Left-Right Asymmetry in Invertebrates: From Molecules to Organisms.

Although most animals appear symmetric externally, they exhibit chirality within their body cavity, i.e., in terms of asymmetric organ position, directional organ looping, and lateralized organ function. Left-right (LR) asymmetry is determined genetically by intricate molecular interactions that occur during development. Key genes have been elucidated in several species. There are common mechanisms in vertebrates and invertebrates, but some appear to exhibit unique mechanisms. This review focuses on LR asymmetry formation in invertebrates, particularly Drosophila, ascidians, and mollusks. It aims to understand the role of the genes that are key to creating LR asymmetry and how chirality information is converted/transmitted across the hierarchies from molecules to cells and from cells to tissues.

Fast and artifact-free circular dichroism measurement of solid-state structural changes.

A novel chiroptical spectrophotometer, Multichannel (MC)-circular dichroism (CD), which does not require a wavelength scan and provides artifact-free CD spectra in seconds, was developed by solving the incompatibility problem between data acquisition and modulation timescales. The design and instrumentation are compared with the Universal Chiroptical Spectrophotometer (UCS)-1, which can measure artifact-free CD spectra in the solid state. Enantiomeric single crystals composed of achiral components, α-Ni(H2 O)6 ・SO4 , and achiral films with substantial macroscopic anisotropies were measured on both MC-CD and UCS-1 and compared.

Use of Conglomerate Mixed Crystals to Deracemize a Stable Racemic-Compound-Forming System.

Deracemization extended to racemic-compound-forming systems is demonstrated. We present here the first results of an alternative for the resolution of systems that exhibit a stable racemic compound but also a closely related conglomerate-forming system. If the couples of enantiomers forming the racemic compound and the enantiomers of the stable conglomerate can syncrystallize in mirror-related partial solid solutions, it is possible to deracemize the racemic mixture of mixed crystals to access to a single handedness. The evidence for this possibility is given in three examples by using temperature-cycling-induced deracemization.

Neurobiological mechanisms of dialectical behavior therapy and Morita therapy, two psychotherapies inspired by Zen.

Psychotherapy is a learning process. Updating the prediction models of the brain may be the mechanism underlying psychotherapeutic changes. Although developed in different eras and cultures, dialectical behavior therapy (DBT) and Morita therapy are influenced by Zen principles, and both emphasize the acceptance of reality and suffering. This article reviews these two treatments, their common and distinct therapeutic factors, and their neuroscientific implications. Additionally, it proposes a framework that includes the predictive function of the mind, constructed emotions, mindfulness, therapeutic relationship, and changes enabled via reward predictions. Brain networks, including the Default Mode Network (DMN), amygdala, fear circuitry, and reward pathways, contribute to the constructive process of brain predictions. Both treatments target the assimilation of prediction errors, gradual reorganization of predictive models, and creation of a life with step-by-step constructive rewards. By elucidating the possible neurobiological mechanisms of these psychotherapeutic techniques, this article is expected to serve as the first step towards filling the cultural gap and creating more teaching methods based on these concepts.

The development of CRISPR for a mollusc establishes the formin Lsdia1 as the long-sought gene for snail dextral/sinistral coiling.

The establishment of left-right body asymmetry is a key biological process that is tightly regulated genetically. In the first application of CRISPR/Cas9 to a mollusc, we show decisively that the actin-related diaphanous gene Lsdia1 is the single maternal gene that determines the shell coiling direction of the freshwater snail Lymnaea stagnalis Biallelic frameshift mutations of the gene produced sinistrally coiled offspring generation after generation, in the otherwise totally dextral genetic background. This is the gene sought for over a century. We also show that the gene sets the chirality at the one-cell stage, the earliest observed symmetry-breaking event linked directly to body handedness in the animal kingdom. The early intracellular chirality is superseded by the inter-cellular chirality during the 3rd cleavage, leading to asymmetric nodal and Pitx expression, and then to organismal body handedness. Thus, our findings have important implications for chiromorphogenesis in invertebrates as well as vertebrates, including humans, and for the evolution of snail chirality. This article has an associated 'The people behind the papers' interview.

Statistical modeling for temporal dominance of sensations data incorporating individual characteristics of panelists: an application to data of milk chocolate.

