Exploratory study of cold hypersensitivity in Japanese women: genetic associations and somatic symptom burden.

Temperature perception is essential for humans to discern the environment and maintain homeostasis. However, some individuals experience cold hypersensitivity, characterized by a subjective feeling of coldness despite ambient environmental temperatures being normal, the underlying mechanisms of which are unknown. In this study, we aimed to investigate the relationship between subjective cold symptoms and somatic burden or single nucleotide polymorphisms to understand the causes of cold hypersensitivity. We conducted an online questionnaire survey [comprising 30 questions, including past medical history, subjective symptoms of cold hypersensitivity, and the Somatic Symptom Scale-8 (SSS-8)]. Respondents were 1200 Japanese adult female volunteers (age: 20-59 years), recruited between April 21 and May 25, 2022, who were customers of MYCODE, a personal genome service in Japan. Among the 1111 participants, 599 (54%) reported cold hypersensitivity. Higher cold hypersensitivity severity was positively associated with the SSS-8 scores. Additionally, a genome-wide association study for cold hypersensitivity was conducted using array-based genomic data obtained from genetic testing. We identified 11 lead variants showing suggestive associations (P < 1 × 10-5) with cold hypersensitivity, some of which showed a reasonable change in expression in specific tissues in the Genotype-Tissue Expression database. The study findings shed light on the underlying causes of cold hypersensitivity.

A web-based survey on various symptoms of computer vision syndrome and the genetic understanding based on a multi-trait genome-wide association study.

A variety of eye-related symptoms due to the overuse of digital devices is collectively referred to as computer vision syndrome (CVS). In this study, a web-based survey about mind and body functions, including eye strain, was conducted on 1998 Japanese volunteers. To investigate the biological mechanisms behind CVS, a multi-trait genome-wide association study (GWAS), a multivariate analysis on individual-level multivariate data, was performed based on the structural equation modeling methodology assuming a causal pathway for a genetic variant to influence each symptom via a single common latent variable. Twelve loci containing lead variants with a suggestive level of significance were identified. Two loci showed relatively strong signals and were associated with TRABD2B relative to the Wnt signaling pathway and SDK1 having neuronal adhesion and immune functions, respectively. By utilizing publicly available eQTL data, colocalization between GWAS and eQTL signals for four loci was detected, and a locus on 2p25.3 showed a strong colocalization (PPH4 > 0.9) on retinal MYT1L, known to play an important role in neuronal differentiation. This study suggested that the use of multivariate questionnaire data and multi-trait GWAS can lead to biologically reasonable findings and enhance our genetic understanding of complex relationships among symptoms related to CVS.

Genome-wide association studies and heritability analysis reveal the involvement of host genetics in the Japanese gut microbiota.

Numerous host extrinsic and intrinsic factors affect the gut microbiota composition, but their cumulative effects do not sufficiently explain the variation in the microbiota, suggesting contributions of missing factors. The Japanese population possesses homogeneous genetic features suitable for genome-wide association study (GWAS). Here, we performed GWASs for human gut microbiota using 1068 healthy Japanese adults. To precisely evaluate genetic effects, we corrected for the impacts of numerous host extrinsic and demographic factors by introducing them as covariates, enabling us to discover five loci significantly associated with microbiome diversity measures: HS3ST4, C2CD2, 2p16.1, 10p15.1, and 18q12.2. Nevertheless, these five variants explain only a small fraction of the variation in the gut microbiota. We subsequently investigated the heritability of each of the 21 core genera and found that the abundances of six genera are heritable. We propose that the gut microbiota composition is affected by a highly polygenic architecture rather than several strongly associated variants in the Japanese population.

Association between functional lactase variants and a high abundance of Bifidobacterium in the gut of healthy Japanese people.

Previous studies have shown that Japanese people exhibit a higher abundance of Bifidobacterium compared to people from other countries. Among the possible factors affecting the gut microbiota composition, an association of functional lactase gene variants with a higher abundance of Bifidobacterium in the gut has been proposed in some reports. However, no Japanese subjects were included in these studies. In this study, we investigated the possible contribution of functional lactase loci to the high abundance of Bifidobacterium in Japanese populations. Based on a data analysis assessing 1,068 healthy Japanese adults, a number of subjects is at least seven times greater than that reported in available online data. all subjects possessed CC genotype at rs4988235 and the GG at rs182549, which are associated with low lactase activity. We observed a positive correlation between dairy product intake and Bifidobacterium abundance in the gut. Considering previous reports, which revealed that four additional functional lactase loci, rs145946881, rs41380347, rs41525747 and rs869051967 (ss820486563), are also associated with low lactase activity in Japanese people, our findings imply the possible contribution of host genetic variation-associated low lactase activity to the high abundance of Bifidobacterium in the Japanese population.

