1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: further insights into a class of triple re-uptake inhibitors

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.     

Social Environment and Agonistic Interactions: Strategies in a Small Social Mammal

In group‐living species, the development of agonistic interactions among conspecifics may be affected by socio‐ecological factors, such as size and composition of social group, and availability of nests and food. We analysed the importance of size and composition of social groups on agonistic interactions among males in the Southern mountain cavy (Microcavia australis). We made behavioural observations in four social groups of different size and composition. We recorded two types of agonistic interactions: agonistic displays and direct agonistic behaviours; both types increased in the breeding season. A social group composed of a high number of males was associated with high frequency of agonistic displays. Direct agonistic behaviours were also influenced by the interaction of season and number of males per social group and number of females per social group. Agonistic interactions were also recorded among males of different socials groups in the breeding season. Agonistic displays were most frequent among males of the same social group, whereas direct agonistic behaviours were most common among males of different social groups. These results suggest that social factors affect agonistic interactions among males of Southern mountain cavy and that in a conflict situation, males develop different strategies, such as increased frequency of agonistic behaviours in breeding season and intragroup cooperation for defence of oestrous females.     

The FANC pathway is activated by adenovirus infection and promotes viral replication-dependent recombination

Deciphering the crosstalk between a host cell and a virus during infection is important not only to better define viral biology but also to improve our understanding of cellular processes. We identified the FANC pathway as a helper of viral replication and recombination by searching for cellular targets that are modified by adenovirus (Ad) infection and are involved in its outcome. This pathway, which is involved in the DNA damage response and checkpoint control, is altered in Fanconi anaemia, a rare cancer predisposition syndrome. We show here that Ad5 infection activates the FANC pathway independent of the classical DNA damage response. Infection with a non-replicating Ad shows that the presence of viral DNA is not sufficient to induce the monoubiquitination of FANCD2 but still activates the DNA damage response coordinated by phospho-NBS1 and phospho-CHK1. E1A expression alone fails to induce FANCD2 monoubiquitination, indicating that a productive viral infection and/or replication is required for FANC pathway activation. Our data indicate that Ad5 infection induces FANCD2 activation to promote its own replication. Specifically, we show that FANCD2 is involved in the recombination process that accompanies viral DNA replication. This study provides evidence of a DNA damage-independent function of the FANC pathway and identifies a cellular system involved in Ad5 recombination.     

Life Span and Locomotor Activity Modification by Glucose and Polyphenols in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> Chronically Exposed to Oxidative Stress-stimuli: Implications in Parkinson’s Disease

Previous studies have shown that polyphenols might be potent neuroprotective agents in Drosophila melanogaster, a valid model for PD, acutely treated with oxidative stress-stimulants. This study report for the first time that polyphenols exposure prolong life span (P < 0.05 by log-rang test) and restore locomotor activity (i.e., climbing capability, P < 0.05 by χ² test) of Drosophila melanogaster chronically exposed to paraquat compared to flies treated with paraquat alone in 1% glucose. We found that (10%) glucose partially prolongs life span and climbing in Drosophila exposed to iron, PQ or in combination, suggesting that both stimuli enhance a movement disorder in a concentration-dependent and temporal-related fashion. Moreover, chronic exposure of (1 mM) PQ/(0.5 mM) iron synergistically affect both survival and locomotor function independently of the temporal order of the exposure to the toxicants, but the survival is modulated in a concentration and temporal fashion by glucose. This investigation is the first to report that Ddc-GAL4 transgenic flies chronically fed with polyphenols increase life span (P < 0.05 by log-rang test) and enhance movement abilities (P < 0.05 by χ² test) compared to untreated Ddc-GAL4 or treated with paraquat in 1% glucose. Our present findings support the notion that Drosophila melanogaster might be a suitable model to study genetic, environmental and nutritional factors as causal and/or modulators in the development of PD. Most importantly, according to our model, we have demonstrated for the first time chronic polyphenols exposure as potential therapeutic compounds in the treatment of PD. These findings altogether open new avenues for the screening, testing and development of novel antioxidant drugs against oxidative stress stimuli.     

