Discovery of an Active RAG Transposon Illuminates the Origins of V(D)J Recombination.

Co-option of RAG1 and RAG2 for antigen receptor gene assembly by V(D)J recombination was a crucial event in the evolution of jawed vertebrate adaptive immunity. RAG1/2 are proposed to have arisen from a transposable element, but definitive evidence for this is lacking. Here, we report the discovery of ProtoRAG, a DNA transposon family from lancelets, the most basal extant chordates. A typical ProtoRAG is flanked by 5-bp target site duplications and a pair of terminal inverted repeats (TIRs) resembling V(D)J recombination signal sequences. Between the TIRs reside tail-to-tail-oriented, intron-containing RAG1-like and RAG2-like genes. We demonstrate that ProtoRAG was recently active in the lancelet germline and that the lancelet RAG1/2-like proteins can mediate TIR-dependent transposon excision, host DNA recombination, transposition, and low-efficiency TIR rejoining using reaction mechanisms similar to those used by vertebrate RAGs. We propose that ProtoRAG represents a molecular "living fossil" of the long-sought RAG transposon.

Utilising intraoperative respiratory dynamic features for developing and validating an explainable machine learning model for postoperative pulmonary complications.

BACKGROUND: Timely detection of modifiable risk factors for postoperative pulmonary complications (PPCs) could inform ventilation strategies that attenuate lung injury. We sought to develop, validate, and internally test machine learning models that use intraoperative respiratory features to predict PPCs. METHODS: We analysed perioperative data from a cohort comprising patients aged 65 yr and older at an academic medical centre from 2019 to 2023. Two linear and four nonlinear learning models were developed and compared with the current gold-standard risk assessment tool ARISCAT (Assess Respiratory Risk in Surgical Patients in Catalonia Tool). The Shapley additive explanation of artificial intelligence was utilised to interpret feature importance and interactions. RESULTS: Perioperative data were obtained from 10 284 patients who underwent 10 484 operations (mean age [range] 71 [65-98] yr; 42% female). An optimised XGBoost model that used preoperative variables and intraoperative respiratory variables had area under the receiver operating characteristic curves (AUROCs) of 0.878 (0.866-0.891) and 0.881 (0.879-0.883) in the validation and prospective cohorts, respectively. These models outperformed ARISCAT (AUROC: 0.496-0.533). The intraoperative dynamic features of respiratory dynamic system compliance, mechanical power, and driving pressure were identified as key modifiable contributors to PPCs. A simplified model based on XGBoost including 20 variables generated an AUROC of 0.864 (0.852-0.875) in an internal testing cohort. This has been developed into a web-based tool for further external validation (https://aorm.wchscu.cn/). CONCLUSIONS: These findings suggest that real-time identification of surgical patients' risk of postoperative pulmonary complications could help personalise intraoperative ventilatory strategies and reduce postoperative pulmonary complications.

MICROVASCULATURE ALTERATIONS OF PERIPAPILLARY RETINA AND MACULA IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITHOUT OCULAR INVOLVEMENT BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To evaluate microvasculature alterations of the peripapillary retina and macula and to assess whether the changes can detect preclinical retinopathy in systemic lupus erythematosus patients. METHODS: Cross-sectional study of 32 systemic lupus erythematosus patients without retinopathy and 22 normal controls. Optical coherence tomography angiography was used to measure the microvasculature of the peripapillary retina and macula. Vessel densities (VD, %) and fractal dimensions of superficial capillary plexus (SCP) and deep capillary plexus were calculated. RESULTS: Compared with controls, macular vessel densities of the whole image SCP (macular vessel density of SCP-wi) and macular vessel density of inferior SCP (macular vessel density of SCP-i) were significantly reduced in systemic lupus erythematosus patients ( P < 0.05). The peripapillary vessel densities (peripapillary vessel density [pVD]) of a 2.5-mm circle of SCP (pVD of SCP Φ2.5 ), pVD of SCP Φ3.5 , and pVD of inferior region of the inner circle of SCP (pVD of SCP-ii) were significantly reduced in patients treated with hydroxychloroquine >5 years. Macular vessel density of SCP-wi declined with age (ß = -0.12; P < 0.01) and pVD of SCP-ii declined with hydroxychloroquine cumulative dose (ß = -0.01; P < 0.01). Macular vessel density of SCP-i had the best discrimination power of 0.77 ( P < 0.01). CONCLUSION: Systemic lupus erythematosus patients without ocular involvement had microvasculature alterations that were particularly evident in the SCP. Peripapillary retina microvasculature may be reduced in patients with longer hydroxychloroquine treatment.

