Biogenic and synthetic polyamines bind cationic dendrimers

Biogenic polyamines are essential for cell growth and differentiation, while polyamine analogues exert antitumor activity in multiple experimental model systems, including breast and lung cancer. Dendrimers are widely used for drug delivery in vitro and in vivo. We report the bindings of biogenic polyamines, spermine (spm), and spermidine (spmd), and their synthetic analogues, 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) to dendrimers of different compositions, mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4). FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyze polyamine binding mode, the binding constant and the effects of polyamine complexation on dendrimer stability and conformation. Structural analysis showed that polyamines bound dendrimers through both hydrophobic and hydrophilic contacts with overall binding constants of K(spm-mPEG-G3) = 7.6 × 10(4) M(-1), K(spm-mPEG-PAMAM-G4) = 4.6 × 10(4) M(-1), K(spm-PAMAM-G4) = 6.6 × 10(4) M(-1), K(spmd-mPEG-G3) = 1.0 × 10(5) M(-1), K(spmd-mPEG-PAMAM-G4) = 5.5 × 10(4) M(-1), K(spmd-PAMAM-G4) = 9.2 × 10(4) M(-1), K(BE-333-mPEG-G3) = 4.2 × 10(4) M(-1), K(Be-333-mPEG-PAMAM-G4) = 3.2 × 10(4) M(-1), K(BE-333-PAMAM-G4) = 3.6 × 10(4) M(-1), K(BE-3333-mPEG-G3) = 2.2 × 10(4) M(-1), K(Be-3333-mPEG-PAMAM-G4) = 2.4 × 10(4) M(-1), K(BE-3333-PAMAM-G4) = 2.3 × 10(4) M(-1). Biogenic polyamines showed stronger affinity toward dendrimers than those of synthetic polyamines, while weaker interaction was observed as polyamine cationic charges increased. The free binding energies calculated from docking studies were: -3.2 (spermine), -3.5 (spermidine) and -3.03 (BE-3333) kcal/mol, with the following order of binding affinity: spermidine-PAMAM-G-4>spermine-PAMMAM-G4>BE-3333-PAMAM-G4 consistent with spectroscopic data. Our results suggest that dendrimers can act as carrier vehicles for delivering antitumor polyamine analogues to target tissues.     

Atypical mitogen-activated protein kinases: structure, regulation and functions

Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that play a central role in transducing extracellular cues into a variety of intracellular responses ranging from lineage specification to cell division and adaptation. Fourteen MAP kinase genes have been identified in the human genome, which define 7 distinct MAP kinase signaling pathways. MAP kinases can be classified into conventional or atypical enzymes, based on their ability to get phosphorylated and activated by members of the MAP kinase kinase (MAPKK)/MEK family. Conventional MAP kinases comprise ERK1/ERK2, p38s, JNKs, and ERK5, which are all substrates of MAPKKs. Atypical MAP kinases include ERK3/ERK4, NLK and ERK7. Much less is known about the regulation, substrate specificity and physiological functions of atypical MAP kinases.     

Synthesis and antimalarial activities of novel 3,3,6,6-tetraalkyl-1,2,4,5-tetraoxanes

The oxidative system H2O2/fluorinated alcohol (TFE, HFIP) was used for direct acid- and MeReO3-catalyzed synthesis of 1,2,4,5-tetraoxanes from cyclic (C6, C7, and C12) and acyclic ketones. The influence of ring size and alkyl chain length were studied and antimalarial activities of synthetic 3,3,6,6-tetraalkyl-1,2,4,5-tetraoxanes were determined. Variations in their antimalarial activities were significant, although they share similar electrochemical properties of the peroxide bond.     

