Activation-induced Deaminase (AID)-directed Hypermutation in the Immunoglobulin Sμ Region: Implication of AID Involvement in a Common Step of Class Switch Recombination and Somatic Hypermutation

Somatic hypermutation (SHM) and class switch recombination (CSR) cause distinct genetic alterations at different regions of immunoglobulin genes in B lymphocytes: point mutations in variable regions and large deletions in S regions, respectively. Yet both depend on activation-induced deaminase (AID), the function of which in the two reactions has been an enigma. Here we report that B cell stimulation which induces CSR but not SHM, leads to AID-dependent accumulation of SHM-like point mutations in the switch μ region, uncoupled with CSR. These findings strongly suggest that AID itself or a single molecule generated by RNA editing function of AID may mediate a common step of SHM and CSR, which is likely to be involved in DNA cleavage

Gastrointestinal Endoscopy for Patients with High Levels of Serum CEA and CA19-9

Serum levels of tumor markers, such as carcinoembryonic antigen （CEA） and carbohydrate antigen 19-9 （CA19-9）, are often measured to detect potential malignancy. When these levels are high, the presence or absence of malignancy is confirmed via a more detailed examination using gastrointestinal （GI） endoscopy and computed tomography. The rate of confirmation of malignancy upon such a follow-up is unknown. This study aimed to investigate the malignancy detection rate via GI endoscopy for patients with high levels of serum CEA and CA19-9. All patients who underwent such GI endoscopy between January 2018 and February 2019 at Showa University Hospital were included in this study. The patients were divided into a follow-up group and a screening group, depending on the purpose of measuring their serum CEA/CA19-9 levels. There were 156 patients who underwent GI endoscopy because of high CEA/CA19-9 levels within the study period. Advanced malignant lesions were detected in 10 patients （6.4％）, including seven cases of colorectal cancer and three cases of upper GI malignancies. In the screening group, six cases （5.7％） of GI malignancies were detected, none of which were found in asymptomatic patients without anemia. In the follow-up group, four cases （7.8％） of GI malignancies were detected; three patients were asymptomatic, and one patient had anemia. Our findings suggest that high serum CEA/CA19-9 levels in asymptomatic patients without anemia and without a history of malignancy do not indicate the presence of malignancy. However, high serum CEA/CA19-9 levels may indicate the potential presence of GI malignancies for patients with a history of malignant tumors, even if they are asymptomatic and do not have anemia

In Vivo Ocular Pharmacokinetic Model for Designing Dosage Schedules and Formulations of Ophthalmic Drugs in Human

The purpose of this study was to develop an in vivo pharmacokinetic model and parameters for predicting the concentrations of ophthalmic drugs in the anterior chamber after instillation into human eyes. We have already reported the usefulness of mathematical model including a diffusion process in rabbits 1). Timolol was used as a model ophthalmic drug. The concentrations of timolol and fluorescein in the tear fluid were determined after instillation into the eyes of human volunteers. The in vivo pharmacokinetic parameters in the tear fluid were estimated by the elimination profile according to a one-compartment model. The concentrations of timolol in the aqueous humor were obtained from the data previously reported 2),3). Other parameters of timolol were estimated from the concentration profiles of timolol in the aqueous humor according to a pharmacokinetic model including a corneal diffusion process. The parameters for human were almost equal to those for rabbits reported previously 1). This mathematical model and in vivo parameters will be effective to estimate the adequate regimen for ophthalmic chemotherapy and develop the ocular drug delivery systems

A deep ATCA 20cm radio survey of the AKARI Deep Field South near the South Ecliptic Pole

The results of a deep 20 cm radio survey at 20 cm are reported of the AKARI Deep Field South (ADF-S) near the South Ecliptic Pole (SEP), using the Australia Telescope Compact Array telescope, ATCA. The survey has 1 sigma detection limits ranging from 18.7--50 microJy per beam over an area of ~1.1 sq degrees, and ~2.5 sq degrees to lower sensitivity. The observations, data reduction and source count analysis are presented, along with a description of the overall scientific objectives, and a catalogue containing 530 radio sources detected with a resolution of 6.2" x 4.9". The derived differential source counts show a pronounced excess of sources fainter than ~1 mJy, consistent with an emerging population of star forming galaxies. Cross-correlating the radio with AKARI sources and archival data we find 95 cross matches, with most galaxies having optical R-magnitudes in the range 18-24 mag, and 52 components lying within 1" of a radio position in at least one further catalogue (either IR or optical). We have reported redshifts for a sub-sample of our catalogue finding that they vary between galaxies in the local universe to those having redshifts of up to 0.825. Associating the radio sources with the Spitzer catalogue at 24 microns, we find 173 matches within one Spitzer pixel, of which a small sample of the identifications are clearly radio loud compared to the bulk of the galaxies. The radio luminosity plot and a colour-colour analysis suggest that the majority of the radio sources are in fact luminous star forming galaxies, rather than radio-loud AGN. There are additionally five cross matches between ASTE or BLAST submillimetre galaxies and radio sources from this survey, two of which are also detected at 90 microns, and 41 cross-matches with submillimetre sources detected in the Herschel HerMES survey Public Data release.Comment: MNRAS accepted and in press 9 July 2012: 28 pages, 15 Figures, 17 Table

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

新たなイントラクライン機構を用いた加齢性眼疾患治療へ --眼局所のホルモンの加齢変化とサーカディアンリズムが鍵--. 京都大学プレスリリース. 2022-02-14.Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction

Prevalence of and risk factors for postoperative complications after lower third molar extraction : A multicenter prospective observational study in Japan

Lower third molar extraction is the most common surgical treatment among routine dental and oral surgical procedures. while the surgical procedures for lower third molar extraction are well established, the difficulty of tooth extraction and the frequency of postoperative complications differ depending on the patient’s background. To establish a management protocol for the lower third molars, the prevalence of and risk factors for postoperative complications after lower third molar extraction were investigated in a large number of Japanese patients in a multicenter prospective study. During 6 consecutive months in 2020, 1826 lower third molar extractions were performed at the 20 participating institutions. The medical records of the patients were reviewed, and relevant data were extracted. The prevalence of and risk factors for postoperative complications were analyzed. The prevalence of postoperative complications after lower third molar extraction was 10.0%. Multivariate analysis indicated that age (≤32 vs >32, odds ratio [OR]: 1.428, 95% confidence interval [95% CI]: 1.040–1.962, P < .05), the radiographic anatomical relationship between the tooth roots and mandibular canal (overlapping of the roots and canal vs no close anatomical relationship between the roots and the superior border of the canal, OR: 2.078, 95% CI: 1.333–3.238, P < .01; overlapping of the roots and canal vs roots impinging on the superior border of the canal, OR: 1.599, 95% CI: 1.050–2.435, P < .05), and impaction depth according to the Pell and Gregory classification (position C vs position A, OR: 3.7622, 95% CI: 2.079–6.310, P < .001; position C vs position B, OR: 2.574, 95% CI: 1.574–4.210, P < .001) are significant independent risk factors for postoperative complications after lower third molar extraction. These results suggested that higher age and a deeply impacted tooth might be significant independent risk factors for postoperative complications after lower third molar extraction