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The carboxyl terminal domain of beta adrenergic receptor kinase (beta-ARK) is isolated from Escherichia coli as a recombinant His 6 fusion protein. This domain inhibits G(sub beta-gamma) activation of type 2 adenylyl cyclase in systems of reconstituted membranes and intact cells.

We present a case of pontine infarction caused by subclavian steal phenomenon (SSP) due to subclavian artery stenosis (SAS) and an arteriovenous shunt in the forearm in a 74-year-old man with hemodialysis and stenting for SAS with improvement of SSP. He developed dysarthria during dialysis. He was admitted to our hospital and diagnosed with a pontine infarction. As the basilar artery appeared to be occluded on magnetic resonance angiography, an emergency diagnostic angiography was performed. Aortagram showed severe stenosis of the left subclavian artery. Right vertebral artery (VA) angiogram revealed retrograde arterial blood flow from the right VA to the left VA via the VA union, which suggested SSP. In addition, the steal was augmented by an ipsilateral hemodialysis arteriovenous shunt. Percutaneous subclavian artery stenting was performed 12 days later, and there was no recurrence of symptoms in the follow-up period. To our knowledge, this study is the first to report a patient with SSP who developed a pontine infarction due to SAS and an arteriovenous shunt during hemodialysis and who underwent subclavian artery stenting and had a good outcome., Competing Interests: The authors declare no conflict of interest., (© 2024 The Japan Neurosurgical Society.)

Pheromones are specialized chemical messengers used for inter-individual communication within the same species, playing crucial roles in modulating behaviors and physiological states. The detection mechanisms of these signals at the peripheral organ and their transduction to the brain have been unclear. However, recent identification of pheromone molecules, their corresponding receptors, and advancements in neuroscientific technology have started to elucidate these processes. In mammals, the detection and interpretation of pheromone signals are primarily attributed to the vomeronasal system, which is a specialized olfactory apparatus predominantly dedicated to decoding socio-chemical cues. In this mini-review, we aim to delineate the vomeronasal signal transduction pathway initiated by specific vomeronasal receptor-ligand interactions in mice. First, we catalog the previously identified pheromone ligands and their corresponding receptor pairs, providing a foundational understanding of the specificity inherent in pheromonal communication. Subsequently, we examine the neural circuits involved in processing each pheromone signal. We focus on the anatomical pathways, the sexually dimorphic and physiological state-dependent aspects of signal transduction, and the neural coding strategies underlying behavioral responses to pheromonal cues. These insights provide further critical questions regarding the development of innate circuit formation and plasticity within these circuits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Murata, Itakura and Touhara.)

Treatment strategies for unruptured intracranial aneurysms (UIAs) should be carefully considered with reference to rupture and complication rates. It is also important to minimize the length of hospital stay (LOS) and to ensure a high quality of medical care. In this study, we aim to clarify the factors that affect the LOS of patients treated for UIAs using the Inpatient Clinico-Occupational Database of the Rosai Hospital Group (ICOD-R). This was a nationwide-multicenter study based on ICOD-R data from 2000 to 2019. Patients diagnosed with UIAs who were treated with clipping or coiling were included in the study. Multivariate analysis was performed to identify the factors affecting LOS. LOS was also compared between groups classified by surgical procedure or treatment period. We identified 3294 patients on the database who underwent clipping or coiling of UIAs during the study period. Multivariate analysis revealed hospital admission during the early 2000s and the late 2010s, age, and treating institution to be significantly correlated with LOS (p < 0.05). There was a significant difference between the mean LOS of the clipping group (20.3 days) and the coiling group (9.65 days) (p < 0.001). Compared by treatment period, LOS significantly shortened over time. Our results suggest that the type of treatment, time of treatment, patient age, and the treating institution affect postoperative LOS for UIAs. Although coiling was found to lead to a lower average LOS than clipping, treatment selection should take the characteristics of each patient's aneurysm into consideration.

