Phosphatidic acid-dependent localization and basal de-phosphorylation of RA-GEFs regulate lymphocyte trafficking

Background: Lymphocytes circulate between peripheral lymphoid tissues via blood and lymphatic systems, and chemokine-induced migration is important in trafficking lymphocytes to distant sites. The small GTPase Rap1 is important in mediating lymphocyte motility, and Rap1-GEFs are involved in chemokine-mediated Rap1 activation. Here, we describe the roles and mechanisms of Rap1-GEFs in lymphocyte trafficking. Results: In this study, we show that RA-GEF-1 and 2 (also known as Rapgef2 and 6) are key guanine nucleotide exchange factors (GEF) for Rap1 in lymphocyte trafficking. Mice harboring T cell-specific knockouts of Rapgef2/6 demonstrate defective homing and egress of T cells. Sphingosine-1-phosphate (S1P) as well as chemokines activates Rap1 in a RA-GEF-1/2-dependent manner, and their deficiency in T cells impairs Mst1 phosphorylation, cell polarization, and chemotaxis toward S1P gradient. On the other hand, B cell-specific knockouts of Rapgef2/6 impair chemokine-dependent retention of B cells in the bone marrow and passively facilitate egress. Phospholipase D2-dependent production of phosphatidic acid by these chemotactic factors determines spatial distribution of Rap1-GTP subsequent to membrane localization of RA-GEFs and induces the development of front membrane. On the other hand, basal de-phosphorylation of RA-GEFs is necessary for chemotactic factor-dependent increase in GEF activity for Rap1. Conclusions: We demonstrate here that subcellular distribution and activation of RA-GEFs are key factors for a directional movement of lymphocytes and that phosphatidic acid is critical for membrane translocation of RA-GEFs with chemokine stimulation

Dietary acrylamide intake and the risk of liver cancer: The japan public health center-based prospective study

Acrylamide has been studied for its carcinogenicity in experimental animals, causing tumors at several organ sites, and has been considered probably carcinogenic to humans as well. Given the small number of epidemiological studies that have been conducted, it is still uncertain whether the consumption of acrylamide is associated with liver cancer. Therefore, we investigated a study to determine the possible relationship between acrylamide intake and the risk of developing liver cancer in the Japanese population. A total of 85,305 participants, from the Japan Public Health Center-based Prospective Study, who provided a validated food-frequency questionnaire were enrolled between 1995 and 1998. During a median of 16.0 years follow-up, 744 new liver cancer cases were identified. Compared to the lowest tertile of acrylamide consumption (<4.8 μg/day), the multivariate hazard ratio (HR) for the highest tertile (≥7.6 μg/day) was 0.79 (95% confidence interval [CI] = 0.65-0.95) for liver cancer using multivariable model 1, adjusted for smoking status, body mass index (BMI), physical activity, medical history, and alcohol consumption; whereas the inverse relationship disappeared after additionally adjusting for coffee consumption in multivariable model 2 with HR of 1.08 (95% CI = 0.87-1.34) for the highest tertile. The effect of dietary acrylamide intake on the risk of liver cancer was not observed in the Japanese population.Zha, L.; Sobue, T.; Kitamura, T.; Kitamura, Y.; Ishihara, J.; Kotemori, A.; Liu, R.; Ikeda, S.; Sawada, N.; Iwasaki, M.; Tsugane, S.; JPHC Study Group, f.t. Dietary Acrylamide Intake and the Risk of Liver Cancer: The Japan Public Health Center-Based Prospective Study. Nutrients 2020, 12, 2503. https://doi.org/10.3390/nu1209250

A case report on refractory ulcerative stomatitis associated with acute lymphoblastic leukemia

