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Abstract Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP’s function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.

Many current electronic medical record (EMR) sharing schemes that use proxy re-encryption and blockchain do not fully consider the potential threat of malicious node impersonation attacks. This oversight could lead to data leakage as attackers masquerade as legitimate users or proxy nodes during the sharing process. To deal with this problem, we propose an EMR sharing scheme based on proxy re-encryption and blockchain to protect against impersonation attacks. First, we prevent the potential threat of impersonation attacks by generating a shared temporary key and assigning tasks to multiple proxy nodes. Second, we use a random function to ensure that the selection of encrypted proxy nodes is fair. Third, we use a combination of blockchain and the InterPlanetary File System to solve the problem of insufficient storage capacity of shared processes and ensure the storage security of EMRs. Through the security proof, our scheme guarantees anti-impersonation, anti-collusion, and anti-chosen plaintext attack capability in the sharing process of EMRs. Additionally, experiments on the blockchain platform, namely Chain33, show that our scheme significantly increases efficiency.

Summary: Purpose: Numerous barriers hinder individuals with mental illness from seeking medical assistance in rural regions, yet a comprehensive understanding of these challenges remains elusive. This meta-synthesis aims to understand the barriers and facilitators in medical help-seeking among rural individuals with mental illness. Methods: We systematically searched seven databases [PubMed, CINAHL, Medline (OVID), PsycINFO (OVID), Cochrane, Embase, and ProQuest] in May 2023 and included the studies if they reported the barriers or/and facilitators to seek healthcare in rural patients with mental illness. We conducted hand search and citation search on Google Scholar for literature supplements. Thematic analysis was employed. Results: The study included 27 articles reporting on the barriers and facilitators to seeking medical help in this population from 2007 to 2023. We ultimately identified themes at three levels: navigating the terrain of vulnerability and empowerment (the individual with mental illness), navigating the terrain of external environment (the external environment) and connectivity within the healthcare ecosystem for mental health (the health service system). Conclusions: We must design more effective strategies to improve mental healthcare access for rural patients, considering cultural nuances and health service utilization patterns. This requires a multi-level approach, tailored to the unique needs of diverse populations.

Abstract Background Patients with lung cancer surgery often suffer pain after discharge. However, there is limited evidence to describe the pain experience from the qualitative investigation. This study was designed to describe the pain experience of lung cancer patients during home recovery after surgery and to provide evidence for developing pain management strategies. Methods This qualitative descriptive study recruited 35 patients who had received lung resection and were discharged by purposive sampling from May to July 2022. Mobile phone interviews were conducted to collect views on patients' pain experience after discharge. The interviews were audio‐recorded and converted verbatim into standard text, and the data were iteratively thematic analyzed. Results A thematic framework was identified for three themes: perception and impact of pain, coping styles for pain, and unmet needs for pain. Whether short or long‐term after discharge, patients complain that they suffer from different degrees and types of pain, causing them a “double burden” physically and mentally. The lack of knowledge about pain may lead them to adopt very different coping styles and desire professional continuous pain management. Conclusions This study may help clarify the status of pain problems that patients face after lung cancer surgery and provides multiple dimensions of pain assessment and management objectives for quantitative research. We call on medical staff to pay attention to patients' perspectives and related needs after discharge and formulate targeted management strategies to reduce pain and improve their quality of life.

Abstract The study was design to investigate the functional roles of Wilms tumor 1-associated protein (WTAP), an enzyme catalyzes m6A modification, in the pathogenesis of osteoarthritis (OA) and further elucidate its possible regulatory mechanism. Herein, we discovered that WTAP was outstandingly upregulated in chondrocyte stimulated with Lipopolysaccharide (LPS) and cartilage tissue of patients with OA. Functional studies have demonstrated that WTAP knockdown enhances proliferation ability, suppresses apoptosis, and reduces extracellular matrix (ECM) degradation in an LPS—induced OA chondrocyte injury model and ameliorates cartilage damage in a destabilizing the medial meniscus (DMM)—induced OA mice model. Conversely, overexpression of WTAP contributes to the opposite effects. Mechanistically, our data has demonstrated that m6A modification mediated by WTAP promotes the maturation of pri-miR-92b to miR-92b-5p, thereby enhancing the targeted inhibitory function of miR-92b-5p on TIMP4. Furthermore, we have discovered that WTAP can directly facilitate the degradation of TIMP4 mRNAs in a YTHDF2-dependent manner. In a nutshell, our findings suggested that WTAP knockdown alleviated OA progression by modulating the miR-92b-5p/TIMP4 axis in an m6A-dependent manner. Our study disclosed that WTAP-mediated m6A modification displayed a crucial role in OA development and suggested that targeting WTAP could be a promising preventive and therapeutic target for patients with OA. Video Abstract

