Sources,metabolism, and regulation of circulating sphingosine-1-phosphate

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts either as an intracellular messenger or as a ligand for its membrane receptors. S1P is a normal constituent of blood, where it is found both in plasma and blood cells. Compared with other cell types, sphingolipid metabolism in erythrocytes and platelets has unique features that allow the erythrocytes and platelets to accumulate S1P. In plasma, S1P is bound mainly to HDLs and albumin. Of note, metabolism and biological activity of S1P is to a large extent affected by the type of its carrier. Plasma S1P is characterized by a short half-life, indicating rapid clearance by degradative enzymes and the presence of high-capacity sources involved in maintaining its high concentration. These sources include blood cells, vascular endothelium, and hepatocytes. However, the extent to which each of these contributes to the plasma pool of S1P is a matter of debate. Circulating S1P plays a significant physiological role. It was found to be the key regulator of lymphocyte trafficking, endothelial barrier function, and vascular tone. The purpose of this review is to summarize the present state of knowledge on the metabolism, transport, and origin of plasma S1P, and to discuss the mechanisms regulating its homeostasis in blood.     

Identification of the chromosome complement and the spontaneous 1R/1V translocations in allotetraploid <Emphasis Type="Italic">Secale cereale</Emphasis> × <Emphasis Type="Italic">Dasypyrum villosum</Emphasis> hybrids through cytogenetic approaches

Genome modifications that occur at the initial interspecific hybridization event are dynamic and can be consolidated during the process of stabilization in successive generations of allopolyploids. This study identifies the number and chromosomal location of ribosomal DNA (rDNA) sites between Secale cereale, Dasypyrum villosum, and their allotetraploid S. cereale × D. villosum hybrids. For the first time, we show the advantages of FISH to reveal chromosome rearrangements in the tetraploid Secale × Dasypyrum hybrids. Based on the specific hybridization patterns of ribosomal 5S, 35S DNA and rye species-specific pSc200 DNA probes, a set of genotypes with numerous Secale/Dasypyrum translocations of 1R/1V chromosomes were identified in successive generations of allotetraploid S. cereale × D. villosum hybrids. In addition we analyse rye chromosome pairs using FISH with chromosome-specific DNA sequences on S. cereale × D. villosum hybrids.     

Land-Use Legacies Are Important Determinants of Lake Eutrophication in the Anthropocene

Background

A hallmark of the latter half of the 20^th century is the widespread, rapid intensification of a variety of anthropogenically-driven environmental changes—a “Great Acceleration.” While there is evidence of a Great Acceleration in a variety of factors known to be linked to water quality degradation, such as conversion of land to agriculture and intensification of fertilizer use, it is not known whether there has been a similar acceleration of freshwater eutrophication.

Methodology/Principal Findings

Using quantitative reconstructions of diatom-inferred total phosphorus (DI-TP) as a proxy for lake trophic state, we synthesized results from 67 paleolimnological studies from across Europe and North America to evaluate whether most lakes showed a pattern of eutrophication with time and whether this trend was accelerated after 1945 CE, indicative of a Great Acceleration. We found that European lakes have experienced widespread increases in DI-TP over the 20^th century and that 33% of these lakes show patterns consistent with a post-1945 CE Great Acceleration. In North America, the proportion of lakes that increased in DI-TP over time is much lower and only 9% exhibited a Great Acceleration of eutrophication.

Conclusions/Significance

The longer and more widespread history of anthropogenic influence in Europe, the leading cause for the relatively pervasive freshwater eutrophication, provides an important cautionary tale; our current path of intensive agriculture around the world may lead to an acceleration of eutrophication in downstream lakes that could take centuries from which to recover.     

Trifluoromethyl group as a pharmacophore: effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand

Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.     

