Visualizing genetic constraints

Principal Components Analysis (PCA) is a common way to study the sources of variation in a high-dimensional data set. Typically, the leading principal components are used to understand the variation in the data or to reduce the dimension of the data for subsequent analysis. The remaining principal components are ignored since they explain little of the variation in the data. However, evolutionary biologists gain important insights from these low variation directions. Specifically, they are interested in directions of low genetic variability that are biologically interpretable. These directions are called genetic constraints and indicate directions in which a trait cannot evolve through selection. Here, we propose studying the subspace spanned by low variance principal components by determining vectors in this subspace that are simplest. Our method and accompanying graphical displays enhance the biologist's ability to visualize the subspace and identify interpretable directions of low genetic variability that align with simple directions.Comment: Published in at http://dx.doi.org/10.1214/12-AOAS603 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Maintenance Therapy in Advanced Non-small Cell Lung Cancer: Current Status and Future Implications

Maintenance therapy for patients with advanced non-small cell lung cancer has been an area of intense investigation. Maintenance therapy has been divided into two broad categories: continuation maintenance when the chemotherapy or targeted agent was part of a defined number of cycles of combination therapy and in the absence of disease progression is continued as a single agent or switch maintenance when a third agent is initiated after four cycles of platinum-based double-agent chemotherapy in the absence of disease progression. Two monoclonal antibodies, cetuximab and bevacizumab, are used as continuation maintenance, but the incremental benefit of the maintenance therapy with these agents is undetermined. Phase III trials have not revealed an overall survival benefit for continuation maintenance chemotherapy, and this approach should be considered investigational. Phase III trials have demonstrated an improvement in overall survival with switch maintenance therapy with pemetrexed compared with placebo in patients with nonsquamous histology and erlotinib compared with placebo. Phase III trials have not revealed an improvement in quality of life with maintenance therapy. In the trials of maintenance therapy, 30 to 40% of patients enrolled in the observation or placebo arm did not receive second-line therapy, and among the patients who did receive second-line therapy, there was significant heterogeneity in the therapy. The development of maintenance therapy has raised issues about the role of treatment-free intervals in routine clinical care, trial design issues such as the optimal endpoint, the ethics of a placebo arm, and the implications of maintenance therapy for first-line trials

Treatment Paradigms for Advanced Stage Non-small Cell Lung Cancer in the Era of Multiple Lines of Therapy

Abstract:: The duration of first-line and the timing of second-line therapy for advanced non-small cell lung cancer has been an area of recent investigation. Five trials have been performed that have investigated shorter (3–4 cycles) versus longer duration of platinum-based therapy; four trials revealed an equivalent overall survival with the shorter duration of therapy, and one trial revealed superior survival with the longer duration of therapy. The toxicity and quality of life data has either been equivalent or favored the shorter duration of therapy. Two trials have investigated the timing of a second-line therapy after completion of four cycles of platinum-based therapy versus the standard treatment paradigm of initiating second-line therapy upon disease progression. Both of these trials have revealed a statistically significant improvement in the progression-free survival, and a trend towards improved survival for the earlier use of second-line therapy. Only 50 to 60% of patients on the standard treatment arm initiated second-line therapy, and the promising results observed are most likely related to the fact that a higher percentage of patients received second-line therapy on the experimental arm. Several trials have investigated maintenance chemotherapy, and these trials have not revealed a survival benefit probably due to the fact that many patients experience disease progression or unacceptable toxicity during the initial or maintenance therapy. The addition of a targeted agent (bevacizumab or cetuximab) to the initial chemotherapy and the continuation of the targeted agent after completion of the chemotherapy have yielded superior overall survival in comparison to chemotherapy alone. The incremental benefit of the maintenance therapy with the targeted agent is unknown

Environmental drivers of coccolithophore abundance and calcification across Drake Passage (Southern Ocean)

