The evolution of conditional dispersal and reproductive isolation along environmental gradients

Dispersal modulates gene flow throughout a population's spatial range. Gene flow affects adaptation at local spatial scales, and consequently impacts the evolution of reproductive isolation. A recent theoretical investigation has demonstrated that local adaptation along an environmental gradient, facilitated by the evolution of limited dispersal, can lead to parapatric speciation even in the absence of assortative mating. This and other studies assumed unconditional dispersal, so individuals start dispersing without regard to local environmental conditions. However, many species disperse conditionally; their propensity to disperse is contingent upon environmental cues, such as the degree of local crowding or the availability of suitable mates. Here, we use an individual-based model in continuous space to investigate by numerical simulation the relationship between the evolution of threshold-based conditional dispersal and parapatric speciation driven by frequency-dependent competition along environmental gradients. We find that, as with unconditional dispersal, parapatric speciation occurs under a broad range of conditions when reproduction is asexual, and under a more restricted range of conditions when reproduction is sexual. In both the asexual and sexual cases, the evolution of conditional dispersal is strongly influenced by the slope of the environmental gradient: shallow environmental gradients result in low dispersal thresholds and high dispersal distances, while steep environmental gradients result in high dispersal thresholds and low dispersal distances. The latter, however, remain higher than under unconditional dispersal, thus undermining isolation by distance, and hindering speciation in sexual populations. Consequently, the speciation of sexual populations under conditional dispersal is triggered by a steeper gradient than under unconditional dispersal. Enhancing the disruptiveness of frequency-dependent selection, more box-shaped competition kernels dramatically lower the speciation-enabling slope of the environmental gradient.     

Core-modified sordaricin derivatives: synthesis and antifungal activity

Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.     

Role of the T-cell system in glomerulonephritis induced in rats by human serum albumin (HSA)

The primary role of the T-cell system in immune-complex glomerulonephritis induced by intravenous weekly injections of human serum albumin (HSA) in rats has been demonstrated. The development of histological, ultrastructural and immunological glomerular alterations which are clearly recognizable in intact animals was prevented by neonatal thymectomy. In vitro tests of cellular immunity (LIF and PHA responsiveness) revealed a close relationship between the involvement of functioning T-cell subpopulations (at least T-helper) and the development of the classic glomerulonephritic pattern. In other words HSA antigen recognition by T lymphocytes, their cooperation with B lymphocytes, and the activation of the latter with related antibody response represent the immunological sequence which leads to the formation of the soluble circulating immune-complexes responsible for the glomerular injury. Our findings suggest that the same immunological sequence can represent the pathogenetic basis for many forms of glomerulonephritis in which T-dependent antigen stimulation is demonstrable. Our data are also discussed in the light of results obtained by others in immuneglomerulonephritis induced in nude athymic mice.     

Synthesis of lipopeptides of the immunodominant epitope hMBP(83–99) containing amide or C-C bond linked hydrophobic chains for the study of T cell response

We previously demonstrated that the lipopeptide of the myelin basic protein (MBP) immunodominant epitope in Lewis rat Palm-GpMBP(74–85) (Gp: guinea pig), which induced experimental autoimmune encephalomyelitis in vivo strongly increased the T cell proliferative response in vitro. We extended this study to the human immunodominant epitope hMBP(83–99), synthesizing different lipophilic peptides bearing a hydrophobic chain linked through an amide or a C-C bond. To this aim, we developed a synthetic pathway for (±)-N-Fmoc-Ahd-OH (Ahd: 2-aminohexadecanoic acid) which was used to synthesize diastereomeric peptides which were successfully separated by reverse-phase high-performance liquid chromatography. MBP-specific T cell lines recognizing the immunodominant epitope hMBP(83–99) have been generated from patients affected by multiple sclerosis. Their proliferative response to the native peptide and to some lipoderivatives has been investigated. In contrast to the animal model, none of the investigated lipopeptides exhibited superagonist activity.     

Synthesis of lipopeptides of the immunodominant epitope hMBP(83–99) containing amide or C-C bond linked hydrophobic chains for the study of T cell response

Summary We previously demonstrated that the lipopeptide of the myelin basic protein (MBP) immunodominant epitope in Lewis rat Palm-GpMBP(74-85) (Gp: guinea pig), which induced experimental autoimmune encephalomyelitisin vivo strongly increased the T cell proliferative responsein vitro. We extended this study to the human immunodominant epitope hMBP(83-99), synthesizing different lipophilic peptides bearing a hydrophobic chain linked through an amide or a C-C bond. To this aim, we developed a synthetic pathway for (±)-N-Fmoc-Ahd-OH (Ahd: 2-aminohexadecanoic acid) which was used to synthesize diastereomeric peptides which were successfully separated by reverse-phase high-performance liquid chromatography. MBP-specific T cell lines recognizing the immunodominant epitope hMBP(83-99) have been generated from patients affected by multiple sclerosis. Their proliferative response to the native peptide and to some lipoderivatives has been investigated. In contrast to the animal model, none of the investigated lipopeptides exhibited ‘superagonist’ activity. Prof. L. Amaducci passed away on 11 January 1998. His memory will hearten those pursuing this research.     

