Monolithic tunable dual-wavelength laser utilizing erbium-doped lithium niobate on an insulator.

We demonstrate a monolithic tunable dual-wavelength laser fabricated on erbium-doped lithium niobate on an insulator (Er:LNOI). The dual-wavelength laser enables independent tuning with a continuously linear electro-optic (EO)-modulated tuning range of 11.875 GHz at a tuning efficiency of 0.63 pm/V. Tunable microwave generation within 50 GHz with a maximum extinction ratio of 35 dB is experimentally demonstrated by further exploring the charge accumulation effect in LNOI. The monolithic design of this work paves the way for microscale integration of laser devices, presenting significant prospects in photonics research and applications.

The effects of loving-kindness meditation on doctors' communication anxiety, trust, calling and defensive medicine practice.

OBJECTIVE: The study investigated the effects of loving-kindness meditation (LKM) on doctors' communication anxiety, trust, calling, and defensive medicine practice. METHODS: This study recruited 94 doctors from a hospital in China, randomized them to an LKM group (n = 47), and waited for the control group (n = 47). The experimental group accepted an 8-week LKM interference while the waiting for the control group underwent no interference. Researchers measured four major variable factors (communication anxiety, trust, calling, and defensive medicine practice) before and after the LKM intervention. RESULTS: In the experimental group, trust, and calling were significantly higher, and communication anxiety, and defensive medicine practice were significantly lower than in the control group. In the control group, there were no noticeable differences in any of the four variables between the pre-test and post-test. CONCLUSIONS: The results of this study demonstrate that LKM may help to improve trust, and calling, and reduce communication anxiety and defensive medicine practice. The finding of LKM's effect extends the understanding of the integrative effects of positive psychology on the decrease of defensive medicine practice. TRIAL REGISTRATION: ChiCTR2300074568. Registered in Chinese Clinical Trial Registry (ChiCTR), 9 August, 2023.

Impact of drug-linker on method selection for analytical characterization and purification of antibody-drug conjugates.

In addition to traditional characterisation methods of hydrophobic interaction (HIC) and reverse phase (RP) chromatography, an anion exchange chromatography (AIEX) was developed to analyse and purify antibody drug conjugates (ADCs). Since different drug antibody ratio (DAR) species may impact biological activity, therapeutic index, PK parameters or even potential immunogenicity, homogenous ADC DAR demands have been significantly increasing. To accelerate linker designs, drug screening and ADC DAR purification for in vitro and in vivo studies, we built the analytical toolbox including HIC, RP, AIEX, icIEF, SEC, and MS for downstream ADC DAR purification using HIC and AIEX. The established analytical methods can quickly assess the quality of ADC DAR profiles and provide important information to select the proper ADC DAR purification method. Since drug-linker structures can significantly affect ADC physicochemical properties, and highly impact on selections of analytical methods, we applied both HIC and AIEX characterisation and purification platforms to achieve ADC DAR homogenous. Our experiments also implied that unlike HIC, AIEX could be used to separate DAR4 positional isomers.

Clinicopathologic characteristics and outcomes of prostate cancer incidentally discovered at the time of radical cystoprostatectomy: a population-based cohort study.

OBJECTIVE: This study aimed to comprehensively analyze the clinical characteristics and prognosis of patients with concomitant bladder cancer (BCa) and prostate cancer (PCa) using a large population-based database. METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019), we identified patient with concomitant PCa at the time of radical cystoprostatectomy (RCP). Logistic regression and propensity score matching (PSM) analyses were employed to identify risk factors and mitigate confounders, respectively. Kaplan-Meier survival curves were used to estimate cancer-specific survival (CSS). RESULTS: A total of 14,199 BCa patients undergoing RCP were identified, with 28.8% incidentally discovered to have concurrent PCa. Among them, 89.9% exhibited organ-confined (T1-2) PCa. An increased risk of concomitant tumors was observed among older age, white race, and high tumor grade of BCa. Survival analysis revealed no significant difference in CSS between patients with BCa alone and those with concurrent PCa (5-year CSS rate: 71.3% vs. 67.2%, P =0.076). Subgroup analysis and multivariable analysis, however, indicated that concurrent high-risk PCa adversely impacted survival (5-year CSS rate: 71.3% vs. 63.4%, HR 1.27, 95% CI 1.01-1.58, P =0.038) compared to solitary BCa. Notably, the presence of low/intermediate-risk PCa did not affect survival outcomes ( P =0.584). CONCLUSION: In conclusion, incidentally discovered PCa in RCP specimens is frequent and characterized by organ-confined presentation, lower PSA levels, and Gleason scores. Patients with concurrent high-risk PCa have a worse prognosis compared to those with solitary BCa, while the presence of low/intermediate-risk PCa does not influence oncological prognosis.

IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFß.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFß. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFß signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFß at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFß-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.

Anti-cancer agent piperlongumine is an inhibitor of transient receptor potential melastatin 7 channel in oral squamous cell carcinoma.

OBJECTIVES: To elucidate the association between the anticancer activities of piperlongumine (PL) and its potential target, transient receptor potential melastatin 7 channel (TRPM7), in oral squamous cell carcinoma (OSCC). METHODS: The expression levels and electrical characteristics of TRPM7 as well as cell viability in response to various PL treatments were investigated in the OSCC cell line Cal27. RESULTS: PL treatment resulted in a concentration- and time-dependent reduction in TRPM7 mRNA and protein expression in Cal27 cells. Furthermore, PL treatment inhibited TRPM7-like rectifying currents in Cal27 cells; however, this inhibition was less effective than that of the TRPM7 antagonist waixenicin A. Rapid perfusion and washout experiments revealed an immediate inhibitory effect of PL on TRPM7-like currents. The antagonistic effect of PL occurred within 1 min and was not completely reversed following washout. Notably, the extracellular Ca2+ concentration still influenced PL-induced changes in the TRPM7-like current, indicating that PL can directly but gently antagonize the TRPM7 channel. Functional changes in TRPM7 correlated with the observed antiproliferative and cytotoxic effects of PL in Cal27 cells. CONCLUSIONS: These findings suggest that PL exhibits potent inhibitory effects on TRPM7 and exerts its anti-cancer effects by downregulating TRPM7 expression and antagonizing channel currents.

Linker substitution influences succinimide ring hydrolysis equilibrium impacting the stability of attachment to antibody-drug conjugates.

Maleimide chemistry is widely used in antibody-drug conjugate (ADC) generation to connect drugs to antibodies through a succinimide linker. The resulting ADC is prone to payload loss via a reverse Michael reaction, leading to premature drug release in vivo. Complete succinimide hydrolysis is an effective strategy to overcome the instability of ADC. However, we discovered through previous work that hydrolysed succinimide rings can close again in a liquid formulation during storage and under thermal stress conditions. In this work, a set of maleimide linkers with hydrolysis-prone groups were designed. The corresponding ADCs were prepared and subjected to thermal stress conditions. The extent of succinimide hydrolysis and drug release was measured, and ADC properties such as SEC, DAR, pI and clog P of linkers were calculated. Our results demonstrated that even though all these groups increased the hydrolysis rate, they have different impacts on maintaining the hydrolysed succinimide ring in an open conformation and ADC stability in a liquid formulation.

Ce doped V-W/Ti as selective catalytic reduction catalysts for cement kiln flue gas denitration.

In cement industry, the selection of catalyst temperature window and the inhibition effect of dust composition in flue gas on catalyst are the key issues of flue gas denitrification. In this article, a pilot study with Ce doped V-W/Ti catalyst on the removal of NOx by selective catalytic reduction with ammonia (NH3-SCR) from the cement kiln flue gas was presented. Cement kiln dust loading on catalysts obviously decreased the NO conversion in the absence of SO2 and H2O, while the denitration efficiency restored from 75 to 98% at 280 ℃ after SO2 and H2O introduced into the reaction system, which mainly because the SO2 may enhance the acidic site on the catalyst surface, and prefer to be bonded with the coordinated Ca species, releasing the active sites poisoned by dust. The NH3-temperature programmed desorption (NH3-TPD), X-ray photoelectron spectroscopy (XPS), and H2-temperature programmed reduction (H2-TPR) detections were performed to reveal that the appropriate Ce and W ratios catalyst contributed better denitrification activity. The optimum ratio of Ce doped catalyst was amplified to form the standard honeycomb monomer catalyst, and then, the activity of catalyst was verified on the side line of cement kiln. The effect of temperature and space velocity on denitrification efficiency was investigated, and the denitration efficiency reached to 92.5% at 300℃ and 3000 h-1 space velocity. Moreover, the life of catalyst was verified and predicted by GM (1,1) grey model. The study realized the innovation from the laboratory data rules to the industrial pilot application, providing positive promoting value for the industrial large-scale demonstration application of the catalyst.