Robot Learning Method for Human-like Arm Skills Based on the Hybrid Primitive Framework.

This paper addresses the issue of how to endow robots with motion skills, flexibility, and adaptability similar to human arms. It innovatively proposes a hybrid-primitive-frame-based robot skill learning algorithm and utilizes the policy improvement with a path integral algorithm to optimize the parameters of the hybrid primitive framework, enabling robots to possess skills similar to human arms. Firstly, the end of the robot is dynamically modeled using an admittance control model to give the robot flexibility. Secondly, the dynamic movement primitives are employed to model the robot's motion trajectory. Additionally, novel stiffness primitives and damping primitives are introduced to model the stiffness and damping parameters in the impedance model. The combination of the dynamic movement primitives, stiffness primitives, and damping primitives is called the hybrid primitive framework. Simulated experiments are designed to validate the effectiveness of the hybrid-primitive-frame-based robot skill learning algorithm, including point-to-point motion under external force disturbance and trajectory tracking under variable stiffness conditions.

Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.

Incidence and trends of hepatic cancer among children and adolescents in the United States from 2000 to 2017: Evidence from the Surveillance, Epidemiology, and End Results registry data.

OBJECTIVE: Primary liver tumors are rare pediatric malignancies. Knowledge of the epidemiology of pediatric liver tumors is limited. This study aims to present the national incidence trends of pediatric liver tumors over 18 years, according to sociodemographic and histological subtype variation. METHODS: The Surveillance, Epidemiology, and End Results registry was queried from 2000 to 2017 for 1,099 patients between ages 0 and 19 with liver tumors. Age-standardized incidence rates by age, sex, and race/ethnicity were examined among histological subtypes. Annual percentage change (APC) was calculated via joinpoint regression for various sociodemographic and histotype subgroups. RESULTS: An increase of age-adjusted incidence rate of pediatric hepatic cancers was observed between 2000 and 2017 (APC, 1.7% [95% confidence interval or CI: 0.6%-2.8%], p-value = 0.006), which may likely attribute to the increasing incidence of hepatoblastoma and mesenchymal tumors (APC, 2.5% [95% CI: 1.1%-3.8%], p-value = 0.001). The incidence trend of hepatocellular carcinoma remained stable in the study period. The non-Hispanic Asian/Pacific Islander children and adolescents had a higher risk of hepatic tumors (incidence rate ratio or IRR, 1.42 [95% CI: 1.16-1.72], p-value = 0.0007) when compared with the non-Hispanic white subgroup, while a non-Hispanic black child was associated with a lower incidence rate (IRR, 0.64 [95% CI: 0.50-0.80], p-value < 0.0001). Significantly lower hepatic tumor incidence occurred in females than males, with an incidence rate ratio of 0.69 (95% CI: 0.61-0.78; p-value < 0.0001). Hepatic tumor incidence was also significantly lower in those aged 1-4 years (IRR, 0.47 [95% CI: 0.40-0.54]; p-value < 0.001) and 5-19 years (IRR, 0.09 [95% CI: 0.08-0.10]; p-value < 0.001) when compared with the youngest age group aged less than 1 year. These significant differences were also detected for the subgroup of hepatoblastoma and mesenchymal liver tumors but less among hepatocellular carcinomas (all p-values less than 0.0001). CONCLUSION: Continued increasing incidence of pediatric hepatoblastoma and mesenchymal liver tumors was discovered and warranted further investigation. Additional findings include a lower incidence of hepatic cancer among non-Hispanic black individuals and higher incidence of hepatic cancer in non-Hispanic Asian/Pacific Islander, male, and aged 1-4-year children and adolescents.

