Ear tag induced Staphylococcus infection in mice

Mice used in a 2-year oral toxicity study developed a progressive, moist dermatitis. The initial lesions were seen around the ears in which metal identification tags had been placed and usually progressed to include the skin of the neck and shoulder. Clinically, the mice were pruritic, lost weight, had rough coats, and became moribund. The predominant finding at necropsy was pale brown kidneys with irregular granular surfaces. Histologically, there was inflammation and focal-to-diffuse necrosis in the visceral organs and affected skin. The predominant organism isolated from the skin, kidneys and heart blood was Staphylococcus aureus. This bacterium is a common inhabitant of the skin of conventionally housed mice and its isolation from the kidneys and blood suggested that the portal of entry was the wound caused by the insertion of the metal ear tag.     

Conjugation of folate via gelonin carbohydrate residues retains ribosomal-inactivating properties of the toxin and permits targeting to folate receptor positive cells

Conjugation of folate to proteins permits receptor-mediated endocytosis via the folate receptor (FR) and delivery of the conjugate into the cytoplasm of cells. Since many cancers up-regulate the FR it has enabled the targeting of toxins to tumor cells resulting in specific cell death. However, current conjugation methods rely on chemistries that can affect certain catalytic subunits, such as the A-chain of the plant toxin gelonin. As a result many folate-targeted toxins are a compromise between receptor/ligand interaction and toxin activity. We describe the first example of folate conjugated to a protein via carbohydrate residues, using a novel SH-folate intermediate. The folate-gelonin conjugate retains over 99% of toxin activity in a cell-free translational assay compared with unmodified gelonin and is able to bind the FR at the same affinity as free folic acid (10(-10) m). Additionally, the conjugate exhibits prolonged inhibition of protein synthesis in FR positive cell lines in vitro. Folate linked to gelonin via amino conjugation exhibits the same affinity for FR as free folic acid but the toxin is 225-fold less active in a cell-free translational assay. The effect of different conjugation methods on toxin activity and the implications for folate targeting of other glycoproteins are discussed.     

Impact of Visual Context on Public Perceptions of Non-Human Primate Performers

Prior research has shown that the use of apes, specifically chimpanzees, as performers in the media negatively impacts public attitudes of their conservation status and desirability as a pet, yet it is unclear whether these findings generalize to other non-human primates (specifically non-ape species). We evaluated the impact of viewing an image of a monkey or prosimian in an anthropomorphic or naturalistic setting, either in contact with or in the absence of a human. Viewing the primate in an anthropomorphic setting while in contact with a person significantly increased their desirability as a pet, which also correlated with increased likelihood of believing the animal was not endangered. The majority of viewers felt that the primates in all tested images were “nervous.” When shown in contact with a human, viewers felt they were “sad” and “scared”, while also being less “funny.” Our findings highlight the potential broader implications of the use of non-human primate performers by the entertainment industry.     

Behavioral Responses of Silverback Gorillas (Gorilla gorilla gorilla) to Videos

This study examined the impact of video presentations on the behavior of 4 silverback, western lowland gorillas (Gorilla gorilla gorilla). On each of 5 occasions, gorillas viewed 6 types of videos (blue screen, humans, an all-male or mixed-sex group engaged in low activity, and an all-male or mixed-sex group engaged in agonistic behavior). The study recorded behavioral responses and watching rates. All gorillas preferred dynamic over static videos; 3 watched videos depicting gorillas significantly more than those depicting humans. Among the gorilla videos, the gorillas clearly preferred watching the mixed-sex group engaged in agonistic behavior; yet, this did not lead to an increase in aggression or behavior indicating agitation. Further, habituation to videos depicting gorillas did not occur. This supports the effectiveness of this form of enrichment, particularly for a nonhuman animal needing to be separated temporarily due to illness, shipment quarantine, social restructuring, or exhibit modification.     

Ultrasound-Mediated Stimulation of Microbubbles after Acute Myocardial Infarction and Reperfusion Ameliorates Left-Ventricular Remodelling in Mice via Improvement of Borderzone Vascularization

Aims

Post-infarction remodelling (PIR) determines left-ventricular (LV) function and prognosis after myocardial infarction. The aim of this study was to evaluate transthoracic ultrasound-mediated microbubble stimulation (UMS) as a novel gene- and cell-free therapeutic option after acute myocardial infarction and reperfusion (AMI/R) in mice.

Methods and Results

For myocardial delivery of UMS, a novel therapeutic ultrasound-system (TIPS, Philips Medical) and commercially available microbubbles (BR1, Bracco Suisse SA) were utilized in a closed-chest mouse model. UMS was performed as myocardial post-conditioning (PC) on day four after 30 minutes of coronary occlusion and reperfusion. LV-morphology, as well as global and regional function were measured repeatedly with reconstructive 3-dimensional echocardiography applying an additional low-dose dobutamine protocol after two weeks. Scar size was quantified by means of histomorphometry. A total of 41 mice were investigated; 17 received PC with UMS. Mean ejection fraction (EF) prior UMS was similar in both groups 53%±10 (w/o UMS) and 53%±14 (UMS, p = 0.5), reflecting comparable myocardial mass at risk 17%±8 (w/o UMS), 16%±13 (UMS, p = 0.5). Two weeks after AMI/R, mice undergoing UMS demonstrated significantly better global LV-function (EF = 53%±7) as compared to the group without PC (EF = 39%±11, p<0.01). The fraction of akinetic myocardial mass was significantly lower among mice undergoing UMS after AMI/R [27%±10 (w/o UMS), 13%±8 (UMS), p<0.001)]. Our experiments showed a fast onset of transient, UMS-induced upregulation of vascular-endothelial and insulin-like growth factor (VEGF-a, IGF-1), as well as caveolin-3 (Cav-3). The mice undergoing PC with UMS after AMI/R showed a significantly lower scar size. In addition, the microvascular density was significantly higher in the borderzone of UMS-treated animals.

Conclusion

UMS following AMI/R ameliorates PIR in mice via up-regulation of VEGF-a, IGF-1 and Cav-3, and consecutive improvement of myocardial borderzone vascularization.     

Chloride intracellular channels modulate acute ethanol behaviors in Drosophila, Caenorhabditis elegans and mice

Identifying genes that influence behavioral responses to alcohol is critical for understanding the molecular basis of alcoholism and ultimately developing therapeutic interventions for the disease. Using an integrated approach that combined the power of the Drosophila, Caenorhabditis elegans and mouse model systems with bioinformatics analyses, we established a novel, conserved role for chloride intracellular channels (CLICs) in alcohol-related behavior. CLIC proteins might have several biochemical functions including intracellular chloride channel activity, modulation of transforming growth factor (TGF)-β signaling, and regulation of ryanodine receptors and A-kinase anchoring proteins. We initially identified vertebrate Clic4 as a candidate ethanol-responsive gene via bioinformatic analysis of data from published microarray studies of mouse and human ethanol-related genes. We confirmed that Clic4 expression was increased by ethanol treatment in mouse prefrontal cortex and also uncovered a correlation between basal expression of Clic4 in prefrontal cortex and the locomotor activating and sedating properties of ethanol across the BXD mouse genetic reference panel. Furthermore, we found that disruption of the sole Clic Drosophila orthologue significantly blunted sensitivity to alcohol in flies, that mutations in two C. elegans Clic orthologues, exc-4 and exl-1, altered behavioral responses to acute ethanol in worms and that viral-mediated overexpression of Clic4 in mouse brain decreased the sedating properties of ethanol. Together, our studies demonstrate key roles for Clic genes in behavioral responses to acute alcohol in Drosophila, C. elegans and mice.