Abstract Background Knee osteoarthritis (KOA) is an age-related degenerative disease characterized by abrasion of articular cartilage. Tongbi Huoluo Decoction (TBHLD) has been transformed from the famous traditional Chinese medicine Duhuo Jisheng Decoction, which can effectively alleviate pain symptoms in KOA. However, the active components and mechanisms of TBHLD in treating KOA have not yet been elucidated. The purpose of the study was to demonstrate the molecular mechanism of TBHLD in treating KOA. Methods The components and targets of TBHLD and KOA were collected from multiple databases, and the protein to protein interaction (PPI) network was constructed. Next, we performed topological calculation and enrichment analysis. Besides, we performed virtual screening for molecular docking and molecular dynamics simulation (MDS). Furthermore, the vitro and vivo experiments were performed to evaluate the validity and mechanism of TBHLD. Results 206 active components and 187 potential targets were screened from Tongbi Huoluo Decoction. A total of 50 intersecting genes were identified between TBHLD and KOA, 20 core targets were calculated by network topology analysis. The core targets were enriched in the ECM interaction pathways. The results of virtual screening for molecular docking and MDS showed that the active components of TBHLD had steady binding conformations with core genes. Moreover, we identified 32 differential serum components in TBHLD-containing serum using LC–MS, including 22 upregulated and 10 downregulated serum components. TBHLD improved the proliferation activity of OA chondrocytes, decreased the expression of Col1a1, Col1a2, Mmp2, Mmp13 in OA chondrocytes, ameliorated the cartilage lesions and restored the cartilage abrasion. Conclusion TBHLD inhibited degradation of cartilage ECM by regulating the expression of type I collagens and Mmps to ameliorate cartilage degeneration in KOA.

Objectives We aimed to explore the epidemiological characteristics of suspected adenomyosis within a physical examination population in China.Design A retrospective, nested case-control study; we matched healthy people and those with potential adenomyosis on a 1:2 ratio by age.Setting A tertiary hospital health management centre.Participants We included 15–60 years old women who underwent at least one uterine examination from October 2017 to December 2020, excluding those who had undergone hysterectomy and menopause.Primary and secondary outcome measures We estimated the incidence and prevalence rate of suspected adenomyosis. Conditional logistic regression was used to estimate associations between serum biomarkers and potential adenomyosis. Areas under the receiver-operating characteristic curves (AUC) were used to determine the cut-off point of the cancer antigen 125 (CA125) level for suspected adenomyosis.Results A total of 30 629 women had uterus-related imaging examinations; 877 had suspected adenomyosis. The standardised incidence and prevalence of suspected adenomyosis was 1.32% and 2.35%, respectively, for all age groups. The conditional logistic regression analysis results showed that total bilirubin≥18.81 µmol/L (HR: 2.129; 95% CI 1.067 to 4.249; p24 kg/m2 (HR: 1.262; 95% CI 1.055 to 1.511; p

ABSTRACT The use of combination antibiotics has been useful in the treatment of multidrug-resistant bacterial infections. The synergistic effect of amoxicillin/clavulanate and aztreonam combination against Escherichia coli carrying New Delhi metallo-β-lactamase (NDM) was primarily due to clavulanate inhibiting aztreonam degradation. In the present study, we employed metabolomic analysis to investigate the downstream changes in E. coli after treatment with aztreonam and clavulanate. E. coli metabolomes were compared at 1 and 24 h following treatments with clavulanate (4 µg/mL) and aztreonam (4 µg/mL) alone and in combination. Excluding false positives, 198 metabolites were identified to be affected by antibiotic treatment. Aztreonam/clavulanate combination inhibited cell wall synthesis more aggressively at 1 h and 24 h than aztreonam alone. The purine and pyrimidine metabolism, the central carbon metabolism, and the amino acid metabolism were also disrupted resulting in a prolonged bactericidal effect. This study reveals the synergistic killing mechanism of clavulanate and aztreonam combination against E. coli harboring NDM and provides a theoretical basis for the combined use of aztreonam/clavulanate in the treatment of multidrug-resistant E. coli infection.IMPORTANCEMultidrug-resistant Escherichia coli is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.

IntroductionRice black-streaked dwarf virus disease (RBSDVD) is one of the most destructive rice viral diseases, leading to severe yield losses in rice production. However, little is known about the yield-related components associated with the disease and no resistance cultivars have been successfully used in rice breeding.MethodsSeven rice cultivars were analyzed in this study, including six commercial rice varieties and a new line Zhongjian No. 201 (ZJ201) containing the resistance gene OsAP47. Resistance levels of these cultivars were evaluated by artificial inoculation and yield components were collected, including panicle length (PL), spikelets per panicle (SPP), ripened grains per panicle (RGPP), as well as panicles per square meter (PPSM) and 1000-grain weight (TGW). Seed setting rate (SSR) were calculated with the data of SPP and RGPP.Results and discussionThe results showed that ZJ201 displayed the highest resistance level and most of the commercial rice cultivars exhibited susceptible to RBSDVD. Yields of all the rice cultivars were significantly declined except ZJ201 and yield losses produced by RBSDVD were mainly due to the reduction of PL, SPP, RGPP, and TGW, suggesting that developments of these traits are associated with RBSDV infection. Resistant rice cultivar could reduce yield losses by maintaining normal development of these traits. Significant correlations were identified between resistance levels and the yield components except SSR and PPSM. The results provided useful clues for understanding the mechanisms of RBSDV invasion and its effect on rice production. ZJ201 was demonstrated as a resistance material that could be used in rice breeding.