Tissue distribution of a menthyl-conjugated oligodeoxyribonucleotide antisense to PAI-1 mRNA

The inhibitory effect of numerous analogues of PO-16, an hexadecadeoxyribonucleotide antisense to sequences -22 to -17 of PAI-1 mRNA coding for a fragment of the signal peptide, on the expression of PAI-1 in endothelial cells, and physiological consequences of the subsequently reduced PAI-1 activity tested in vitro and in vivo, were described in our previous studies. Of particular interest was PO-16 5'-O-conjugated with menthyl phosphorothioate (MPO-16R). In this work, tissue localisation of MPO-16R labelled with [(35)S] phosphorothioate at the 3'-end, was determined. [(35)S]MPO-16R and control [(35)S]MPO-16R-SENSE oligonucleotides were administered intravenously into 22 rats and organ distribution of the labelled bioconjugates was assessed after 24 and 48 h. For this purpose, tissue sections were subjected to autoradiography, and quantitated by liquid scintillation after solubilisation. Overall clearance of radioactivity was already seen after 24 h, with the radioactivity recovered mainly in the kidney and liver. A smaller fraction of radioactivity was also retained in the spleen and heart. The kidney concentration of the labelled probe was higher than that of liver by 50%. The distribution of PAI-1 mRNA in untreated rat kidney, liver, spleen and heart established by two independent techniques: Ribonuclease Protection Assay and Real-Time PCR, shows the same pattern as that observed for [(35)S]MPO-16R antisense.     

Choice of isolation procedure for endotoxins from the outer membrane of the bacteria Desulfovibrio desulfuricans

The chemical structure determining properties and biological functions of endotoxins derived from Desulfovibrio desulfuricans species has not been recognized, which considerably hinders the choice of an effective extraction procedure of these lipopolysaccharides (LPS) from the bacterial outer cell membrane. We aimed at selecting the most effective method of LPS isolation from D. desulfuricans in terms of the most efficient extraction solution, the appropriate conditions of isolation and adequate purification technique. For this purpose we tested a few literature-based procedures utilizing various extraction mixtures (phenol-water, phenol-chloroform-petroleum ether and Tri-Reagent, i.e. aqueous solution of guanidinum thiocyanate and phenol). The best yield and purity of the isolated LPS were provided by the application of the extraction with phenol-water according to the modified by Shnyra et.al. (2000) procedure of Westphal et. al. (1952). A satisfactory method of isolation in micro scale appeared to be that based on Tri-Reagent and propagated by Yi and Hackett in 2000. The extraction of LPS from D. desulfuricans with phenol-chloroform-petroleum ether should not be recommended due to its low efficiency.     

Gene Genealogies Strongly Distorted by Weakly Interfering Mutations in Constant Environments

