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Achieving space-based gravitational wave detection requires the establishment of an interferometer constellation. It is necessary to establish and maintain stable laser interferometric links using the differential wavefront sensing (DWS) technnique. When the distant measurement beam experiences pointing jitter, it causes beam walk on the surface of the local detector. The reduced overlap between the local reference spot and the distant spot increases the nonlinear errors in the DWS technique, which need to be suppressed. Numerical analysis was conducted on the spatial beam interference signals of the DWS technique when the distant measurement beam experienced pointing jitter. An experimental measurement system was designed, and the beam walk was suppressed using a conjugate imaging system. The results show that within a range of 300 μrad, the optical path with the imaging system can reduce measurement errors by at least 83%. This way also helps to reduce pointing jitter noise in inter-satellite links, thereby improving laser pointing control accuracy.This method would provide a valuable reference for future DWS measurement systems.

Esmolol hydrochloride injection is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. The potential toxic impurities in pharmaceuticals at micro levels or trace levels are of increasing concern to both pharmaceutical industries and regulatory agencies, due to their potential risk to human health. The impurity investigation of esmolol remains incomplete. Thereby, efficient impurities monitoring and potential toxicity assessment should be emphasized to assure drug safety. Impurity profiling methods of esmolol were developed using ultraperformance liquid chromatography plus Q-Exactive Orbitrap tandem mass spectrometry (UPLC-QE-MS) based multiple mass defect filter and chemometrics. Impurities were characterized by both UPLC-QE-MS and reference substance comparison. The toxicities of esmolol impurities were predicted by employing quantitative structure–activity relationship. The results showed that a total of 20 impurities were detected and identified using the above integrated strategy, 14 impurities (EP2-3, EP5-6, EP8-9, EP12-13, EP15-20) have firstly found. EP20 was predicted as hepatotoxic and mutagenic using QSAR model, and its hepatotoxicity were verified in vivo. The EP1 contents showed maximum volatility in all batches, and varied by sample. EP1 and its accompanying product of methanol were measured. This UPLC-MS/MS based chemometrics strategy is useful for monitoring the manufacturing process and quality control of esmolol hydrochloride injection.

Cyclocarya paliurus, as an important edible and medicinal plant, its effects and mechanisms on hyperuricemic nephropathy remain unclear. Herein, we investigated the hypouricemic and nephroprotective effects of the water extracts of C. paliurus leaves (CPE) in a hyperuricemic nephropathy rat model induced by adenine and ethambutol. The results showed that CPE could significantly decrease plasma uric acid (PUA) and urea nitrogen (PUN), as well as reduce renal fibrosis in the hyperuricemic nephropathy rat model. Plasma metabolomics indicated that CPE improved the disordered arachidonic acid metabolism. Meanwhile, CPE reduced renal inflammation via inhibition of COX--2. Moreover, CPE could improve disturbed purine metabolism by inhibiting the hepatic xanthine oxidase (XOD), reversing the renal urate transporter 1 (URAT1) and organic anion transporter 1 (OAT1). Collectively, this study demonstrated that CPE could exhibit hypouricemic effect by improving purine metabolism, and attenuate kidney injury by improving arachidonic acid metabolism and alleviating kidney inflammation.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features.Methods: Reports of PJP recorded in FAERS (January 2004–December 2022) were identified through the preferred term “Pneumocystis jirovecii pneumonia”. Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence.Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed.Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

Quality control of traditional Chinese medicine (TCM) should be linked with the authentication and efficacy of TCM. Selaginella tamariscina is a frequently used traditional Chinese herbal medicine. However, its quality control is still difficult due to its multiple adulterants. We established quality markers (Q-markers) of S. tamariscina by using metabolomics, molecular networking and network pharmacology to improve the authenticity study and quality control of S. tamariscina. In this study, ultra high performance liquid chromatography-mass spectrum (UHPLC-MS) coupled with multivariate statistical analyses was applied to distinguish between S. tamariscina samples and their confusing adulterants. Principal component analysis, hierarchical clustering analysis (PCA), hierarchical clustering analysis (HCA) and partial least squares discriminant analysis (PLS-DA) were employed to screen the distinguishing markers from S. tamariscina samples and their adulterants. The top-2 distinguishing markers were isolated from S. tamariscina and identified by molecular networking together with nuclear magnetic resonance spectroscopy (NMR). Network pharmacology predicted the bioactivity and cytotoxicity of the top-2 distinguishing markers. The top-2 distinguishing markers were adopted as Q-markers of S. tamariscina for content determination. Based on the results of ultra performance liquid chromatography-quardrupole-time of flight mass spectrometry (UHPLC-QTOF-MS) metabolomics, we revealed that selaginellins could only be detected in S. tamariscina samples and contributed greatly to discriminating S. tamariscina samples from their confused species. The top-2 distinguishing markers were isolated and purified from S. tamariscina extract. Then, they were further identified as selaginellin and selaginellin A by molecular networking and NMR. Network pharmacology predicted the antitumor activity of selaginellin and selaginellin A, while the cytotoxicity assay verified their bioactivity. In conclusion, selaginellin and selaginellin A were selected as Q-markers for the determination and quality evaluation of S. tamariscina based on ultra performance liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-QQQ-MS). The ranges of the concentrations of selaginellin and selaginellin A were 41.57–44.89 μg/g and 15.09–16.75 μg/g, respectively. This study provides a novel strategy combining Ultra performance liquid chromatography mass spectrometry based (UHPLC-MS-based) metabolomics with molecular networking for rapid species identification of S. tamariscina and discovery of the Q-markers of TCM.

Cyclocarya paliurus flavonoids (CPF) are the main active ingredients, showed hypolipidemic, hypoglycemic, anti-lipogenic, and anti-inflammatory activities. However, the biomarkers associated with lipid metabolism and the underlying mechanisms for non-alcoholic steatohepatitis (NASH) of CPF have remained unclear. Herein, we combined lipidomics with proteomics to clarify its efficacy and related mechanisms of preventing NASH in mice. CPF supplementation (100 mg/kg) not only significantly decreased body and liver weight gain, cholesterol and triacylglycerols (TGs) levels in NASH mice without affecting feeding, but also ameliorated hepatic steatosis via significantly reducing liver inflammation score and the area of liver fibrosis. Lipidomics indicated that the efficacy of preventing NASH was closely associated with the decreasing levels of TGs, diacylglycerols (DGs), and ceramides (Cers). Moreover, proteomics also revealed that CPF promoted metabolic homeostasis in liver. The related target, acetyl-CoA carboxylase 1 and collagen type I alpha 1, were validated by proteomics and PCR. These above findings indicated that the remodulation of lipid homeostasis may be the pivotal pathway for the potential mechanisms of CPF in protecting against NASH.

Introduction: Antibody–drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies.Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis.Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses.Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p