Olfactory perception depends not only on olfactory inputs but also on semantic context. Although multi-voxel activity patterns of the piriform cortex, a part of the primary olfactory cortex, have been shown to represent odor perception, it remains unclear whether semantic contexts modulate odor representation in this region. Here, we investigated whether multi-voxel activity patterns in the piriform cortex change when semantic context modulates odor perception and, if so, whether the modulated areas communicate with brain regions involved in semantic and memory processing beyond the piriform cortex. We also explored regional differences within the piriform cortex, which are influenced by olfactory input and semantic context. We used 2 × 2 combinations of word labels and odorants that were perceived as congruent and measured piriform activity with a 1-mm isotropic resolution using 7T MRI. We found that identical odorants labeled with different words were perceived differently. This labeling effect was observed in multi-voxel activity patterns in the piriform cortex, as the searchlight decoding analysis distinguished identical odors with different labels for half of the examined stimulus pairs. Significant functional connectivity was observed between parts of the piriform cortex that were modulated by labels and regions associated with semantic and memory processing. While the piriform multi-voxel patterns evoked by different olfactory inputs were also distinguishable, the decoding accuracy was significant for only one stimulus pair, preventing definitive conclusions regarding the locational differences between areas influenced by word labels and olfactory inputs. These results suggest that multi-voxel patterns of piriform activity can be modulated by semantic context, possibly due to communication between the piriform cortex and the semantic and memory regions., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Chemical senses, including olfaction, pheromones, and taste, are crucial for the survival of most animals. There has long been a debate about whether different types of senses might influence each other. For instance, primates with a strong sense of vision are thought to have weakened olfactory abilities, although the oversimplified trade-off theory is now being questioned. It is uncertain whether such interactions between different chemical senses occur during evolution. To address this question, we examined four receptor gene families related to olfaction, pheromones, and taste: olfactory receptor (OR), vomeronasal receptor type 1 and type 2 (V1R and V2R), and bitter taste receptor (T2R) genes in Hystricomorpha, which is morphologically and ecologically the most diverse group of rodents. We also sequenced and assembled the genome of the grasscutter, Thryonomys swinderianus. By examining 16 available genome assemblies alongside the grasscutter genome, we identified orthologous gene groups among hystricomorph rodents for these gene families to separate the gene gain and loss events in each phylogenetic branch of the Hystricomorpha evolutionary tree. Our analysis revealed that the expansion or contraction of the four gene families occurred synchronously, indicating that when one chemical sense develops or deteriorates, the others follow suit. The results also showed that V1R/V2R genes underwent the fastest evolution, followed by OR genes, and T2R genes were the most evolutionarily stable. This variation likely reflects the difference in ligands of V1R/V2Rs, ORs, and T2Rs: species-specific pheromones, environment-based scents, and toxic substances common to many animals, respectively., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Bifrontal craniotomy frequently involves opening the frontal sinus and mucosal injury. We report a new technique for mucosal repair in the frontal sinus using surgical titanium microclips. Six consecutive patients who underwent bifrontal craniotomy with frontal sinus exposure and mucosal injury underwent mucosal repair using surgical titanium microclips between April 2019 and August 2022. In all cases, the frontal sinus mucosa was peeled from the inner walls of the frontal sinus to ensure sufficient mucosal margin for clipping using ORBEYE. The repair was accomplished with the microclips in all cases. We also sealed the mucosal wound using fibrin glue and sufficiently filled the frontal sinus with bone debris, resulting in zero incidence of postoperative liquorrhea in all cases. Repairing the mucosa using surgical titanium microclips using ORBEYE may be a simple and quick technique when the frontal sinus mucosa is injured during craniotomy.

