Structural insights into the agonists binding and receptor selectivity of human histamine H₄ receptor

慢性アレルギー疾患に関わるヒスタミン受容体の構造解明 --新規アトピー性皮膚炎・喘息治療薬の開発に貢献--. 京都大学プレスリリース. 2023-10-23.Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H₄ receptor (H₄R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H₄R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344[7.39], which, in turn, form the “aromatic slot”. The results provide insights into the molecular underpinnings of the agonism of H₄R and subtype selectivity of histamine receptors, and show that the H₄R structures may be valuable in rational drug design of drugs targeting the H₄R

Development of a finger like multi-joint articulated surgical retractor for use in endoscopic surgery

The authors have developed an articulated medical instrument which assists with the movement of and maintenance of the position of such as a lung during surgery to assist providing improved viewability and providing the necessary space required to work efficiently and effectively. Conventionally holding such as, a lung in a given position is achieved by arranging gauze in an appropriate configuration with the aid of a simple shaft like surgical instrument, however for various reasons the gauze requires constant replacement and rearrangement resulting in significant surgical inefficiency. By using an articulated mechanism that mimics the functionality of fingers, we have developed a surgical device that inherently provides greater mechanical stability and does not require the use of gauze, thus enabling more efficient surgery. The prototyping process was assisted with the use of 3D-CAD to simulate static and dynamic conditions and a 3D-printer to confirm the concept and then a working prototype was created. In order to validate the dynamic functionality of this surgical instrument, it was tested on a porcine lung which closely approximates human lungs by a clinical doctor of thoracic surgery. The result was that the developed prototype articulated mechanism was able to stably move and hold the lung in position during surgery thus confirming the dynamic efficacy of the mechanism

Terahertz wireless communication at 560-GHz band using Kerr micro-resonator soliton comb

Terahertz (THz) waves have attracted attention as carrier waves for next-generation wireless communications (6G). Electronic THz emitters are widely used in current mobile communications; however, they may face technical limitations in 6G with upper-frequency limits. We demonstrate wireless communication in a 560-GHz band by using a photonic THz emitter based on photomixing of a 560-GHz-spacing soliton microcomb in a uni-travelling carrier photodiode together with a THz receiver of Schottky barrier diode. The on-off keying data transfer with 2-Gbit/s achieves a Q-factor of 3.4, thus, satisfying the limit of forward error correction.Comment: 17 pages, 4 figur

Terahertz wireless communication in a 560-GHz band using a Kerr micro-resonator soliton comb

Terahertz (THz) waves have attracted attention as carrier waves for next-generation wireless communications (6 G). Electronic THz emitters are widely used in current mobile communications; however, they may face technical limitations in 6 G with upper-frequency limits. We demonstrate wireless communication in a 560-GHz band by using a photonic THz emitter based on photomixing of a 560-GHz-spacing soliton microcomb in a uni-travelling carrier photodiode together with a THz receiver of Schottky barrier diode. The on-off keying data transfer with 2-Gbit/s achieves a Q-factor of 3.4, thus, satisfying the limit of forward error correction

Wireless data transmission in a 560-GHz band using low-phase-noise terahertz wave generated by photomixing of a pair of distributed feedback lasers injection-locking to Kerr micro-resonator soliton comb

The demand for higher data rates in next-generation mobile wireless communication systems (6G) has led to significant interest in terahertz (THz) waves as a high-frequency, broad modulation bandwidth carrier wave. In this study, we propose and demonstrate a wireless data transfer in the 560-GHz band using low-phase-noise THz waves generated by photomixing of a pair of distributed feedback lasers injection-locking to Kerr micro-resonator soliton comb. Experimental results showed near-error-free on-off keying (OOK) data transfer at 1 Gbit/s in the 560-GHz band, with a Q-factor of 6.23, surpassing the error-free limit. Also, modulation formats of binary phase shift keying (BPSK) and quadrature phase shift keying (QPSK) were successfully used, showing clear constellation diagrams and relatively low root mean squared error vector magnitude (rms EVM) values of 23.9% and 23.6%, respectively. Moreover, data transfer at 0.4 Gbit/s in 16 quadrature amplitude modulation (16QAM) demonstrated clear isolated symbols and achieved a low rms EVM value of 8.1%, complying with the IEEE 802.15.3d standard amendment. These demonstrations highlight the potential of using injection-locked DFB lasers with the Kerr micro-resonator soliton comb to achieve high-quality, high-speed wireless data transfer in the 560-GHz band. These findings contribute significantly to the advancement of wireless communication technology in the THz frequency range and pave the way for the realization of 6G wireless communication systems

Carrier conversion from terahertz wave to dual-wavelength near-infrared light injection-locking to optical comb using asynchronous nonpolarimetric electro-optic downconversion with electro-optic polymer modulator

