New ferrocenic pyrrolo[1,2-a]quinoxaline derivatives: synthesis, and in vitro antimalarial activity

Following our search for antimalarial compounds, novel series of ferrocenic pyrrolo[1,2-a]quinoxaline derivatives 1-2 were synthesized from various substituted nitroanilines and tested for in vitro activity upon the erythrocytic development of Plasmodiumfalciparum strains with different chloroquine-resistance status. The pyrrolo[1,2-a]quinoxalines 1 were prepared in 6-8 steps through a regioselective palladium-catalyzed monoamination by coupling 4-chloropyrrolo[1,2-a]quinoxalines with 1,3-bis(aminopropyl)piperazine or -methylamine using Xantphos as the ligand. The ferrocenic bispyrrolo[1,2-a]quinoxalines 2 were prepared by reductive amination of previously described bispyrrolo[1,2-a]quinoxalines 9 with ferrocene-carboxaldehyde, by treatment with NaHB(OAc)(3). The best results were observed with ferrocenic pyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine. Moreover, it was observed that a methoxy group on the pyrrolo[1,2-a]quinoxaline nucleus and no substitution on the terminal N-ferrocenylmethylamine function enhanced the pharmacological activity. Selected compounds 1b, 1f-h, 1l and 2a were tested for their ability to inhibit beta-haematin formation, the synthetic equivalent of hemozoin, by using the HPIA (heme polymerization inhibitory activity) assay. Of the tested compounds, only 2a showed a beta-haematin formation inhibition, but no inhibition of haem polymerization was observed with the other selected ferrocenic monopyrrolo[1,2-a]quinoxaline derivatives 1b, 1f-h and 1l, as the IC(50) values were superior to 10 equivalents.     

Genetic and phenotypic studies of the dark-like mutant mouse

The dark-like (dal) mutant mouse has a pleiotropic phenotype that includes dark dorsal hairs and reproductive degeneration. Their pigmentation phenotype is similar to Attractin (Atrn) mutants, which also develop vacuoles throughout the brain. In further characterizing the testicular degeneration of dal mutant males, we found that they had reduced serum testosterone and developed vacuoles in their testes. Genetic crosses placed dal upstream of the melanocortin 1 receptor (Mc1r) and downstream of agouti, although dal suppressed the effect of agouti on pigmentation but not body weight. Atrn(mg-3J) and dal showed additive effects on pigmentation, testicular vacuolation, and spongiform neurodegeneration, but transgenic overexpression of Attractin-like-1 (Atrnl1), which compensates for loss of ATRN, did not rescue dal mutant phenotypes. Our results suggest dal and Atrn function in the same pathway and that identification of the dal gene will provide insight into molecular mechanisms of vacuolation in multiple cell types.     

Cell Elongation and Revolving Movement in Phaseolus vulgaris L. Twining Shoots

In Phaseolus vulgaris L., the shoot displays a revolving movementthat occurs rhythmically in a highly regular manner. Previousdata led to think that revolving movement is driven by turgorand volume changes in the epidermal cells of the bending zone.To document this hypothesis, the time course of in situ celllength variations in the bending zone was measured during themovement of the shoot and related to the phase of the revolvingmovement. Each ten minutes, a photograph of cells was takenand the revolving movement was simultaneously recorded usingtime-lapse microphotography and video-monitoring. In the movingpart of the shoot, epidermal cells displayed partly reversiblelength variations during their growth. Data were processed byFourier analysis to determine whether or not a periodicity exists.Rhythm in cell length variations was evidenced only when initialcell lengths were ranged between 60 and 120 µM. In thiscase, the period corresponds to that of the revolving movement. Thus, revolving movement is related to partly reversible lengthvariations in the cells of the bending zone. These results agreewith the hypothesis of an involvement of turgor mediated volumechanges in the revolving movement (Received September 16, 1997; Accepted June 18, 1998)     

Numerical modelling of vertical suspended solids concentrations and irradiance in a turbid shallow system (Vaccares,Se France)

In shallow ecosystems, the short temporal variability of available underwater irradiance is considered a major process controlling submerged macrophytes development. Mechanistic models that estimate photosynthetically available radiation (PAR) in shallow ecosystems at very short time scales are needed for use in predicting submerged macrophyte growth and persistence. We coupled a 2D horizontal circulation model with, first, a 1D vertical numerical model of suspended solid (SS) re-suspension, diffusion and settling, and next, with a model of vertical extinction of irradiance, previously validated at the same site. The study site was the Vaccarès lagoon (France) where a large data set of high frequency bottom irradiance and SS concentration were available. SS and irradiance measurements were conducted at a vertical study station, monitored over a 6 month period (from December 1995 to May 1996) characterized by wide-ranging wind velocities (1.5–18 ms⁻¹). In addition, grain-size analyses conducted over the whole lagoon, allowed adaptation of the 1D numerical model to the silt-sized (7 μm) and clay-sized (0.3 μm) fractions that prevail in the local sediment. First, model results showed that about 60% of the variance in bottom irradiance time series can be explained by our deterministic formulations, thus representing the same level of efficiency than those already obtained by a stochastic model previously developed with the same data set. Second, model results showed that the fit of the model to the field data (SS concentrations and bottom irradiance) depended mainly on storm occurrence and season (winter or spring). Finally, model results suggested that the underwater irradiance regime was controlled by seasonal succession of the horizontal circulation of turbid water in the lagoon, with increased solids concentrations in winter, followed by submerged canopy development and decreased solids concentrations in spring.     