Homoeostatic regulation of the acid-base balance is essential for cellular functional integrity. However, little is known about the molecular mechanism through which the acid-base balance regulates cellular responses. Here, we report that bicarbonate ions activate a G protein-coupled receptor (GPCR), i.e., GPR30, which leads to G q -coupled calcium responses. Gpr30-Venus knock-in mice reveal predominant expression of GPR30 in brain mural cells. Primary culture and fresh isolation of brain mural cells demonstrate bicarbonate-induced, GPR30-dependent calcium responses. GPR30-deficient male mice are protected against ischemia-reperfusion injury by a rapid blood flow recovery. Collectively, we identify a bicarbonate-sensing GPCR in brain mural cells that regulates blood flow and ischemia-reperfusion injury. Our results provide a perspective on the modulation of GPR30 signalling in the development of innovative therapies for ischaemic stroke. Moreover, our findings provide perspectives on acid/base sensing GPCRs, concomitantly modulating cellular responses depending on fluctuating ion concentrations under the acid-base homoeostasis., (© 2024. The Author(s).)

There have been a number of anastomosis methods of bypass techniques reported for moyamoya disease. However, there are yet no randomized controlled trials conducted on the anastomosis method. Retrograde blood flow of the superficial temporal artery (STA) may be used as one of the donor options. Here, we examined the tolerability of retrograde bypass using a distal stump of the parietal STA (dsPSTA). Anastomosis between the dsPSTA and middle cerebral artery (MCA) was performed for consecutive patients with moyamoya disease whose parietal STA was visualized to be longer than 10 cm using contrast-enhanced computed tomography preoperatively. Retrospectively, we have examined its patency and clinical outcome. Retrograde dsPSTA-MCA bypass was performed in 22 hemispheres of 17 patients. The patency of retrograde dsPSTA-MCA bypass in all 22 anastomoses could be confirmed during follow-up periods (mean: 5.5, range: 2-15 years). No recurrence of ischemic events was observed. The dsPSTA-MCA bypass using retrograde blood flow has been determined as one of the many promising anastomosis methods, and long-term patency was achieved in moyamoya disease.

A 54-year-old man with no medical history presented to our hospital with vomiting, left hemiplegia, and seizures. On arrival, he was experiencing generalized tonic-clonic seizures, which required him to be intubated and deeply sedated. Contrast-enhanced computed tomography revealed extensive venous sinus obstruction from the superior sagittal sinus to the bilateral sigmoid sinus and cerebral edema with intracranial hemorrhage. An intracranial pressure (ICP) monitor was immediately placed intracranially, and mechanical thrombectomy (MT) was performed under ICP monitoring. MT was immediately terminated when the venous sinus was partially recanalized enough to decrease the ICP; then, anticoagulation therapy was initiated. Postoperative follow-up angiography revealed that venous sinus obstruction and intracranial venous perfusion improved over time. Although he had intracranial hemorrhage-induced left hemiplegia and sensory deficits, his condition improved with rehabilitation, and the patient was eventually discharged home. The indication criteria and techniques for MT for cerebral venous sinus thrombosis are yet to be established. As in this case, in patients with impaired consciousness due to intracranial hemorrhage or epilepsy, preoperative ICP monitor placement is deemed useful to evaluate venous perfusion during MT and decide the treatment goal., Competing Interests: The authors declare no conflict of interest., (© 2023 The Japan Neurosurgical Society.)

Spatiotemporal control of gene expression is important for neural development and function. Here, we show that heterogeneous nuclear ribonucleoprotein (hnRNP) A/B is highly expressed in developing olfactory sensory neurons (OSNs), and its knockout results in reduction in mature OSNs and aberrant targeting of OSN axons to the olfactory bulb. RNA immunoprecipitation analysis reveals that hnRNP A/B binds to a group of mRNAs that are highly related to axon projections and synapse assembly. Approximately 11% of the identified hnRNP A/B targets, including Pcdha and Ncam2, encode cell adhesion molecules. In Hnrnpab knockout mice, PCDHA and NCAM2 levels are significantly reduced at the axon terminals of OSNs. Furthermore, deletion of the hnRNP A/B-recognition motif in the 3' UTR of Pcdha leads to impaired PCDHA expression at the OSN axon terminals. Therefore, we propose that hnRNP A/B facilitates OSN maturation and axon projection by regulating the local expression of its target genes at axon terminals., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Extracranial internal carotid artery aneurysms (ECAAs) are rare. We herein describe a case of overlapped stenting with two double-layer micromesh stents for a giant ECAA., Case Presentation: A 73-year-old man presented to our hospital with an enlarged right posterior cervical mass. A right internal carotid artery (ICA) angiogram revealed a giant aneurysm of 50 × 60 mm. We chose a carotid double-layer micromesh stent for stenting. With the patient under general anesthesia, the first double-layer micromesh stent (CASPER Rx, 10 × 30 mm; Terumo, Tokyo, Japan) was deployed between the ICA distal to the aneurysm and the common carotid artery (CCA). The second stent was also deployed from a site more proximal than the first one. Ten coils were then placed from a microcatheter that had been placed in the aneurysm. A right CCA angiogram after the procedure revealed a flow-diversion effect for the aneurysm. The patient was discharged with no complications. At the 6-month follow-up angiogram, blood flow into the aneurysm had completely disappeared., Conclusion: A flow-diversion effect using overlapped double-layer micromesh stents can result in thrombosis and healing of giant ECAAs., Competing Interests: The authors declare that there are no conflicts of interest., (©2023 The Japanese Society for Neuroendovascular Therapy.)