Light and electron microscopic studies of the intestinal epithelium in Notoplana humilis (Platyhelminthes, Polycladida): the contribution of mesodermal/gastrodermal neoblasts to intestinal regeneration.

Some free-living flatworms in the phylum Platyhelminthes possess strong regenerative capability that depends on putative pluripotent stem cells known as neoblasts. These neoblasts are defined based on several criteria, including their proliferative capacity and the presence of cellular components known as chromatoid bodies. Polyclads, which are marine flatworms, have the potential to be a good model system for stem cell research, yet little information is available regarding neoblasts and regeneration. In this study, transmission electron microscopy and immunostaining analyses, using antibodies against phospho-histone H3 and BrdU, were used to identify two populations of neoblasts in the polyclad Notoplana humilis: mesodermal neoblasts (located in the mesenchymal space) and gastrodermal neoblasts (located within the intestine, where granular club cells and phagocytic cells are also located). Light and electron microscopic analyses also suggested that phagocytic cells and mesodermal/gastrodermal neoblasts, but not granular club cells, migrated into blastemas and remodeled the intestine during regeneration. Therefore, we suggest that, in polyclads, intestinal regeneration is accomplished by mechanisms underlying both morphallaxis (remodeling of pre-existing tissues) and epimorphosis (de novo tissue formation derived from mesodermal/gastrodermal neoblasts). Based on the assumption that gastrodermal neoblasts, which are derived from mesodermal neoblasts, are intestinal stem cells, we propose a model to study intestinal regeneration.

Phospholipase C-ß1 and ß4 contribute to non-genetic cell-to-cell variability in histamine-induced calcium signals in HeLa cells.

A uniform extracellular stimulus triggers cell-specific patterns of Ca(2+) signals, even in genetically identical cell populations. However, the underlying mechanism that generates the cell-to-cell variability remains unknown. We monitored cytosolic inositol 1,4,5-trisphosphate (IP3) concentration changes using a fluorescent IP3 sensor in single HeLa cells showing different patterns of histamine-induced Ca(2+) oscillations in terms of the time constant of Ca(2+) spike amplitude decay and the Ca(2+) oscillation frequency. HeLa cells stimulated with histamine exhibited a considerable variation in the temporal pattern of Ca(2+) signals and we found that there were cell-specific IP3 dynamics depending on the patterns of Ca(2+) signals. RT-PCR and western blot analyses showed that phospholipase C (PLC)-ß1, -ß3, -ß4, -γ1, -δ3 and -ε were expressed at relatively high levels in HeLa cells. Small interfering RNA-mediated silencing of PLC isozymes revealed that PLC-ß1 and PLC-ß4 were specifically involved in the histamine-induced IP3 increases in HeLa cells. Modulation of IP3 dynamics by knockdown or overexpression of the isozymes PLC-ß1 and PLC-ß4 resulted in specific changes in the characteristics of Ca(2+) oscillations, such as the time constant of the temporal changes in the Ca(2+) spike amplitude and the Ca(2+) oscillation frequency, within the range of the cell-to-cell variability found in wild-type cell populations. These findings indicate that the heterogeneity in the process of IP3 production, rather than IP3-induced Ca(2+) release, can cause cell-to-cell variability in the patterns of Ca(2+) signals and that PLC-ß1 and PLC-ß4 contribute to generate cell-specific Ca(2+) signals evoked by G protein-coupled receptor stimulation.

[Thoracoscopic radical esophagectomy for cancer treatment].

More than 15 years have passed since thoracoscopic surgery was first employed in Japan as a treatment for esophageal cancer with curative intent. Because of the proliferation of techniques that can be used to obtain an adequate operative field, such as hand assist, placing the patient in the prone position, etc., the number of approaches to thoracoscopic surgery has been increasing, contrary to expectations of standardization. The technique of mediastinal dissection has been refined with increasing knowledge of microanatomy, which can be clarified under the magnified view provided in thoracoscopic surgery. Comparable pulmonary function and survival are achieved after both thoracoscopic surgery and open-chest surgery. The accreditation board of the Japan Society for Endoscopic Surgery is now standardizing the thoracoscopic technique. To avoid surgical mistakes, thorough knowledge and adherence to the proper indications are essential.

