concise and efficient preparation of the core, 2-(4-hydroxyphenyl)-6-methoxy-3-methylquinazolin-4(3H)-one. In vitro binding assays showed that the fluorinated analog was selective towards β(1)-adrenergic receptors over β(2)-adrenergic and 5-HT(1A) receptors. An X-ray crystallographic characterization of the fluorinated analog is also reported.     

Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of pyridone-substituted piperidines

An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.     

LasR-deficient Pseudomonas aeruginosa variants increase airway epithelial mICAM-1 expression and enhance neutrophilic lung inflammation

Pseudomonas aeruginosa causes chronic airway infections, a major determinant of lung inflammation and damage in cystic fibrosis (CF). Loss-of-function lasR mutants commonly arise during chronic CF infections, are associated with accelerated lung function decline in CF patients and induce exaggerated neutrophilic inflammation in model systems. In this study, we investigated how lasR mutants modulate airway epithelial membrane bound ICAM-1 (mICAM-1), a surface adhesion molecule, and determined its impact on neutrophilic inflammation in vitro and in vivo. We demonstrated that LasR-deficient strains induce increased mICAM-1 levels in airway epithelial cells compared to wild-type strains, an effect attributable to the loss of mICAM-1 degradation by LasR-regulated proteases and associated with enhanced neutrophil adhesion. In a subacute airway infection model, we also observed that lasR mutant-infected mice displayed greater airway epithelial ICAM-1 expression and increased neutrophilic pulmonary inflammation. Our findings provide new insights into the intricate interplay between lasR mutants, LasR-regulated proteases and airway epithelial ICAM-1 expression, and reveal a new mechanism involved in the exaggerated inflammatory response induced by lasR mutants.     

Prolonged Instability Prior to a Regime Shift

Regime shifts are generally defined as the point of ‘abrupt’ change in the state of a system. However, a seemingly abrupt transition can be the product of a system reorganization that has been ongoing much longer than is evident in statistical analysis of a single component of the system. Using both univariate and multivariate statistical methods, we tested a long-term high-resolution paleoecological dataset with a known change in species assemblage for a regime shift. Analysis of this dataset with Fisher Information and multivariate time series modeling showed that there was a∼2000 year period of instability prior to the regime shift. This period of instability and the subsequent regime shift coincide with regional climate change, indicating that the system is undergoing extrinsic forcing. Paleoecological records offer a unique opportunity to test tools for the detection of thresholds and stable-states, and thus to examine the long-term stability of ecosystems over periods of multiple millennia.     

Compositional vegetation changes and increased red spruce abundance during the Little Ice Age in a sugar maple forest of north-eastern North America

In north-eastern North America, the recent red spruce decline has been linked to atmospheric pollution, notably acid rain, although climate was also advocated as a potential factor. A high resolution lake sediment pollen stratigraphy was obtained to elucidate long-term trends in tree-species abundance in a sugar maple??yellow birch forest. The reconstructed history (~250?C1996?A.D.) showed a steady increase of red spruce after 1300?A.D., with a peak between 1600 and 1900?A.D. followed by a strong decline in the last century, while sugar maple and yellow birch experienced an opposite trend. Red spruce abundance reached its apogee during the cool Little Ice Age (LIA) and decreased abruptly when annual temperature in the region increased by 2?°C in the last 125?years. American Beech was much more abundant in the forest before the LIA, typifying a sugar maple??American beech forest as the dominant forest type during the Late Holocene. Our results suggest that climate warming has played an important role in the current red spruce decline, the latter having been initiated well before acidic depositions reached deleterious potential effects on red spruce. Climate warming probably acted as a long-term predisposing factor that was aggravated by atmospheric pollution, in the last decades.     

Design and synthesis of potent, isoxazole-containing renin inhibitors

The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.     

The effect of seasonal drying on sulphate dynamics in streams across southeastern Canada and the northeastern USA

Within the southeast Canada and northeast USA region, a peak in sulphate (SO₄ ^2?) concentration has been reported for some streams following periods of substantial catchment drying during the summer months (ON, Canada; VT, NH and NY, USA). However, it is currently unclear if a SO₄ ^2? response to seasonal drying is widespread across the broader region, or to what extent the level of response varies among catchments. In our study, SO₄ ^2? response to seasonal drying was compared in 20 catchments from 11 locations across southeastern Canada (ON, QC and NS) and northeastern USA (NH, NY, VT, WV and ME). Using long-term monitoring data of stream discharge and chemistry, the number of days for each month of the dry season (# d) when discharge (Q) was below a threshold level (25th percentile; Q₂₅) was calculated for each catchment to give a measure of ‘seasonal dryness’ (# d Q < Q₂₅). A SO₄ ^2? response score (rs) was then calculated for each catchment based on linear regression analysis of # d Q < Q₂₅ versus either the annual SO₄ ^2? concentration, or the residual of annual SO₄ ^2? concentration as a function of time (year). The final rs values for each catchment provided an estimate of the proportion of variation in annual SO₄ ^2? concentration which could be explained by seasonal drying (possible rs range = 0–1). Of the 20 catchments, 13 exhibited some level of a SO₄ ^2? response to seasonal drying (rs = 0.04–0.72) with an additional two catchments exhibiting a SO₄ ^2? response for one or more seasons. SO₄ ^2? response scores were positively related to percent wetland area (w) (rs = 1.000 ? 0.978e^{?0.054* w} , r ² = 0.44) and percent saturated area (sat) (rs = 0.481 ? 0.488e^{?0.101* sat}, r ² = 0.54) indicating that wetlands/saturated areas were an important driver of regional variation in the SO₄ ^2? response to seasonal drying. Our results suggest that any shift towards drier summers as a result of climate change could impact SO₄ ^2? dynamics in a large number of catchments throughout the region.