Humans have significant individual variations in odor perception, derived from their experience or sometimes from differences in the olfactory receptor (OR) gene repertoire. In several cases, the genetic variation of a single OR affects the perception of its cognate odor ligand. Musks are widely used for fragrance and are known to demonstrate specific anosmia. It, however, remains to be elucidated whether the OR polymorphism contributes to individual variations in musk odor perception. Previous studies reported that responses of the human musk receptor OR5AN1 to a variety of musks in vitro correlated well with perceptual sensitivity to those odors in humans and that the mouse ortholog, Olfr1440 (MOR215-1), plays a critical role in muscone perception. Here, we took advantage of genetic variation in OR5AN1 to examine how changes in receptor sensitivity are associated with human musk perception. We investigated the functional differences between OR5AN1 variants in an in vitro assay and measured both perceived intensity and detection threshold in human subjects with different OR5AN1 genotypes. Human subjects homozygous for the more sensitive L289F allele had a lower detection threshold for muscone and found macrocyclic musks to be more intense than subjects homozygous for the reference allele. These results demonstrate that the genetic variation in OR5AN1 contributes to perceptual differences for some musks. In addition, we found that the more functional variant of OR5A1, a receptor involved in β-ionone perception, is associated with the less functional variant of OR5AN1, suggesting that the perceived intensities of macrocyclic musks and β-ionone are inversely correlated., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Insect gustatory receptors play roles in sensing tastants, such as sugars and bitter substances. We previously demonstrated that the BmGr9 silkworm gustatory receptor is a d-fructose-gated ion channel receptor. However, the molecular mechanism of how d-fructose could initiate channel opening were unclear. Herein, we present a structural model for a channel pore and a d-fructose-binding site in BmGr9. Since the membrane topology and oligomeric state of BmGr9 appeared to be similar to those of an insect odorant receptor coreceptor, Orco, we constructed a structural model of BmGr9 based on the cryo-EM Orco structure. Our site-directed mutagenesis data suggested that the transmembrane region 7 forms channel pore and controls channel gating. This model also suggested that a pocket formed by transmembrane helices 2 to 4 and 6 binds d-fructose. Using mutagenesis experiments in combination with docking simulations, we were able to determine the potent binding mode of d-fructose. Finally, based on these data, we propose a conformational change that leads to channel opening upon d-fructose binding. Taken together, these findings detail the molecular mechanism by which an insect gustatory receptor can be activated by its ligand molecule., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

A 72-year-old man who had undergone a lumboperitoneal shunt for idiopathic normal pressure hydrocephalus was admitted to our emergency department with fever and disturbance of consciousness 8 days after placement. Computed tomography scan showed pneumocephalus and a right-sided temporal porencephalic cyst with a small bone defect in the right petrous bone. Shunt valve pressure was raised from 145 mmH 2 O to "virtual off" setting. After 2 weeks, follow-up computed tomography showed improvement of pneumocephalus, and the shunt valve pressure was lowered to 215 mmH 2 O. Since that time, the patient has a good clinical course without recurrence. Tension pneumocephalus following shunt placement for idiopathic normal pressure hydrocephalus is rare and has never been reported in the early postoperative stage after lumboperitoneal shunt, except for the present one. Temporary raising shunt valve pressure is effective in improving the pneumocephalus. Preoperative screening for congenital bone defects by thin-slice computed tomography may be useful for selecting types of shunt valve and determining postoperative pressure setting., Competing Interests: The authors declare no conflict of interest., (© 2022 The Japan Neurosurgical Society.)