Abstract Objectives Increasing evidence have demonstrated the N6-methyladenosine (m6A) plays critical roles in osteoarthritis (OA) progression, but the role of m6A in OA has not been completely illuminated. Herein, we investigated the function and underlying mechanism of m6A demethylase fat mass and obesity-associated protein (FTO) in OA progression. Materials and methods The FTO expression was detected in mice OA cartilage tissues and lipopolysaccharide (LPS)-stimulated chondrocytes. Gain-of-function assays was used to evaluate the role of FTO in OA cartilage injury in vitro and in vivo. The miRNA-sequencing, RNA-binding protein immunoprecipitation (RIP), luciferase reporter assay, and in vitro pri-miRNA processing assays were conducted to confirm that FTO modulated the pri-miR-3591 process in an m6A-dependent manner and then the binding sites of miR-3591-5p with PRKAA2. Results FTO was outstandingly downregulated in LPS-stimulated chondrocytes and OA cartilage tissues. FTO overexpression enhanced the proliferation, suppressed apoptosis, and decreased degradation of extracellular matrix in LPS-induced chondrocytes, whereas FTO knockdown contributed to the opposite effects. In vivo animal experiments showed that FTO overexpression markedly alleviated OA mice cartilage injury. Mechanically, FTO-mediated m6A demethylation of pri-miR-3591 leaded to a maturation block of miR-3591-5p, which relieved the inhibitory effect of miR-3591-5p on PRKAA2 and then promoted the increase of PRKAA2, thereby alleviating OA cartilage damage. Conclusions Our results attested that FTO alleviated the OA cartilage damage by mediating FTO/miR-3591-5p/PRKAA2 axis, which provided fresh insights into the therapeutic strategies for OA.

Addressing the issue of inadequate temperature tolerance in traditional polymers, in this study, we successfully executed a one-step synthesis of intelligent–responsive polymers which have excellent adaptability in water–gas alternating displacement scenarios. Utilizing the fatty acid method, we produced OANND from oleic acid (OA) and N,N-dimethyl-1,3-propanediamine (NND). Upon testing the average particle size in the aqueous solution both prior and subsequent to CO2 passage, it became evident that OANND assumes the form of a small-molecule particle in the aqueous phase, minimizing damage during formation. Notably, upon CO2 exposure, it promptly organizes into stable micelles with an average size of 88 nm and a relatively uniform particle distribution. This unique characteristic endows it with a rapid CO2 response mechanism and the ability to form a highly resilient gel. In the exploration of viscoelastic fluids, we observed the remarkable behavior of the AONND aqueous solution when CO2/N2 was introduced. This system displayed repeatable transitions between aqueous and gel states, with the highest viscosity peaking at approximately 3895 mPa·s, highlighting its viscosity reversibility and reusability properties. The rheological property results that we obtained indicate that an elongated micellar structure is present in the solution system, with the optimal concentration ratio for its formation determined as 0.8, which is the molar ratio of the OANND-NaOA system. In the sealing performance tests, a 1.0 wt% concentration of the gel system exhibited excellent injectability properties. At 80 °C, this gel effectively reduced the permeability of a sand-filled model to 94.5% of its initial value, effectively sealing potential leakage paths or gas fluxes. This remarkable ability to block leakage paths and reduce seepage capacity highlights the material’s superior blocking effect and erosion resistance properties. Furthermore, even at a temperature of 90 °C and an injection pore volume (PV) of 3, this plugging system could reduce the permeability of a high-permeability sand-filled model to over 90% of its initial value.

The contamination of aquatic ecosystems by the heavy metal copper (Cu) is an important environmental issue and poses significant risks to the physiological functions of aquatic organisms. Macrobrachium rosenbergii is one of the most important freshwater-cultured prawns in the world. The hepatopancreas of crustaceans is a key organ for immune defense, heavy metal accumulation, and detoxification, playing a pivotal role in toxicological research. However, research on the molecular response of the hepatopancreas in M. rosenbergii to Cu exposure is still lacking. In this study, the transcriptomic response in the hepatopancreas of M. rosenbergii was studied after Cu exposure for 3 and 48 h. Compared with the control group, 11,164 (7288 up-regulated and 3876 down-regulated genes) and 10,937 (6630 up-regulated and 4307 down-regulated genes) differentially expressed genes (DEGs) were identified after 3 and 48 h exposure, respectively. Most of these DEGs were up-regulated, implying that gene expressions were largely induced by Cu. Functional enrichment analysis of these DEGs revealed that immunity, copper homeostasis, detoxification, DNA damage repair, and apoptosis were differentially regulated by Cu. Seven genes involved in immunity, detoxification, and metabolism were selected for validation by qRT-PCR, and the results confirmed the reliability of RNA-Seq. All these findings suggest that M. rosenbergii attempts to resist the toxicity of Cu by up-regulating the expression of genes related to immunity, metabolism, and detoxification. However, with the excessive accumulation of reactive oxygen species (ROS), the antioxidant enzyme system was destroyed. As a result, DNA damage repair and the cellular stress response were inhibited, thereby exacerbating cell damage. In order to maintain the normal function of the hepatopancreas, M. rosenbergii removes damaged cells by activating the apoptosis mechanism. Our study not only facilitates an understanding of the molecular response mechanisms of M. rosenbergii underlying Cu toxicity effects but also helps us to identify potential biomarkers associated with the stress response in other crustaceans.