症例は難治性潰瘍性口内炎を契機に判明した急性リンパ性白血病の 1 例である．患者は 60 歳台，女性．下口唇に難治性潰瘍を認め紹介となった．血液検査にて汎血球減少を認めたため，血液疾患を疑った．骨髄検査にて，Ph 染色体陰性急性 B 細胞性リンパ性白血病と診断され，初診の 4 日後からステロイド療法が開始された．なお，下口唇生検の病理組織には明らかな白血病細胞の浸潤は認めなかった．口腔症状が白血病の初発症状となることがあり，これを主訴に受診した白血病患者を早期診断することは大変重要である．しかし，口腔病変の原因は多彩であり，さまざまな科が対応することが多く，各科が連携して診療にあたることが重要と考える．We herein report a case on refractory ulcerative stomatitis associated with acute lymphoblastic leukemia. The female patient in her 60s showed refractory ulcer on her lower lip ; and the referral was made. Since pancytopenia was found by a blood test, hematologic disease was suspected. Bone marrow examination presented the diagnosis of Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia. Based on this diagnosis, steroid therapy had been initiated from four days after the first visit. On biopsy of lower lip, the pathological tissue did not show obvious infiltration of leukemia cells. Since oral manifestation may sometimes be an initial symptom of leukemia, an early diagnosis on leukemia patient with main complaint of oral symptom is critically important. Oral lesions, however, have various causes, and it thus often requires care of various clinical department. Based on this, it is considered to be important to implement treatment with cooperation among each clinical department

Control of Cortical Axon Elongation by a GABA-Driven Ca<sup style="margin: 0px; padding: 0px; border: 0px; outline-style: none; font-weight: inherit; font-style: inherit; font-size: 0.85em; font-family: inherit; line-height: 0; text-align: inherit; vertical-align: super;">2+/Calmodulin-Dependent Protein Kinase Cascade</sup>

Ca(2+) signaling plays important roles during both axonal and dendritic growth. Yet, whether and how Ca(2+) rises may trigger and contribute to the development of long range cortical connections remains largely unknown. Here we demonstrate that two separate limbs of CaMK kinase (CaMKK) - CaMKI cascades, CaMKK-CaMKIα and CaMKK-CaMKIγ, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly α-isoform-specific kinase activity of CaMKI. Unexpectedly, treatment with muscimol, a GABA(A) receptor agonist, selectively stimulated elongation of axons but not of dendrites, and the CaMKK-CaMKIα cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKIα significantly impaired the terminal axonal extension, and thereby perturbed the refinement of the interhemispheric callosal projections into the contralateral cortices. Our findings thus indicate a novel role for the GABA-driven CaMKK-CaMKIα cascade as a mechanism critical for accurate cortical axon pathfinding, an essential process which may contribute to fine-tuning the formation of interhemispheric connectivity during the perinatal development of the central nervous system

Seismic Exploration Using Active Sources at Kuchierabujima Volcano, Southwest Japan

Seismic exploration using artificial sources was conducted at Kuchierabujima volcano, southwest Japan in November 2004 by 40 participants from 9 national universities andJapan Meteorological Agency to investigate the subsurface seismic structure. The exploration was the 11th joint experiment under the National Project for Prediction of Volcanic Eruptions. A total of 183 temporal stations equippedwith a 2 Hz vertical component seismometer (including 75 3component seismometers) and a portable data logger were deployed on Kuchierabu Island. Dynamite shots with charges of 10-115 kg were detonated at 19 locations, and seismic signals were successfully recorded. To reveal the P-wave velocity structure, 2955 arrival times of the first motion were picked from the seismograms, and 2187 were classified into ranks A and B. From the record sections and the arrival time data, characteristics reflecting the geological structure were identified. Refracted waves of 5 km/s were observed at stations＞5km from the shot points. Apparent velocities near the shot points depend on the surface geology around the shots. P-wave arrived earlier at stations near the summits. Strongly scattered waves were observed similarly near the summits

A polymer-based chemical tongue for the non-invasive monitoring of osteogenic stem-cell differentiation by pattern recognition of serum-supplemented spent media