Although coccolithophores are not as numerically common or as diverse in the Southern Ocean as they are in subpolar waters of the North Atlantic, a few species, such as Emiliania huxleyi, are found during the summer months. Little is actually known about the calcite production (CP) of these communities or how their distribution and physiology relate to environmental variables in this region. In February 2009, we made observations across Drake Passage (between South America and the Antarctic Peninsula) of coccolithophore distribution, CP, primary production, chlorophyll a and macronutrient concentrations, irradiance and carbonate chemistry. Although CP represented less than 1% of total carbon fixation, coccolithophores were widespread across Drake Passage. The B/C morphotype of E. huxleyi was the dominant coccolithophore, with low estimates of coccolith calcite ( 0.01 pmol C coccolith-/ from biometric measurements. Both cell-normalised calcification (0.01–0.16 pmol C cell-1 d-1/ and total CP (< 20 μmol C m-1 d-1/were much lower than those observed in the subpolar North Atlantic where E. huxleyi morphotype A is dominant. However, estimates of coccolith production rates were similar (0.1–1.2 coccoliths cell-1 h-1/ to previous measurements made in the subpolar North Atlantic. A multivariate statistical approach found that temperature and irradiance together were best able to explain the observed variation in species distribution and abundance (Spearman’s rank correlation D0.4, p < 0.01). Rates of calcification per cell and coccolith production, as well as community CP and E. huxleyi abundance, were all positively correlated (p < 0.05) to the strong latitudinal gradient in temperature, irradiance and calcite saturation states across Drake Passage. Broadly, our results lend support to recent suggestions that coccolithophores, especially E. huxleyi, are advancing polewards. However, our in situ observations indicate that this may owe more to sea-surface warming and increasing irradiance rather than increasing CO2 concentrations

Biogeographical patterns and environmental controls of phytoplankton communities from contrasting hydrographical zones of the Labrador Sea

The Labrador Sea is an important oceanic sink for atmospheric CO2 because of intensive convective mixing during winter and extensive phytoplankton blooms that occur during spring and summer. Therefore, a broad-scale investigation of the responses of phytoplankton community composition to environmental forcing is essential for understanding planktonic food-web organisation and biogeochemical functioning in the Labrador Sea. Here, we investigated the phytoplankton community structure (>4 μm) from near surface blooms (1.2 mg chla m−3) occurred on and near the shelves in May and in offshore waters of the central Labrador Sea in June due to haline- and thermal-stratification, respectively. Sea ice-related (Fragilariopsis cylindrus and F. oceanica) and Arctic diatoms (Fossula arctica, Bacterosira bathyomphala and Thalassiosira hyalina) dominated the relatively cold (<0 °C) and fresh (salinity < 33) waters over the Labrador shelf (e.g., on the southwestern side of the Labrador Sea), where sea-ice melt and Arctic outflow predominates. On the northeastern side of the Labrador Sea, intense blooms of the colonial prymnesiophyte Phaeocystis pouchetii and diatoms, such as Thalassiosira nordenskioeldii, Pseudo-nitzschia granii and Chaetoceros socialis, occurred in the lower nutrient waters (nitrate < 3.6 μM) of the West Greenland Current. The central Labrador Sea bloom occurred later in the season (June) and was dominated by Atlantic diatoms, such as Ephemera planamembranacea and Fragilariopsis atlantica. The data presented here demonstrate that the Labrador Sea spring and early summer blooms are composed of contrasting phytoplankton communities, for which taxonomic segregation appears to be controlled by the physical and biogeochemical characteristics of the dominant water masses

Plankton patchiness investigated using simultaneous nitrate and chlorophyll observations

The complex patterns observed in marine phytoplankton distributions arise from the interplay of biological and physical processes, but the nature of the balance remains uncertain centuries after the first observations. Previous observations have shown a consistent trend of decreasing variability with decreasing length-scale. Influenced by similar scaling found for the properties of the water that the phytoplankton inhabit, ‘universal' theories have been proposed that simultaneously explain the variability seen from meters to hundreds of kilometers. However, data on the distribution of phytoplankton alone has proved insufficient to differentiate between the many causal mechanisms that have been suggested. Here we present novel observations from a cruise in the North Atlantic in which fluorescence (proxy for phytoplankton), nitrate and temperature were measured simultaneously at scales from 10 m to 100 km for the first time in the open ocean. These show a change in spectra between the small scale (10–100 m) and the mesoscale (10–100 km) which is different for the three tracers. We discuss these observations in relation to the current theories for phytoplankton patchiness

Marine nutrient subsidies promote biogeochemical hotspots in undisturbed, highly humic estuaries