Plant invasion is associated with higher plant–soil nutrient concentrations in nutrient‐poor environments

Plant invasion is an emerging driver of global change worldwide. We aimed to disentangle its impacts on plant–soil nutrient concentrations. We conducted a meta‐analysis of 215 peer‐reviewed articles and 1233 observations. Invasive plant species had globally higher N and P concentrations in photosynthetic tissues but not in foliar litter, in comparison with their native competitors. Invasive plants were also associated with higher soil C and N stocks and N, P, and K availabilities. The differences in N and P concentrations in photosynthetic tissues and in soil total C and N, soil N, P, and K availabilities between invasive and native species decreased when the environment was richer in nutrient resources. The results thus suggested higher nutrient resorption efficiencies in invasive than in native species in nutrient‐poor environments. There were differences in soil total N concentrations but not in total P concentrations, indicating that the differences associated to invasive plants were related with biological processes, not with geochemical processes. The results suggest that invasiveness is not only a driver of changes in ecosystem species composition but that it is also associated with significant changes in plant–soil elemental composition and stoichiometry.     

Design, synthesis and biological activity of novel dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine as potent, selective, and orally-bioavailable 5-HT(1D) agonists

A novel series of highly potent human 5-HT_1D agonists, dimethyl-{2-[6-substituted-indol-1-yl]-ethyl}-amine, was synthesized. Structure–activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (K_i=2.4 nM) agonist at the human 5-HT_1D receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (F_po=51%).     

Rôle of eyes,optic lobes,and pars intercerebralis in locomotory and stridulatory circadian rhythms of Teleogryllus commodus

Locomotory and stridulatory activity rhythms of male crickets (Teleogryllus commodus) were assayed simultaneously following various experimental procedures. These included (a) severing the pathways between the ocelli and the brain, between the ommatidia and the optic lobes, or between the optic lobes and the brain, and (b) RF cauterization of the pars intercerebralis. The results indicate that (1) light-dark cycles which entrain both rhythms are perceived by the compound eyes and not by the ocelli; (2) loss of connexion between the brain and the optic lobes leads to arrhythmicity in both behaviours, but a single optic lobe can maintain rhythmicity; (3) absence of neurosecretory cells in the pars intercerebralis is correlated with loss of stridulatory activity and arrhythmicity in locomotory behaviour. It is suggested that the pars intercerebralis serves as a site of coupling between a circadian pacemaker and various overt behaviours. However, intermediate control by the pars intercerebralis is assumed to be exerted via channels that can be either hormonal or purely neuronal in nature.     

Acoustical and sexual behaviour in the grasshopper Chimarocephala pacifica pacifica (Oedipodinae)

The oedipodine grasshopper Chimarocephala pacifica pacifica employs a variety of acoustic and visual signals for communication between the sexes and between members of the same sex. These signals, which are expressed in the form of stridulations and vibrations by the male or as the waving-gesture by both sexes, characterize either the premating and mating state or the state of disturbance and defence, depending on the circumstances that elicit these expressions. The occurrence and timing of copulation are dictated by the cyclic sexual receptivity and non-receptivity behaviour phases of the female. Oscillograms and spectrograms of vibration and stridulation by the male are presented. The behaviour terminology employed in grasshopper studies is critically reviewed.

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Zusammenfassung Die Heuschrecke Chimarocephala pacifica pacifica (Oedipodinae) verwendet eine Anzahl verschiedener akustischer und visueller Signale zur Verständigung zwischen Männchen und Weibchen und zwischen gleichgeschlechtigen Artgenossen. Diese Signale, die vom Männchen in Form von Gesängen und Vibrationen erzeugt werden, und von beiden Geschlechtern als Winkgebärden, charakterisieren den Zustand entweder vor oder während der Geschlechtsreife, oder sie sind typisch für die Abwehrphase. Das zeitliche Auftreten der Paarung wird bestimmt von der zyklischen sexuellen Bereitschaft bzw. der Abwehr des Weibchens. Spektrogramme und Oszillogramme von der Vibration und Stridulation des Männchens werden gezeigt. Die bei Heuschreckenstudien verwendete Verhaltensterminologie wird kritisch überprüft.