We discuss the modeling of temporal dominance of sensations (TDS) data, time series data appearing in sensory analysis, that describe temporal changes of the dominant taste in the oral cavity. Our aims were to obtain the transition process of attributes (tastes and mouthfeels) in the oral cavity, to express the tendency of dominance durations of attributes, and to specify factors (such as sex, age, food preference, dietary habits, and sensitivity to a particular taste) affecting dominance durations, simultaneously. To achieve these aims, we propose an analysis procedure applying models based on the semi-Markov chain and the negative binomial regression, one of the generalized linear models. By using our method, we can take differences among individual panelists and dominant attributes into account. We analyzed TDS data for milk chocolate with the proposed method and verified the performance of our model compared with conventional analysis methods. We found that our proposed model outperformed conventional ones; moreover, we identified factors that have effects on dominance durations. Results of an experiment support the importance of reflecting characteristics of panelists and attributes. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-021-05260-9.

Correction to: Statistical modeling for temporal dominance of sensations data incorporating individual characteristics of panelists: an application to data of milk chocolate.

[This corrects the article DOI: 10.1007/s13197-021-05260-9.].

Workplace Bullying and Patient Aggression Related to COVID-19 and its Association with Psychological Distress among Health Care Professionals during the COVID-19 Pandemic in Japan.

The novel coronavirus disease (COVID-19) pandemic has spread throughout the world. Poor mental health has been reported among healthcare professionals responding to COVID-19. However, no study has examined the impact of COVID-19-related workplace bullying or patient aggression on the mental health of healthcare professionals during the COVID-19 outbreak. This study examined the prevalence of COVID-19-related workplace bullying and patient aggression and its association with psychological distress among healthcare professionals during the COVID-19 outbreak in Japan. This was a cross-sectional study conducted from May 22 to 26, 2020, inviting participants (n = 1,421) from an online survey of full-time employees. We limited the sample to healthcare professionals for further analyses. Using an online self-report questionnaire, workplace bullying and patient aggression related to COVID-19 was measured using nine items with dichotomous response options. Psychological distress was measured using the Japanese version of Brief Job Stress Questionnaire. Among 1,032 participants (72.6%) who completed the survey, 111 healthcare professionals were identified. Among them, 19 participants (17.1%) had experienced any COVID-19-related workplace bullying or patient aggression: 11 participants (9.9%) had experienced any workplace bullying and 12 participants (10.8%) had experienced any patient aggression. Multiple linear regression analysis showed that any bullying or patient aggression related to COVID-19 significantly correlated with psychological distress. It was suggested that a non-negligible proportion of participants experienced workplace bullying or patient aggression related to COVID-19. Preventing and reducing workplace bullying and patient aggression may be effective in improving mental health of healthcare professionals during the COVID-19 outbreak.

GSK3ß controls the timing and pattern of the fifth spiral cleavage at the 2-4 cell stage in Lymnaea stagnalis.

Establishment of the body plan of multicellular organisms by the primary body axis determination and cell-fate specification is a key issue in biology. We have examined the mRNA localization of three Wnt pathway components gsk3ß, ß-catenin, and disheveled and investigated the effects of four selective inhibitors of these proteins on the early developmental stages of the spiral cleavage embryo of the fresh water snail Lymnaea (L.) stagnalis. mRNAs for gsk3ß and ß-catenin were distributed uniformly throughout the embryo during development whereas disheveled mRNA showed specific localization with intra- and inter-blastomere differences in concentration along the A-V axis during spiral cleavages. Remarkably, through inhibitor studies, we identified a short sensitive period from the 2- to 4-cell stage in which GSK3ß inhibition by the highly specific 1-azakenpaullone (AZ) and by LiCl induced a subsequent dramatic developmental delay and alteration of the cleavage patterns of blastomeres at the fifth cleavage (16- to 24-cell stage) resulting in exogastrulation and other abnormalities in later stages. Inhibition of ß-Catenin or Disheveled had no effect. Our inhibitor experiments establish a novel role for GSK3ß in the developmental timing and orientated cell division of the snail embryo. Further work will be needed to identify the downstream targets of the kinase.

Stereospecific Synthesis of Tris-heteroleptic Tris-cyclometalated Iridium(III) Complexes via Different Heteroleptic Halogen-Bridged Iridium(III) Dimers and Their Photophysical Properties.

