Neural basis for pheromone signal transduction in mice.

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.

Design and implementation of a hybrid cloud system for large-scale human genomic research.

In the field of genomic medical research, the amount of large-scale information continues to increase due to advances in measurement technologies, such as high-performance sequencing and spatial omics, as well as the progress made in genomic cohort studies involving more than one million individuals. Therefore, researchers require more computational resources to analyze this information. Here, we introduce a hybrid cloud system consisting of an on-premise supercomputer, science cloud, and public cloud at the Kyoto University Center for Genomic Medicine in Japan as a solution. This system can flexibly handle various heterogeneous computational resource-demanding bioinformatics tools while scaling the computational capacity. In the hybrid cloud system, we demonstrate the way to properly perform joint genotyping of whole-genome sequencing data for a large population of 11,238, which can be a bottleneck in sequencing data analysis. This system can be one of the reference implementations when dealing with large amounts of genomic medical data in research centers and organizations.

A single vomeronasal receptor promotes intermale aggression through dedicated hypothalamic neurons.

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.

Comparison of erector spinae fatigability between female patients with Parkinson's disease and healthy individuals: a cross sectional pilot study.

BACKGROUND: Postural abnormality is one of the main symptoms of Parkinson's disease (PD). The erector spinae muscles play an important role in maintaining an upright posture, but the fatigability of the erector spinae in patients with PD is unknown. The purpose of this study was to compare the trunk extension maximum voluntary contraction (MVC) and the fatigability of the erector spinae between female patients with PD and healthy volunteers. METHODS: Th participants of this cross-sectional pilot study comprised 19 patients with PD and nine healthy volunteers matched for sex, age, and physical characteristics as a control group. The MVC of all participants was measured, and after sufficient rest, the Sørensen back endurance test was conducted to the point of exhaustion. The muscle activity of the erector spinae during the Sørensen back endurance test was measured using surface electromyography. The median frequency (MF) slope, which is an index of fatigability, was calculated from the recorded surface muscle activity by means of power spectrum analysis using a Fast Fourier transformation. RESULTS: Nine of the 19 patients with PD were unable to perform the Sørensen back endurance test, and a lower proportion of the PD group were able to perform it compared with the control group. The MVC of those patients with PD who were able to perform the Sørensen back endurance test was lower than that of the control group, and the time for which the pose could be maintained was shorter. There was no significant difference between the MF slope on the left and right side in the PD group, and it was higher on both sides than in the control group. CONCLUSION: This is the first study to demonstrate a reduction of maximum muscle strength and great fatigability of the erector spinae in patients with PD. This discovery strongly underlines the need for paraspinal muscle training from an early stage with the aim of preventing the progression of postural abnormality in patients with PD.

Step-bunching instability of growing interfaces between ice and supercooled water.

SignificanceStep-bunching instability (SBI) is one of the interfacial instabilities driven by self-organization of elementary step flow associated with crystal-growth dynamics, which has been observed in diverse crystalline materials. However, despite theoretical suggestions of its presence, no direct observations of SBI for simple melt growth have been achieved so far. Here, with the aid of a type of optical microscope and its combination with a two-beam interferometer, we realized quantitative in situ observations of the spatiotemporal dynamics of the SBI. This enables us to examine the origin of the SBI at the level of the step-step interaction. We also found that the SBI spontaneously induces a highly stable spiral growth mode, governing the late stage of the growth process.

Hemoglobin in the blood acts as a chemosensory signal via the mouse vomeronasal system.

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.

CUBIC-Cloud provides an integrative computational framework toward community-driven whole-mouse-brain mapping.

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 Aß 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.

Origin and Evolution of the Gene Family of Proteinaceous Pheromones, the Exocrine Gland-Secreting Peptides, in Rodents.

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.

Increased large-scale inter-network connectivity in relation to impulsivity in Parkinson's disease.