Genetically proxied intestinal microbiota and risk of erectile dysfunction.

BACKGROUND: The interaction between intestinal microbiota and erectile dysfunction (ED) is less investigated. This study was performed to explore the association between intestinal microbiota and ED. METHODS: In this two-sample Mendelian randomization (MR) study, genetic variants of gut microbiota were obtained from MiBioGen consortium containing 18,340 individuals. Six methods including inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR robust adjusted profile score, and MR pleiotropy residual sum and outlier were used to investigate the causal links between intestinal microbiota and ED. Furthermore, reverse MR analysis was performed to exclude the causal impact of ED on gut microbiota. RESULTS: As revealed by the IVW estimator, the risks of ED were raised by genetically proxied Lachnospiraceae (OR: 1.27), Lachnospiraceae NC2004 group (OR: 1.17), Oscillibacter (OR: 1.20), Senegalimassilia (OR: 1.32) (All P < 0.05) and Tyzzerella-3 (OR: 1.14, P < 0.05). It was observed that Ruminococcaceae UCG013 exerted protective effect against ED (OR: 0.77, P < 0.05). These results were consistent with other estimators in sensitivity analyses. In reverse MR analyses, genetic liability to ED did not alter the abundances of Lachnospiraceae, Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella-3, and Ruminococcaceae UCG013 (All P > 0.05). No heterogeneity and pleiotropy were detected by Cochran's Q-test, MR-Egger, and global test (All P > 0.05). CONCLUSIONS: This study provided novel evidence that genetically proxied Lachnospiraceae, Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella-3, and Ruminococcaceae UCG013 had potentially causal effects on ED. Further studies are needed to clarify the biological mechanisms linking intestinal microbiota to ED.

The effects of short video app-guided loving-kindness meditation on college students' mindfulness, self-compassion, positive psychological capital, and suicide ideation.

OBJECTIVE: The study investigated the effects of a short video app guided loving-kindness meditation (LKM) on college students' mindfulness, self-compassion, positive psychological capital, and suicide ideation. The purpose of the study is to investigate the intervention effect of LKM training on suicidal ideation among college students with the help of the short video application and to provide an empirical basis for the exploration of early suicide intervention strategies for college students. METHODS: We recruited 80 college students from a university in China. The final 74 eligible participants were divided into two groups: app use group (n = 37) and the control group (n = 37). The app group accepted an 8-week app use interference, while the control group underwent no interference. We measured four major variable factors (mindfulness, self-compassion, positive psychological capital, and suicide ideation) before and after the app use intervention. RESULTS: In the app group, self-compassion and positive psychological capital were significantly higher, and suicide ideation was significantly lower than the control group. In the control group, there were no noticeable differences in any of the four variables between the pre-test and post-test. CONCLUSIONS: Our findings demonstrate that the short video app guided LKM may help to improve self-compassion, and positive psychological capital, and reduce suicide ideation. The finding of the short video app-guided LKM's effect extends our understanding of the integrative effects of positive psychology and digital media on the reduction of suicide ideation.

In-depth analysis of human virus-specific CD8+ T cells delineates unique phenotypic signatures for T cell specificity prediction.

Following viral infection, the human immune system generates CD8+ T cell responses to virus antigens that differ in specificity, abundance, and phenotype. A characterization of virus-specific T cell responses allows one to assess infection history and to understand its contribution to protective immunity. Here, we perform in-depth profiling of CD8+ T cells binding to CMV-, EBV-, influenza-, and SARS-CoV-2-derived antigens in peripheral blood samples from 114 healthy donors and 55 cancer patients using high-dimensional mass cytometry and single-cell RNA sequencing. We analyze over 500 antigen-specific T cell responses across six different HLA alleles and observed unique phenotypes of T cells specific for antigens from different virus categories. Using machine learning, we extract phenotypic signatures of antigen-specific T cells, predict virus specificity for bulk CD8+ T cells, and validate these predictions, suggesting that machine learning can be used to accurately predict antigen specificity from T cell phenotypes.