To be or not to be a flatworm: the acoel controversy.

Since first described, acoels were considered members of the flatworms (Platyhelminthes). However, no clear synapomorphies among the three large flatworm taxa -- the Catenulida, the Acoelomorpha and the Rhabditophora -- have been characterized to date. Molecular phylogenies, on the other hand, commonly positioned acoels separate from other flatworms. Accordingly, our own multi-locus phylogenetic analysis using 43 genes and 23 animal species places the acoel flatworm Isodiametra pulchra at the base of all Bilateria, distant from other flatworms. By contrast, novel data on the distribution and proliferation of stem cells and the specific mode of epidermal replacement constitute a strong synapomorphy for the Acoela plus the major group of flatworms, the Rhabditophora. The expression of a piwi-like gene not only in gonadal, but also in adult somatic stem cells is another unique feature among bilaterians. These two independent stem-cell-related characters put the Acoela into the Platyhelminthes-Lophotrochozoa clade and account for the most parsimonious evolutionary explanation of epidermal cell renewal in the Bilateria. Most available multigene analyses produce conflicting results regarding the position of the acoels in the tree of life. Given these phylogenomic conflicts and the contradiction of developmental and morphological data with phylogenomic results, the monophyly of the phylum Platyhelminthes and the position of the Acoela remain unresolved. By these data, both the inclusion of Acoela within Platyhelminthes, and their separation from flatworms as basal bilaterians are well-supported alternatives.

Detection and changes in levels of testosterone during spermatogenesis in the freshwater planarian Bdellocephala brunnea.

It was reported recently that vertebrate-type steroids exist and control reproduction in several groups of invertebrates, including molluscs. Sexually reproductive freshwater planarians of the species Bdellocephala brunnea have a limited breeding season in their natural habitat. This phenomenon suggests that some endogenous reproductive hormones might play a role in vivo. However, to date, sex steroids such as androgen, estrogen, and progesterone have not been found in planarians. The goal of the present study was to determine whether androgen is present in sexual planarians such as B. brunnea. The presence of testosterone was detected by high-pressure liquid chromatography and, in sexually reproductive individuals in which no seminal vesicles were visible, the level of testosterone was about twice than that in individuals with visible seminal vesicles. An enzyme-linked immunosorbent assay revealed that the levels of testosterone during terminal spermatogenesis were three times higher than during the spermatocyte-building phase. Our results indicate that sexually reproductive freshwater planarians such as B. brunnea might have vertebrate-type steroids and show variation in testosterone levels during spermatogenesis.

Motility recovery during the process of regeneration in freshwater planarians.

Planarians are phylogenetically considered to be the most primitive animals to have acquired a central nervous system and a bilateral symmetry. However, very little is known about the relationship between planarian brain integration and motility. A behavioural and histological study was therefore undertaken in an aspect of planarian motility recovery during its process of regeneration. Quantitative analysis showed that the tail-regenerates recovered their motility gradually as the new heads reformed, while the non-head reforming tail fragments showed no signs of recovery. The head fragments recovered their motility soon after cutting. The cephalic margin was not a function of the motility. The brain regenerated back to its original form in approximately two weeks, the same amount of time it took for the decapitated tails to recover their motility to initial levels. This study provides quantitative evidence that the planarian motility recovered in relation to the head formation during its process of regeneration. Our results reinforce the view that the brain plays a functional part in activating planarian motility.

Rhodopsin-like proteins in planarian eye and auricle: detection and functional analysis

The presence of rhodopsin-like proteins in the eyes and auricles of the freshwater planarian Dugesia japonica was confirmed using anti-frog-rhodopsin rabbit IgG. The apparent relative molecular masses of these proteins were 65x10(3) and 62x10(3), and positive reactions to IgG were localized to the microvilli of the photoreceptor cells in the eyes and to the sensory cilia, rootlets and microvilli in the auricles. Eye- or head-excised planarians showed no negative phototaxis, whereas intact or auricle-excised planarians did. During regeneration in head-excised planarians, the appearance of rhodopsin-like proteins in the regenerating eyes corresponded to the recovery of negative phototaxis behaviour. Head or auricle excision enhanced asexual fission under continuous illumination. However, eye excision had no such effect. These results suggest that the rhodopsin-like proteins in the eyes work as photoreceptors for negative phototaxis behaviour and that, in the auricles, they are involved in asexual fission originating from the circadian rhythm.