Neutral nucleotide diversity does not scale with population size as expected, and this “paradox of variation” is especially severe for animal mitochondria. Adaptive selective sweeps are often proposed as a major cause, but a plausible alternative is selection against large numbers of weakly deleterious mutations subject to Hill–Robertson interference. The mitochondrial genealogies of several species of whale lice (Amphipoda: Cyamus) are consistently too short relative to neutral-theory expectations, and they are also distorted in shape (branch-length proportions) and topology (relative sister-clade sizes). This pattern is not easily explained by adaptive sweeps or demographic history, but it can be reproduced in models of interference among forward and back mutations at large numbers of sites on a nonrecombining chromosome. A coalescent simulation algorithm was used to study this model over a wide range of parameter values. The genealogical distortions are all maximized when the selection coefficients are of critical intermediate sizes, such that Muller''s ratchet begins to turn. In this regime, linked neutral nucleotide diversity becomes nearly insensitive to N. Mutations of this size dominate the dynamics even if there are also large numbers of more strongly and more weakly selected sites in the genome. A genealogical perspective on Hill–Robertson interference leads directly to a generalized background-selection model in which the effective population size is progressively reduced going back in time from the present.OBSERVED levels of apparently neutral nucleotide diversity (π_n) are typically lower than expected under the assumptions of standard equilibrium theories, and they vary much less among species than do estimates of long-term effective population sizes (Nei and Grauer 1984; Bazin et al. 2006; Nabholz et al. 2008). Many explanations have been proposed for the apparent shortfalls and the lack of proportionality with population size, including (1) complex demographic histories (e.g., recurring population bottlenecks), (2) adaptive selective sweeps (Maynard Smith and Haigh 1974; Gillespie 1999), and (3) selection against deleterious mutations (Charlesworth et al. 1993, 1995; McVean and Charlesworth 2000; Comeron et al. 2008). Of these three possibilities, bottlenecks and sweeps are by far the most frequently mentioned, even though deleterious mutations occur at high rates in all species, regardless of ecological circumstances (Eyre-Walker and Keightley 2007). Here we show that weakly deleterious mutations can distort genealogies in three different ways and dramatically reduce nucleotide diversities in large populations of nonrecombining chromosomes. The mitochondrial genealogies of several species of whale lice (Kaliszewska et al. 2005) are distorted in exactly these ways, and several lines of evidence suggest that bottlenecks and adaptive sweeps are not likely to be the primary causes.Mitochondria have been proposed to be especially sensitive to selective sweeps. Animal mitochondrial genomes contain more than three dozen essential protein and structural RNA genes, so they are large targets for both mutation and selection (Ballard and Whitlock 2004). They do not undergo sexual recombination, so every advantageous mutation that fixes will reduce variation throughout the genome. Mitochondrial nucleotide diversity therefore could depend strongly on rates of environmental change, which could be similar for species with very different population sizes. Indeed, if rates of mitochondrial adaptation were mutation limited, then larger populations might actually experience higher rates of adaptive substitution and as a result show lower average levels of neutral diversity than smaller populations (Gillespie 2000, 2001). This idea was recently invoked to explain the remarkable similarity of average levels of mitochondrial nucleotide diversity among the major animal classes which appear to have very different average population sizes and substantially different average levels of nuclear nucleotide and amino acid diversity (Bazin et al. 2006).Unconditionally deleterious mutations can also depress linked neutral diversity by reducing the effective population size either through (1) background selection against relatively strongly selected mutations (Charlesworth et al. 1993, 1995) or (2) Hill–Robertson interference (Hill and Robertson 1966) among large numbers of relatively weakly selected mutations (reviewed by Comeron et al. 2008). The second of these processes, called “weak-selection Hill–Robertson interference” (wsHRi) by McVean and Charlesworth (2000) and “interference selection” (IS) by Comeron and Kreitman (2002), can shorten genealogies, give them strongly nonneutral branch-length proportions, and skew their topologies (Higgs and Woodcock 1995; Maia et al. 2004).To date, weak interference has mainly been studied by forward simulation, with the aim of assessing its possible effects on patterns of optimal synonymous codon use within eukaryotic nuclear genes and genomes, in the presence of recombination (Comeron and Guthrie 2005; Loewe and Charlesworth 2007; Comeron et al. 2008). In an attempt to understand the striking genealogical distortions seen in whale-louse mitochondria (Kaliszewska et al. 2005), we have developed a structured-coalescent algorithm that accurately models selection of arbitrary strength on a nonrecombining chromosome of finite length. All of the distortions seen in the whale-louse mitochondria are replicated under parameters that might plausibly apply to whale lice and many other animal species, and these distortions scale only weakly with population size.Whale lice are permanent, obligate