BackgroundUnlike research project–based health data collection (questionnaires and interviews), social media platforms allow patients to freely discuss their health status and obtain peer support. Previous literature has pointed out that both public and private social platforms can serve as data sources for analysis. ObjectiveThis study aimed to use natural language processing (NLP) techniques to identify concerns regarding the postoperative quality of life and symptom burdens in patients with uterine fibroids after focused ultrasound ablation surgery. MethodsScreenshots taken from clinician-patient WeChat groups were converted into free texts using image text recognition technology and used as the research object of this study. From 408 patients diagnosed with uterine fibroids in Chongqing Haifu Hospital between 2010 and 2020, we searched for symptom burdens in over 900,000 words of WeChat group chats. We first built a corpus of symptoms by manually coding 30% of the WeChat texts and then used regular expressions in Python to crawl symptom information from the remaining texts based on this corpus. We compared the results with a manual review (gold standard) of the same records. Finally, we analyzed the relationship between the population baseline data and conceptual symptoms; quantitative and qualitative results were examined. ResultsA total of 408 patients with uterine fibroids were included in the study; 190,000 words of free text were obtained after data cleaning. The mean age of the patients was 39.94 (SD 6.81) years, and their mean BMI was 22.18 (SD 2.78) kg/m2. The median reporting times of the 7 major symptoms were 21, 26, 57, 2, 18, 30, and 49 days. Logistic regression models identified preoperative menstrual duration (odds ratio [OR] 1.14, 95% CI 5.86-6.37; P=.009), age of menophania (OR –1.02 , 95% CI 11.96-13.47; P=.03), and the number (OR 2.34, 95% CI 1.45-1.83; P=.04) and size of fibroids (OR 0.12, 95% CI 2.43-3.51; P=.04) as significant risk factors for postoperative symptoms. ConclusionsUnstructured free texts from social media platforms extracted by NLP technology can be used for analysis. By extracting the conceptual information about patients’ health-related quality of life, we can adopt personalized treatment for patients at different stages of recovery to improve their quality of life. Python-based text mining of free-text data can accurately extract symptom burden and save considerable time compared to manual review, maximizing the utility of the extant information in population-based electronic health records for comparative effectiveness research.

The rapid development of internet technology has brought convenience to people’s lives, increasingly making their work and personal activities inseparable from the internet. However, the various types of information data in the Internet are very large, and accurately obtaining useful information from them has become particularly important. Therefore, clustering analysis technology is widely applied in various fields. The elastic network algorithm is vulnerable to noise and other factors in clustering analysis, resulting in low accuracy of clustering results. To solve this problem, this study proposes an elastic network algorithm based on weighted properties for clustering analysis. After comparative experiments, the results showed that the accuracy of the proposed algorithm was 98%. The area under the precision recall curve was 0.86. The maximum F-value was 0.93. The area under the working characteristic curve of the subject was 0.94. The precision ultimately stabilized at 97%. All values were higher than the comparison algorithm. In the experiment, the running time of the algorithm was 11 seconds and the average error was 7%, both of which were lower than the comparison algorithm. When the algorithm was affected by Statistical dispersion and threshold parameters, the accuracy of the proposed algorithm was 71%, 69% and 67% respectively, which were better than the comparison algorithm. In conclusion, the proposed elastic network algorithm based on the weighted characteristics has high accuracy, strong stability and advantages in clustering.

As one of the most densely populated and rapidly growing metropolitan areas worldwide, the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) of China has been developing extensive metro networks to relieve the escalating traffic congestion inner cities and to shorten public transport time inter cities. Metro construction possibly triggers ground deformation, which may result in damage to the tunnel, pipeline, and ground structures. Fast and efficient monitoring ground deformation along metro lines is vital not only to the metro itself but also to these structures. This study provides a comprehensive investigation of ground deformation along 67 metro lines within the GBA, based on multi-temporal synthetic aperture radar interferometry (MT-InSAR) by using Sentinel-1 from March 2017 to February 2022. The results reveal that deformation velocity in this area ranges from –39.4 mm/year to 14.2 mm/year, which is mainly caused by the tunnel excavation, adjacent excavation and construction, and unfavorable geological conditions. Furthermore, risk levels have been evaluated based on the InSAR-derived results with the proposed median absolute deviation heatmap clustering method. The risky area accounts for 16.31% (∼205.24 km2) of the whole study area in the GBA, among which 13.76%, 2.16%, and 0.39% are classified as three risk levels, with mean deformation velocities of –2.2 mm/year, –3.4 mm/year, and –6.5 mm/year, respectively. This study presents a comprehensive megalopolitan-scale ground deformation monitoring, for the first time, along metro lines in six cities of the GBA, which provides important insights into future metro line constructing, operating and planning.

