المؤلفون: Jin Liu, Yike Gui, Jingxin Rao, Jingjing Sun, Gang Wang, Qun Ren, Ning Qu, Buying Niu, Zhiyi Chen, Xia Sheng, Yitian Wang, Mingyue Zheng, Xutong Li

المصدر: Acta Pharmaceutica Sinica B, Vol 14, Iss 7, Pp 2927-2941 (2024)

مصطلحات موضوعية: Drug safety, Off-target prediction, Adverse drug reactions, Toxicity, Molecular representation, Artificial intelligence, Therapeutics. Pharmacology, RM1-950

الوصف: Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in adverse drug reaction (ADR) enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211383524000844Test; https://doaj.org/toc/2211-3835Test

الوصول الحر: https://doaj.org/article/062c5287154b4c81a56d547d7f1470daTest

المؤلفون: Xia Sheng, Chunmei Zhang, Jiwei Zhao, Jianping Xu, Peng Zhang, Quanju Ding, Jingfa Zhang

المصدر: Cell & Bioscience, Vol 14, Iss 1, Pp 1-30 (2024)

مصطلحات موضوعية: Diabetic retinopathy, Inner blood-retinal barrier, Neurovascular unit, Microvascular destabilization, Endothelial cell, Pericyte, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436

الوصف: Abstract Microvascular destabilization is the primary cause of the inner blood-retinal barrier (iBRB) breakdown and increased vascular leakage in diabetic retinopathy (DR). Microvascular destabilization results from the combinational effects of increased levels of growth factors and cytokines, involvement of inflammation, and the changed cell-to-cell interactions, especially the loss of endothelial cells and pericytes, due to hyperglycemia and hypoxia. As the manifestation of microvascular destabilization, the fluid transports via paracellular and transcellular routes increase due to the disruption of endothelial intercellular junctional complexes and/or the altered caveolar transcellular transport across the retinal vascular endothelium. With diabetes progression, the functional and the structural changes of the iBRB components, including the cellular and noncellular components, further facilitate and aggravate microvascular destabilization, resulting in macular edema, the neuroretinal damage and the dysfunction of retinal inner neurovascular unit (iNVU). Although there have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying the microvascular destabilization, some still remain to be fully elucidated. Recent data indicate that targeting the intricate signaling pathways may allow to against the microvascular destabilization. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in the microvascular destabilization in DR. In this review, we discuss: (1) the brief introduction of DR and microvascular destabilization; (2) the cellular and molecular components of iBRB and iNVU, and the breakdown of iBRB; (3) the matrix and cell-to-cell contacts to maintain microvascular stabilization, including the endothelial glycocalyx, basement membrane, and various cell–cell interactions; (4) the molecular mechanisms mediated cell–cell contacts and vascular cell death; (5) the altered cytokines and signaling pathways as well as the intricate network of the cytokines involved in microvascular destabilization. This comprehensive review aimed to provide the insights for microvascular destabilization by targeting the key molecules or specific iBRB cells, thus restoring the function and structure of iBRB and iNVU, to treat DR.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-3701Test

الوصول الحر: https://doaj.org/article/d5fca0003ed2467d9db98b5108d44beeTest

المؤلفون: Juan Zhen, Xia Sheng, Tianlong Chen, Haitao Yu

المصدر: Cell Death and Disease, Vol 15, Iss 6, Pp 1-13 (2024)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Abstract Diabetic cardiomyopathy (DCM) is a prevalent myocardial microvascular complication of the myocardium with a complex pathogenesis. Investigating the pathogenesis of DCM can significantly contribute to enhancing its prevention and treatment strategies. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Functionally, inhibition of Kat2a effectively ameliorated high glucose-induced cardiomyocyte injury both in vitro and in vivo by suppressing ferroptosis. Mechanistically, Demethylase alkB homolog 5 (Alkbh5) was found to reduce m6A methylation levels on Kat2a mRNA, leading to its upregulation. YTH domain family 2 (Ythdf2) played a crucial role as an m6A reader protein mediating the degradation of Kat2a mRNA. Furthermore, Kat2a promoted ferroptosis by increasing Tfrc and Hmox1 expression via enhancing the enrichment of H3K27ac and H3K9ac on their promoter regions. In conclusion, our findings unveil a novel role for the Kat2a-ferroptosis axis in DCM pathogenesis, providing valuable insights for potential clinical interventions.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-4889Test