ectoparasites of cetaceans. They feed on the dead outer surface of their host''s skin, and they appear to be harmless. They are amphipod Crustacea comprising a monophyletic family, Cyamidae, with ∼50 described species in several genera. Three of these species (Cyamus ovalis, C. gracilis, and C. erraticus) occur on right whales (Eubalaena spp.) but not regularly on any other hosts. Most adult right whales carry large populations of all three species.Right whales in the North Pacific, the North Atlantic, and the southern hemisphere have been separated for ∼5 million years, and so have their cyamids (Rosenbaum et al. 2000; Gaines et al. 2005; Kaliszewska et al. 2005). For this reason the right whales in different ocean systems are now considered distinct species (Eubalaena japonica, E. glacialis, and E. australis), and we refer to their cyamids as North Pacific C. ovalis, North Atlantic C. ovalis, southern C. ovalis, and so on, in anticipation that a future revision of the genus Cyamus will recognize them as “triplet” sibling species (3 × 3 = 9 species in all). We studied their mitochondrial population genetics with the initial aim of quantifying patterns of genetic differentiation among the cyamid populations on individual whales within local populations (Kaliszewska et al. 2005).We had reasoned (incorrectly) that the pattern of differentiation among whales might say something about their social interactions, since cyamids can transfer only between whales that are in direct physical contact with each other. We found very low levels of differentiation among whales and to our surprise literally no differentiation among the major southern hemisphere breeding aggregations that calve off the coasts of South America, South Africa, Australia, and New Zealand (Kaliszewska et al. 2005). This absence of population structure seems remarkable by terrestrial standards but is easily explained by modest rates of cyamid exchange among whales within local populations and between the major breeding aggregations, given the enormous sizes of cyamid populations. Right whales are highly gregarious (spending hours per day in social interactions), mobile (traveling thousands of kilometers per year on annual foraging migrations), and mortal (carrying their cyamid populations to the sea floor when they die). Thus cyamids have many opportunities to transfer between whales, and they might be expected to have evolved an inclination to do so when the opportunity presents itself (Hamilton and May 1977).The well-defined ecology of right-whale cyamids allows their population sizes to be estimated directly. The number of adult cyamids per whale (∼500–10,000, varying by species) times the number of whales per ocean (∼50,000–200,000, prior to human exploitation) equals the number of cyamids per species (Kaliszewska et al. 2005). Thus for all three nominal species of right-whale cyamids, long-term census population sizes are expected to have been in the range 2.5 × 10⁷–2 × 10⁹. Given conservative estimates of the per-generation mitochondrial mutation rate, even the lower end of this range predicts levels of synonymous nucleotide diversity at least an order of magnitude larger than those actually seen in the cyamids, which are consistently modest and similar to those seen in typical terrestrial arthropods (Kaliszewska et al. 2005). The three North Atlantic and southern hemisphere sibling-species pairs are strongly reciprocally monophyletic, as illustrated for C. ovalis in Figure 1. This is not expected at mutation–drift equilibrium, given their very large population sizes.Open in a separate windowFigure 1.—Mitochondrial gene genealogies for North Atlantic and southern hemisphere Cyamus ovalis, estimated by UPGMA from partial COI sequences. Left: The intraspecific genealogies coalesce globally at ∼0.5 and 1 MY and share an ancestor at ∼5 MY (Kaliszewska et al. 2005). Center and right: Each intraspecific genealogy is aligned with a generalized skyline plot (Strimmer and Pybus 2001) showing estimates of θ at different times in the past under a piecewise constant model of population size change fit by GENIE 3.0 (Pybus and Rambaut 2002). Three different point estimates of present-day θ are also indicated on the plots (synonymous-site nucleotide diversity π, Watterson''s θ estimated from synonymous sites, and θ estimated jointly with the apparent exponential growth rate by the MCMC coalescent algorithm in LAMARC). Values of Tajima''s D are lower (−1.5 to −1.6) when estimated from the sequences than when estimated from the branch lengths of the trees (−2.1 to −2.4), as expected because multiple substitutions occur at some sites. Similar values of D_T (−2.3 for both species) were obtained from the highest-likelihood trees found by BEAST with a fully parameterized GTR substitution model and a coalescent prior. Those trees have standardized imbalance statistics (−I_S) of −3.7 (southern hemisphere C. ovalis) and −2.2 (North Atlantic C. ovalis). The trees shown here have more extreme values of −I_S (−5.5 and −4.0, respectively), probably as a consequence of artificially pectinate branching orders induced by UPGMA among sets of identical sequences. Slightly different sets of sequences were used to make the two-species genealogy on the left and the single-species genealogies in the center. The long interspecific branches in the two-species tree are based on a multispecies maximum-likelihood analysis involving smaller numbers of much longer (4.1 kb) sequences (Kaliszewskaet al. 2005, Figure 3).These dramatic deficits of variation are not easily explained by population bottlenecks or adaptive selective sweeps. The bottleneck hypothesis is especially problematic