Association Between Daily Internet Use and Incidence of Chronic Diseases Among Older Adults: Prospective Cohort Study.

BACKGROUND: Chronic disease incidence among the elderly is increasing, which is correlated with the acceleration of population aging. Evolving internet technologies may help prevent and provide interventions for chronic diseases in an accelerating aging process. However, the impact of daily internet use on the incidence of chronic diseases is not well understood. OBJECTIVE: This study aims to investigate whether daily internet use by middle-aged and older adults may inhibit or promote the occurrence of chronic diseases. METHODS: We included participants from the China Health and Retirement Longitudinal Study (CHARLS), a longitudinal survey of Chinese residents aged ≥45 years. We assessed 8-year data from wave 1 (June 2011-March 2012) to wave 4 (July-September 2018) in CHARLS. Data from wave 4 were used for a cross-sectional study, and data from all 4 waves were used for a longitudinal study. Self-reported data were used to track variables, including internet use, use frequency, and the incidence of different chronic diseases. Cox proportional hazards modeling was applied in the longitudinal study to examine the relationship between daily internet use and chronic diseases among middle-aged and older adults, while adjusting for sociodemographic characteristics and health behaviors. In addition, longitudinal data were used to analyze internet usage trends, and cross-sectional data were used to analyze the factors influencing internet use. RESULTS: Among the 20,113 participants included in the longitudinal analyses, internet use increased significantly, from 2% to 12.3%, between 2011 and 2018. The adjusted model found statistically significant relationships between daily internet use and a lower incidence of the following chronic diseases: hypertension (hazard ratio [HR] 0.78, 95% CI 0.65-0.95, P=.01), chronic lung disease (HR 0.74, 95% CI 0.57-0.97, P=.03), stroke (HR 0.69, 95% CI 0.50-0.94, P=.02), digestive disease (HR 0.73, 95% CI 0.58-0.91, P=.005), memory-related disorders (HR 0.58, 95% CI 0.37-0.91, P=.02), arthritis or rheumatism (HR 0.60, 95% CI 0.48-0.76, P<.001), asthma (HR 0.52, 95% CI 0.33-0.84, P=.007), depression (HR 0.80, 95% CI 0.71-0.89, P<.001), and vision impairment (HR 0.83, 95% CI 0.74-0.93, P=.004). Moreover, our study also showed that with increasing frequency of internet use, the risk of some chronic diseases decreases. CONCLUSIONS: This study found that middle-aged and older adults who use the internet have a reduced risk of developing chronic diseases versus those who do not use the internet. The increasing prevalence of daily internet use among middle-aged and older adults may stimulate contemplation of the potential role of internet platforms in future research on chronic disease prevention.

Impact of different structures of biochar on decreasing methane emissions from sewage sludge composting.

Methane (CH4) emissions from sewage sludge composting can be reduced by using biochar more effectively. This study investigates the impact of different structure of biochar on CH4 emissions during sewage sludge composting. Corncob biochar (CB, pore size = 35.3990 nm), rice husk biochar (RB, pore size = 3.4242 nm) and wood biochar (WB, pore size = 1.6691 nm) were applied to the composting. The results showed that biochar decreased CH4 emissions, mainly through the indirect effect of improving the pile environment. Compared with the control group (CK), the biochars with smaller pore structures, WB and RB, reduced CH4 emissions by 41.83% and 33.59%, respectively, compared to only 8.20% for CB, which has a larger pore structure. In addition, RB and WB increased the free air space (FAS) by more than 10% and CB improved the microbial diversity. Methanothermobacter was reported in WB and RB, with an abundance of 45.45% in WB. Redundancy analysis (RDA) showed that pore size was positively correlated with the CH4 emission rate. The results of this study can provide a theoretical reference for CH4 reduction from biochar co-composting of sewage sludge.