THz waves are promising wireless carriers for next-generation wireless communications, where a seamless connection from wireless to optical communication is required. In this study, we demonstrate carrier conversion from THz waves to dual-wavelength NIR light injection-locking to an optical frequency comb using asynchronous nonpolarimetric electro-optic downconversion with an electro-optic polymer modulator. THz wave in the W band was obtained as a stable photonic RF beat signal of 1 GHz with a signal-to-noise ratio of 25 dB via the proposed THz-to-NIR carrier conversion. In addition, the results imply the potential of the photonic detection of THz waves for wireless-to-optical seamless communication.Comment: 15 pages, 5 figure

Pretreatment glasgow prognostic score predicts survival among patients administered first-line atezolizumab plus carboplatin and etoposide for small cell lung cancer

BackgroundThere are no established predictive biomarkers for the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with small-cell lung cancer (SCLC). Therefore, the current study aimed to investigate whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can predict the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with extensive-disease SCLC.MethodsWe reviewed data from 84 patients who received first-line atezolizumab plus carboplatin and etoposide therapy for SCLC at nine Japanese institutions between August 2019 and May 2021. Further, we evaluated the prognostic value of the GPS, NLR, and BMI. The Kaplan–Meier and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). Moreover, the GPS, NLR, and BMI consisted of C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively.ResultsThe response rate was 72.6% (95% confidence interval: 63.0–82.1%). The median PFS and OS from the initiation of treatment were 5.4 (95% CI: 4.9–5.9) months and 15.4 (95% CI: 11.4–16.8) months, respectively. The GPS independently predicted the effectiveness of first-line atezolizumab plus carboplatin and etoposide treatment, as a favorable GPS (GPS 0–1) was correlated with significantly better PFS and OS rates compared to a poor GPS (GPS 2) (PFS: 5.8 vs. 3.8 months, p = 0.0005; OS: 16.5 vs. 8.4 months, p<0.0001).ConclusionsThis is the first analysis to evaluate the association between the GPS, NLR, and BMI and the treatment effectiveness of survival among patients receiving first-line atezolizumab plus carboplatin and etoposide therapy for SCLC. Among patients receiving this treatment for SCLC, GPS was significantly associated with the PFS and OS rates, suggesting that GPS might be useful for evaluating therapeutic outcomes in these patients

Receptor for Activated Protein Kinase C: Requirement for Efficient MicroRNA Function and Reduced Expression in Hepatocellular Carcinoma

MicroRNAs (miRNAs) are important regulators of gene expression that control physiological and pathological processes. A global reduction in miRNA abundance and function is a general trait of human cancers, playing a causal role in the transformed phenotype. Here, we sought to newly identify genes involved in the regulation of miRNA function by performing a genetic screen using reporter constructs that measure miRNA function and retrovirus-based random gene disruption. Of the six genes identified, RACK1, which encodes “receptor for activated protein kinase C” (RACK1), was confirmed to be necessary for full miRNA function. RACK1 binds to KH-type splicing regulatory protein (KSRP), a member of the Dicer complex, and is required for the recruitment of mature miRNAs to the RNA-induced silencing complex (RISC). In addition, RACK1 expression was frequently found to be reduced in hepatocellular carcinoma. These findings suggest the involvement of RACK1 in miRNA function and indicate that reduced miRNA function, due to decreased expression of RACK1, may have pathologically relevant roles in liver cancers

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Oncocytoma様所見を呈した内分泌非活性型副腎皮質腺腫の1例

内分泌非活性副腎腫瘍は比較的稀な疾患であるが, 今回われわれはその組織所見がoncocytoma様所見を呈した内分泌非活性型副腎皮質腺腫を経験したので報告する.症例は41歳女性, 軽度な甲状腺機能充進症で本院内科で精査中であったが腹部エコー.腹部CTスキャンにて偶然, 左副腎腫瘍を発見され, 当科へ紹介された.内分泌検査, RI検査などで, 内分泌非活性副腎腫瘍と診断し, 1983年12月21日全身麻酔下に左副腎摘出術を施行した.摘出重量は5×4.5×3.Ocm, 30gであった.組織所見は光顕および電顕上, 副腎のoncocytomaと考えられたが, 副腎皮質腺腫にはoncocytomaの概念がないのでadrenal, corticaladenoma, compactcelltypeと診断した,We report a case of non-hormonal adrenocortical adenoma. The tumor was removed en block with the adrenal gland. The specimen was 5.0 X 4.5 X 3.0 cm, weighed 30 g and was solid. Histologically, this tumor had an oncocytoma-like appearance. However, as there is no concept of oncocytoma in connection with adrenocortical adenoma, this case was diagnosed as adrenocortical adenoma. A case with such histological findings has never been reported