Stochastic scheduling of autonomous mobile robots at hospitals.

This paper studies the scheduling of autonomous mobile robots (AMRs) at hospitals where the stochastic travel times and service times of AMRs are affected by the surrounding environment. The routes of AMRs are planned to minimize the daily cost of the hospital (including the AMR fixed cost, penalty cost of violating the time window, and transportation cost). To efficiently generate high-quality solutions, some properties are identified and incorporated into an improved tabu search (I-TS) algorithm for problem-solving. Experimental evaluations demonstrate that the I-TS algorithm outperforms existing methods by producing high-quality solutions. Based on the characteristics of healthcare requests and the AMR working environment, scheduling AMRs reasonably can effectively provide medical services, improve the utilization of medical resources, and reduce hospital costs.

Discovery of a glucocorticoid receptor (GR) activity signature correlates with immune cell infiltration in adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy, of which >40% present with glucocorticoid excess. Glucocorticoids and glucocorticoid receptor (GR) signaling have long been thought to suppress immunity and promote tumor progression by acting on immune cells. Here, we provide new insights into the interaction between GR signaling activity and the immune signature of ACC as a potential explanation for immune escape and resistance to immunotherapy. METHODS: First, GR immunohistochemical staining and immunofluorescence analysis of tumor-infiltrating lymphocyte (CD4 T, CD8 T cells, natural killer (NK) cells, dendritic cells and macrophages) were performed in 78 primary ACC tissue specimens. Quantitative data of immune cell infiltration in ACC were correlated with clinical characteristics. Second, we discovered a GR activity signature (GRsig) using GR-targeted gene networks derived from global gene expression data of primary ACC. Finally, we identified two GRsig-related subtypes based on the GRsig and assessed the differences in immune characteristics and prognostic stratification between the two subtypes. RESULTS: GR was expressed in 90% of the ACC tumors, and CD8+ cytotoxic T lymphocytes were the most common infiltrating cell type in ACC specimens (88%, 8.6 cells/high power field). GR expression positively correlated with CD8+ T cell (Phi=0.342, p<0.001), CD4+ T cell (Phi=0.280, p<0.001), NK cell (Phi=0.280, p<0.001), macrophage (Phi=0.285, p<0.001), and dendritic cell (Phi=0.397, p<0.001) infiltration. Clustering heatmap analysis also displayed high immune cell infiltration in GR high-expressing tumors and low immune cell infiltration in GR-low tumors. High GR expression and high immune cell infiltration were significantly associated with better survival. Glucocorticoid excess is associated with low immune cell abundance and unfavorable prognosis. A GRsig comprizing n=34 GR-associated genes was derived from Gene Expression Omnibus/The Cancer Genome Atlas (TCGA) data sets and used to define two GRsig-related subtypes in the TCGA cohort. We demonstrated distinct differences in the immune landscape and clinical outcomes between the two subtypes. CONCLUSION: GR expression positively correlates with tumor-infiltrating immune cells in ACC. The GRsig could serve as a prognostic biomarker and may be helpful for prognosis prediction and response to immunotherapy. Consequently, targeting the GR signaling pathway might be pivotal and should be investigated in clinical studies.

Genetic Insights into Intestinal Microbiota and Risk of Infertility: A Mendelian Randomization Study.