Eco-risk management of tylosin fermentation residues using vermicomposting.

Tylosin fermentation residues (TFR) pose an ecotoxicological risk through antibiotic resistant bacteria (ARBs) and their corresponding genes (ARGs). This study evaluated the ecotoxicity of TFR to soil biological activity, and further explored the mechanisms of vermicomposting to reduce the toxicological risk. The results showed that tylosin (TYL) was moderately degradable with a half-life (t1/2) of 37.5 d, inducing 28-44% inhibition rate of nitrogen transformation in soil, and the EC50 of earthworm avoidance was 880 mg/kg. The 30-d vermicomposting reduced the pH and OM content, while increased the EC and TN content, accelerated compost maturation (C/N ratio up to 20), and enriched the microbial community. ARGs were reduced by earthworm through removal of TYL (>70% degradation, t1/2 of <20 d), inhibiting abundance of intI1 and ARBs. We conclude that vermicomposting is an efficient method for TFR treatment and its eco-risk management.

Molecular dynamics study of enhanced autophosphorylation by S904F mutation of the RET kinase domain.

The aberrant kinase activity of RET (rearranged during transfection), a transmembrane tyrosine kinase, is associated with human cancer. A point mutation caused by the replacement of solvent-front hydrophilic S904, located on the activation loop (A-loop), with a bulky hydrophobic phenylalanine residue can induce resistance to the type I kinase inhibitor vandetanib. A possible mechanism of this drug resistance is the release of a cis-autoinhibited conformation of RET for autophosphorylation, which activates RET kinase. Because the association between S904F mutation and enhanced autophosphorylation is unclear, we conducted molecular modeling analysis to compare unphosphorylated apo wild-type and S904F mutant structures. The structural compactness of the A-loop promoted ATP binding. When the A-loop is extended, the αC helix moves toward the glycine-rich loop, resulting in the protrusion of F735. The extruded F735 connects with E734 and R912 and constrains the ATP pocket entrance. Contrarily, a contracted A-loop pulls the αC helix away from the glycine-rich loop, burying F734 and making the ATP pocket accessible. The mutated F904 stabilizes the contracted A-loop and releases the autoinhibited conformation of RET, thereby facilitating autophosphorylation. We also simulated two ATP-bound systems. The binding free energies of ATP, estimated through the molecular mechanics with a generalized Born and surface area solvation approach, revealed that the S904F mutant was bound more tightly than was the wild type with the ATP. The findings support the premise of autophosphorylation promotion in the S904F mutant.

Impacts of the zero mark-up drug policy on hospitalization expenses of COPD inpatients in Sichuan province, western China: an interrupted time series analysis.

BACKGROUND: Since 1950, the hospitals had been permitted to take a 15% mark-up of drug purchase price to remedy the loss of public hospitals and doctors' salaries in China due to tight government budget. This policy resulted in an increasing over-prescriptions which increased burden for patients eventually. The soaring medical expenditures prompted Chinese government to launch the zero mark-up drug policy (ZMDP) in 2009, which aims to eliminate physicians' financial incentives and lighten patients' economic burden through cancelling the 15% mark-up. The purpose of this study is to assess the impacts of the ZMDP on hospitalization expenses for inpatients with chronic obstructive pulmonary disease (COPD) in western China. METHOD: An interrupted time series was used to assess the impact of the ZMDP in 25 tertiary hospitals of Sichuan province, in which the policy was implemented in 2017. Monthly average total hospitalization expenses including drug expenses, medical service expenses and diagnosis expenses of COPD inpatients were analyzed with segmented regression model developed from January 2015 to June 2018. RESULTS: After the intervention of the ZMDP, the total hospitalization expenses of COPD patients significantly decreased immediately by 1022.06 CNY (P = .011). The post-policy long-term trend was decreasing by 125.32 CNY (P < .001) per month compared to the pre-policy period. The drug expenses kept downward trend both before and after the policy implementation. It had decreased by 46.42 CNY (P < .001) per month on average before the policy implementation and then dropped 1073.58 CNY (P < .001) immediately after the policy was implemented. Meanwhile, the medical service expenses had an increasing baseline trend of 14.93 CNY (P < .001) per month before the policy intervention, but it increased 197.75 CNY immediately after the policy was implemented (P = .011). The pre-policy period long-term trend of diagnosis expenses had increased by 25.78 CNY (P < .001) per month and decreased immediately by 310.78 CNY (P = .010). The post-policy trend was decreasing by 35.60 CNY (P = .001) per month compared to the pre-policy period. CONCLUSION: Our study suggested that the ZMDP have been an effective intervention to curb the increase of hospitalization expenses for inpatients with COPD, especially the drug expenses in western region of China.