Sensory signals are critical to perform adaptive social behavior. During copulation, male mice emit ultrasonic vocalizations (USVs). Our previous studies have shown that female mice exhibit approach behavior toward sound sources of male USVs and that, after being exposed to a male pheromone, exocrine gland-secreting peptide 1 (ESP1), female mice exhibited a preference toward a particular type of male USVs. These findings suggest that male USVs modulate female courtship behavior. However, it remains unclear which brain regions and what cell types of neurons are involved in neuronal processing of male USVs. To clarify this issue, immediate early gene analysis, behavioral analysis, and neurochemical analysis were performed. The in situ hybridization analysis of c-fos mRNA in multiple brain regions showed that neurons in the prelimbic cortex were responsive to presentation of male USVs in the presence of ESP1. Furthermore, this study found that activity of prelimbic cortex was correlated with the duration of female exploration behavior toward a sound source of the USVs. Finally, by using double immunohistochemistry, the present study showed that the prelimbic neurons responding to the presentation of male USVs were presumably excitatory glutamatergic neurons. These results suggest that the prelimbic cortex may facilitate female courtship behavior in response to male USVs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Asaba, Nomoto, Osakada, Matsuo, Kobayakawa, Kobayakawa, Touhara, Mogi and Kikusui.)

The pheromonal information received by the vomeronasal system plays a crucial role in regulating social behaviors such as aggression in mice. Despite accumulating knowledge of the brain regions involved in aggression, the specific vomeronasal receptors and the exact neural circuits responsible for pheromone-mediated aggression remain unknown. Here, we identified one murine vomeronasal receptor, Vmn2r53, that is activated by urine from males of various strains and is responsible for evoking intermale aggression. We prepared a purified pheromonal fraction and Vmn2r53 knockout mice and applied genetic tools for neuronal activity recording, manipulation, and circuit tracing to decipher the neural mechanisms underlying Vmn2r53-mediated aggression. We found that Vmn2r53-mediated aggression is regulated by specific neuronal populations in the ventral premammillary nucleus and the ventromedial hypothalamic nucleus. Together, our results shed light on the hypothalamic regulation of male aggression mediated by a single vomeronasal receptor., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

How the human brain translates olfactory inputs into diverse perceptions, from pleasurable floral smells to sickening smells of decay, is one of the fundamental questions in olfaction. To examine how different aspects of olfactory perception emerge in space and time in the human brain, we performed time-resolved multivariate pattern analysis of scalp-recorded electroencephalogram responses to 10 perceptually diverse odors and associated the resulting decoding accuracies with perception and source activities. Mean decoding accuracies of odors exceeded the chance level 100 ms after odor onset and reached maxima at 350 ms. The result suggests that the neural representations of individual odors were maximally separated at 350 ms. Perceptual representations emerged following the decoding peak: unipolar unpleasantness (neutral to unpleasant) from 300 ms, and pleasantness (neutral to pleasant) and perceptual quality (applicability to verbal descriptors such as “fruity” or “flowery”) from 500 ms after odor onset, with all these perceptual representations reaching their maxima after 600 ms. A source estimation showed that the areas representing the odor information, estimated based on the decoding accuracies, were localized in and around the primary and secondary olfactory areas at 100 to 350 ms after odor onset. Odor representations then expanded into larger areas associated with emotional, semantic, and memory processing, with the activities of these later areas being significantly associated with perception. These results suggest that initial odor information coded in the olfactory areas (<350 ms) evolves into their perceptual realizations (300 to >600 ms) through computations in widely distributed cortical regions, with different perceptual aspects having different spatiotemporal dynamics.

