RNA Modification in Inflammatory Bowel Diseases

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by damage to the intestinal mucosa, which is caused by a combination of factors. These include genetic and epigenetic alterations, environmental influence, microorganism interactions, and immune conditions. Some populations with IBD show a cancer-prone phenotype. Recent studies have provided insight into the involvement of RNA modifications in the specific pathogenesis of IBD through regulation of RNA biology in epithelial and immune cells. Studies of several RNA modification-targeting reagents have shown preferable outcomes in patients with colitis. Here, we note a new awareness of RNA modification in the targeting of IBD and related diseases, which will contribute to early diagnosis, disease monitoring, and possible control by innovative therapeutic approaches

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world postmarketing surveillance data

Postmarketing surveillance is useful to collect safety data in real-world clinical settings. In this study, we applied postmarketing real-world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin-treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony-stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time =\ua0104.5\ua0h, neutrophil proliferation rate constant =\ua00.0377\ua0h−1, neutrophil elimination rate constant =\ua00.0295\ua0h−1, and linear coefficient of drug effect =\ua00.0413\ua0mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model-based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis

The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

神経細胞死を抑制する新たな分子を発見 --脳卒中やアルツハイマー病への応用に期待--. 京都大学プレスリリース. 2021-06-30.While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca²⁺-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b⁻/⁻ mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca²⁺ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b⁻/⁻ neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca²⁺-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b⁻/⁻ and Calr⁺/⁻ mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca²⁺ homeostasis

Influence of renal function and demographic data on intrarenal Doppler ultrasonography

Intrarenal Doppler ultrasonography is a non-invasive method to evaluate the renal blood flow in patients with renal arterial stenosis as well as chronic kidney diseases (CKD). Until recently, the relationship between ultrasonography findings and CKD stage has not been fully understood. Overall, 162 patients with CKD without apparent renal arterial stenosis were included in this study, and the pulsed-wave Doppler ultrasonography findings were evaluated in terms of the following parameters: peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) at the renal arterial trunk, hilum, segmental, and interlobar regions. Age showed a significant negative correlation with the estimated glomerular filtration rate (eGFR), kidney size, and aortic PSV. Additionally, age showed a significant positive correlation with RI in all 4 regions. The eGFR showed a positive correlation with the aortic PSV and kidney size, but a negative correlation with RI. Both age and eGFR were found to be independently associated with aortic blood flow. On the intrarenal ultrasound, EDV and RI showed stronger correlations with eGFR than PSV, suggesting that the former indices would be better markers of renal function. In particular, the interlobar EDV was found to be the best index that reflects renal function. Although the RI is also a good marker of renal function, it is confounded by age; thus, its utility would be weaker than that of the EDV. In conclusion, intrarenal pulsed-wave Doppler ultrasonography is a useful tool to estimate and evaluate the renal function; the interlobar EDV may be the best index to estimate the effective perfusion and filtration of the kidneys

11β-Hydroxysteroid Dehydrogenase-1 Is a Novel Regulator of Skin Homeostasis and a Candidate Target for Promoting Tissue Repair

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the interconversion of cortisone and cortisol within the endoplasmic reticulum. 11β-HSD1 is expressed widely, most notably in the liver, adipose tissue, and central nervous system. It has been studied intensely over the last 10 years because its activity is reported to be increased in visceral adipose tissue of obese people. Epidermal keratinocytes and dermal fibroblasts also express 11β-HSD1. However, the function of the enzymatic activity 11β-HSD1 in skin is not known. We found that 11β-HSD1 was expressed in human and murine epidermis, and this expression increased as keratinocytes differentiate. The expression of 11β-HSD1 by normal human epidermal keratinocytes (NHEKs) was increased by starvation or calcium-induced differentiation in vitro. A selective inhibitor of 11β-HSD1 promoted proliferation of NHEKs and normal human dermal fibroblasts, but did not alter the differentiation of NHEKs. Topical application of selective 11β-HSD1 inhibitor to the dorsal skin of hairless mice caused proliferation of keratinocytes. Taken together, these data suggest that 11β-HSD1 is involved in tissue remodeling of the skin. This hypothesis was further supported by the observation that topical application of the selective 11β-HSD1 inhibitor enhanced cutaneous wound healing in C57BL/6 mice and ob/ob mice. Collectively, we conclude that 11β-HSD1 is negatively regulating the proliferation of keratinocytes and fibroblasts, and cutaneous wound healing. Hence, 11β-HSD1 might maintain skin homeostasis by regulating the proliferation of keratinocytes and dermal fibroblasts. Thus 11β-HSD1 is a novel candidate target for the design of skin disease treatments

Mapping of the nuclear matrix-bound chromatin hubs by a new M3C experimental procedure

We have developed an experimental procedure to analyze the spatial proximity of nuclear matrix-bound DNA fragments. This protocol, referred to as Matrix 3C (M3C), includes a high salt extraction of nuclei, the removal of distal parts of unfolded DNA loops using restriction enzyme treatment, ligation of the nuclear matrix-bound DNA fragments and a subsequent analysis of ligation frequencies. Using the M3C procedure, we have demonstrated that CpG islands of at least three housekeeping genes that surround the chicken α-globin gene domain are assembled into a complex (presumably, a transcription factory) that is stabilized by the nuclear matrix in both erythroid and non-erythroid cells. In erythroid cells, the regulatory elements of the α-globin genes are attracted to this complex to form a new assembly: an active chromatin hub that is linked to the pre-existing transcription factory. The erythroid-specific part of the assembly is removed by high salt extraction. Based on these observations, we propose that mixed transcription factories that mediate the transcription of both housekeeping and tissue-specific genes are composed of a permanent compartment containing integrated into the nuclear matrix promoters of housekeeping genes and a ‘guest’ compartment where promoters and regulatory elements of tissue-specific genes can be temporarily recruited

専門医療機関の口唇裂・口蓋裂の子どもをもつ母親に対する看護援助の内容とその問題

本研究は、口唇裂・口蓋裂（以後CLP とする）児の専門医療機関での経験豊かな看護師11名のCLP 児の母親に対す る看護援助の内容と援助する上で感じている問題を明らかにすることを目的とした。看護援助は、【専門医療機関内での看護援助の実際】と【出向での看護の実際】に、援助する上での問題は【看護実践 の基盤】と【専門医療機関での問題意識と対応】のコアカテゴリーが抽出できた。本論文では、主に【専門医療機関内 での看護援助の実際】除くコアカテゴリーの内容を述べた。看護師は、専門医療機関内での看護援助とともに、地域に出向く看護援助の母親に与える効果や意義を認識している。 病院内外の看護援助を実施する際には、看護師内面と職場の特色を基にするとともに、援助する上でシステムや連携の問題を認識していることが明らかになった

Spatial distribution of summer temperature in tokyo wards : observation results of metros

The urban heat island phenomena in summer over Tokyo Wards was studied by using the data obtained from METROS (Metropolitan Environmental Temperature and Rainfall Observation System), which is the high density heat island phenomena observation network. The observational results clarified the detailed spatial distributions of temperature never known before. Concerning the spatial distribution of daily maximum temperature, the region with a relatively high temperature extends from the central Tokyo district toward the northern and northwestern area. On the other hand, relatively high values in the daily minimum temperature are distributed around the coastal area of Tokyo Bay including the central Tokyo district. Since the central Tokyo district has significantly high temperatures both in the daytime and in the nighttime, and also raises the temperature in the adjacent north and northeast area, it is necessary to take countermeasures preferentially to this district