Pupillary dilation response reflects surprising moments in music

There are indications that the pupillary dilation response (PDR) reflects surprising moments in an auditory sequence such as the appearance of a deviant noise against repetitively presented pure tones (Liao, Yoneya, Kidani, Kashino, & Furukawa, 2016), and salient and loud sounds that are evaluated by human participants subjectively (Liao, Kidani, Yoneya, Kashino, & Furukawa, 2016). In the current study, we further examined whether the reflection of PDR in auditory surprise can be accumulated and revealed in complex and yet structured auditory stimuli, i.e., music, and when the surprise is defined subjectively. Participants listened to 15 excerpts of music while their pupillary responses were recorded. In the surprise-rating session, participants rated how surprising an instance in the excerpt was, i.e., rich in variation versus monotonous, while they listened to it. In the passive-listening session, they listened to the same 15 excerpts again but were not involved in any task. The pupil diameter data obtained from both sessions were time-aligned to the rating data obtained from the surprise-rating session. Results showed that in both sessions, mean pupil diameter was larger at moments rated more surprising than unsurprising. The result suggests that the PDR reflects surprise in music automatically

Osteoclasts adapt to physioxia perturbation through DNA demethylation

Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two-photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia-inducible factor activity. We observe that hypoxia decreases ten-eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen-dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation.Nishikawa K., Seno S., Yoshihara T., et al. Osteoclasts adapt to physioxia perturbation through DNA demethylation. EMBO Reports 22, e53035 (2021); https://doi.org/10.15252/embr.202153035

GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion

Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes. We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36). GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by β-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca entry via voltage-gated Ca channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content. We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action. [Abstract copyright: © 2023. The Author(s).

GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.We thank David Wiggins for excellent technical assistance. This work was supported by the Medical Research Council, Diabetes UK (to R. Ramracheya ), Oxford Biomedical Research Centre (to A. Tarasov), the Wellcome Trust (Senior Investigator Awards to A. Galione and P. Rorsman), the Warwick Impact Fund (to C. Weston and G. Ladds), the Biotechnology and Biological Sciences Research Council (to G. Ladds), the Knut and Alice Wallenberg Foundation (to P. Rorsman), and the Swedish Research Council (to P. Rorsman). The initial stages of M. Shigeto’s stay in Oxford were supported by a fellowship from Kawasaki Medical School.This is the final version of the article. It was first available from the American Society for Clinical Investigation via http://dx.doi.org/10.1172/JCI8197

Improved detectability of small-bowel lesions via capsule endoscopy with computed virtual chromoendoscopy: A pilot study

Objective. Real-time video capsule endoscopy (CE) with flexible spectral imaging color enhancement (FICE) improves visibility of small-bowel lesions. This article aims to clarify whether CE-FICE also improves detectability of small-bowel lesions. Patients and methods. A total of 55 patients who underwent CE at Hiroshima University Hospital during the period November 2009 through March 2010 were enrolled in the study. Five patients were excluded from the study because residues and transit delays prevented sufficient evaluation. Thus, 50 patients participated. Two experienced endoscopists (each having interpreted more than 50 capsule videos) analyzed the images. One interpreted conventional capsule videos; the other, blinded to interpretation of the conventional images, interpreted CE-FICE images obtained at settings 1-3 (setting 1: red 595 nm, green 540 nm, blue 535 nm; setting 2: red 420 nm, green 520 nm, blue 530 nm; setting 3: red 595 nm, green 570 nm, blue 415 nm). Lesions were classified as angioectasia, erosion, ulceration, or tumor. Detectability was compared between the two modalities. Time taken to interpret the capsule videos was also determined. Results. Seventeen angioectasias were identified by conventional CE; 48 were detected by CE-FICE at setting 1, 45 at setting 2, and 24 at setting 3, with significant differences at settings 1 and 2 (p = 0.0003, p < 0.0001, respectively). Detection of erosion, ulceration, and tumor did not differ statistically between conventional CE and CE-FICE, nor did interpretation time (conventional CE 36 ± 6.9 min; CE-FICE setting 1, 36 ± 6.4 min; setting 2, 38 ± 5.8 min; setting 3, 35 ± 6.7 min). Conclusions. CE-FICE is superior in the lesion detection in comparison with conventional CE and improves detection of angioectasia

Sediment-Associated Phytoplankton Release From the Seafloor in Response to Wind-Induced Barotropic Currents in the Bering Strait

Bering Strait is the single gateway between the Arctic and Pacific Oceans, and has localized strong currents, which can exceed 100 cm s^-1. Although massive spring phytoplankton blooms and the subsequent production of particulate organic matter that sinks to the seafloor are observed in the surrounding regions of the Bering Strait, the impact of the locally strong current on the horizontal and vertical transport of the particles remains unclear. Therefore, we conducted year-round mooring measurements from 2016 to 2017 by focusing on near-bottom processes associated with ocean currents. Our time-series analysis showed that high-turbidity events, triggered by strong barotropic currents, occurred near the seafloor in all seasons. Consequently, the fluorescence sensor detected highly concentrated chlorophyll a in the resuspended sediment; however, the amount of chlorophyll a release was seasonal, with large and small amounts being released during the warm and cold seasons, respectively. The small amounts of chlorophyll a may be attributed to small amounts of phytoplankton in the sediment owing to less input of fresh phytoplankton from the overlaying water column and organic matter decomposition in the sediments under no-light conditions. The barotropic currents were modulated by surface winds associated with an intercontinental atmospheric pattern having a 5000-km spatial scale on a timescale of 6 days. The locally strong ocean current in the Bering Strait, driving the upward transport of sediment and the subsequent horizontal transport, may play a vital role in supplying particulate organic matter/phytoplankton/nutrients to the downstream region of the southern Chukchi Sea where the formation of biological hotspots is reported

Human pupillary dilation response to deviant auditory stimuli: Effects of stimulus properties and voluntary attention

A unique sound that deviates from a repetitive background sound induces signature neural responses, such as mismatch negativity and novelty P3 response in electro-encephalography studies. Here we show that a deviant auditory stimulus induces a human pupillary dilation response (PDR) that is sensitive to the stimulus properties and irrespective whether attention is directed to the sounds or not. In an auditory oddball sequence, we used white noise and 2000-Hz tones as oddballs against repeated 1000-Hz tones. Participants’ pupillary responses were recorded while they listened to the auditory oddball sequence. In Experiment 1, they were not involved in any task. Results show that pupils dilated to the noise oddballs for approximately 4 s, but no such PDR was found for the 2000-Hz tone oddballs. In Experiments 2, two types of visual oddballs were presented synchronously with the auditory oddballs. Participants discriminated the auditory or visual oddballs while trying to ignore stimuli from the other modality. The purpose of this manipulation was to direct attention to or away from the auditory sequence. In Experiment 3, the visual oddballs and the auditory oddballs were always presented asynchronously to prevent residuals of attention on to-be-ignored oddballs due to the concurrence with the attended oddballs. Results show that pupils dilated to both the noise and 2000-Hz tone oddballs in all conditions. Most importantly, PDRs to noise were larger than those to the 2000-Hz tone oddballs regardless of the attention condition in both experiments. The overall results suggest that the stimulus-dependent factor of the PDR appears to be independent of attention