The vomeronasal system plays an essential role in sensing various environmental chemical cues. Here we show that mice exposed to blood and, consequently, hemoglobin results in the activation of vomeronasal sensory neurons expressing a specific vomeronasal G protein-coupled receptor, Vmn2r88, which is mediated by the interaction site, Gly17, on hemoglobin. The hemoglobin signal reaches the medial amygdala (MeA) in both male and female mice. However, it activates the dorsal part of ventromedial hypothalamus (VMHd) only in lactating female mice. As a result, in lactating mothers, hemoglobin enhances digging and rearing behavior. Manipulation of steroidogenic factor 1 (SF1)-expressing neurons in the VMHd is sufficient to induce the hemoglobin-mediated behaviors. Our results suggest that the oxygen-carrier hemoglobin plays a role as a chemosensory signal, eliciting behavioral responses in mice in a state-dependent fashion., (© 2022. The Author(s).)

Recent advancements in tissue clearing technologies have offered unparalleled opportunities for researchers to explore the whole mouse brain at cellular resolution. With the expansion of this experimental technique, however, a scalable and easy-to-use computational tool is in demand to effectively analyze and integrate whole-brain mapping datasets. To that end, here we present CUBIC-Cloud, a cloud-based framework to quantify, visualize, and integrate mouse brain data. CUBIC-Cloud is a fully automated system where users can upload their whole-brain data, run analyses, and publish the results. We demonstrate the generality of CUBIC-Cloud by a variety of applications. First, we investigated the brain-wide distribution of five cell types. Second, we quantified Aβ plaque deposition in Alzheimer's disease model mouse brains. Third, we reconstructed a neuronal activity profile under LPS-induced inflammation by c-Fos immunostaining. Last, we show brain-wide connectivity mapping by pseudotyped rabies virus. Together, CUBIC-Cloud provides an integrative platform to advance scalable and collaborative whole-brain mapping., Competing Interests: T.M., R.G.Y., and E.A.S are employees of CUBICStars, Inc. H.R.U. is a founder and CTO of CUBICStars, Inc. T.M. and H.R.U. are co-inventors on patent applications filed by CUBICStars, Inc., regarding the CUBIC-Cloud framework. CUBIC-Cloud web service is provided and maintained by CUBICStars, Inc. H.R.U. is a co-inventor on patents and patent applications owned or filed by RIKEN covering the CUBIC reagents., (© 2021 The Authors.)

