Comment on Nahok et al. Monosodium Glutamate Induces Changes in Hepatic and Renal Metabolic Profiles and Gut Microbiome of Wistar Rats. Nutrients 2021, 13, 1865.

This letter is to comment on the study of Nahok, K. et al. [...].

A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models.

Genetic and epidemiological evidence has suggested that genetic factors are important in schizophrenia, although its pathophysiology is poorly understood. This study used whole-exome sequencing to investigate potential novel schizophrenia-causing genes in a Japanese family containing several members affected by severe or treatment-resistant schizophrenia. A missense variant, chr12:132064747C>T (rs200626129, P2805L), in the E1A-binding protein P400 (EP400) gene completely segregated with schizophrenia in this family. Furthermore, numerous other EP400 mutations were identified in the targeted sequencing of a schizophrenia patient cohort. We also created two lines of Ep400 gene-edited mice, which had anxiety-like behaviours and reduced axon diameters. Our findings suggest that rs200626129 in EP400 is likely to cause schizophrenia in this Japanese family, and may lead to a better understanding and treatment of schizophrenia.

Visualizing the helical stacking of octahedral metallomesogens with a chiral core.

A combination of grazing-incidence X-ray diffraction and molecular dynamics simulation studies led to the visualization of the stacking structure of a helical columnar liquid crystal formed by enantiopure octahedral metallomesogens with ΔΛ chirality. The helical structure was elucidated as a hybrid of two major proposed structures.

Double-Gyroid Nanostructure Formation by Aggregation-Induced Atropisomerization and Co-Assembly of Ionic Liquid-Crystalline Amphiphiles.

We report a new molecular-design principle for creating double-gyroid nanostructured molecular assemblies based on atropisomerization. Ionic amphiphiles containing two imidazolium rings close to each other were designed and synthesized. NMR data revealed that the rotation of the imidazolium rings is restricted, with an activation energy as high as 63 kJ mol-1 in DMSO-d6 solution (DFT prediction for a model compound in the vacuum: 90-100 kJ mol-1 ). Due to the restricted rotation, the amphiphiles feature "double" atropisomeric axes in their ionic segments and form three stable atropisomers: meso, R, and S. These isomers co-organize into I a 3 ‾ d -type bicontinuous cubic liquid-crystalline mesophases through nanosegregation of the ionic and non-ionic parts. Considering the intrinsic characteristic of I a 3 ‾ d -type bicontinuous cubic structures that they are composed of intertwined right- and left-handed single gyroids, we propose that the simultaneous presence of both R- and S-atropisomers is an important contributor to the formation of double-gyroid structures.

Detection and recognition thresholds for five basic tastes in patients with mild cognitive impairment and Alzheimer's disease dementia.

BACKGROUND: Patients with Alzheimer's disease dementia (ADD) are thought to exhibit taste disorders; however, this has not been extensively studied. We investigated gustatory functions and factors affecting taste in patients with ADD or mild cognitive impairment (MCI) and in non-demented controls (NDCs) and evaluated associations between cognitive impairment and gustatory functions. METHODS: We recruited 29 patients with ADD, 43 with MCI, and 14 with NDCs. We obtained medical and medication history, measured salivary secretion volumes, and performed cognitive function tests, blood tests, whole-mouth gustatory tests, and dietary and gustatory questionnaires. RESULTS: Patients with ADD showed significantly higher recognition threshold values than NDCs (p < 0.05). Many individuals did not recognize umami at the maximum concentration, and this happened more frequently in patients with ADD or MCI than in NDCs. Evaluation items other than cognitive function tests did not show significant differences among the groups, but many individuals had decreased salivation, low serum zinc levels, and were on multiple medications. We found a significant correlation between recognition threshold and age (r = 0.229, p < 0.05) and cognitive function test score (r = 0.268, p < 0.05). CONCLUSIONS: Patients with ADD showed impairment of gustatory function. Gustatory impairment in patients with MCI could not be confirmed. However, many individuals with MCI did not recognize umami, either. Our results suggest that taste disorders in elderly people with cognitive decline occur independently of factors affecting taste such as salivation, zinc levels, or prescription drugs. TRIAL REGISTRATION: The study was registered in the UMIN Clinical Trials Registry on February 10, 2017, with reference number UMIN000026087.