because it requires the long-term near extinction of right whales in all three ocean systems. (Short bottlenecks such as those caused by human exploitation of right whales are not expected to have a noticeable effect on cyamid genetic diversity because cyamid populations remain large, and rates of genetic drift low, even when there are few whales.) That all three right whales have survived for millions of years suggests that they have maintained reasonably large population sizes, and the mitochondrial nucleotide diversity of southern right whales is consistent with this assumption (Kaliszewska et al. 2005), as is the nucleotide diversity of a cyamid nuclear gene (described below). Right whales eat copepods and krill, which are relatively close to the base of marine food webs, and right-whale populations are thought to be food limited. Thus a long-term, severe depression of their numbers would also seem to imply a collapse of marine ecosystems worldwide, for which there is no evidence.Several features of cyamid mitochondrial nucleotide diversity are also inconsistent with the bottleneck model and with adaptive sweeps as well. The most obvious of these features is the uniformity of cyamid mitochondrial diversity among species (π = 0.007–0.015 for COI sequences in the seven species surveyed by Kaliszewska et al. 2005). Gene genealogies estimated from these sequences also seem remarkably uniform in total depth, with last common ancestors differing in age by only a factor of 3 and in six of the seven species by less than a factor of 2 (see Kaliszewska et al. 2005, Figure 4). Adaptive sweeps might be expected to occur at roughly random intervals and not to be well coordinated in time among seven species in three different ocean systems. Interspecific coordination of such sweeps (over the whole globe) would seem to be required if they were to be a plausible primary cause of the genealogical shortening.Open in a separate windowFigure 4.—Apparent average effective sizes of ancestral populations, for models with different values of s. Values of N_e are given on the vertical axis (logarithmically scaled). They are estimated from the variance of expected contributions to the present, for the adults of any given generation. The parameters are those of Figure 2 (N = 65,536 = “64k,” μ = 1.5 × 10⁻⁶, L_s = 2048, U = 0.0031). In theory the curve for s = 0 should be perfectly horizontal. The discrepancy appears to be caused by subtle flaws in the shape of the very broad “idealized” simulated distribution that was used in this calculation. The curves for strong-selection cases are perfectly horizontal at times beyond a few thousand generations because the mutation-number distributions are compact, with little stochastic variation. The two lowest curves are those for the selection coefficients (s = 2⁻¹⁰, U/s = 3.2, and s = 2⁻¹¹, U/s = 6.3) that produce the most extreme values of the polymorphism and tree-shape statistics, given the other parameters (Figure 2).In addition to showing too little nucleotide variation, the cyamid mitochondrial genomes show strong and consistent excesses of rare nucleotide states, reflecting the “comb-like” or “star-like” shapes of the genealogies, in which deeper branches tend to be much too short relative to terminal branches (as if the trees had been “squished” from behind). This kind of distortion causes negative values of Tajima''s (1989) D and related statistics. It can be caused by population expansion from a bottleneck or by lineage expansion under positive selection (Kaplan et al. 1989; Slatkin and Hudson 1991; Rogers and Harpending 1992; Bamshad and Wooding 2003). However, the form of branch-length distortion seen in the cyamid genealogies suggests a slow, steady, roughly exponential form of population or lineage growth, not the relatively sudden increases suggested by the bottleneck and selective-sweep hypotheses. Generalized skyline plots (Strimmer and Pybus 2001) describing the histories of population size implied by the shapes of the northern and southern C. ovalis gene genealogies are shown in Figure 1. They are remarkably similar, as are the growth rates and estimates of present-day θ (= 2N_fμ_n) obtained by fitting exponential growth models using the coalescent algorithms in LAMARC (Kuhner et al. 1998, 2004) or BEAST (Drummond and Rambaut 2007).Cyamid populations cannot have grown in numbers as seemingly implied by these analyses. The number of cyamids on each whale appears to be set mainly by microhabitat limitations (e.g., by the area of rough callosity tissue on the head, where C. ovalis and C. gracilis live), and these features of their environment have hardly changed for millions of years, as demonstrated by the strong similarities of northern and southern right whales and their cyamids. Likewise, the numbers of right whales cannot have increased gradually from vanishingly small numbers over several hundred thousand years, for the reasons discussed above.The genealogical signals of “growth” therefore seem likely to be caused by selection. Environmental change is the most obvious potential cause of selection, but the apparent rate of growth seen here is strangely slow—in fact, slower than glacial. The orbitally forced Plio-Pleistocene glacial climate cycles have a major period of ∼100,000 years (Lambert et al. 2008 and references therein), but all seven of the right-whale cyamids for which we have mitochondrial population samples appear to have been “expanding,” more or less continuously, through at least several such cycles. The seemingly fairly consistent rate of branch-length foreshortening seen in the genealogies therefore suggests the action of a process that is relatively