Maternal mammals exhibit heightened motivation to care for offspring, but the underlying neuromolecular mechanisms have yet to be clarified. Here, we report that the calcitonin receptor (Calcr) and its ligand amylin are expressed in distinct neuronal populations in the medial preoptic area (MPOA) and are upregulated in mothers. Calcr+ MPOA neurons activated by parental care project to somatomotor and monoaminergic brainstem nuclei. Retrograde monosynaptic tracing reveals that significant modification of afferents to Calcr+ neurons occurs in mothers. Knockdown of either Calcr or amylin gene expression hampers risk-taking maternal care, and specific silencing of Calcr+ MPOA neurons inhibits nurturing behaviors, while pharmacogenetic activation prevents infanticide in virgin males. These data indicate that Calcr+ MPOA neurons are required for both maternal and allomaternal nurturing behaviors and that upregulation of amylin-Calcr signaling in the MPOA at least partially mediates risk-taking maternal care, possibly via modified connectomics of Calcr+ neurons postpartum., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The exocrine-gland secreting peptide (ESP)gene family encodes proteinaceous pheromones that are recognized by the vomeronasal organ in mice. For example, ESP1 is a male pheromone secreted in tear fluid that regulates socio-sexual behavior, and ESP22 is a juvenile pheromone that suppresses adult sexual behavior. The family consists of multiple genes and has been identified only in mouse and rat genomes. The coding region of a mouse ESP gene is separated into two exons, each encoding signal and mature sequences. Here, we report the origin and evolution of the ESP gene family. ESP genes were found only in the Muridea and Cricetidae families of rodents, suggesting a recent origin of ESP genes in the common ancestor of murids and cricetids. ESP genes show a great diversity in number, length, and sequence among different species as well as mouse strains. Some ESPs in rats and golden hamsters are expressed in the lacrimal gland and the salivary gland. We also found that a mature sequence of an ESP gene showed overall sequence similarity to the α-globin gene. The ancestral ESP gene seems to be generated by recombination of a retrotransposed α-globin gene with the signal-encoding exon of the CRISP2 gene located adjacent to the ESP gene cluster. This study provides an intriguing example of molecular tinkering in rapidly evolving species-specific proteinaceous pheromone genes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The revision of the sub-order Microchiroptera is one of the most intriguing outcomes in recent mammalian molecular phylogeny. The unexpected sister-taxon relationship between rhinolophoid microbats and megabats, with the exclusion of other microbats, suggests that megabats arose in a relatively short period of time from a microbat-like ancestor. In order to understand the genetic mechanism underlying adaptive evolution in megabats, we determined the whole-genome sequences of two rousette megabats, Leschenault's rousette (Rousettus leschenaultia) and the Egyptian fruit bat (R. aegyptiacus). The sequences were compared with those of 22 other mammals, including nine bats, available in the database. We identified that megabat genomes are distinct in that they have extremely low activity of SINE retrotranspositions, expansion of two chemosensory gene families, including the trace amine receptor (TAAR) and olfactory receptor (OR), and elevation of the dN/dS ratio in genes for immunity and protein catabolism. The adaptive signatures discovered in the genomes of megabats may provide crucial insight into their distinct evolution, including key processes such as virus resistance, loss of echolocation, and frugivorous feeding., (© The Author(s) 2020. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

Among rodents, information about the external world is mainly acquired via the olfactory system, which is one of five sensory modalities. Several semiochemical signals are used for inter- and intraspecies communication [1]. In contrast, primates are generally regarded as vision-oriented mammals, and have been thought to trade their olfactory sensitivity for good sight. However, strepsirrhines have a well-developed olfactory system [2] and a larger repertoire of functional olfactory and vomeronasal receptor genes than haplorhines [3, 4]. Moreover, strepsirrhines are well known for their use of olfactory communication in social behavior. Ring-tailed lemurs are a species of Malagasy strepsirrhines, and use olfactory cues for conspecific communication. Male lemurs mark their scent by spreading volatiles from the antebrachial gland on their wrists. This study combined ethological and chemical approaches to identify a key odorant(s) in antebrachial secretions involved in the sexual communication of lemurs. The results of a behavioral assay indicated that females sniff the males' antebrachial secretions longer during the breeding season than during the nonbreeding season. By examining seasonal changes in volatiles using gas chromatography-mass spectrometry, we found that the secretion of three C12 and C14 aldehydes with a fruity and floral scent significantly increased during the breeding season in a testosterone-dependent manner. Females sniffed for longer at biologically relevant concentrations of two of the aldehydes (12-methyltridecanal and tetradecanal) and were attracted to a mixture of these plus the third aldehyde, dodecanal. Our results suggest that these aldehydes are putative lemur pheromones involved in the attractiveness of males to females during the breeding season., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In response to the COVID-19 pandemic, countries have implemented various strategies to reduce and slow the spread of the disease in the general population. For countries that have implemented restrictions on its population in a step-wise manner, monitoring of COVID-19 prevalence is of importance to guide decision on when to impose new, or when to abolish old, restrictions. We are here determining whether measures of odor intensity in a large sample can serve as one such measure. Online measures of how intense common household odors are perceived and symptoms of COVID-19 were collected from 2440 Swedes. Average odor intensity ratings were then compared to predicted COVID-19 population prevalence over time in the Swedish population and were found to closely track each other (r=-0.83). Moreover, we found that there was a large difference in rated intensity between individuals with and without COVID-19 symptoms and number of symptoms was related to odor intensity ratings. Finally, we found that individuals progressing from reporting no symptoms to subsequently reporting COVID-19 symptoms demonstrated a large drop in olfactory performance. These data suggest that measures of odor intensity, if obtained in a large and representative sample, can be used as an indicator of COVID-19 disease in the general population. Importantly, this simple measure could easily be implemented in countries without widespread access to COVID-19 testing or implemented as a fast early response before wide-spread testing can be facilitated., (© The Author(s) 2020. Published by Oxford University Press.)