Sordaricin antifungal agents

Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.     

Early mitral deceleration and left atrial stiffness

Left ventricular (LV) filling deceleration time (DT) is determined by the sum of atrial and ventricular stiffnesses (KLA + KLV). If KLA, however, is close to zero, then DT would reflect KLV only. The purpose of this study was to quantify KLA during DT. In 15 patients, KLV was assessed, immediately after cardiopulmonary bypass, from E wave DT as derived from mitral tracings obtained by transesophageal echocardiography and computed according to a validated formula. In each patient, a left atrial (LA) volume curve was also obtained combining mitral and pulmonary vein (PV) cumulative flow plus LA volume measured at end diastole. Time-adjusted LA pressure was measured simultaneously with Doppler data in all patients. KLA was then calculated during the ascending limb of the V loop and during DT. LA volume decreased by 7.3 +/- 6.5 ml/m2 during the first of mitral DT, whereas LV volume increased 9.4 +/- 8.4 ml/m2 (both P < 0.001). There was a small amount of blood coming from the PV during the same time interval, with the cumulative flow averaging 3.2 +/- 2.4 ml/m(2) (P < 0.001). Mean LA pressure was 10.0 +/- 5.1 mmHg, and it did not change during DT [from 7.8 +/- 4.3 to 8.0 +/- 4.3 mmHg, not significant (NS)], making KLA, which averaged 0.46 +/- 0.39 mmHg/ml during the V loop, close to zero during DT [KLA(DT): from -0.002 +/- 0.08 to -0.001 +/- 0.031 mmHg/ml, NS]. KLV, as assessed noninvasively from DT, averaged 0.25 +/- 0.32 mmHg/ml. In conclusion, notwithstanding the significant decrement in LA volume, KLA does not change and can be considered not different from zero during DT. Thus KLA does not affect the estimation of KLV from Doppler parameters.     

Conserved fungal genes as potential targets for broad-spectrum antifungal drug discovery

The discovery of novel classes of antifungal drugs depends to a certain extent on the identification of new, unexplored targets that are essential for growth of fungal pathogens. Likewise, the broad-spectrum capacity of future antifungals requires the target gene(s) to be conserved among key fungal pathogens. Using a genome comparison (or concordance) tool, we identified 240 conserved genes as candidates for potential antifungal targets in 10 fungal genomes. To facilitate the identification of essential genes in Candida albicans, we developed a repressible C. albicans MET3 (CaMET3) promoter system capable of evaluating gene essentiality on a genome-wide scale. The CaMET3 promoter was found to be highly amenable to controlled gene expression, a prerequisite for use in target-based whole-cell screening. When the expression of the known antifungal target C. albicans ERG1 was reduced via down-regulation of the CaMET3 promoter, the CaERG1 conditional mutant strain became hypersensitive, specifically to its inhibitor, terbinafine. Furthermore, parallel screening against a small compound library using the CaERG1 conditional mutant under normal and repressed conditions uncovered several hypersensitive compound hits. This work therefore demonstrates a streamlined process for proceeding from selection and validation of candidate antifungal targets to screening for specific inhibitors.     

The influence of habitat boundaries on evolutionary branching along environmental gradients

It is well known that habitat boundaries affect ecological dynamics, but their influence on evolutionary dynamics is less well understood. Here, we study the effects of different kinds of boundaries on evolutionary branching in clonal populations along environmental gradients by systematically analyzing individual-based stochastic models in small- and large-range systems, as well as their large-population-size limits through deterministic approximations. Specifically, we examine four prototypical kinds of boundaries: impermeable boundaries at which individuals stop (“stopping”), or from which they continue back into the interior as if bouncing back mechanically (“reflecting”), or that let them abort the dispersal attempt, return to their original position and try a different direction (“reprising”), and semipermeable boundaries that can be crossed without hindrance, but do not allow the crossing individual to return (“absorbing”).We find that boundary conditions shape branching patterns only in small-range systems, where stopping boundaries generate disruptive selection for a wide range of parameters, whereas absorbing boundaries always generate stabilizing selection. Reflecting and reprising boundaries generate disruptive selection at low individual mobilities, and stabilizing selection at high mobilities. To further analyze these findings, we introduce a simple approximation of the invasion fitness in a mobile population, which predicts the observed outcome. The effect of stochasticity on evolutionary outcomes is small even in small populations: stochasticity causes random branch extinctions at steeper slopes and higher mobilities. In large-range systems, frequency-dependent interactions alone induce evolutionary branching for almost all parameters and independent of boundary conditions.