الوصول الحر: https://doaj.org/article/cc5b8c0f9130455e86e367b78f76c9c4Test

المؤلفون: Bassem Tossoun, Di Liang, Stanley Cheung, Zhuoran Fang, Xia Sheng, John Paul Strachan, Raymond G. Beausoleil

المصدر: Nature Communications, Vol 15, Iss 1, Pp 1-8 (2024)

مصطلحات موضوعية: Science

الوصف: Abstract Recently, interest in programmable photonics integrated circuits has grown as a potential hardware framework for deep neural networks, quantum computing, and field programmable arrays (FPGAs). However, these circuits are constrained by the limited tuning speed and large power consumption of the phase shifters used. In this paper, we introduce the memresonator, a metal-oxide memristor heterogeneously integrated with a microring resonator, as a non-volatile silicon photonic phase shifter. These devices are capable of retention times of 12 hours, switching voltages lower than 5 V, and an endurance of 1000 switching cycles. Also, these memresonators have been switched using 300 ps long voltage pulses with a record low switching energy of 0.15 pJ. Furthermore, these memresonators are fabricated on a heterogeneous III-V-on-Si platform capable of integrating a rich family of active and passive optoelectronic devices directly on-chip to enable in-memory photonic computing and further advance the scalability of integrated photonic processors.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/901ba1b027e7440383aca76578e992dbTest

المؤلفون: Jianmin Qin, Jinwei Zhang, Nannan Lai, Xia Sheng, Xiaoli Xie, Yuanyuan Yang

المصدر: Intractable & Rare Diseases Research. 2023, 12(4):267

المؤلفون: Ning Huang, Peng Li, Xiaolin Sun, Li Tong, Xinyi Dong, Xuemei Zhang, Jifeng Duan, Xia Sheng, Hong Xin

المصدر: npj Breast Cancer, Vol 9, Iss 1, Pp 1-11 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive type of breast cancer with a poor prognosis and a high recurrence rate. Chemotherapy is still the mainstay of treatment for cancer patients without a genetic BRCA mutation, despite the approval of Olaparib, an inhibitor of the poly (ADP-ribose) polymerase (PARP) enzyme. Tripartite motif containing-21 (TRIM21) is one of the TRIM family members that has been investigated in various types of cancer. Here, we found that a low TRIM21 expression level was correlated with poor overall survival of TNBC patients. Knockout of TRIM21 promoted the proliferation of TNBC cells in vivo and in vitro, as well as migratory and invasive capabilities in vitro. Importantly, breast cancer susceptibility gene 1 (BRCA1) was identified as a ubiquitination substrate of TRIM21. It was confirmed that BRCA1 was upregulated after Olaparib treatment, which may explain the relative resistance of BRCA1-proficient TNBC cells to Olaparib. Moreover, Sorafenib, a standard treatment for hepatocellular carcinoma, increased the sensitivity of TNBC cells to Olaparib by promoting TRIM21-mediated ubiquitination degradation of BRCA1. Thus, a synergic effect of Olaparib and Sorafenib was found in vitro and in vivo. This combined treatment also aggravated DNA damage, cell cycle arrest, and apoptosis of TNBC cells. In summary, the findings verified the synergistic effect of Olaparib and Sorafenib and revealed TRIM21 as a potential target for TNBC therapy.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2374-4677Test

الوصول الحر: https://doaj.org/article/33c5d55a7a9047feba8f87e1f96ef20dTest

المؤلفون: Yu Shan, Maoning Lin, Xia Sheng, Jiefang Zhang, Yaxun Sun, Guosheng Fu, Min Wang

المصدر: Frontiers in Cardiovascular Medicine, Vol 10 (2023)

