Dopamine modulates the optomotor response to unreliable visual stimuli in Drosophila melanogaster

State‐dependent modulation of sensory systems has been studied in many organisms and is possibly mediated through neuromodulators such as monoamine neurotransmitters. Among these, dopamine is involved in many aspects of animal behaviour, including movement control, attention, motivation and cognition. However, the precise neural mechanism underlying dopaminergic modulation of behaviour induced by sensory stimuli remains poorly understood. Here, we used Drosophila melanogaster to show that dopamine can modulate the optomotor response to moving visual stimuli including noise. The optomotor response is the head‐turning response to moving objects, which is observed in most sight‐reliant animals including mammals and insects. First, the effects of the dopamine system on the optomotor response were investigated in mutant flies deficient in dopamine receptors D1R1 or D1R2, which are involved in the modulation of sleep‐arousal in flies. We examined the optomotor response in D1R1 knockout (D1R1 KO) and D1R2 knockout (D1R2 KO) flies and found that it was not affected in D1R1 KO flies; however, it was significantly reduced in D1R2 KO flies compared with the wild type. Using cell‐type‐specific expression of an RNA interference construct of D1R2, we identified the fan‐shaped body, a part of the central complex, responsible for dopamine‐mediated modulation of the optomotor response. In particular, pontine cells in the fan‐shaped body seemed important in the modulation of the optomotor response, and their neural activity was required for the optomotor response. These results suggest a novel role of the central complex in the modulation of a behaviour based on the processing of sensory stimulations.     

Significant association between high serum CCL5 levels and better disease‐free survival of patients with early breast cancer

Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C‐C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead‐based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease‐free survival (DFS) of patients with high CCL5 levels (cut‐off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10‐0.39; P < .0001). An improved overall survival was observed in patients with high CCL5 levels compared to those with low CCL5 levels (P = .024). On the contrary, high immunohistochemical expression of CCL5 in cancer cells was significantly associated with decreased DFS. As serum CCL5 levels did not correlate with CCL5 expression in cancer cells and the relative expression of mRNA CCL5 was elevated in stromal cells in relation to cancer cells, serum CCL5 might be derived not from cancer cells, but from stromal cells. Expression of CCL5 in serum, but not in cancer cells, might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms. Determination of circulating CCL5 levels could be useful for predicting patient prognosis.     

Observation of a Flat and Extended Surface State in a Topological Semimetal

A flat band structure in momentum space is considered key for the realization of novel phenomena. A topological flat band, also known as a drumhead state, is an ideal platform to drive new exotic topological quantum phases. Using angle-resolved photoemission spectroscopy experiments, we reveal the emergence of a highly localized surface state in a topological semimetal BaAl4 and provide its full energy and momentum space topology. We find that the observed surface state is localized in momentum, inside a square-shaped bulk Dirac nodal loop, and in energy, leading to a flat band and a peak in the density of state. These results imply this class of materials as an experimental realization of drumhead surface states and provide an important reference for future studies of the fundamental physics of correlated quantum effects in topological materials.     

Blood flow distribution during heat stress: cerebral and systemic blood flow

The purpose of the present study was to assess the effect of heat stress-induced changes in systemic circulation on intra- and extracranial blood flows and its distribution. Twelve healthy subjects with a mean age of 22±2 (s.d.) years dressed in a tube-lined suit and rested in a supine position. Cardiac output (Q), internal carotid artery (ICA), external carotid artery (ECA), and vertebral artery (VA) blood flows were measured by ultrasonography before and during whole body heating. Esophageal temperature increased from 37.0±0.2°C to 38.4±0.2°C during whole body heating. Despite an increase in Q (59±31%, P<0.001), ICA and VA decreased to 83±15% (P=0.001) and 87±8% (P=0.002), respectively, whereas ECA blood flow gradually increased from 188±72 to 422±189 mL/minute (+135%, P<0.001). These findings indicate that heat stress modified the effect of Q on blood flows at each artery; the increased Q due to heat stress was redistributed to extracranial vascular beds.     