Subthalamic Nucleus Stimulation Affects Theory of Mind Network: A PET Study in Parkinson's Disease

Background

There appears to be an overlap between the limbic system, which is modulated by subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson''s disease (PD), and the brain network that mediates theory of mind (ToM). Accordingly, the aim of the present study was to investigate the effects of STN DBS on ToM of PD patients and to correlate ToM modifications with changes in glucose metabolism.

Methodology/Principal Findings

To this end, we conducted ¹⁸FDG-PET scans in 13 PD patients in pre- and post-STN DBS conditions and correlated changes in their glucose metabolism with modified performances on the Eyes test, a visual ToM task requiring them to describe thoughts or feelings conveyed by photographs of the eye region. Postoperative PD performances on this emotion recognition task were significantly worse than either preoperative PD performances or those of healthy controls (HC), whereas there was no significant difference between preoperative PD and HC. Conversely, PD patients in the postoperative condition performed within the normal range on the gender attribution task included in the Eyes test. As far as the metabolic results are concerned, there were correlations between decreased cerebral glucose metabolism and impaired ToM in several cortical areas: the bilateral cingulate gyrus (BA 31), right middle frontal gyrus (BA 8, 9 and 10), left middle frontal gyrus (BA 6), temporal lobe (fusiform gyrus, BA 20), bilateral parietal lobe (right BA 3 and right and left BA 7) and bilateral occipital lobe (BA 19). There were also correlations between increased cerebral glucose metabolism and impaired ToM in the left superior temporal gyrus (BA 22), left inferior frontal gyrus (BA 13 and BA 47) and right inferior frontal gyrus (BA 47). All these structures overlap with the brain network that mediates ToM.

Conclusion/Significance

These results seem to confirm that STN DBS hinders the ability to infer the mental states of others and modulates a distributed network known to subtend ToM.     

Mitochondrial function declines with age within individuals but is not linked to the pattern of growth or mortality risk in zebra finch

Mitochondrial dysfunction is considered a highly conserved hallmark of ageing. However, most of the studies in both model and non-model organisms are cross-sectional in design; therefore, little is known, at the individual level, on how mitochondrial function changes with age, its link to early developmental conditions or its relationship with survival. Here we manipulated the postnatal growth in zebra finches (Taeniopygia guttata) via dietary modification that induced accelerated growth without changing adult body size. In the same individuals, we examined blood cells mitochondrial functioning (mainly erythrocytes) when they were young (ca. 36 weeks) and again in mid-aged (ca. 91 weeks) adulthood. Mitochondrial function was strongly influenced by age but not by postnatal growth conditions. Across all groups, within individual ROUTINE respiration, OXPHOS and OXPHOS coupling efficiency significantly declined with age, while LEAK respiration increased. However, we found no link between mitochondrial function and the probability of survival into relatively old age (ca. 4 years). Our results suggest that the association between accelerated growth and reduced longevity, evident in this as in other species, is not attributable to age-related changes in any of the measured mitochondrial function traits.     

Intact satellite cells lead to remarkable protection against Smn gene defect in differentiated skeletal muscle

Deletion of murine Smn exon 7, the most frequent mutation found in spinal muscular atrophy, has been directed to either both satellite cells, the muscle progenitor cells and fused myotubes, or fused myotubes only. When satellite cells were mutated, mutant mice develop severe myopathic process, progressive motor paralysis, and early death at 1 mo of age (severe mutant). Impaired muscle regeneration of severe mutants correlated with defect of myogenic precursor cells both in vitro and in vivo. In contrast, when satellite cells remained intact, mutant mice develop similar myopathic process but exhibit mild phenotype with median survival of 8 mo and motor performance similar to that of controls (mild mutant). High proportion of regenerating myofibers expressing SMN was observed in mild mutants compensating for progressive loss of mature myofibers within the first 6 mo of age. Then, in spite of normal contractile properties of myofibers, mild mutants develop reduction of muscle force and mass. Progressive decline of muscle regeneration process was no more able to counterbalance muscle degeneration leading to dramatic loss of myofibers. These data indicate that intact satellite cells remarkably improve the survival and motor performance of mutant mice suffering from chronic myopathy, and suggest a limited potential of satellite cells to regenerate skeletal muscle.