Information Disclosure During the COVID-19 Epidemic in China: City-Level Observational Study.

BACKGROUND: Information disclosure is a top priority for official responses to the COVID-19 pandemic. The timely and standardized information published by authorities as a response to the crisis can better inform the public and enable better preparations for the pandemic; however, there is limited evidence of any systematic analyses of the disclosed epidemic information. This in turn has important implications for risk communication. OBJECTIVE: This study aimed to describe and compare the officially released content regarding local epidemic situations as well as analyze the characteristics of information disclosure through local communication in major cities in China. METHODS: The 31 capital cities in mainland China were included in this city-level observational study. Data were retrieved from local municipalities and health commission websites as of March 18, 2020. A checklist was employed as a rapid qualitative assessment tool to analyze the information disclosure performance of each city. Descriptive analyses and data visualizations were produced to present and compare the comparative performances of the cities. RESULTS: In total, 29 of 31 cities (93.5%) established specific COVID-19 webpages to disclose information. Among them, 12 of the city webpages were added to their corresponding municipal websites. A majority of the cities (21/31, 67.7%) published their first cases of infection in a timely manner on the actual day of confirmation. Regarding the information disclosures highlighted on the websites, news updates from local media or press briefings were the most prevalent (28/29, 96.6%), followed by epidemic surveillance (25/29, 86.2%), and advice for the public (25/29, 86.2%). Clarifications of misinformation and frequently asked questions were largely overlooked as only 2 cities provided this valuable information. The median daily update frequency of epidemic surveillance summaries was 1.2 times per day (IQR 1.0-1.3 times), and the majority of these summaries (18/25, 72.0%) also provided detailed information regarding confirmed cases. The reporting of key indicators in the epidemic surveillance summaries, as well as critical facts included in the confirmed case reports, varied substantially between cities. In general, the best performance in terms of timely reporting and the transparency of information disclosures were observed in the municipalities directly administered by the central government compared to the other cities. CONCLUSIONS: Timely and effective efforts to disclose information related to the COVID-19 epidemic have been made in major cities in China. Continued improvements to local authority reporting will contribute to more effective public communication and efficient public health research responses. The development of protocols and the standardization of epidemic message templates-as well as the use of uniform operating procedures to provide regular information updates-should be prioritized to ensure a coordinated national response.

Patients' Perceptions of Barriers and Facilitators to the Adoption of E-Hospitals: Cross-Sectional Study in Western China.