Herein, we report on the stereospecific synthesis of two single isomers of tris-heteroleptic tris-cyclometalated iridium(III) (Ir(III)) complexes composed of three different nonsymmetric cyclometalating ligands via heteroleptic halogen-bridged Ir dimers [Ir(tpy)(F2ppy)(µ-Br)]2 17b and [Ir(mpiq)(F2ppy)(µ-Br)]2 27b (tpyH: (2-(4'-tolyl)pyridine) and F2ppyH: (2-(4',6'-difluorophenyl)pyridine), and mpiqH: (1-(4'-methylphenyl)isoquinoline)) prepared by Zn2+-promoted degradation of Ir(tpy)2(F2ppy) 21 and Ir(mpiq)2(F2ppy) 26, as reported by us. Subsequently, 17b and 27b were converted to the tris-heteroleptic tris-cyclometalated Ir complexes Ir(tpy)(F2ppy)(mpiq) 25 consisting of tpy, F2ppy, and mpiq, as confirmed by spectroscopic data and X-ray crystal structure analysis. The first important point in this work is the selective synthesis of specific isomers among eight possible stereoisomers of Ir complexes having the same combination of three cyclometalating ligands. Namely, two meridional forms of 25 were synthesized and isolated. The second finding is that the different stereoisomers of 25 have different stability. Finally, different stereoisomers exhibit different emission spectra. Namely, one of its stereoisomers 25a exhibits a single broad emission from ca. 550 nm to ca. 650 nm (orange emission), while stereoisomer 25c emits dual emission at ca. 509 nm and ca. 600 nm (pale pink emission), as supported by time-dependent density functional theory calculation. To the best of our knowledge, this is the first report of the selective and efficient synthesis of different stereoisomers of tris-heteroleptic tris-cyclometalated Ir(III) complexes that have different stabilities and different photophysical properties.

Design and synthesis of boron containing monosaccharides by the hydroboration of d-glucal for use in boron neutron capture therapy (BNCT).

Boron neutron capture therapy (BNCT) is one of the radiotherapies that involves the use of boron-containing compounds for the treatment of cancer. Boron-10 (10B) containing compounds that can accumulate in tumor tissue are expected to be suitable agents for BNCT. We report herein on the design and synthesis of some new BNCT agents based on a d-glucose scaffold, since glycoconjugation has been recognized as a useful strategy for the specific targeting of tumors. To introduce a boryl group into a d-glucose scaffold, we focused on the hydroboration of d-glucal derivatives, which have a double bond between the C1 and C2 positions. It was hypothesized that a C-B bond could be introduced at the C2 position of d-glucose by the hydroboration of d-glucal derivatives and that the products could be stabilized by conversion to the corresponding boronic acid ester. To test this hypothesis, we prepared some 2-boryl-1,2-dideoxy-d-glucose derivatives as boron carriers and evaluated their cytotoxicity and cellular uptake activity to cancer cells, especially under hypoxic conditions.

Conformation change of hornet silk proteins in the solid phase in response to external stimulation.

Hornet silks adopt a variety of morphology such as fibers, sponge, films, and gels depending on the preparation methods. We have studied the conformation change of hornet silk proteins (Vespa mandarina) as regenerated films, using chiroptical spectrophotometer universal chiroptical spectrophotometer 1, which can measure true circular dichroism spectra without artifact signals that are intrinsic to solid-state samples. The spectra showed that the proteins in films alter the conformation rapidly from the α-helix to the coiled coil and then to a ß-sheet structure in response to heat/moisture treatment, but the transformation stopped at the coiled coil state when the sample was soaked in EtOH/water solution. Water is required for the α-helix to the coiled coil transition, and extra energy is required for the further transition to a ß-sheet structure. This is the first successful circular dichroism study of fibril silk proteins to follow the conformation changes in the solid state. This work shows that proteins can undergo conformational changes easily even in the solid phase in response to external stimuli, and this can be traced by solid-phase-feasible chiroptical spectrophotometers. Application of unnatural stress to proteins gives valuable insights into their structure and characteristics.