The development of non-invasive techniques to characterize cultured cells is invaluable not only to ensure the reproducibility of cell research, but also for quality assurance of industrial cell products for purposes such as regenerative medicine. Here, we present a polymer-based ‘chemical tongue’, i.e., a biosensing technique that mimics the human taste system, that is capable of non-invasively generating fluorescence response patterns that reflect the proteins secreted, and also partially consumed, by cultured cells, even from serum-supplemented media containing abundant interferants. Analysis of the spent media collected during cell culture using our chemical tongue, which consists of cationic polymers of different scaffolds appended with environmentally responsive dansyl fluorophores, led to the successful (i) identification of human-derived cell lines, (ii) monitoring of the differentiation process of stem cells, even at the stage when conventional staining was negative, and (iii) detection of cancer-cell contamination in stem cells. Since the characterization of cultured cells is usually performed via invasive methods that result in cell death, our chemical-tongue approach, which is of high practical utility, will offer a new means of addressing the growing demand for highly controlled cell production in the medical and environmental fields

A Multi-Fluorescent DNA/Graphene Oxide Conjugate Sensor for Signature-Based Protein Discrimination

Signature-based protein sensing has recently emerged as a promising prospective alternative to conventional lock-and-key methods. However, most of the current examples require the measurement of optical signals from spatially-separated materials for the generation of signatures. Herein, we present a new approach for the construction of multi-fluorescent sensing systems with high accessibility and tunability, which allows generating protein fluorescent signatures from a single microplate well. This approach is based on conjugates between nano-graphene oxide (nGO) and three single-stranded DNAs (ssDNAs) that exhibit different sequences and fluorophores. Initially, the three fluorophore-modified ssDNAs were quenched simultaneously by binding to nGO. Subsequent addition of analyte proteins caused a partial recovery in fluorescent intensity of the individual ssDNAs. Based on this scheme, we have succeeded in acquiring fluorescence signatures unique to (i) ten proteins that differ with respect to pI and molecular weight and (ii) biochemical marker proteins in the presence of interferent human serum. Pattern-recognition methods demonstrated high levels of discrimination for this system. The high discriminatory power and simple format of this sensor system should enable an easy and fast evaluation of proteins and protein mixtures

Idiopathic first bite syndrome improved by Rikkosan : A case report

ファーストバイト症候群（first bite syndrome：以下、FBS）は、食事開始時に耳下腺部痛を生じ数回の咀嚼により徐々に軽快することを特徴とする。手術既往や腫瘍性疾患がない FBS は特発性 FBS と分類される。特発性 FBS に対する治療法として少数ではあるが立効散の内服が報告されており、本症例でも立効散が奏功した。特発性 FBS の治療法は未確立であり、有害事象の少ない立効散は食事療法と並んでまず考慮すべき治療法であると考える。First bite syndrome (FBS) is characterized by severe paroxysmal pain in the parotid region at the first bite of a meal, which gradually decreases as mastication continues. When FBS occurs with no history of head and neck surgery and no evidence of a tumor, it is classified as idiopathic. The effectiveness of Rikkosan has been reported by several studies, and we also experienced a case in which idiopathic FBS improved with Rikkosan. There is no established treatment method for idiopathic FBS. Rikkosan, which is associated with few adverse events, should be considered as a first-line treatment, along with diet therapy

A Single Amino Acid Substitution Converts γ-Glutamyltranspeptidase to a Class IV Cephalosporin Acylase (Glutaryl-7-Aminocephalosporanic Acid Acylase)

The aspartyl residue at position 433 of γ-glutamyltranspeptidase of Escherichia coli K-12 was replaced by an asparaginyl residue. This substitution enabled γ-glutamyltranspeptidase to deacylate glutaryl-7-aminocephalosporanic acid, producing 7-aminocephalosporanic acid, which is a starting material for the synthesis of semisynthetic cephalosporins