Impulsivity is a neuropsychiatric feature of Parkinson's disease (PD). We investigated the pathophysiology of impulsivity in PD using resting-state functional magnetic resonance imaging (rs-fMRI). We investigated 45 patients with idiopathic PD and 21 healthy controls. Based on Barratt Impulsiveness Scale (BIS-11) score, PD patients were classified as higher (PD-HI) or lower impulsivity (PD-LI). Functional connectivity (FC) between various large-scale brain networks were analysed using the CONN toolbox. FC between the right frontoparietal network (FPN) and medial visual network (MVN) was significantly higher in PD-HI patients than PD-LI patients (false discovery rate [FDR]-adjusted p = 0.0315). FC between the right FPN and MVN had a significant positive correlation with total BIS-11 score (FDR-adjusted p = 0.010) and the attentional impulsivity (FDR-adjusted p = 0.046) and non-planning impulsivity subscale scores (FDR-adjusted p = 0.018). On the other hand, motor impulsivity subscale score had a significant negative correlation with the FC between the default-mode and salience networks (right supramarginal gyrus, FDR-adjusted p = 0.018; anterior cingulate cortex, FDR-adjusted p = 0.027); this trend was observed in healthy controls. The attentional and non-planning impulsivity, regarded as 'cognitive' impulsivity, may be associated with dysfunction in integration of perceptual information and flexible cognitive control in PD.

Hypothalamic neuronal circuits regulating hunger-induced taste modification.

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.

The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent muscle disease in elderly people, affecting the daily activities. sIBM is progressive with unknown cause and without effective treatment. In 2015, sIBM was classified as an intractable disease by the Japanese government, and the treatment cost was partly covered by the government. This study aimed to examine the changes in the number of patients with sIBM over the last 10 years and to elucidate the cross-sectional profile of Japanese patients with sIBM. METHODS: The number of sIBM patients was estimated through a reply-paid postcard questionnaire for attending physicians. Only patients diagnosed as "definite" or "probable" sIBM by clinical and biopsy sIBM criteria were included in this study (Lancet Neurol 6:620-631, 2007, Neuromuscul Disord 23:1044-1055, 2013). Additionally, a registered self-administered questionnaire was also sent to 106 patients who agreed to reply via their attending physician, between November 2016 and March 2017. RESULTS: The number of patients diagnosed with sIBM for each 5-year period was 286 and 384 in 2011 and 2016, respectively. Inability to stand-up, cane-dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair-bound should be included as sIBM milestones. Eight patients were positive for anti-hepatitis C virus antibody; three of them were administered interferon before sIBM onset. Steroids were administered to 33 patients (31.1%) and intravenous immunoglobulin to 46 patients (43.4%). From 2016 to 2017, total of 70 patients applied for the designated incurable disease medical expenses subsidy program. Although the treatment cost was partly covered by the government, many patients expressed psychological/mental and financial anxieties. CONCLUSIONS: We determined the cross-sectional profile of Japanese patients with sIBM. Continuous support and prospective surveys are warranted.

Link between molecular mobility and order parameter during liquid-liquid transition of a molecular liquid.

Liquid-liquid transition (LLT) is the transformation of one liquid to another via first-order phase transition. For example, LLT in a molecular liquid, triphenyl phosphite, is macroscopically the transformation from liquid I in a supercooled state to liquid II in a glassy state. Reflecting the transformation from the liquid to glassy state, the LLT is accompanied by considerable slowing down of overall molecular dynamics, but little is known about how this proceeds at a molecular level coupled with the evolution of the order parameter. We report such information by performing time-resolved simultaneous measurements of dielectric spectroscopy and phase contrast microscopy/Raman spectroscopy by using a dielectric cell with transparent electrodes. We find that the temporal change in molecular mobility crucially depends on whether LLT is nucleation growth type occurring in the metastable state or SD type occurring in the unstable state. Furthermore, our results suggest that the molecular mobility is controlled by the local order parameter: more specifically, the local activation energy of molecular rotation is controlled by the local fraction of locally favored structures formed in the liquid. Our study sheds light on the temporal change in the molecular dynamics during LLT and its link to the order parameter evolution.

Crystal-plane-dependent effects of antifreeze glycoprotein impurity for ice growth dynamics.

An impurity effect on ice crystal growth in supercooled water is an important subject in relation to ice crystal formation in various conditions in the Earth's cryosphere regions. In this review, we consider antifreeze glycoprotein molecules as an impurity. These molecules are well known as functional molecules for controlling ice crystal growth by their adsorption on growing ice/water interfaces. Experiments on free growth of ice crystals in supercooled water containing an antifreeze protein were conducted on the ground and in the International Space Station, and the normal growth rates for the main crystallographic faces of ice, namely, basal and prismatic faces, were precisely measured as functions of growth conditions and time. The crystal-plane-dependent functions of AFGP molecules for ice crystal growth were clearly shown. Based on the magnitude relationship for normal growth rates among basal, prismatic and pyramidal faces, we explain the formation of a dodecahedral external shape of an ice crystal in relation to the key principle governing the growth of polyhedral crystals. Finally, we emphasize that the crystal-plane dependence of the function of antifreeze proteins on ice crystal growth relates to the freezing prevention of living organisms in sub-zero temperature conditions. This article is part of the theme issue 'The physics and chemistry of ice: scaffolding across scales, from the viability of life to the formation of planets'.