IntroductionThe emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination.MethodsMetabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L).ResultsThe triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics.ConclusionThe metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii.

Abstract Background There is great productivity of rice(Oryza sativa L. spp. japonica) straw in China, which is a potential source of biomass for biofuel and forage. However, the high levels of lignins in rice straw limited its usage and induced the formation of agricultural waste. In order to modify the lignins contents to improve biofuel production and forage digestibility, we selected Soybean hull peroxidase (SHP) and Glyoxal oxidase (GLOX) as candidate genes to improve quality of rice straw. SHP, a class III plant peroxidase, is derived from multiple sources. It has several advantages, such as high resistance to heat, high stability under acidic and alkaline conditions, and a broad substrate range. SHP is speculated to be useful for lignin degradation. Glyoxal oxidase (GLOX) is an extracellular oxidase that can oxidize glyoxal and methylglyoxal in the extracellular medium to generate H2O2. Results In the present study, the SHP and GLOX genes in pCAMBIA3301-glycine-rich protein (GRP)-SHP-GLOX, designated the K167 vector, were optimized and introduced into rice embryos using Agrobacterium-mediated transformation. Positive transgenic rice embryos were examined using molecular, physiological, biochemical and fermentation tests. The outcomes suggested that SHP degraded lignin effectively. Conclusions This research has created a rice breeding material with normal growth and yield but stalks that are more amenable to degradation in the later stage for use in breeding rice varieties whose stalks are easily used for energy. Our results will improve the industrial and commercial applications of rice straw.

Abstract Neuromorphic computing employs a great number of artificial synapses which transfer information between neurons. Conventional two‐ or three‐terminal artificial synapses with homosynaptic plasticity suffer from a positive feedback loop problem. Synapses with heterosynaptic plasticity are thus required to perform learning, processing and modulating simultaneously. Here, complementary metal‐oxide‐semiconductor compatible artificial synapses based on ferroelectric polarization modulated Schottky diodes (FEMOD) on silicon, which enables heterosynaptic plasticity with multi‐functionalities, high endurance, low power consumption, and high speed, are presented. High accuracy is obtained in the supervised learning simulation of artificial neural networks due to the large number of conductance states, good linearity, and small variations of FEMOD synapses. Boolean functions are demonstrated with only one or two FEMOD devices operating at low voltage and low power consumption. The proposed device structure performs multi‐functions of biological synapse and Boolean logic, thus provides high potential for the future large scale and low power neuromorphic computing applications.

Cadmium (Cd) is a toxic heavy metal in soil that seriously threatens crop production, food security, and human health. Syntaxins, a prototype family of Soluble N-ethyl-maleimide-associated protein receptors (SNAREs) involved in vesicle trafficking, are implicated in resistance to abiotic stresses, including Cd stress, but the molecular mechanisms underlying the involvement of syntaxins in Cd tolerance in plants are unclear. In this study, we isolated and functionally characterized the syntaxin gene RtSYP121 from Reaumuria trigyna to evaluate its potential for phytoremediation. RtSYP121 resides in the plasma membrane. The transcriptional level of RtSYP121 was strongly increased by salt, drought, and Cd stress. Overexpression of RtSYP121 significantly enhanced the Cd tolerance of transgenic Arabidopsis. The Cd tolerance of transgenic plants mainly depended on elevated vesicle trafficking, which increased the content of K+ and Ca2+ and thus decreased the accumulation of Cd2+ by regulating the delivery or activity of ion transporters, channels, and pumps. Moreover, overexpression of RtSYP121 in Arabidopsis ameliorated Cd stress–induced phytotoxic effects, including growth inhibition, ROS burst, photosynthetic impairment, and cell death. Therefore, we suggest that RtSYP121 plays multiple roles in the plant response to Cd stress by promoting vesicle trafficking, maintaining ion homeostasis, and alleviating photosynthetic inhibition.