Validation of preferred salt concentration in soup based on a randomized blinded experiment in multiple regions in Japan-influence of umami (L-glutamate) on saltiness and palatability of low-salt solutions.

Sodium reduction is an important public health goal. Individual and population approaches are necessary for reducing the sodium content of processed foods and meals. The aim of the present study is to affirm the effect of monosodium L-glutamate (MSG), an umami substance, on the saltiness or palatability of low-salt solutions and to explore the preferred salt concentration in soup. Five hundred and eighty-four healthy participants from nineteen regions in Japan tasted 0.3, 0.6, and 0.9% NaCl solutions with or without 0.3% MSG. Evaluations of saltiness and palatability for each solution were conducted using a visual analog scale in a double-blinded randomized manner. Saltiness gradually increased depending on the concentration of NaCl. The saltiness of the 0.3% NaCl solution with MSG was rated significantly higher than that without MSG. The palatability ratings were higher for the solutions with MSG than for those without MSG for all NaCl concentrations. In particular, the palatability rating of the 0.3% NaCl solution with MSG was twice as high as that without MSG and was significantly higher than that of the other five test solutions. Furthermore, these results were observed to be approximately the same, irrespective of sex, age, region, etc. Salt reduction is believed to result in a loss of palatability. However, our results suggest that umami can compensate for the loss of palatability caused by salt reduction and that the addition of an appropriate amount of an umami substance can facilitate salt reduction from 0.9 to 0.3% without sacrificing palatability.

Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities.

OBJECTIVE: To identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH. METHODS: We performed whole-exome sequencing (WES) on a Japanese family with multiple individuals with NPH and identified a candidate gene. Then we generated knockout mouse using CRISPR/Cas9 to confirm the effect of the candidate gene on the pathogenesis of hydrocephalus. RESULTS: In WES, we identified a loss-of-function variant in CFAP43 that segregated with the disease. CFAP43 encoding cilia- and flagella-associated protein is preferentially expressed in the testis. Recent studies have revealed that mutations in this gene cause male infertility owing to morphologic abnormalities of sperm flagella. We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia. CONCLUSION: Our results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.

Identification of a novel HLA-A24-restricted cytotoxic T lymphocyte epitope peptide derived from mesothelin in pancreatic cancer.

Pancreatic cancer involves highly malignant tumors, and the development of new therapeutic strategies is critical. Mesothelin is overexpressed in infiltrating pancreatic cancer cells and plays an important role in the invasion and migration processes. In this study, we focused on mesothelin as a tumor-specific antigen target for a pancreatic cancer vaccine. We first investigated the mesothelin-derived epitope peptide restricted to HLA-A*2402. A total of 19 candidate peptides were synthesized, and we then determined their potential to induce peptide-specific cytotoxic T lymphocytes (CTLs). Peptide-specific CTLs were induced by five peptides derived from mesothelin, and these CTLs successfully exhibited peptide-specific IFN-γ production. After the expansion of each CTL, two CTL lines were established, which were induced by mesothelin-10-5 peptide (AFYPGYLCSL). These CTL lines exhibited peptide-specific cytotoxicity and IFN-γ production. Moreover, we were able to generate mesothelin-10-5 peptide-specific CTL clones. These CTL clones also had specific cytotoxic activity against HLA-A*2402-positive pancreatic cancer cells that endogenously expressed mesothelin. These results indicate that the mesothelin-10-5 peptide is a novel HLA-A*2402 restricted CTL epitope and that it is a promising candidate target for antigen-specific immunotherapy against pancreatic cancers.

Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder.

Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case-control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case-control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.

Dissociation of biomolecules in liquid environments during fast heavy-ion irradiation.