BACKGROUND: As an innovative approach to providing web-based health care services from physical hospitals to patients at a distance, e-hospitals (ie, extended care hospitals through the internet) have been extensively developed in China. This closed health care delivery chain was developed by combining e-hospitals with physical hospitals; treatment begins with web-based consultation and registration, and then, patients are diagnosed and treated in a physical hospital. This approach is promising in its ability to improve accessibility, efficiency, and quality of health care. However, there is limited research on end users' acceptance of e-hospitals and the effectiveness of strategies aimed to prompt the adoption of e-hospitals in China. OBJECTIVE: This study aimed to provide insights regarding the adoption of e-hospitals by investigating patients' willingness to use e-hospitals and analyzing the barriers and facilitators to the adoption of this technology. METHODS: We used a pretested self-administered questionnaire and performed a cross-sectional analysis in 1032 patients across three hierarchical hospitals in West China from June to August 2019. Patients' sociodemographic characteristics, medical history, current disease status, proficiency with electronic devices, previous experience with web-based health services, willingness to use e-hospitals, and perceived facilitators and barriers were surveyed. Multiple significance tests were employed to examine disparities across four age groups, as well as those between patients who were willing to use e-hospitals and those who were not. Multivariate logistic regression was also performed to identify the potential predictors of willingness to use e-hospitals. RESULTS: Overall, it was found that 65.6% (677/1032) of participants were willing to use e-hospitals. The significant predictors of willingness to use e-hospitals were employment status (P=.02), living with children (P<.001), education level (P=.046), information technology skills (P<.001), and prior experience with web-based health care services (P<.001), whereas age, income, medical insurance, and familiarity with e-hospitals were not predictors. Additionally, the prominent facilitators of e-hospitals were convenience (641/677, 94.7%) and accessibility to skilled medical experts (489/677, 72.2%). The most frequently perceived barrier varied among age groups; seniors most often reported their inability to operate technological devices as a barrier (144/166, 86.7%), whereas young participants most often reported that they avoided e-hospital services because they were accustomed to face-to-face consultation (39/52, 75%). CONCLUSIONS: We identified the variables, facilitators, and barriers that play essential roles in the adoption of e-hospitals. Based on our findings, we suggest that efforts to increase the adoption of e-hospitals should focus on making target populations accustomed to web-based health care services while maximizing ease of use and providing assistance for technological inquiries.

The effects of ventilation on left-to-right shunt and regional cerebral oxygen saturation: a self-controlled trial.

BACKGROUND: Increase of pulmonary vascular resistance (PVR) is an efficient method of modulating pulmonary and systemic blood flows (Qp/Qs) for patients with left-to-right (L-R) shunt, and is also closely associated with insufficient oxygen exchange for pulmonary hypoperfusion. So that it might be a preferred regime of maintaining arterial partial pressure of carbon dioxide tension (PaCO2) within an optimal boundary via ventilation management in congenital heart disease (CHD) patients for the inconvenient measure of the PVR and Qp/Qs. However, the appropriate range of PaCO2 and patient-specific mechanical ventilation settings remain controversial for CHD children with L-R shunt. METHODS: Thirty-one pediatric patients with L-R shunt, 1-6 yr of age, were included in this observation study. Patients were ventilated with tidal volume (VT) of 10, 8 and 6 ml/kg in sequence, and 15 min stabilization period for individual VT. The velocity time integral (VTI) of L-R shunt, pulmonary artery (PA) and descending aorta (DA) were measured with transesophageal echocardiography (TEE) after an initial 15 min stabilization period for each VT, with arterial blood gas analysis. Near-infrared spectroscopy sensor were positioned on the surface of the bilateral temporal artery to monitor the change in regional cerebral oxygen saturation (rScO2). RESULTS: PaCO2 was 31.51 ± 0.65 mmHg at VT 10 ml/kg vs. 37.15 ± 0.75 mmHg at VT 8 ml/kg (P < 0.03), with 44.24 ± 0.99 mmHg at VT 6 ml/kg significantly higher than 37.15 ± 0.75 mmHg at VT 8 ml/kg. However, PaO2 at a VT of 6 ml/kg was lower than that at a VT of 10 ml/kg (P = 0.05). Meanwhile, 72% (22/31) patients had PaCO2 in the range of 40-50 mmHg at VT 6 ml/kg. VTI of L-R shunt and PA at VT 6 ml/kg were lower than that at VT of 8 and 10 ml/kg (P < 0.05). rScO2 at a VT of 6 ml/kg was higher than that at a VT of 8 and 10 ml/kg (P < 0.05), with a significantly correlation between rScO2 and PaCO2 (r = 0.53). VTI of PA in patients with defect diameter > 10 mm was higher that that in patients with defect diameter ≤ 10 mm. CONCLUSIONS: Maintaining PaCO2 in the boundary of 40-50 mmHg with VT 6 ml/kg might be a feasible ventilation regime to achieve better oxygenation for patients with L-R shunt. Continue raising PaCO2 should be careful. TRAIL REGISTRATION: Clinical Trial Registry of China (http://www.chictr.org.cn) identifier: ChiCTR-OOC-17011338 , prospectively registered on May 9, 2017.