The water effect on the kinetic of the bovine liver catalase

Catalase is an enzyme that occurs in almost all aerobic organisms. Its main metabolic function is to prevent oxidative damage to tissues induced by hydrogen peroxide which is a strong oxidizing agent. Catalase is very effective in performing this task, since it has the highest turnover rate among all the enzymes. The properties of catalase have been investigated extensively for many years; however, the role of the solvent molecules in the catalytic reaction of this enzyme has not yet been investigated. Therefore, the objective of this work was to investigate the contribution of the solvent molecules on the catalytic reaction of bovine liver catalase with its substrate H2O2 by the osmotic stress method. As a probe for protein structural changes in solution, the differential number of water molecules released during the transition from free to bound form of the enzyme was measured. These assays were correlated with protein structural data provided by the SAXS technique and crystallographic structures of free and CN(-) bonded enzymes. The results showed that the difference in surface accessible area of the crystal structures does not reflect the variation that is observed in solution. Moreover, catalase is not influenced by the solvent during the catalytic reaction, which represents a lower energy barrier to be crossed in the overall energetics of the reaction, a fact that contributes to the high turnover rate of catalase.     

Calpain inhibitors prevent p38 MAPK activation and germ cell apoptosis after heat stress in pubertal rat testes

Testicular injuries like torsion or cryptorchidism can cause massive germ cell death, which could have great impact on male reproductive health. In addition, it has been proposed that modern life style, in the form of underwear or sedentary work position, could increase the testicular temperature, induce germ cell apoptosis, reduce spermatozoa quality and promote male infertility. In this work we showed that a heat stress stimulus induced massive germ cells apoptosis, which was associated with p38 mitogen-activated protein kinase (MAPK) phosphorylation along with an increase in the levels of mRNA encoding calpain 2. Synthetic calpain inhibitors prevented heat stress-induced germ cell apoptosis through inhibition of p38 MAPK phosphorylation. Thus, our results indicate that the blockage of calpains suppresses p38 MAPK phosphorylation, and identifies calpain activation (most likely calpain 2) as an early event in heat stress-induced male germ cell apoptosis. J. Cell. Physiol. 221: 296–305, 2009. © 2009 Wiley-Liss, Inc.     

Energetics of locomotion and load carriage in the nectar feeding ant, Camponotus rufipes

Abstract.  To investigate if there is an energetic constraint influencing a nectar feeding ant's decision to come back to the nest with partial loads, the energetic costs of running and carrying a load in the ant Camponotus rufipes are measured. Metabolic rates of individuals are measured in a running tube respirometer while they are unladen and laden at 25 °C. Workers voluntarily collect a load of 6 µL of a 30% sucrose solution (mass = 6.8 mg), which results in an internal load of about 50% of the ant mass and is close to a full load for ants within this size range. The gross cost of unladen running is 264 J kg⁻¹ m⁻¹, while that of laden running is 225 J kg⁻¹ m⁻¹. The mass used to calculate the cost of laden running includes body mass of ant and load carried. Load carriage cost in C. rufipes foragers is calculated to be about 60% as much as body carriage per unit mass. Internal load carriage in C. rufipes is energetically cheaper compared with external carriage in other ant species. Such low carriage costs make it unlikely that the collection of partial crop loads in C. rufipes foragers is based on a minimization of foraging costs, as suggested for honeybees.     

Post-Conflict Anxiety in Japanese Macaques (Macaca fuscata): Aggressor's and Victim's Perspectives

The aim of this study was to investigate the short‐term consequences of aggression in socially living Japanese macaques (Macaca fuscata) focusing on the emotional response of both aggressors and victims of aggression. Both individuals involved showed an increase in the rate of scratching (a behavioural indicator of anxiety) in the minutes following the aggressive confrontation. Such increase was larger in victims than in aggressors. Multivariate analyses of the factors modulating post‐conflict scratching showed that for both the aggressor and the victim the main predictor of post‐conflict scratching was its opponent’s post‐conflict scratching. These results suggest both opponents shared the same perception of the consequences of aggression, and responded with similar emotional arousal.     

The Receptor for Advanced Glycation End-Products (RAGE) Is Only Present in Mammals,and Belongs to a Family of Cell Adhesion Molecules (CAMs)

The human receptor for advanced glycation endproducts (RAGE) is a multiligand cell surface protein belonging to the immunoglobulin superfamily, and is involved in inflammatory and immune responses. Most importantly, RAGE is considered a receptor for HMGB1 and several S100 proteins, which are Damage-Associated Molecular Pattern molecules (DAMPs) released during tissue damage. In this study we show that the Ager gene coding for RAGE first appeared in mammals, and is closely related to other genes coding for cell adhesion molecules (CAMs) such as ALCAM, BCAM and MCAM that appeared earlier during metazoan evolution. RAGE is expressed at very low levels in most cells, but when expressed at high levels, it mediates cell adhesion to extracellular matrix components and to other cells through homophilic interactions. Our results suggest that RAGE evolved from a family of CAMs, and might still act as an adhesion molecule, in particular in the lung where it is highly expressed or under pathological conditions characterized by an increase of its protein levels.