Effects of chocolate containing Leuconostoc mesenteroides strain NTM048 on immune function: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Previous reports showed that oral administration of Leuconostoc mesenteroides strain NTM048 increases IgA levels and CD4+ T cell population in feces and mice, respectively, as revealed by flow cytometric analysis of splenocytes. This study aimed to evaluate the effect of chocolate supplemented with L. mesenteroides strain NTM048 (> 1.00 × 109 CFU/day, NTM048) on the immune parameters of healthy subjects, using a randomized, placebo-controlled, double-blinded study design. METHODS: Participants (mean age: 46.3 years) ingested 28 g of test food daily, at a time of their own choice, for 4 weeks. The immunological parameters of all participants were evaluated two times (pre- and post- ingestion). At the end of the study, various immunological parameters of the participants were measured and scoring of immunological vigor (SIV) was performed using a comprehensive algorithm. RESULTS: Ingestion of NTM048-supplemented chocolate significantly improved SIV in the NTM048 group (18.6 ± 1.6) compared to that in the placebo group (17.8 ± 2.0) after 4 weeks (p = 0.049). Several immunological parameters (CD8+T cells, CD8+CD28+ T cells, and memory T cells) were significantly elevated in the NTM048 group as compared to the placebo group (all p < 0.05). In addition, T cell proliferation index at post-ingestion significantly increased compared with that at pre-ingestion in the NTM048 (p = 0.017) and placebo groups (p = 0.037), although no differences were observed between the two groups. CONCLUSION: Our results suggest that ingestion of chocolate supplemented with NTM048 is effective against the age-related decline in T cell-related immune functions. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000021989. Registered 19 April 2016, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000025321.

A twisting story: how a single gene twists a snail? Mechanogenetics.

Left-right (l-r) symmetry breaking and the establishment of asymmetric animal body plan during embryonic development are fundamental questions in nature. The molecular basis of l-r symmetry breaking of snails is a fascinating topic as it is determined by a maternal single handedness-determining locus at a very early developmental stage. This perspective describes the current state of the art of the chiromorphogenesis, mainly based on our own work, i.e. the first step of l-r symmetry breaking, as proven by our "Mechanogenetics", before the start of zygotic gene expression, transfer of chirality information to the cell-fate determining stage, and the expression of nodal at the blastula stage. The Nodal signalling pathway is a common mechanism in vertebrates' chiromorphogenesis in later development. Studies on snails, especially Lymnaea (L.) stagnalis, shall give important insights into the molecular basis of chiromorphogenesis not only in Lophotrochozoa but in vertebrates as well.

Efficient Synthesis of Tris-Heteroleptic Iridium(III) Complexes Based on the Zn2+-Promoted Degradation of Tris-Cyclometalated Iridium(III) Complexes and Their Photophysical Properties.

We report on the efficient synthesis of tris-heteroleptic iridium (Ir) complexes based on the degradation of tris-cyclometalated Ir complexes (IrL3, L: cyclometalating ligand) in the presence of Brønsted and Lewis acids such as HCl (in 1,4-dioxane), AlCl3, TMSCl, and ZnX2 (X = Br or Cl), which affords the corresponding halogen-bridged Ir dimers (µ-complexes). Tris-cyclometalated Ir complexes containing electron-withdrawing groups such as fluorine, nitro, or CF3 moieties on the ligands were less reactive. This different reactivity was applied to the selective degradation of heteroleptic Ir complexes such as fac-Ir(tpy)2(F2ppy) (fac-12) (tpy: 2-(4'-tolyl)pyridine and F2ppy: 2-(4',6'-difluorophenyl)pyridine), mer-Ir(tpy)2(F2ppy) (mer-12), and mer-Ir(mpiq)2(F2ppy) (mer-15) (mpiq: 1-(4'-methylphenyl)isoquinoline). For example, the reaction of mer-12 with ZnBr2 gave the heteroleptic µ-complex [{Ir(tpy)(F2ppy)(µ-Br)}2] 27b as a major product, resulting from the selective elimination of the tpy ligand of mer-12, and treatment of 27b with acetylacetone (acacH) afforded the corresponding tris-heteroleptic Ir complex Ir(tpy)(F2ppy)(acac)18. In addition, another tris-heteroleptic Ir complex 35a having 8-benzenesulfonylamidoquinoline (8BSQ) ligand was synthesized. Mechanistic studies of this degradation reaction and the photochemical properties, especially a dual emission, of these newly synthesized tris-heteroleptic Ir complexes are also reported.

Site-selective anion recognition of an interlocked dimer.

