Navigating a tool end in a specific direction: stick-tool use in kea (Nestor notabilis)

This study depicts how captive kea, New Zealand parrots, which are not known to use tools in the wild, employ a stick-tool to retrieve a food reward after receiving demonstration trials. Four out of six animals succeeded in doing so despite physical (beak curvature) and ecological (no stick-like materials used during nest construction) constraints when handling elongated objects. We further demonstrate that the same animals can thereafter direct the functional end of a stick-tool into a desired direction, aiming at a positive option while avoiding a negative one.     

The heme synthesis defect of mutants impaired in mitochondrial iron-sulfur protein biogenesis is caused by reversible inhibition of ferrochelatase

Mitochondria are responsible for the synthesis of both iron-sulfur clusters and heme, but the potential connection between the two major iron-consuming pathways is unknown. Here, we have shown that mutants in the yeast mitochondrial iron-sulfur cluster (ISC) assembly machinery displayed reduced cytochrome levels and diminished activity of the heme-containing cytochrome c oxidase, in addition to iron-sulfur protein defects. In contrast, mutants in components of the mitochondrial ISC export machinery, which are specifically required for maturation of cytosolic iron-sulfur proteins, were not decreased in heme synthesis or cytochrome levels. Heme synthesis does not involve the function of mitochondrial ISC components, because immunological depletion of various ISC proteins from mitochondrial extracts did not affect the formation and amounts of heme. The heme synthesis defects of ISC mutants were found in vivo in isolated mitochondria and in mitochondrial detergent extracts and were confined to an inhibition of ferrochelatase, the enzyme catalyzing the insertion of iron into protoporphyrin IX. In support of these findings, immunopurification of ferrochelatase from ISC mutants restored its activity to wild-type levels. We conclude that the reversible inhibition of ferrochelatase is the molecular reason for the heme deficiency in ISC assembly mutants. This inhibitory mechanism may be used for regulation of iron distribution between the two iron-consuming processes.     

From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC)

Backgrounds

Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit.

Methods

Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified.

Results

There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828–2.525; p <0.001).

Conclusions

Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies.     

Endocrine and behavioral effects of neuromedin S

The present experiments focused on the effects of neuromedin S on hypothalamic–pituitary–adrenal (HPA) activation and behavior. The peptide (0.25–1 nmol) was administered intracerebroventricularly to rats, the behavior of which was monitored by means of telemetry, open field observations and an elevated plus-maze (EPM) test. Autonomic functions such as the temperature and the heart rate were recorded by telemetry. The action on the HPA axis was assessed via measurements of the plasma corticosterone and ACTH levels. To reveal the transmission of the endocrine responses, animals were pretreated with corticotrophin releasing hormone receptor (CRHR) antagonists (1 nmol). In the open field test, the animals were pretreated with either a CRHR₁ antagonist (antalarmin) or haloperidol (10 μg/kg), while in the EPM test they were pretreated with antalarmin or diazepam (1 mg/kg). The dopamine release from striatal and amygdala slices after peptide treatment was measured with a superfusion apparatus. Neuromedin S exerted dose-dependent effects on the HPA system, which were inhibited by antalarmin. It also activated grooming and decreased the entries to and time spent in the open arms during the EPM test. The grooming response was abolished by haloperidol and antalarmin pretreatment, while diazepam and antalarmin showed a tendency to attenuate the response evoked in the EPM test. In the superfusion studies, neuromedin S enhanced the dopamine release from the amygdala slices. These results demonstrate that neuromedin S stimulates the HPA axis through the CRHR₁ pathway and evokes stereotyped behavior and anxiety through mesolimbic dopamine and corticotrophin releasing hormone release.     

Regional effect of monosodium-L-glutamate on the superficial layers of superior colliculus in rat

Summary Systemic administration of monosodium-1-gluta-mate by single injections of 4 mg/g body weight in infant rats (2–10 days of age) results in acute swelling of cytoplasm and nuclear pyknosis of neurons in the stratum zonale and stratum griseum superficiale of the superior colliculus. Multiple daily doses of 4 mg/g body weight monosodium-1-glutamate result in an almost complete loss of neurons in these two superficial layers. The deeper layers appear not to be affected. No pathological effects were observed in the lateral geniculate body or pretectal complex.Light-and electron-microscopic studies reveal that the optic nerves are remarkably shrunken and many myelinated as well as unmyelinated axons are lost. Injection of ³Hproline into the vitreous body of one eye results in limited transport to the suprachiasmatic nucleus, lateral geniculate body and to lateral portions of the superior colliculus.The small percentage of intact axons in the optic nerve, as well as the limited proline transport from the eye, suggest that administration of monosodium-1-glutamate leaves intact some optic fibers, a portion of which belongs to the retinohypothalamic tract.     

Picture – Object Recognition in Kea (Nestor notabilis)

Although pictures are widely used as stimuli in cognitive experiments with both humans and animals, the question of how subjects interpret pictures receives less attention. Gaining a better understanding of this is especially important when working with avian subjects, as their visual anatomy and processing is different from that of humans, and even differs from one avian species to another. Successful testing for picture recognition in birds has been carried out mainly with pigeons, but no such research has been explicitly performed with ‘brainy’ birds like parrots, despite the fact that these have been the subject of exciting cognitive research. This study tested kea (Nestor notabilis) mountain parrots for picture–object recognition using a procedure which required the transfer of a learned discrimination task between pictures and objects. Kea successfully showed both picture‐to‐object and object‐to‐picture transfer and performed at a comparable level when pictures were displayed on a touch screen or as printed photographs.     

Biochemical background of toxic interaction between tiamulin and monensin

Tiamulin, a diterpene antibiotic, is used for treatment of pulmonary and gastrointestinal infections in swine and poultry. Combined administration of tiamulin and ionophores (e.g. monensin) to farm animals may lead to intoxication manifested in severe clinical symptoms. Tiamulin metabolite complex with cytochrome P450 has been suggested to be the basis of drug-interactions. However, the formation of metabolic intermediate complex is questionable. The effect of tiamulin-treatment on cytochrome P450 activities was investigated in rats. Ethylmorphine and aminopyrine N-demethylation activities as well as monensin metabolism (O-demethylation) increased in liver microsomes of tiamulin-treated (200 mg/kg) animals. CYP3A1 induction caused by tiamulin was confirmed by the results of Western blot analysis. To test metabolic intermediate complex formation as a result of tiamulin treatment, cytochrome P450 activities were also determined in the presence of potassium ferricyanide. The findings together with those of in vitro complex formation suggested that formation of metabolic intermediate complexes of tiamulin with cytochrome P450 could be excluded. On the other hand, the results of inhibition studies showed significant decrease of ethylmorphine or aminopyrine as well as monensin demethylation in the presence of tiamulin. Our results proved that tiamulin has dual effect on cytochromes P450. It is able to induce and directly inhibit CYP3A enzymes, which are predominantly responsible for monensin O-demethylation. The direct effect of tiamulin as an inhibitor might play a more important role in toxicity than its putative effect as a chemical inducer of CYP3A enzymes.