Whole-organ/body three-dimensional (3D) staining and imaging have been enduring challenges in histology. By dissecting the complex physicochemical environment of the staining system, we developed a highly optimized 3D staining imaging pipeline based on CUBIC. Based on our precise characterization of biological tissues as an electrolyte gel, we experimentally evaluated broad 3D staining conditions by using an artificial tissue-mimicking material. The combination of optimized conditions allows a bottom-up design of a superior 3D staining protocol that can uniformly label whole adult mouse brains, an adult marmoset brain hemisphere, an ~1 cm 3 tissue block of a postmortem adult human cerebellum, and an entire infant marmoset body with dozens of antibodies and cell-impermeant nuclear stains. The whole-organ 3D images collected by light-sheet microscopy are used for computational analyses and whole-organ comparison analysis between species. This pipeline, named CUBIC-HistoVIsion, thus offers advanced opportunities for organ- and organism-scale histological analysis of multicellular systems.

Atypical sensory reactivities are pervasive among people with autism spectrum disorder (ASD). With respect to olfaction, most previous studies have used psychophysical or questionnaire-based methodologies; thus, the neural basis of olfactory processing in ASD remains unclear. This study aimed to determine the stages of olfactory processing that are altered in ASD. Fourteen young adults with high-functioning ASD (mean age, 21 years; 3 females) were compared with 19 age-matched typically developing (TD) controls (mean age, 21 years; 4 females). Olfactory event-related potentials (OERPs) for 2-phenylethyl alcohol-a rose-like odor-were measured with 64 scalp electrodes while participants performed a simple odor detection task. Significant group differences in OERPs were found in 3 time windows 542 ms after the stimulus onset. The cortical source activities in these time windows, estimated using standardized low-resolution brain electromagnetic tomography, were significantly higher in ASD than in TD in and around the posterior cingulate cortex, which is known to play a crucial role in modality-general cognitive processing. Supplemental Bayesian analysis provided substantial evidence for an alteration in the later stages of olfactory processing, whereas conclusive evidence was not provided for the earlier stages. These results suggest that olfactory processing in ASD is altered at least at the later, modality-general processing stage., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting.

In this study, we examined the mode of metabolism of food odorant molecules in the human nasal/oral cavity in vitro and in vivo. We selected 4 odorants, 2-furfurylthiol (2-FT), hexanal, benzyl acetate, and methyl raspberry ketone, which are potentially important for designing food flavors. In vitro metabolic assays of odorants with saliva/nasal mucus analyzed by gas chromatography mass spectrometry revealed that human saliva and nasal mucus exhibit the following 3 enzymatic activities: (i) methylation of 2-FT into furfuryl methylsulfide (FMS); (ii) reduction of hexanal into hexanol; and (iii) hydrolysis of benzyl acetate into benzyl alcohol. However, (iv) demethylation of methyl raspberry ketone was not observed. Real-time in vivo analysis using proton transfer reaction-mass spectrometry demonstrated that the application of 2-FT and hexanal through 3 different pathways via the nostril or through the mouth generated the metabolites FMS and hexanol within a few seconds. The concentration of FMS and hexanol in the exhaled air was above the perception threshold. A cross-adaptation study based on the activation pattern of human odorant receptors suggested that this metabolism affects odor perception. These results suggest that some odorants in food are metabolized in the human nasal mucus/saliva, and the resulting metabolites are perceived as part of the odor quality of the substrates. Our results help improve the understanding of the mechanism of food odor perception and may enable improved design and development of foods in relation to odor., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)