Neural coding underlying the cue preference for celestial orientation

Diurnal and nocturnal African dung beetles use celestial cues, such as the sun, the moon, and the polarization pattern, to roll dung balls along straight paths across the savanna. Although nocturnal beetles move in the same manner through the same environment as their diurnal relatives, they do so when light conditions are at least 1 million-fold dimmer. Here, we show, for the first time to our knowledge, that the celestial cue preference differs between nocturnal and diurnal beetles in a manner that reflects their contrasting visual ecologies. We also demonstrate how these cue preferences are reflected in the activity of compass neurons in the brain. At night, polarized skylight is the dominant orientation cue for nocturnal beetles. However, if we coerce them to roll during the day, they instead use a celestial body (the sun) as their primary orientation cue. Diurnal beetles, however, persist in using a celestial body for their compass, day or night. Compass neurons in the central complex of diurnal beetles are tuned only to the sun, whereas the same neurons in the nocturnal species switch exclusively to polarized light at lunar light intensities. Thus, these neurons encode the preferences for particular celestial cues and alter their weighting according to ambient light conditions. This flexible encoding of celestial cue preferences relative to the prevailing visual scenery provides a simple, yet effective, mechanism for enabling visual orientation at any light intensity.The blue sky is a rich source of visual cues that are used by many animals during orientation or navigation (1, 2). Besides the sun, celestial phenomena, such as the skylight intensity gradient or the more complex polarization pattern, can serve as references for spatial orientation (3–5). Polarized skylight is generated by scattered sunlight in the atmosphere, and to a terrestrial observer, the resulting alignment of the electric field vectors extends across the entire sky, forming concentric circles around the position of the sun (Fig. 1A). A similar distribution of brightness and polarization pattern is also created around the moon (6). Although this nocturnal pattern is 1 million-fold dimmer than the daylight pattern (6), some animals, such as South African ball-rolling dung beetles, can use this lunar polarization pattern for orientation (7). To avoid competition for food at the dung pile, these beetles detach a piece of dung, shape it into a ball, and roll it away along a straight-line path. For this type of straight-line orientation, nocturnal beetles seem to rely exclusively on celestial cues (8), such as the moon or polarized light.Open in a separate windowFig. 1.Celestial cue preference in dung beetles under a natural sky. (A) Schematic illustration of the polarization pattern around a celestial body (sun or moon). Change of direction in diurnal (D, Left) and nocturnal (N, Right) beetles rolling under a sun-lit (B) or moon-lit (C) sky. The change of direction was calculated as the angular difference between two consecutive rolls, either without manipulation (control, ●) or when the sun or moon was reflected to the opposite sky hemisphere between the two rolls (test, ○). The mean directions (μ) are indicated by black (control) or red (test) lines, and error bars indicate circular SDs. (B) Without manipulation, both species kept the direction [P < 0.001 by V test; μ_diurnal (±SD) = 2.6° ± 17.98°, n = 20; μ_nocturnal = −8.7° ± 38.34°, n = 20). When the sun was reflected to the opposite sky hemisphere (and the real sun was shaded), both species responded to this change (P < 0.001 by V-test; μ_diurnal = 178.9° ± 54.6°, n = 20; μ_nocturnal = 163.8° ± 46.58°, n = 20). (C) Under the moon in the control experiments, both species showed a constant rolling direction (P < 0.001 by V test; μ_diurnal = 3.1° ± 35.39°, n = 20; μ_nocturnal = −3.3° ± 37.87°, n = 20). When the moon was reflected to the opposite sky hemisphere, the diurnal species followed the position change of the moon (P = 0.002 by V test; μ = 179.5° ± 72.37°, n = 20), whereas the nocturnal species continued rolling in the original rolling direction (P < 0.001 by V test; μ = −13.4° ± 74.27°, n = 20).As with all nocturnal animals, night-active beetles have to overcome a major challenge: They need to maintain high orientation precision even under extremely dim light conditions. Indeed, recent experiments have shown that nocturnal dung beetles orient at night with the same precision as their diurnal relatives during the day (9), an ability partly due to the fact that their eyes are considerably more sensitive than the eyes of species that are active at brighter light levels (10–12). Nonetheless, for each species, orientation precision relies on being tuned to the most reliable celestial compass cue that is available during the animal’s normal activity window. How salient are these cues for nocturnal and diurnal species? Do diurnal species have a different celestial cue preference than nocturnal species? If so, how are these preferences represented neurally in the brain?In this study, we present a detailed picture of how the orientation systems of two closely related nocturnal and diurnal animals have been adapted to the ambient light conditions, combining behavioral experiments from the field with electrophysiological investigations of the underlying neural networks. Using behavioral experiments, we show that nocturnal dung beetles switch from a compass that uses a discrete celestial body (the sun) during the day to a celestial polarization compass for dim light orientation at night, whereas diurnal beetles use a celestial body (the sun or moon) for orientation at all light levels. In a second step, we simulated these skylight cues (the sun or moon and the polarization pattern) while electrophysiologically recording responses from neurons in the dung beetle’s central complex, a brain area that has been suggested to house the internal compass for celestial orientation (13, 14). These neural data precisely matched the cue preferences observed in behavioral field trials and show how an animal’s visual ecology influences the neural activity of its sky compass neurons. Our results also reveal, for the first time to our knowledge, how a weighting of celestial orientation cues could be neurally encoded in an animal brain.     

Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTEN-deficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.     