This study evaluated the effect of a 0.5% chloramine T solution on a chemical-cured universal adhesive by comparing the light-cured, one-step, self-etch adhesive for the bonding performance, mechanical properties, and resin–dentin interfacial characteristics. Caries-free human molars were randomly assigned into eight groups based on the bonding systems employed (Bond Force II, BF and Bondmer Lightless, BL), the immersion solutions used before bonding (0.5% chloramine T solution and distilled water), and the immersion durations (5 and 60 min). Microtensile bond strength (μTBS), nanoleakage evaluation, and nanoindentation tests were performed, and the surface morphology of the resin–dentin interface was examined using a focus ion beam/scanning ion microscopy system. Immersion in chloramine-T for 5 min significantly decreased the μTBS of Bondmer Lightless (from 22.62 to 12.87 MPa) compared with that in distilled water. Moreover, there was also a decreasing trend after immersing in chloramine-T for 60 min (from 19.11 to 13.93 MPa). Chloramine T was found to have no effect on the hardness, elastic modulus, or morphological characteristics of the ion-beam milled resin–dentin interfacial surfaces in the tested adhesives, suggesting that chloramine T might reduce the bond strength by interfering with the interaction and the sealing between the adhesive resin and dentin in the chemical-cured universal adhesive, albeit without affecting the mechanical properties.

The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the fractions of time over the 24-h in terms of free drug concentration within the MSW (fTMSW) and above the MPC (fT>MPC) were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h, 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h, and 3 g q8h, respectively, in patients with normal renal function. Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies and future clinical confirmation is warranted.

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fTMSW and fT>MPC from drug exposures in the blood. Mean fT>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fTMSW was reduced to

Empirical therapies using polymyxins combined with other antibiotics are recommended in the treatment of Acinetobacter baumannii infections. In the present study, the synergistic activities of polymyxin-B, meropenem, and sulbactam as combination therapy were investigated using metabolomic analysis. The metabolome of A. baumannii was investigated after treatment with polymyxin-B alone (2 mg/l), meropenem (2 mg/l) alone, combination of polymyxin-B/meropenem at their clinical breakpoints, and triple-antibiotic combination of polymyxin-B/meropenem and 4 mg/l sulbactam. The triple-antibiotic combination significantly changed the metabolite levels involved in cell outer membrane and cell wall biosynthesis, including fatty acid, glycerophospholipid, lipopolysaccharide, peptidoglycan, and nucleotide within 15 min of administration. In contrast, significant changes in metabolome were observed after 1 h in sample treated with either meropenem or polymyxin-B alone. After 1 h of administration, the double and triple combination therapies significantly disrupted nucleotide and amino acid biosynthesis pathways as well as the central carbon metabolism, including pentose phosphate and glycolysis/gluconeogenesis pathways, and tricarboxylic acid cycle. The addition of sulbactam to polymyxin-B and meropenem combination appeared to be an early disruptor of A. baumannii metabolome, which paves the way for further antibiotic penetration into bacteria cells. Combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can effectively confer susceptibility to A. baumannii harboring OXA-23 and other drug resistant genes. Metabolomic profiling reveals underlying mechanisms of synergistic effects of polymyxin-B combined with meropenem and sulbactam against multi-drug resistant A. baumannii.

The use of herbs to treat various human diseases has been recorded for thousands of years. In Asia's current medical system, numerous herbal formulas have been repeatedly verified to confirm their effectiveness in different periods, which is a great resource for drug innovation and discovery. Through the mining of these clinical effective formulas by network pharmacology and bioinformatics analysis, important biologically active ingredients derived from these natural products might be discovered. As modern medicine requires a combination of multiple drugs for the treatment of complex diseases, previously clinical formulas are also combinations of various herbs according to the main causes and accompanying symptoms. However, the herbs that play a major role in the treatment of diseases are always unclear. Therefore, how to rank each herb's relative importance and determine the core herbs, is the first step to assisting herb selection for active ingredients discovery. To solve this problem, we built the platform FangNet, which ranks all herbs on their relative topological importance using the PageRank algorithm, based on the constructed symptom-herb network from a collection of clinical empirical prescriptions. Three types of herb hidden knowledge, including herb importance rank, herb-herb co-occurrence, and associations to symptoms, were provided in an interactive visualization. Moreover, FangNet has designed role-based permission for teams to store, analyze, and jointly interpret their clinical formulas, in an easy and secure collaboration environment, aiming at creating a central hub for massive symptom-herb connections. FangNet can be accessed at http://fangnet.org or http://fangnet.herb.ac.cn.

Line scan cameras are widely used to acquire pavement images due to their imaging characteristics and low price, but the acquired pavement line array images often have uneven brightness. To eliminate the impact of image greyscale unevenness on subsequent processing, an automatic dodging method is proposed based on mask dodging algorithm. The main idea of the method is to chuck the images into sub-blocks with the approximate greyscale change degree by introducing the cumulative slope conception. The rules to determine the filter size and the parameters required to adjust the sub-block are self-adaptive. The contrast stretching method is improved to make it more suitable for pavement images. The method is compared with other classical dodging algorithms, and the results show that the proposed automatic dodging method is better than others intuitively and quantitatively. The image length has no significant influence on it. Moreover, the crack segmentation results indicate that the proposed dodging method is effective for line array images, and a more accuracy crack segmentation could be achieved if the images preprocessed by the proposed dodging methods.