مصطلحات موضوعية: left bundle branch area pacing (LBBaP), stable coronary artery disease, pacing parameters, heart failure hospitalization (HFH), safety, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: AimsStable coronary artery disease (CAD) is a prevalent comorbidity among patients requiring pacemaker implantation. This comorbidity may have an impact on the safety and prognosis of traditional right ventricular pacing (RVP). Left bundle branch area pacing (LBBaP) is a new physiological pacing modality. Our aim was to investigate the feasibility and safety of LBBaP in patients with the stable CAD.MethodsThis study included 309 patients with symptomatic bradycardia who underwent LBBaP from September 2017 to October 2021. We included 104 patients with stable CAD (CAD group) and 205 patients without CAD (non-CAD group). Additionally, 153 stable CAD patients underwent RVP, and 64 stable CAD patients underwent His-bundle pacing (HBP) were also enrolled in this study. The safety and prognosis of LBBaP was assessed by comparing pacing parameters, procedure-related complications, and clinical events.ResultsDuring a follow-up period of 17.4 ± 5.3 months, the safety assessment revealed that the overall rates of procedure-related complications were similar between the stable CAD group and the non-CAD group (7.7% vs. 3.9%). Likewise, similar rates of heart failure hospitalization (HFH) (4.8% vs. 3.4%, stable CAD vs. non-CAD) and the primary composite outcome including death due to cardiovascular disease, HFH, or the necessity for upgrading to biventricular pacing (6.7% vs. 3.9%, stable CAD vs. non-CAD), were observed. In stable CAD patients, LBBaP demonstrated lower pacing thresholds and higher R wave amplitudes when compared to HBP. Additionally, LBBaP also had significantly lower occurrences of the primary composite outcome (6.7% vs. 19.6%, P = 0.003) and HFH (4.8% vs. 13.1%, P = 0.031) than RVP in stable CAD patients, particularly among patients with the higher ventricular pacing (VP) burden (>20% and >40%).ConclusionCompared with non-CAD patients, LBBaP was found to be attainable in stable CAD patients and exhibited comparable mid-term safety and prognosis. Furthermore, in the stable CAD population, LBBaP has demonstrated more stable pacing parameters than HBP, and better prognostic outcomes compared to RVP.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fcvm.2023.1246846/fullTest; https://doaj.org/toc/2297-055XTest

الوصول الحر: https://doaj.org/article/28053a13a74944569090930da3fe98bdTest

المؤلفون: Ao Zhang, Qingming Ji, Xia Sheng, Hui Wu

المصدر: Biomedicine & Pharmacotherapy, Vol 166, Iss , Pp 115361- (2023)

مصطلحات موضوعية: MRNA vaccine, Gastrointestinal tumors, Gastrointestinal cancers, Immunomodulatory, Immunotherapy, Therapeutics. Pharmacology, RM1-950

الوصف: Gastrointestinal tumors remain a significant healthcare burden worldwide, necessitating the development of innovative therapeutic strategies. mRNA vaccines have emerged as a promising approach in cancer immunotherapy, harnessing the immune system's potential to recognize and eliminate tumor cells. mRNA vaccines offer several advantages, including their ability to elicit both innate and adaptive immune responses, ease of production, and adaptability to different tumor types. In the context of gastrointestinal tumors, mRNA vaccines hold great potential as a therapeutic strategy. In this review, we will delve into the immunomodulatory mechanisms and immunotherapy strategies of mRNA vaccines in gastrointestinal tumors. Additionally, we will discuss the challenges and ongoing research efforts in optimizing mRNA vaccine development, delivery, and stability. By understanding the potential of mRNA vaccines in addressing the unmet medical need of gastrointestinal tumors, we aim to pave the way for improved treatment strategies and better patient outcomes.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332223011526Test; https://doaj.org/toc/0753-3322Test

الوصول الحر: https://doaj.org/article/afe92377daa9497b99628c00266759e1Test

المؤلفون: Xia Sheng, Da Zhang, Chaoyang Que, Minfeng Bi, Yongjun Di, Shiyuan Zu, Huihui Ma

المصدر: 地质科技通报, Vol 42, Iss 1, Pp 158-169 (2023)

مصطلحات موضوعية: fluid inclusion, oxygen-hydrogen stable isotopes, saxi deposit, southeastern yunnan, Geology, QE1-996.5, Engineering geology. Rock mechanics. Soil mechanics. Underground construction, TA703-712