How Do Ice Crystals Grow inside Quasiliquid Layers?

A microscopic understanding of crystal-melt interfaces, inseparably involved in the dynamics of crystallization, is a long-standing challenge in condensed matter physics. Here, using an advanced optical microscopy, we directly visualize growing interfaces between ice basal faces and quasiliquid layers (QLLs) during ice crystal growth. This system serves as a model for studying the molecular incorporation process of the crystal growth from a supercooled melt (the so-called melt growth), often hidden by inevitable latent heat diffusion and/or the extremely high crystal growth rate. We reveal that the growth of basal faces inside QLLs proceeds layer by layer via two-dimensional nucleation of monomolecular islands. We also find that the lateral growth rate of the islands is well described by the Wilson-Frenkel law, taking into account the slowing down of the dynamics of water molecules interfaced with ice. These results clearly indicate that, after averaging surface molecular fluctuations, the layer by layer stacking still survives even at the topmost layer on basal faces, which supports the kink-step-terrace picture even for the melt growth.

Contribution of individual olfactory receptors to odor-induced attractive or aversive behavior in mice.

Odorants are recognized by multiple olfactory receptors (ORs) and induce innate behaviors like attraction or aversion via olfactory system in mice. However, a role of an individual OR is unclear. Muscone is recognized by a few ORs including MOR215-1 and MOR214-3, and attracts male mice. Odor preference tests using MOR215-1 knockout mice revealed that MOR215-1 and other OR(s), possibly including MOR214-3, are involved in the attraction. (Z)-5-tetradecen-1-ol (Z5-14:OH) activates ~3 ORs, including Olfr288, and evokes attraction at low levels but aversion at higher levels. Olfr288 knockout mice show no attraction but aversion, suggesting Olfr288 is involved in preference for Z5-14:OH, whereas activation of other low-affinity Z5-14:OH receptors evokes aversion. Each OR appears to send a signal to a neural circuit that possesses distinct valence, leading to a certain behavior. The final output behavior with multiple ORs stimulation is determined by summation (addition or competition) of valences coded by activated ORs.

Superficial siderosis associated with duplicated dura mater detected by CISS reverse MRI.

Superficial siderosis (SS) of the central nervous system is a rare disease caused by chronic or repeated hemorrhages in the subarachnoid space. Closure of dural defects is an effective therapy for SS. Conventional magnetic resonance imaging (MRI), however, cannot sufficiently detect dural tears. To better detect these defects, we analyzed the clinical data of consecutive patients admitted to our department with SS and performed constructive interference in steady-state (CISS) reverse MRI of the brain and spinal cord. CISS reverse method emphasizes the contrast between the dura and cerebrospinal fluid, enabling detection of dural defects better than usual T2-weighted MRI. CISS reverse MRI detected fluid-filled collections in five of the seven SS patients we studied. These images showed that the fluid-filled collections were packed within duplicated dura mater. In three of the five, dural defects were confirmed intraoperatively. We postulate that fluid-filled collections are actually derived from dissection of the dura mater. In accordance with the Monro-Kellie hypothesis, we propose that CSF transferal into the fluid-filled collections via dural defects induces an increase in blood volume and promotes the exudation of blood from engorged vessels. In patients with SS, it is very important to repair dural defects to prevent further associated neurological impairment. CISS reverse MRI is useful for detecting such dural defects.

Anti-ganglionic AChR antibodies in Japanese patients with motility disorders.

BACKGROUND: The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO). METHODS: First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups. RESULTS: In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia. CONCLUSIONS: These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders.

Liquid-like behavior of UV-irradiated interstellar ice analog at low temperatures.

Interstellar ice is believed to be a cradle of complex organic compounds, commonly found within icy comets and interstellar clouds, in association with ultraviolet (UV) irradiation and subsequent warming. We found that UV-irradiated amorphous ices composed of H2O, CH3OH, and NH3 and of pure H2O behave like liquids over the temperature ranges of 65 to 150 kelvin and 50 to 140 kelvin, respectively. This low-viscosity liquid-like ice may enhance the formation of organic compounds including prebiotic molecules and the accretion of icy dust to form icy planetesimals under certain interstellar conditions.