This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the β-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT>MPC > 90% and fTMSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum β-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in most parts of the world. Although there is no first-line drug approved for the treatment of NAFLD, polyene phosphatidylcholine (PPC) is used by clinicians to treat NAFLD patients. This study aimed to evaluate the efficacy of PPC on a mice model of NAFLD, and to study the PPC’s mechanism of action. The mice were fed a choline-deficient, L-amino acid-defined (CDAA) diet to induce NAFLD and were subsequently treated with PPC. The treatment effects were evaluated by the liver index, histopathological examination, and routine blood chemistry analyses. Lipidomics and metabolomics analyses of 54 samples were carried out using ultraperformance liquid chromatography (UPLC) coupled to a mass spectrometer to select for changes in metabolites associated with CDAA diet-induced NAFLD and the effects of PPC treatment. The intestinal flora of mice were extracted for gene sequencing to find differences before and after the induction of NAFLD and PPC treatment. PPC significantly improved the CDAA diet-induced NAFLD condition in mice. A total of 19 metabolites including 5 polar metabolites and 14 lipids showed marked changes. In addition, significant differences in the abundance of Lactobacillus were associated with NAFLD. We inferred that the protective therapeutic effect of PPC on the liver was related to the supplement of phosphatidylcholine, lysophosphatidylcholine, and sphingomyelin (PC, LPC, and SM, resectively) and acylcarnitine metabolism. This study developed a methodology for exploring the pathogenesis of NAFLD and can be extended to other therapeutic agents for treating NAFLD.

The ending effect describes the phenomenon that at the end of a series of repeated risky decision-making tasks, participants become more likely to engage in risk-taking behavior. Past research has suggested that the ending effect might be caused by a motivational shift induced by changes in time perception. Previous studies mainly tested this phenomenon in a binary decision-making setting (e.g., a decision-making task usually includes two alternatives). However, none of these prior studies included safe options and risky options that differed in risk levels. To address this knowledge gap, the present study replicated the ending effect in a repeated decision-making task that included both a safe option and risky options that differed in risk levels (N = 104). We found that at the end of the decision-making task, participants became more likely to engage in risk-taking and to favor the option with the highest risk. Further, we found that the investment likelihood and investment amount of high-risk options both increased significantly at the ending. In addition, a shift in favoring the safe option emerged in the noninformed condition at the end. We also found that the emotional motivation in the last round could predict the increased preference for high-risk at the ending. This study extended previous findings on the ending effect by adopting a more complex decision-making scenario and, more broadly, helped further our understanding of the psychological consequences of perceived endings.

Abstract Background MicroRNAs (miRNAs) are a class of 21–24 nucleotide endogenous non-coding small RNAs that play important roles in plant development and defense responses to biotic and abiotic stresses. Tobacco curly shoot virus (TbCSV) is a monopartite begomovirus, cause leaf curling and plant stunting symptoms in many Solanaceae plants. The betasatellite of TbCSV (TbCSB) induces more severe symptoms and enhances virus accumulation when co-infect the plants with TbCSV. Methods In this study, miRNAs regulated by TbCSV and TbCSB co-infection in Nicotiana benthamiana were characterized using high-throughput sequencing technology. Results Small RNA sequencing analysis revealed that a total of 13 known miRNAs and 42 novel miRNAs were differentially expressed in TbCSV and TbCSB co-infected N. benthamiana plants. Several potential miRNA-targeted genes were identified through data mining and were involved in both catalytic and metabolic processes, in addition to plant defense mechanisms against virus infections according to Gene Ontology (GO) analyses. In addition, the expressions of several differentially expressed miRNAs and their miRNA-targeted gene were validated through quantitative real time polymerase chain reaction (qRT-PCR) approach. Conclusions A large number of miRNAs are identified, and their target genes, functional annotations also have been explored. Our results provide the information on N. benthamiana miRNAs and would be useful to further understand miRNA regulatory mechanisms after TbCSV and TbCSB co-infection.

Objective: To explore the correlations between five-pattern personality scores and autonomic nervous response indicators in Chinese female college students, to provide a foundation for further exploration of the modern physiological basis of these personality types. Methods: Subjects were asked to fill in “The Five-Pattern Personality Inventory” (revised edition 2008). Taiyang, Shaoyang, yin-yang balance, Taiyin, and Shaoyin personalities were scored. The galvanic skin response and heart rate, and the low frequency (LF), high frequency (HF), and LF/HF ratio of heart rate variability were collected using a 16-channel physiological recorder (BIOPAC MP150). Relationship between the five-pattern personality scores and autonomic nervous response indicators was analyzed using bivariate correlation. Results: The five-pattern personality scores of the subjects were compared with national averages. The Taiyang and Shaoyang personality scores of the subjects were significantly lower than the overall national average, the national female average, and the national female average in the 18–29-year-old age group (all P