الوصف: The Saxi tungsten-beryllium deposit is located in the Laojunshan tungsten-tin polymetallic metallogenic area in southeastern Yunnan. Determining the fluid nature, source, and evolution process of early layered orebodies and late vein-like orebodies and constraining their fluid geochemistry and isotopes can effectively explore the metallogenic mechanism of the Saxi tungsten-beryllium deposit, which is a collection of Laojunshan deposits. This study provides theoretical thinking for future prospecting work in the district. The formation of vein-like ore bodies in this deposit experienced a silicate stage, an oxide-sulfide stage, and a carbonate-fluorite stage. Scheelite and beryl were mainly formed in the first two stages. This article studies the fluid inclusions in quartz at different stages of the orebodies of the Saxi tungsten-beryllium deposit, including petrographic characteristics, microscopic temperature measurements, and laser Raman spectroscopy. The quartz sample's hydrogen-oxygen isotope composition in the ore-like ore body was tested. Three primary types of fluid inclusions (FIs) in vein-like ore bodies are detected, i.e.: liquid-rich FIs, gas-rich FIs, and aughter minerals bearing FIs. The gas phase composition of FIs is mainly H2O, with a small amount of reducing gas such as C2H2, and the liquid phase composition is also mainly H2O. From the silicate stage to the carbonate-fluorite stage, the peak homogenization temperature and salinity (NaCleq) of FIs are 240-360℃, 2.35%-13.81%; 220-310℃, 4.03%-9.86%, and 190-270℃, 2.41%-6.88%. From early to late, both homogenization temperature and salinity of the ore-forming fluid decreased obviously. The ore-forming fluid is generally a medium temperature, low salinity, CO2-poor NaCl-H2O fluid system. The δD and δ18O values of the quartz samples from early quasi-layered ore body are -102.8‰ to -99.0‰ and 11.7‰-13.0‰ respectively, and the corresponding δ18O value of the H2O value is 3.16‰-6.46‰. The δD and δ18O values of the quartz samplesfrom bulk oxide-sulfide section are -99.6‰ to -69.5‰ and 11.2‰-14.1‰ resoectively, and the corresponding δ18O value of H2O value is 3.08‰-6.73‰. This indicates that the ore-forming fluid mainly sourced from magmatic water mixed with a small amount of atmospheric precipitation or organic water.The fluid may boil, forming the precipitation of the main ore-forming minerals in the late vein-like ore body oxide-sulfide stage. The Saxi tungsten-beryllium deposit belong to a medium-to high-temperature hydrothermal system.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2096-8523Test

الوصول الحر: https://doaj.org/article/7fbe0144024048af9a188d29b7c68534Test

المؤلفون: Anxu Zhang, Yuyang Liu, Lipeng Feng, Huan Chen, Yuting Du, Jun Wu, Kai Lv, Hao Liu, Xia Sheng, Xiaoli Huo

المصدر: Photonics, Vol 11, Iss 1, p 88 (2024)

مصطلحات موضوعية: real-time 400 Gbit/s transmission, automatic power optimization, G.654.E fiber, widened C+L band, Applied optics. Photonics, TA1501-1820

الوصف: Power unevenness, mainly induced by stimulated Raman scattering, has been a major problem in multi-band transmission systems, especially in the upcoming field-deployed 400 Gbit/s widened C band plus L band system for backbone long-haul and ultra-long-haul scenarios. To reduce the impact of power unevenness, we propose an automatic power optimization (APO) algorithm to guarantee reliable transmission for all channels, especially the channels at short wavelengths. The simulation results show that the power unevenness of output power after 5-span transmission in the C band is up to 11 dB before APO, while after APO is applied, it is greatly improved to less than 1.6 dB. To further investigate the performance of the APO scheme, we conduct a real-time 44 Tbit/s C+L transmission system over 1900 km G.654.E fiber utilizing 400 Gbit/s transponders. The experimental results show that the power unevenness has been effectively compensated from 12 dB to 4 dB in the entire 11 THz range, making the received optical signal-to-noise ratio relatively flat (3.4 dB). Moreover, the capacity and distance product of this system is 83.6 Pbit/s·km (44 Tbit/s × 1900 km), and to the best of our knowledge, this is a record capacity and distance product in the real-time single-mode fiber transmission system.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2304-6732/11/1/88Test; https://doaj.org/toc/2304-6732Test

الوصول الحر: https://doaj.org/article/16274288cb8b4e1ca7221a9f1bbe7f7eTest