homogeneous in time, in addition to being very slow overall.The cyamid mitochondrial genealogies also appear to be topologically skewed, with sister clades too unequal in size, on average. In random bifurcating trees, the distribution of sister-clade sizes is uniform (Yule 1924; Heard 1992; Rogers 1994). Deviations from this null expectation can be quantified by statistics such as Colless''s (1982) index of tree imbalance (Shao and Sokal 1990; Rogers 1996). Our estimates of the cyamid genealogies tend to be excessively imbalanced (Figure 1). Strong topological imbalance is not caused by classic adaptive sweeps or by population growth following a bottleneck, but previous theoretical work has indicated that it can be caused by selection (Higgs and Woodcock 1995; Maia et al. 2004).To summarize, the cyamid mitochondrial genealogies are consistently much too short, too squished, and too skewed, relative to neutral-theory expectations. Owing to several special features of cyamid and right-whale biology, selection seems to be the only plausible explanation for this set of distortions, but conventional adaptive sweeps do not seem likely to be the primary cause. We therefore asked whether weakly deleterious mutations might be sufficient to generate the observed combination of patterns, in the absence of environmental change. Previous work (mentioned above) showed that interference among weak mutations at many sites can strongly affect linked neutral variation, but this work did not fully explore the parameter space relevant to our system or connect all the patterns in a genealogical setting.To address this question we first carried out forward simulations of populations of nonrecombining chromosomes with large numbers of nucleotide positions subject to forward and back mutations with unconditional fitness effects of size s. Large numbers of linked neutral sites were used to estimate genealogies and to calculate population statistics of interest. We found that for a range of intermediate values of s, considerable fitness variation was maintained and all three of the genealogical distortions (and the signal of apparent exponential growth) seen in the cyamid genealogies reached impressively large maxima. However, the computational burden of full forward simulation prevented us from considering realistic parameter values (i.e., large N and small μ), and it was not obvious that extrapolations based on compound parameters (e.g., Nμ and Ns) would work as hoped in all respects (see Comeron et al. 2008). We developed an equivalent coalescent algorithm that accurately reproduces all results of the forward simulations and allows for realistic parameter values. Under parameters relevant to cyamid mitochondria, the distortions of genealogical depth, proportions, and topology can be even more extreme than those seen in the cyamids, and the mean pairwise coalescence times (and resulting neutral nucleotide diversities) associated with maximally distorting intermediate values of s (U_s/s ∼ 5, where U_s is the total genomic mutation rate at sites with selection coefficents of size s) depend only weakly on N.All parameters of this model (including those of the environment) remain constant over time, yet in some respects it displays apparently nonequilibirum behavior. Under weak to intermediate selection (U_s/s > 10), the effective population size appears to become progressively smaller as time recedes into the past, giving rise to the illusion of growth. And in the maximally distorting range of intermediate selection coefficients, the distributions of deleterious mutation numbers and the shapes of genealogies show conspicuous dynamical instability of a form that could be taken to suggest “adaptive evolution” in response to episodes of environmental change. Adaptive mutations contribute importantly to this process, but they are reversions at some of the many sites previously mutated to mildly deleterious states. Subtle patterns of environmental change that converted previously optimal nucleotide states to slightly suboptimal states could give rise to a category of “virtual reversions” that would augment (or even outnumber) simple reversions, and the effects of such a process might well be consistent with the distortions seen in the cyamid mitochondrial genealogies. However, models with no environmental change of any kind appear to explain the observations surprisingly well.     

Genetic variation in the efficiency of nitrogen utilization and photosynthetic activity of flag leaves among the old and modern germplasm of winter wheat

Genotypic variation in major components of the efficiency of nitrogen utilization and photosynthetic activity of flag leaves among old (released 1881-1963) and modern (released 1969-2003) cultivars of winter wheat was studied in field conditions under varied N fertilization levels (110, 90 and 80 kg N ha-1). Significant genotypic differences were observed for all characters. Their heritabilities ranged from 0.37 to 0.93 and were the lowest for the leaf efficiency of gas exchange, photosynthetic rate, straw N content and the economic index of N utilization efficiency (NUE). Some modern cultivars exhibited an enhanced tolerance to N shortage and several attributes of efficient N utilization (e.g. later senescing and more photosynthetically active flag leaves, increased ability to redistribute N into grains). The genotypes may serve as donors of appropriate characteristics for breeding. The observed cultivar-by-fertilization interactions suggest, however, that evaluations under diverse fertilization regimes may be necessary when searching for improved wheat efficiency and adaptation to less favourable environments.