Modifying and generating facial images with desired attributes are two important and highly related tasks in the field of computer vision. Some current methods can take advantage of their relationship and use a unified model to handle them simultaneously. However, producing high visual quality images on both tasks is still a challenge. To tackle this issue, we propose a novel model called adversarially regularized U-net (ARU-net)-based generative adversarial networks (ARU-GANs). The ARU-net is the major part of the ARU-GAN and is inspired by the design principle of U-net. It uses skip connections to pass different-level features from encoder to decoder, which preserves sufficient attribute-independent details for the modification task. Besides, this U-net-like architecture employs an adversarial regularization term to guide the distribution of latent representation to match the prior distribution, which guarantees to generate meaningful faces from this prior. We also propose a joint training technique for the ARU-GAN, which enables the facial attribute modification and generation tasks to learn together during training. We perform experiments on celebfaces attributes (CelebA) dataset and make visual analysis and quantitative evaluation on both tasks, which demonstrates that our model can successfully produce high visual quality facial images. Also, the results show that learning two tasks jointly can lead to performance improvement compared with learning them individually. At last, we further validate the effectiveness of our method by making an ablation study and experimenting on another dataset.

Abstract Background The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested to be safe and effective for adult acute promyelocytic leukaemia (APL). As of 2010, the role of cytarabine (Ara-C) in APL was controversial. The aim of this study was to test the efficacy and safety of ATRA and ATO in paediatric APL patients. Also, we assessed whether Ara-C could be omitted in ATO and ATRA- based trials in children. Methods We performed a randomized controlled trial in paediatric APL patients (≤14 years of age) in our hospital from May 2010 to December 2016. All of the patients were assigned to receive ATRA plus ATO for induction followed by one course of idarubicin (IDA) and ATO (28 days). The patients were then randomly assigned to receive two courses of daunorubicin (DNR, no- Ara-C group) or DNR + Ara-C (Ara-C group). All of the patients were followed with maintenance therapy with oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years. Results Among the 66 patients, 43 were male and 23 were female. All of the patients achieved complete remission (CR) with the exception of one who gave up the treatment. During induction therapy, all toxicity events were reversed after appropriate management. Thirty patients in the Ara-C group underwent 57 courses of treatment, and 35 patients in the no-Ara-C group underwent 73 courses of treatment. No significant differences in age, genders, white blood cell counts, haemoglobin levels, and platelet counts were found between the Ara-C and no-Ara-c groups. Greater myelosuppression and sepsis were observed in the Ara-C group during the consolidation courses. No patient died at consolidation, and only one patient relapsed. No differences were found in event-free survival, disease-free survival and overall survival between the two groups. Additionally, our analysis of the arsenic levels in the plasma, urine, hair and nails of the patients indicated that no significant accumulation of arsenic occurred after ATO was discontinued for 12 months. Conclusions Overall, ATO and ATRA are safe and effective for paediatric APL patients and Ara-C could be omitted when ATO is used for two courses. Trial registration ClinicalTrials.gov (NCT01191541, retrospectively registered on 18 August 2010).

The begomovirus C4 protein is required for disease symptom development during virus infection in host plants. It can reprogram the cell cycle process for more efficient virus accumulation. In this study, we showed that the Malvastrum yellow vein virus (MaYVV) C4 protein could cause leaf up-ward curling and flower malformation, and increase virus accumulation in plants using PVX-based transient expression technology. We also demonstrated that, in the presence of its cognate betasatellite DNA (MaYVB), a mutant MaYVV, defective in producing the C4 protein (MaYVVΔC4), caused and alleviated infection in Nicotiana benthamiana. Transgenic plants expressing the MaYVV C4 protein showed upward leaf curling and uneven leaf lamina growth. Microscopic analysis showed that the epidermal cells of the C4 transgenic leaves were much smaller than those in the wild type (WT) leaves, and the mesophyll cells size and arrangement of transgenic plants was significantly altered. Inoculation of C4 transgenic plants with MaYVV or MaYVVΔC4 alone or associated with MaYVB showed that the transgenic C4 protein could promote viral and betasatellite accumulation and rescue the accumulation defect of MaYVVΔC4. Other transient expression assays also confirmed that the MaYVV C4 protein could suppress silencing of a GFP gene. In summary, our results indicate that the MaYVV C4 protein is a determinant of disease symptom and viral DNA accumulation. This protein can also function as a suppressor of RNA silencing and alter cell division and expansion.

Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine, facilitating DNA demethylation and generating new epigenetic marks. Here we show that concomitant loss of Tet2 and Tet3 in mice at early B cell stage blocked the pro- to pre-B cell transition in the bone marrow, decreased Irf4 expression and impaired the germline transcription and rearrangement of the Igκ locus. Tet2/3-deficient pro-B cells showed increased CpG methylation at the Igκ 3’ and distal enhancers that was mimicked by depletion of E2A or PU.1, as well as a global decrease in chromatin accessibility at enhancers. Importantly, re-expression of the Tet2 catalytic domain in Tet2/3-deficient B cells resulted in demethylation of the Igκ enhancers and restored their chromatin accessibility. Our data suggest that TET proteins and lineage-specific transcription factors cooperate to influence chromatin accessibility and Igκ enhancer function by modulating the modification status of DNA.