BACKGROUND: The interaction between intestinal microbiota and infertility is less researched. This study was performed to investigate the causal association between gut microbiota and infertility. METHODS: In this two-sample Mendelian randomization (MR) study, genetic variants of intestinal microbiota were obtained from the MiBioGen consortium, which included 18,340 individuals. Inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR Robust adjusted profile score, MR Pleiotropy residual sum, and outlier (MR-PRESSO) methods were used to explore the causal links between intestinal microbiota and infertility. The MR-Egger intercept term and the global test from the MR-PRESSO estimator were used to assess the horizontal pleiotropy. The Cochran Q test was applied to evaluate the heterogeneity of instrumental variables (IVs). RESULTS: As indicated by the IVW estimator, significantly protective effects of the Family XIII AD3011 group (OR = 0.87) and Ruminococcaceae NK4A214 group (OR = 0.85) were identified for female fertility, while Betaproteobacteria (OR = 1.18), Burkholderiales (OR = 1.18), Candidatus Soleaferrea (OR = 1.12), and Lentisphaerae (OR = 1.11) showed adverse effects on female fertility. Meanwhile, Bacteroidaceae (OR = 0.57), Bacteroides (OR = 0.57), and Ruminococcaceae NK4A214 group (OR = 0.61) revealed protective effects on male fertility, and a causal association between Anaerotruncus (OR = 1.81) and male infertility was detected. The effect sizes and directions remained consistent in the other five methods except for Candidatus Soleaferrea. No heterogeneity or pleiotropy were identified by Cochran's Q test, MR-Egger, and global test (all p > 0.05). CONCLUSIONS: This two-sample MR study revealed that genetically proxied intestinal microbiota had potentially causal effects on infertility. In all, the Ruminococcaceae NK4A214 group displayed protective effects against both male and female infertility. Further investigations are needed to establish the biological mechanisms linking gut microbiota and infertility.

Reconstruction of Inferior Vena Cava by Autologous Great Saphenous Vein Grafts in Liver Surgery.

BACKGROUND: To secure surgical margin for hepatic lesion with involvement of the inferior vena cava (IVC), combined radical liver resection and IVC replacement are required. A novel method of replacing IVC by newly customized autologous great saphenous vein (GSV) grafts was introduced by this study. This study aimed at reporting the feasibility and outcome of this novel technique. METHODS: From January 2014 to January 2021, all consecutive patients who underwent concomitant hepatectomy and IVC replacement by autogenous GSV graft were enrolled in this study. Technical insights, intraoperative details, demographic data, postoperative complication, graft patency and survival data were collected and analyzed. RESULTS: Concomitant hepatectomy/autotransplantation (ERAT) with IVC replacement by autogenous GSV graft was successful in 47 patients and there was no 30-day mortality. There were 8 out of the 47 patients whose retrohepatic venae cavae were completely invaded by the lesion and their reconstructed IVCs were totally made from GSV grafts. The other 39 patients whose IVCs were partially invaded had their IVCs reconstructed by both the unaffected part of the IVC wall and newly customized GSV graft. Postoperative complications classified as Clavien-Dindo grade II, III A and III B were observed in 10, 7 and 3 patients, respectively. The median follow-up months were 35 months (29-80 months). No patient developed thrombosis of the graft and 100% patency of the IVC was observed throughout the study. CONCLUSION: In selected patients, hepatectomy/ERAT with IVC replacement by autogenous GSV graft is safe and feasible. The newly customized autologous GVS graft was ideal for reconstruction of the IVC in liver surgery.

The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses.

Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus (Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broad-spectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) phosphorylation and Golgi vesiculation by peruvoside treatment. The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation. Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337 (T1337). We also showed 100% of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum. These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside, host-directed antivirals for positive-sense RNA virus-mediated disease, in the interim where no vaccine is available.

The biological role and immunotherapy of gangliosides and GD3 synthase in cancers.

Gangliosides are a large subfamily of glycosphingolipids that broadly exist in the nervous system and interact with signaling molecules in the lipid rafts. GD3 and GD2 are two types of disialogangliosides (GDs) that include two sialic acid residues. The expression of GD3 and GD2 in various cancers is mostly upregulated and is involved in tumor proliferation, invasion, metastasis, and immune responses. GD3 synthase (GD3S, ST8SiaI), a subclass of sialyltransferases, regulates the biosynthesis of GD3 and GD2. GD3S is also upregulated in most tumors and plays an important role in the development and progression of tumors. Many clinical trials targeting GD2 are ongoing and various immunotherapy studies targeting gangliosides and GD3S are gradually attracting much interest and attention. This review summarizes the function, molecular mechanisms, and ongoing clinical applications of GD3, GD2, and GD3S in abundant types of tumors, which aims to provide novel targets for future cancer therapy.