Interlocked dimer 2, which is composed of two physically interlocked monomers 1, has three cavities (cavity A × 2 and cavity B × 1) and can encapsulate three anions, such as NO3- and BF4-, one anion per cavity. There are six possible encapsulation patterns, A-F; two (A and F) contain only one kind of anion and the others (B-E) contain both NO3- and BF4- at the same time with different ratios and with different positions. Anion competition experiments showed that in addition to F, which encapsulates three NO3- ions, C, in which NO3- and BF4- ions are captured in cavities A and cavity B, respectively, was selectively formed. Detailed investigations have revealed that B-E were formed by dimerization, but three of the four were subjected to anion exchange and converged into C or F. This selective formation can be explained by the fact that NO3- is a better anion template than BF4-, as well as the molecular structure of the interlocked dimer; cavities A are surrounded by four bridging ligands and can be accessed by free anions, whereas no space available for anion exchange is present around cavity B because this cavity is surrounded by eight bridging ligands. Therefore, the BF4- ions in cavities A are expelled by free NO3-, but the BF4- ion in cavity B is not, resulting in the selection of C and F. We have found that the volume of the cavity influenced anion recognition. New interlocked dimer 3, which has smaller cavities than those of 2, captured three NO3- ions to form F, whereas only a small amount of an interlocked dimer that contains both NO3- and BF4- was formed.

Metabolic syndrome components and diabetes incidence according to the presence or absence of impaired fasting glucose: The Japan Epidemiology Collaboration on Occupational Health Study.

BACKGROUND: We prospectively examined the association of diabetes risk with the number of metabolic abnormalities, as well as their combinations, according to the presence or absence of impaired fasting glucose (IFG) in a large-scale Japanese working population. METHODS: Participants included 55,271 workers at 11 companies who received periodic health check-ups between 2008 and 2013. The metabolic syndrome (MetS) components were defined using the 2009 Joint Interim Statement. IFG was defined as fasting plasma glucose 5.6-6.9 mmol/L. Diabetes newly diagnosed after the baseline examination was defined according to the American Diabetes Association criteria. We calculated the hazard ratios (HRs) for diabetes incidence using the Cox proportional hazards model. RESULTS: During the follow-up period (median 4.95 years), 3183 subjects developed diabetes. In individuals with normal fasting glucose levels, the risk of diabetes increased steadily with the increasing number of MetS components; the multivariable-adjusted HRs for incident diabetes for the number of MetS components were 2.0, 4.3, 7.0, and 10.0 for one, two, three, or four MetS components, respectively, compared with the absence of components. A similar association was observed among individuals with IFG; the corresponding HRs were 17.6, 23.8, 33.9, and 40.7. The combinations that included central obesity appeared to be more strongly associated with diabetes risk than other combinations with the same number of MetS components within the same glucose status. CONCLUSIONS: Our findings indicate that risk stratification of individuals by the presence or absence of IFG and the number of MetS components can detect individuals with a high risk of diabetes.

Independent exercise for glottal incompetence to improve vocal problems and prevent aspiration pneumonia in the elderly: a randomized controlled trial.

OBJECTIVES: To evaluate the effect of a self-controlled vocal exercise in elderly people with glottal closure insufficiency. DESIGN: Parallel-arm, individual randomized controlled trial. METHODS: Patients who visited one of 10 medical centers under the National Hospital Organization group in Japan for the first time, aged 60 years or older, complaining of aspiration or hoarseness, and endoscopically confirmed to have glottal closure insufficiency owing to vocal cord atrophy, were enrolled in this study. They were randomly assigned to an intervention or a control group. The patients of the intervention group were given guidance and a DVD about a self-controlled vocal exercise. The maximum phonation time which is a measure of glottal closure was evaluated, and the number of patients who developed pneumonia during the six months was compared between the two groups. RESULTS: Of the 543 patients enrolled in this trial, 259 were allocated into the intervention group and 284 into the control; 60 of the intervention group and 75 of the control were not able to continue the trial. A total of 199 patients (age 73.9 ±7.25 years) in the intervention group and 209 (73.3 ±6.68 years) in the control completed the six-month trial. Intervention of the self-controlled vocal exercise extended the maximum phonation time significantly ( p < 0.001). There were two hospitalizations for pneumonia in the intervention group and 18 in the control group, representing a significant difference ( p < 0.001). CONCLUSION: The self-controlled vocal exercise allowed patients to achieve vocal cord adduction and improve glottal closure insufficiency, which reduced the rate of hospitalization for pneumonia significantly. CLINICAL TRIAL: gov Identifier-UMIN000015567.