The land-ocean dissolved organic carbon (DOC) flux represents a significant term within the global carbon budget, with peatland-dominated regions representing the most intense sources of terrestrial DOC export. As the interface between freshwater and marine systems, estuaries have the potential to act as a filter of the land-ocean carbon flux, removing terrestrially derived DOC, which is present at low concentrations in the oceans, via a combination of physicochemical and biological processes. However, the fate of peat-derived DOC within estuaries remains poorly quantified, partly due to the complicating influences of heterogeneous soils, land-use, point sources, and upstream modification of organic matter. To minimize these modifying factors, we studied DOC and inorganic nutrients in four small, peat-dominated, minimally disturbed, and oligotrophic Falkland Island estuaries. Contrary to expectations, we found limited evidence of physicochemical estuarine DOC removal, and instead observed apparent "hot zones" of biogeochemical activity, where terrestrially-derived silicate mixed with inorganic nitrogen and phosphorus entering the estuaries from the nutrient-rich marine ecosystem. In two estuaries, this coincided with apparent in situ DOC production. We suggest that the observed phenomena of marine nutrient subsidy of estuarine productivity, and flexible utilization of multiple nutrients within the oligotrophic system, may once have been widespread in temperate estuaries. However, this function has been lost in many ecosystems due to catchment eutrophication by agricultural and urban development. We conclude that the estuaries of the Falkland Islands provide a valuable pre-disturbance analogue for natural biogeochemical functioning in temperate estuaries receiving high organic matter inputs

Plankton patchiness investigated using simultaneous nitrate and chlorophyll observations

The complex patterns observed in marine phytoplankton distributions arise from the interplay of biological and physical processes, but the nature of the balance remains uncertain centuries after the first observations. Previous observations have shown a consistent trend of decreasing variability with decreasing length-scale. Influenced by similar scaling found for the properties of the water that the phytoplankton inhabit, ‘universal' theories have been proposed that simultaneously explain the variability seen from meters to hundreds of kilometers. However, data on the distribution of phytoplankton alone has proved insufficient to differentiate between the many causal mechanisms that have been suggested. Here we present novel observations from a cruise in the North Atlantic in which fluorescence (proxy for phytoplankton), nitrate and temperature were measured simultaneously at scales from 10 m to 100 km for the first time in the open ocean. These show a change in spectra between the small scale (10–100 m) and the mesoscale (10–100 km) which is different for the three tracers. We discuss these observations in relation to the current theories for phytoplankton patchiness

Iron cycling during the decline of a South Georgia diatom bloom

The Southern Ocean is the largest high nutrient low chlorophyll (HNLC) oceanic region, where iron limits phytoplankton growth and productivity and ultimately influences the Biological Carbon Pump (BCP). Natural exceptions to the HNLC regime occur where island wakes cause iron to be mixed into surface waters from sediments, enabling large, prolonged phytoplankton blooms and increased carbon drawdown. Interactions between iron and phytoplankton are reciprocal in blooms: with plankton regulating the (re)cycling of iron through cellular uptake and remineralisation. The depth of iron remineralisation then influences either re-supply to the surface mixed layer biota or sequestration into deeper waters. Water column trace metal observations and shipboard experiments, using bioassays and radioisotope (55Fe, 32Si, 14C) cycling, were undertaken to investigate surface mixed layer phytoplankton iron limitation, iron uptake, and mesopelagic iron remineralisation relative to carbon and silica within the November 2017 bloom downstream of South Georgia. Surface phytoplankton residing in the iron depleted mixed layer were iron limited throughout the four-week sampling period. Experiments designed to investigate particulate water column (re)cycling revealed limited iron remineralisation from freshly produced upper ocean particles. The main pathway of iron transfer from particulates into the dissolved phase was through rapid (<2 d) release of extra-cellular adsorbed iron, which, if occurring in situ, could contribute to observed higher sub-surface dissolved Fe concentrations. This was accompanied by a small loss of cellular carbon, likely through respiration of the fixed 14C, and limited dissolution of particulate 32Si to dissolved 32Si. Decoupling of the remineralisation length scales for Fe, C and Si, with Fe having the fastest turnover, is thus likely in the upper mesopelagic zone beneath the bloom