The effect of aqueous environment on fast heavy-ion radiation damage of biomolecules was studied by comparative experiments using liquid- and gas-phase amino acid targets. Three types of amino acids with different chemical structures were used: glycine, proline, and hydroxyproline. Ion-induced reaction products were analyzed by time-of-flight secondary-ion mass spectrometry. The results showed that fragments from the amino acids resulting from the C-Cα bond cleavage were the major products for both types of targets. For liquid-phase targets, specific products originating from chemical reactions in solutions were observed. Interestingly, multiple dissociated atomic fragments were negligible for the liquid-phase targets. We found that the ratio of multifragment to total fragment ion yields was approximately half of that for gas-phase targets. This finding agreed with the results of other studies on biomolecular cluster targets. It is concluded that the suppression of molecular multifragmentation is caused by the energy dispersion to numerous water molecules surrounding the biomolecular solutes.

Current status and future prospects of peptide-based cancer vaccines.

Cancer immunotherapy has attracted attention worldwide owing to the recent development of immune checkpoint inhibitors. However, these therapies have shown limited efficacy, and further advancements are needed before these modalities can progress to widespread use. Immune checkpoint inhibitors are a type of nonspecific cancer immunotherapy, and antitumor effects are only observed when cancer-specific T cells are found within the nonspecifically activated T-cell group. In order to facilitate the development of potent immunotherapies, selective enhancement of cancer-specific T cells is essential. In this report, we discuss current and future perspectives, including the latest clinical trials of cancer-specific immunotherapies, particularly cancer peptide vaccines.

Structure determination of molecules in an alignment laser field by femtosecond photoelectron diffraction using an X-ray free-electron laser.

We have successfully determined the internuclear distance of I2 molecules in an alignment laser field by applying our molecular structure determination methodology to an I 2p X-ray photoelectron diffraction profile observed with femtosecond X-ray free electron laser pulses. Using this methodology, we have found that the internuclear distance of the sample I2 molecules in an alignment Nd:YAG laser field of 6 × 1011 W/cm2 is elongated by from 0.18 to 0.30 Å "in average" relatively to the equilibrium internuclear distance of 2.666 Å. Thus, the present experiment constitutes a critical step towards the goal of femtosecond imaging of chemical reactions and opens a new direction for the study of ultrafast chemical reaction in the gas phase.

[A TUBERCULOUS PSEUDO-ANEURYSM OF THE ABDOMINAL AORTA COMPLICATED BY MILIARY TUBERCULOSIS].

A 66-year-old man was transferred to our hospital on November 2010 owing to a diagnosis of miliary tuberculosis. Treatment was initially started with INH, RFP, PZA, and EB. However, PZA and EB were discontinued because of their adverse effects. Subsequently, chest radiographic and laboratory findings gradually improved. However, the patient experienced lumbago, which exacerbated towards the end of March 2011. An abdominal CT scan showed an abdominal mass at the L3-L5 level between the abdominal aorta and lumbar vertebra. On the basis of the findings of abdominal ultrasonography, MRI, and PET-CT, infectious abdominal aortic aneurysm was highly suspected. Therefore, vascular graft replacement surgery was performed at the beginning of May 2011. The result of histopathological analysis showed the presence of acid-fast bacteria in the aneurysm and the lymph nodes around it, revealing that the aneurysm was due to systemic miliary tuberculosis. After the surgery, the patient was administered LVFX in addition to INH and RFP for 18 months and showed no recurrence.

The protection mechanism of proline from D-galactosamine hepatitis involves the early activation of ROS-eliminating pathway in the liver.

The oral pre-administration of proline, one on the non-essential amino acids, has been shown to effectively protect the liver from D-galactosamine (GalN)-induced liver injury and dramatically improve the survival rate. In the previous study, we reported that protective effect of proline involves the early activation of IL-6/STAT-3 pathway, an anti-inflammatory and regenerative signaling in the liver. Reactive oxygen species (ROS) are mediator of cellular injury and play an important role in hepatic damage during GalN-induced hepatitis. The aim of this study is to investigate the effect of proline on ROS-eliminating system. The activities of major ROS-detoxifying enzymes, i.e., glutathione peroxidase (GP), glutathione reductase (GR), catalase, and the level of glutathione in the liver were determined. Catalase activity was significantly upregulated in proline group from 0 to 3 h after GalN-injection, although GP and GR were downregulated during this period, compared with control group. From 6 to 12 h, the level of reduced glutathione (GSH) was significantly higher and the ratio of GSH/oxidized glutathione (GSSG) tended to be higher in proline group. Consistently with this, at 6 h, the GR activity in the proline group was significantly higher, followed with the higher tendency of GP activity at 12 h. Catalase activity was also significantly higher at 12 h. Taken together, catalase was activated at the beginning, followed with the significant activation of glutathione redox system around 6 to 12 h in proline group. These results suggest that the elimination of ROS in the liver was accelerated in proline group compared with control group at the very early stage of GalN-induced hepatitis.