Soil Behaviour of the Veterinary Drugs Lincomycin, Monensin, and Roxarsone and Their Toxicity on Environmental Organisms.

Lincomycin, monensin, and roxarsone are commonly used veterinary drugs. This study investigated their behaviours in different soils and their toxic effects on environmental organisms. Sorption and mobility analyses were performed to detect the migration capacity of drugs in soils. Toxic effects were evaluated by inhibition or acute toxicity tests on six organism species: algae, plants, daphnia, fish, earthworms and quails. The log Kd values (Freundlich model) of drugs were: lincomycin in laterite soil was 1.82; monensin in laterite soil was 2.76; and roxarsone in black soil was 1.29. The Rf value of lincomycin, roxarsone, monensin were 0.4995, 0.4493 and 0.8348 in laterite soil, and 0.5258, 0.5835 and 0.8033 in black soil, respectively. The EC50 for Scenedesmus obliquus, Arabidopsis thaliana, Daphnia magna and LC50/LD50 for Eisenia fetida, Danio rerio, and Coturnix coturnix were: 13.15 mg/L,32.18 mg/kg dry soil,292.6 mg/L,452.7 mg/L,5.74 g/kg dry soil and 103.9 mg/kg (roxarsone); 1.085 mg/L, 25 mg/kg dry soil, 21.1 mg/L, 4.76 mg/L, 0.346 g/kg dry soil and 672.8 mg/kg (monensin); 0.813 mg/L, 35.40 mg/kg dry soil, >400 mg/L, >2800 mg/L, >15 g/kg dry soil, >2000 mg/kg (lincomycin). These results showed that the environmental effects of veterinary drug residues should not be neglected, due to their mobility in environmental media and potential toxic effects on environmental organisms.

Characterization of Amphioxus IFN Regulatory Factor Family Reveals an Archaic Signaling Framework for Innate Immune Response.

The IFN regulatory factor (IRF) family encodes transcription factors that play important roles in immune defense, stress response, reproduction, development, and carcinogenesis. Although the origin of the IRF family has been dated back to multicellular organisms, invertebrate IRFs differ from vertebrate IRFs in genomic structure and gene synteny, and little is known about their functions. Through comparison of multiple amphioxus genomes, in this study we suggested that amphioxus contains nine IRF members, whose orthologs are supposed to be shared among three amphioxus species. As the orthologs to the vertebrate IRF1 and IRF4 subgroups, Branchiostoma belcheri tsingtauense (bbt)IRF1 and bbtIRF8 bind the IFN-stimulated response element (ISRE) and were upregulated when amphioxus intestinal cells were stimulated with poly(I:C). As amphioxus-specific IRFs, both bbtIRF3 and bbtIRF7 bind ISRE. When activated, they can be phosphorylated by bbtTBK1 and then translocate into nucleus for target gene transcription. As transcriptional repressors, bbtIRF2 and bbtIRF4 can inhibit the transcriptional activities of bbtIRF1, 3, 7, and 8 by competing for the binding of ISRE. Interestingly, amphioxus IRF2, IRF8, and Rel were identified as target genes of bbtIRF1, bbtIRF7, and bbtIRF3, respectively, suggesting a dynamic feedback regulation among amphioxus IRF and NF-κB. Collectively, to our knowledge we present for the first time an archaic IRF signaling framework in a basal chordate, shedding new insights into the origin and evolution of vertebrate IFN-based antiviral networks.

Improving the efficiency of dissolved oxygen control using an on-line control system based on a genetic algorithm evolving FWNN software sensor.

