Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non-cytotoxic inhibitors of Trypanosoma brucei growth in vitro

The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC₅₀ 5?nM), is not cytotoxic (HeLa CC₅₀?>?25,000?nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC₅₀ 8120?nM, P. falciparum EC₅₀ 3624?nM).     

Sex hormone levels in the brain of d-aspartate-treated rats

d-Aspartate (d-Asp) is an endogenous amino acid present in the central nervous system and endocrine glands of various animal taxa. d-Asp is implicated in neurotransmission, physiology of learning, and memory processes. In gonads, it plays a crucial role in sex hormone synthesis. We have investigated the effects of chronic (30 days d-Asp drinking solution) and acute (i.p. injection of 2 μmol/g bw d-Asp) treatments on sex steroid synthesis in rat brain. Furthermore, to verify the direct effect of d-Asp on neurosteroidogenic enzyme activities, brain homogenates were incubated with different substrates (cholesterol, progesterone, or testosterone) with or without the addition of d-Asp. Enzyme activities were measured by evaluating the in vitro conversion rate of (i) cholesterol to progesterone, testosterone, and 17β-estradiol, (ii) progesterone to testosterone and 17β-estradiol, (iii) testosterone to 17β-estradiol. We found that d-Asp oral administration produced an increase of approximately 40% in progesterone, 110% in testosterone, and 35% in 17β-estradiol. Similarly, the results of the acute experiment showed that at 30 min after d-Asp treatment, the progesterone, testosterone, and 17β-estradiol levels increased by 29–35%, and at 8 h they further increased by a 100% increment. In vitro experiments demonstrate that the addition of d-Asp to brain homogenate + substrate induces a significant increase in progesterone, testosterone and 17β-estradiol suggesting that the amino acid upregulates the local activity of steroidogenic enzymes.     

Impact of Triplet Excited States on the Open‐Circuit Voltage of Organic Solar Cells

The best organic solar cells (OSCs) achieve comparable peak external quantum efficiencies and fill factors as conventional photovoltaic devices. However, their voltage losses are much higher, in particular those due to nonradiative recombination. To investigate the possible role of triplet states on the donor or acceptor materials in this process, model systems comprising Zn‐ and Cu‐phthalocyanine (Pc), as well as fluorinated versions of these donors, combined with C₆₀ as acceptor are studied. Fluorination allows tuning the energy level alignment between the lowest energy triplet state (T₁) and the charge‐transfer (CT) state, while the replacement of Zn by Cu as the central metal in the Pcs leads to a largely enhanced spin–orbit coupling. Only in the latter case, a substantial influence of the triplet state on the nonradiative voltage losses is observed. In contrast, it is found that for a large series of typical OSC materials, the relative energy level alignment between T₁ and the CT state does not substantially affect nonradiative voltage losses.     

Genomic islands of divergence in the Yellow Tang and the Brushtail Tang Surgeonfishes

The current ease of obtaining thousands of molecular markers challenges the notion that full phylogenetic concordance, as proposed by phylogenetic species concepts, is a requirement for defining species delimitations. Indeed, the presence of genomic islands of divergence, which may be the cause, or in some cases the consequence, of speciation, precludes concordance. Here, we explore this issue using thousands of RAD markers on two sister species of surgeonfishes (Teleostei: Acanthuridae), Zebrasoma flavescens and Z. scopas, and several populations within each species. Species are readily distinguished based on their colors (solid yellow and solid brown, respectively), yet populations and species are neither distinguishable using mitochondrial markers (cytochrome c oxidase 1), nor using 5193 SNPs (pairwise Φst = 0.034). In contrast, when using outlier loci, some of them presumably under selection, species delimitations, and strong population structure follow recognized taxonomic positions (pairwise Φst = 0.326). Species and population delimitation differences based on neutral and selected markers are likely due to local adaptation, thus being consistent with the idea that these genomic islands of divergence arose as a consequence of isolation. These findings, which are not unique, raise the question of a potentially important pathway of divergence based on local adaptation that is only evident when looking at thousands of loci.     

P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics

1. Download high-res image (223KB)
2. Download full-size image

     

Improvement of combined FISH and immunofluorescence to trace the fate of somatic stem cells after transplantation.