Bone morphogenetic protein-induced inflammatory cyst formation after lumbar fusion causing nerve root compression

Bone morphogenetic protein (BMP) has been reported to cause early inflammatory changes, ectopic bony formation, adjacent level fusion, radiculitis, and osteolysis. The authors describe the case of a patient who developed inflammatory fibroblastic cyst formation around the BMP sponge after a lumbar fusion, resulting in compressive lumbar radiculopathy. A 70-year-old woman presented with left L-4 and L-5 radiculopathy caused by a Grade I spondylolisthesis with a left herniated disc at L4-5. She underwent a minimally invasive transforaminal lumbar interbody fusion with BMP packed into the interbody cage at L4-5. Her neurological symptoms resolved immediately postoperatively. Six weeks later, the patient developed recurrence of radiculopathy. Radiological imaging demonstrated an intraspinal cyst with a fluid-fluid level causing compression of the left L-4 and L-5 nerve roots. Reexpoloration of the fusion was performed, and a cyst arising from the posterior aspect of the cage was found to compress the axilla of the left L-4 nerve root and the shoulder of the L-5 nerve root. The cyst was decompressed, and the wall was partially excised. A collagen BMP sponge was found within the cyst and was removed. Postoperatively, the patient's radiculopathy resolved and she went on to achieve interbody fusion. Bone morphogenetic protein can be associated with inflammatory cyst formation resulting in neural compression. Spine surgeons should be aware of this complication in addition to the other reported BMP-related complications.     

Increasing dietetic referrals: Perceptions of general practitioners,practice nurses and dietitians

Aim: To examine Australian private practice dietitians' relationships with general practitioners and practice nurses as a factor that influences dietetic referrals. Methods: Semistructured telephone interviews and an online survey were conducted with Australian private practice dietitians (n = 52 and n = 90, respectively) between April and May 2008. Semistructured questionnaires were conducted with general practitioners (n = 11) and practice nurses (n = 12) from the ‘GP Access’ Division of General Practice between March and July 2007. Results: General practitioners' relationships with dietitians were believed to be the primary influencing factor on referral, provided by 81% of survey dietitians and 25% of interview dietitians. The most common means of initially forming relationships with general practitioners were face‐to‐face introduction (48%) and introductory letters (37%). Patient feedback via letter, fax or email was the most popular method of maintaining relationships with general practitioners (77%). Meeting with general practitioners in person was believed to be the most effective activity in building relationships with general practitioners and increasing referral rates (42%). Referral was made easier for general practitioners by providing paper (37%) or electronic (19%) referral forms and contact details (19%). The majority of general practitioners and dietitians believed that the ‘Allied Health Services Under Medicare’ made it easier to refer to a dietitian. Conclusions: Dietetic referrals can be encouraged through good relationships between general practitioners, practice nurses and dietitians. Private practice dietitians would benefit from cultivating relationships with general practitioners and practice nurses through personal contact and providing good patient feedback.     

Follow-up of experimental chronic Chagas' disease in dogs: use of polymerase chain reaction (PCR) compared with parasitological and serological methods.

In this study, the polymerase chain reaction (PCR) was compared with parasitological and serological methods to detect the infection in dogs, 5-12 years after experimental infection with Trypanosoma cruzi. The ability of parasitological methods to identify a positive animal was 22 and 11% by hemoculture and xenodiagnosis/xenoculture, respectively. On the other hand, the serological tests, including conventional serology and anti-live trypomastigote antibodies (ALTA) were positive in all infected dogs. Despite its low sensitivity, if considering only one reaction, the PCR analysis showed 100% of positivity, demonstrating the presence of parasite kDNA in all infected dogs. To identify a positive dog required at least two blood samples and up to nine repeated reactions using the same sample. Serial blood sample collection, ranging from 1 to 9, revealed that the percentage of dogs with positive PCR ranged from 67 to 100%. These findings suggested that, although the PCR is useful to detect the parasite in infected hosts, it should not be used isolated for the diagnosis of Chagas' disease and warn for the necessity of serial blood collection and re-tests. Moreover, these data validate once more the dog as a model for Chagas' disease since they demonstrate the permanence of infection by PCR, parasitological and serological methods, reaching relevant requisites for an ideal model to study this disease.     

Differential upregulation in DRG neurons of an α2δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury

The α₂δ-1 protein is an auxiliary subunit of voltage-gated calcium channels, critical for neurotransmitter release. It is upregulated in dorsal root ganglion (DRG) neurons following sensory nerve injury, and is also the therapeutic target of the gabapentinoid drugs, which are efficacious in both experimental and human neuropathic pain conditions. α₂δ-1 has 3 spliced regions: A, B, and C. A and C are cassette exons, whereas B is introduced via an alternative 3′ splice acceptor site. Here we have examined the presence of α₂δ-1 splice variants in DRG neurons, and have found that although the main α₂δ-1 splice variant in DRG is the same as that in brain (α₂δ-1 ΔA+B+C), there is also another α₂δ-1 splice variant (ΔA+BΔC), which is expressed in DRG neurons and is differentially upregulated compared to the main DRG splice variant α₂δ-1 ΔA+B+C following spinal nerve ligation. Furthermore, this differential upregulation occurs preferentially in a small nonmyelinated DRG neuron fraction, obtained by density gradient separation. The α₂δ-1 ΔA+BΔC splice variant supports Ca_V2 calcium currents with unaltered properties compared to α₂δ-1 ΔA+B+C, but shows a significantly reduced affinity for gabapentin. This variant could therefore play a role in determining the efficacy of gabapentin in neuropathic pain.