This work proposes an on-line hybrid intelligent control system based on a genetic algorithm (GA) evolving fuzzy wavelet neural network software sensor to control dissolved oxygen (DO) in an anaerobic/anoxic/oxic process for treating papermaking wastewater. With the self-learning and memory abilities of neural network, handling the uncertainty capacity of fuzzy logic, analyzing local detail superiority of wavelet transform and global search of GA, this proposed control system can extract the dynamic behavior and complex interrelationships between various operation variables. The results indicate that the reasonable forecasting and control performances were achieved with optimal DO, and the effluent quality was stable at and below the desired values in real time. Our proposed hybrid approach proved to be a robust and effective DO control tool, attaining not only adequate effluent quality but also minimizing the demand for energy, and is easily integrated into a global monitoring system for purposes of cost management.

The real-world treatment characteristic and efficacy of immune checkpoint inhibitors in non-small cell lung cancer: Data from a retrospective cohort study.

BACKGROUND: The efficacy and prognosis of immune checkpoint inhibitors (ICIs) remain unresolved issues. Here, we assessed the treatment characteristics and efficacy of ICIs in non-small cell lung cancer (NSCLC) using real-world data and evaluated the predictive value of factors, including programmed death-ligand 1 (PD-L1) expression, for the clinical outcome of ICIs in NSCLC. METHODS: Analyzed data was collected from hospitalized patients in the West China Hospital of Sichuan University between January 2017 and March 2023. The Kaplan-Meier method was utilized for analyzing real-world progression-free survival (rwPFS), while Cox regression models was employed to access the correlation between the efficacy of immunotherapy and sociodemographic characteristics, disease information, and characteristics of ICI treatment. RESULTS: A total of 545 patients were included in the retrospective study and characteristics of immunotherapy varied significantly among PD-L1 expression groups. The median rwPFS for the entire population was 9.76 months. Subgroup analyses revealed that patients with high PD-L1 expression, early TNM stage, first-line immunotherapy, EGFR wild-type and those who have not received radiotherapy and targeted therapy previously were more likely to have better rwPFS. Furthermore, multivariate Cox regression analyses identified PD-L1 expression, EGFR mutation status and previous radiotherapy as the most influential predictors of the response to ICI treatment. CONCLUSIONS: This study presents the real-world experience of Chinese NSCLC patients undergoing ICI treatment, offering guidance for clinical decision-making based on various patient conditions, preferences, and indications for ICIs, through the evaluation of immunotherapy efficacy and predictors in NSCLC patients.

Albiflorin alleviates neuroinflammation of rats after MCAO via PGK1/Nrf2/HO-1 signaling pathway.

Ischemic stroke is acknowledged as one of the most frequent causes of death and disability, in which neuroinflammation plays a critical role. Emerging evidence supports that the PGK1/Nrf2/HO-1 signaling can modulate inflammation and oxidative injury. Albiflorin (ALB), a main component of Radix paeoniae Alba, possesses anti-inflammatory and antioxidative properties. However, how it exerts a protective role still needs further exploration. In our study, the middle cerebral artery occlusion (MCAO) model was established, and the Longa score was applied to investigate the degree of neurological impairment. Dihydroethidium (DHE) staining and Malondialdehyde (MDA) assay were used to detect the level of lipid peroxidation. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining was used to measure the infarct area. Evans blue staining was employed to observe the integrality of the blood-brain barrier (BBB). The injury of brain tissue in each group was observed via HE staining. Immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and western blot assay were used for the measurement of inflammatory factors and protein levels. We finally observed that ALB relieved cerebral infarction symptoms, attenuated oxidative damage in brain tissues, and reduced neuroinflammation and cell injury in MCAO rats. The overexpression of PGK1 abrogated the protective effect of ALB after experimental cerebral infarction. ALB promoted PGK1 degradation and induced Nrf2 signaling cascade activation for subsequent anti-inflammatory and antioxidant damage. Generally speaking, ALB exerted a protective role in treating cerebral ischemia, and it might target at PGK1/Nrf2/HO-1 signaling. Thus, ALB might be a potential therapeutic agent to alleviate neuroinflammation and protect brain cells after cerebral infarction.