Fluorescence in situ hybridization (FISH) combined with immunohistochemistry of tissue-specific markers provides a reliable method for characterizing the fate of somatic stem cells in transplantation experiments. Furthermore, the association between FISH and fluorescent gene reporter detection can unravel cell fusion phenomena, which could account for apparent transdifferentiation events. However, despite the widespread use of these techniques, they still require labor-extensive protocol adjustments to achieve correct and satisfactory simultaneous signal detection. In the present paper, we describe an improvement of simultaneous FISH and immunofluorescence detection. We applied this protocol to the identification of transplanted human and mouse hematopoietic stem cells in murine brain and muscle. This technique provides unique opportunities for following the path taken by transplanted cells and their differentiation into mature cell types.     

Genomic signatures of rapid adaptive evolution in the bluespotted cornetfish,a Mediterranean Lessepsian invader

Biological invasions are increasingly creating ecological and economical problems both on land and in aquatic environments. For over a century, the Mediterranean Sea has steadily been invaded by Indian Ocean/Red Sea species (called Lessepsian invaders) via the Suez Canal, with a current estimate of ~450 species. The bluespotted cornetfish, Fistularia commersonii, considered a ‘Lessepsian sprinter’, entered the Mediterranean in 2000 and by 2007 had spread through the entire basin from Israel to Spain. The situation is unique and interesting both because of its unprecedented rapidity and by the fact that it took this species c. 130 years to immigrate into the Mediterranean. Using genome scans, with restriction site‐associated DNA (RAD) sequencing, we evaluated neutral and selected genomic regions for Mediterranean vs. Red Sea cornetfish individuals. We found that few fixed neutral changes were detectable among populations. However, almost half of the genes associated with the 47 outlier loci (potentially under selection) were related to disease resistance and osmoregulation. Due to the short time elapsed from the beginning of the invasion to our sampling, we interpret these changes as signatures of rapid adaptation that may be explained by several mechanisms including preadaptation and strong local selection. Such genomic regions are therefore good candidates to further study their role in invasion success.     

Climate‐driven vital rates do not always mean climate‐driven population

Current climatic changes have increased the need to forecast population responses to climate variability. A common approach to address this question is through models that project current population state using the functional relationship between demographic rates and climatic variables. We argue that this approach can lead to erroneous conclusions when interpopulation dispersal is not considered. We found that immigration can release the population from climate‐driven trajectories even when local vital rates are climate dependent. We illustrated this using individual‐based data on a trans‐equatorial migratory seabird, the Scopoli's shearwater Calonectris diomedea, in which the variation of vital rates has been associated with large‐scale climatic indices. We compared the population annual growth rate λ_i, estimated using local climate‐driven parameters with ρ_i, a population growth rate directly estimated from individual information and that accounts for immigration. While λ_i varied as a function of climatic variables, reflecting the climate‐dependent parameters, ρ_i did not, indicating that dispersal decouples the relationship between population growth and climate variables from that between climatic variables and vital rates. Our results suggest caution when assessing demographic effects of climatic variability especially in open populations for very mobile organisms such as fish, marine mammals, bats, or birds. When a population model cannot be validated or it is not detailed enough, ignoring immigration might lead to misleading climate‐driven projections.     

Heme methyl 1H chemical shifts as structural parameters in some low-spin ferriheme proteins

 The different paramagnetic shifts of the four methyl groups in ferriheme proteins have been described as being due to the effect of the axial ligand nodal plane orientation. An equation, heuristically found and theoretically explained, describing the relation between contact and pseudocontact shifts and the position of the axial ligand(s) has been derived for bis-histidine ferriheme proteins and for cyanide-histidine ferriheme proteins. The values of the heuristic parameters contained in the equations were found by fitting the shifts of bovine cytochrome b ₅ and several bis-histidine cytochromes c ₃ and histidine-cyanide systems. The agreement between the observed and the calculated shifts was found to be good. Therefore, by taking advantage of this study, information on the position of the axial ligands, that can be used as a constraint for structure determination, can be obtained from the shifts of the methyl protons. Received: 13 April 1999 / Accepted: 4 June 1999