Low-dose CT scan screening for lung cancer: comparison of images and radiation doses between low-dose CT and follow-up standard diagnostic CT.

OBJECTIVES: This study aim to compare image quality and radiation doses between low-dose CT and follow-up standard diagnostic CT for lung cancer screening. METHODS: In a single medical institution, 19 subjects who had been screened for lung cancer by low-dose CT before going through follow-up standard diagnostic CT were randomly selected. Both CT image sets for all subjects were independently evaluated by five specialized physicians. RESULTS: There were no significant differences between low-dose CT screening and follow-up standard diagnostic CT for lung cancer screening in all 11 criteria. The concordance rate for the diagnoses was approximately 80% (p < 0.001) for all categories. Agreement of the evaluation of all categories in the final diagnosis exceeded 94% (p < 0.001). Five physicians detecting and characterizing the pulmonary nodules did not recognized the difference between low-dose CT screening and follow-up standard diagnostic CT. With low-dose CT, the effective dose ranged between 1.3 and 3.4 mSv, whereas in the follow-up diagnostic CT, the effective dose ranged between 8.5 and 14.0 mSv. CONCLUSION: This study suggests that low-dose CT can be effectively used as a follow-up standard diagnostic CT in place of standard-dose CT in order to reduce the radiation dose.

Proline protects liver from D-galactosamine hepatitis by activating the IL-6/STAT3 survival signaling pathway.

The oral administration of proline, one of the non-essential amino acids, has been shown to effectively protect the liver from D-galactosamine (GalN)-induced liver injury and to improve the survival rate. The aim of this study was to investigate the mechanism of this protective action of proline. We paid particular attention to the effect of proline on inflammatory activation, regenerative response, and the associated signal transduction in the liver. Male Fischer rats received intraperitoneal injections of GalN (1.4 g/kg) with or without the oral administration of proline (2 g/kg) 1 h before GalN treatment. Liver pathology, plasma indices of inflammation, and the level of proliferative marker in the liver were monitored. The hepatic activation of interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT)-3 pathway, which is downstream of tumor necrosis factor (TNF)-α/nuclear factor-κB, was also studied. GalN induced massive inflammatory expansion in the liver, leading to a high death rate (60 %) more than 72 h after the treatment. Proline administration significantly suppressed inflammatory infiltration in the live after 48 h, which was accompanied by depletion of plasma TNF-α, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. The mRNA expression of histone H3, a marker of proliferation, was significantly upregulated in the liver of proline-treated animals. Furthermore, IL-6/STAT-3 pathway, an anti-inflammatory and regenerative signaling pathway, was strongly activated prior to these observations, with the upregulated expression of downstream genes. These results suggest that the tissue-protective mechanism of proline involves the early activation of IL-6/STAT-3 pathway in the liver, with subsequent activation of the regenerative response and suppression of massive inflammatory activation.

Determining important regulatory relations of amino acids from dynamic network analysis of plasma amino acids.

The changes in the concentrations of plasma amino acids do not always follow the flow-based metabolic pathway network. We have previously shown that there is a control-based network structure among plasma amino acids besides the metabolic pathway map. Based on this network structure, in this study, we performed dynamic analysis using time-course data of the plasma samples of rats fed single essential amino acid deficient diet. Using S-system model (conceptual mathematical model represented by power-law formalism), we inferred the dynamic network structure which reproduces the actual time-courses within the error allowance of 13.17%. By performing sensitivity analysis, three of the most dominant relations in this network were selected; the control paths from leucine to valine, from methionine to threonine, and from leucine to isoleucine. This result is in good agreement with the biological knowledge regarding branched-chain amino acids, and suggests the biological importance of the effect from methionine to threonine.