Cilostazol reduces ischemic brain damage partly by inducing metallothionein-1 and -2

The neuroprotective effect of cilostazol, an antiplatelet drug, was examined after 24 h permanent middle cerebral artery (MCA) occlusion in mice, and explored the possible underlying mechanism by examining metallothionein (MT)-1 and -2 induction in vivo. Cilostazol (30 mg/kg) was intraperitoneally administered at 12 h before, 1 h before, and just after MCA occlusion. Mice were euthanized at 24 h after the occlusion, and the neuronal damage was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cilostazol significantly reduced the infarct area and volume, especially in the cortex. Real-time RT-PCR revealed increased mRNA expressions for MT-1 and -2 in the cortex of normal brains at 6 h after cilostazol treatment without MCA occlusion. MT-1 and -2 immunoreactivity was also increased in the cortex of such mice, and this immunoreactivity was observed in the ischemic hemisphere at 24 h after MCA occlusion (without cilostazol treatment). The strongest MT-1 and -2 immunoreactivity was detected in MCA-occlused mice treated with cilostazol [in the peri-infarct zone of the cortex (penumbral zone)]. These findings indicate that cilostazol has neuroprotective effects in vivo against permanent focal cerebral ischemia, especially in the penumbral zone in the cortex, and that MT-1 and -2 may be partly responsible for these neuroprotective effects.     

Intramucosal distribution of the glossopharyngeal sensory fibers of cats

In order to determine distribution of the sensory fibers of the glossopharyngeal nerve (IX) in the pharynx of cats, wheat germ agglutinin-horseradish peroxidase was injected into the superior and inferior ganglia of IX. Results were as follows: Labeled peripheral sensory nerve fibers in the pharynx were recognized ipsilaterally. The pharyngeal branch of IX innervated the nasopharyngeal mucosa at the level of the torus tubarius. The tonsillo-lingual branch was divided into four rami. The first ramus innervated the caudal one-third of the tongue and the vallate papillae. The second ramus innervated the palatine tonsil and the caudal half of the soft palate. The third ramus supplied a part of the radix linguae, the vallecula epiglottica and the lingual aspect of the epiglottis. The fourth ramus supplied the hypopharyngeal mucosa rostral to the middle level of the aryepiglottic fold.     

Kindling-induced changes in EEG recorded during stimulation from the site of stimulation. III. Direct pharmacological manipulations of the kindled amygdala

In our previous studies, we hypothesized that activation and subsequent collapse of GABA-mediated inhibition during tetanus is an important seizure-triggering mechanism in the kindled epileptogenic focus. To examine this hypothesis, in the present study, we investigated the effects of pharmacological manipulations of the kindled amygdala with several drugs, and measured the kindled seizures as well as the EEG events during tetanus. The results obtained were: (i) The selective GABA-A agonist, muscimol (1 and 5 nM/1 microliter), suppressed kindled seizures in a dose-dependent fashion, and the 5 nM muscimol significantly prolonged EEG suppression and reduced the number of oscillations in the subsequent rhythmic synchronous discharge. Similar effects followed systemic injection of diazepam (2 mg/kg). (ii) The selective GABA-B agonist, baclofen (5 nM), had no effect on kindled seizures nor on the EEG events during tetanus. (iii) The NMDA antagonist, 2-amino-5-phosphonovaleric acid (80 nM), significantly reduced the afterdischarge duration and significantly delayed the appearance of the rhythmic synchronous discharge. However, these effects were not observed immediately, but 24 to 72 h after microinjection. (iv) The muscarinic cholinergic antagonist, atropine (40 and 80 nM), suppressed kindled seizures in a dose-dependent fashion, but the atropine caused marked synchronous discharge both in the awake resting EEG and during tetanic stimulation. We conclude that the GABA-A system, including the benzodiazepine system, is more involved in the seizure-triggering mechanism of amygdala kindling than the GABA-B system, that there is an interaction between the GABA-A and NMDA system, and that the cholinergic participation is independent of the primary seizure-triggering mechanisms.