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Abstract Formate oxidase (FOx), which contains 8-formyl flavin adenine dinucleotide (FAD), exhibits a distinct advantage in utilizing ambient oxygen molecules for the oxidation of formic acid compared to other glucose-methanol-choline (GMC) oxidoreductase enzymes that contain only the standard FAD cofactor. The FOx-mediated conversion of FAD to 8-formyl FAD results in an approximate 10-fold increase in formate oxidase activity. However, the mechanistic details underlying the autocatalytic formation of 8-formyl FAD are still not well understood, which impedes further utilization of FOx. In this study, we employ molecular dynamics simulation, QM/MM umbrella sampling simulation, enzyme activity assay, site-directed mutagenesis, and spectroscopic analysis to elucidate the oxidation mechanism of FAD to 8-formyl FAD. Our results reveal that a catalytic water molecule, rather than any catalytic amino acids, serves as a general base to deprotonate the C8 methyl group on FAD, thus facilitating the formation of a quinone-methide tautomer intermediate. An oxygen molecule subsequently oxidizes this intermediate, resulting in a C8 methyl hydroperoxide anion that is protonated and dissociated to form OHC-RP and OH−. During the oxidation of FAD to 8-formyl FAD, the energy barrier for the rate-limiting step is calculated to be 22.8 kcal/mol, which corresponds to the required 14-hour transformation time observed experimentally. Further, the elucidated oxidation mechanism reveals that the autocatalytic formation of 8-formyl FAD depends on the proximal arginine and serine residues, R87 and S94, respectively. Enzymatic activity assay validates that the mutation of R87 to lysine reduces the k cat value to 75% of the wild-type, while the mutation to histidine results in a complete loss of activity. Similarly, the mutant S94I also leads to the deactivation of enzyme. This dependency arises because the nucleophilic OH− group and the quinone-methide tautomer intermediate are stabilized through the noncovalent interaction provided by R87 and S94. These findings not only explain the mechanistic details of each reaction step but also clarify the functional role of R87 and S94 during the oxidative maturation of 8-formyl FAD, thereby providing crucial theoretical support for the development of novel flavoenzymes with enhanced redox properties.

ObjectiveThis study aims to evaluate the effects of pleural reconstruction during rib compartment tumor resection surgery on postoperative outcomes, including drainage volume, drainage duration, hospital stay, complications, and pain control.MethodsA retrospective analysis was conducted on 142 patients who underwent rib compartment tumor resection surgery at Beijing Jishuitan Hospital from January 2013 to October 2023. The patients were divided into two groups: those who received pleural reconstruction and those who did not. Data were collected from hospital medical records and outpatient care records, focusing on postoperative drainage volume, total drainage time, length of hospital stay, complications, and pain scores. Continuous variables were compared using t-tests or nonparametric tests, while categorical variables were analyzed using chi-square tests or Fisher's exact tests.ResultsThe analysis showed no significant differences between the two groups in terms of postoperative complications and pain thresholds. However, patients who underwent pleural reconstruction had significantly lower postoperative drainage volume (937.74 ± 855.97 vs. 1,595.26 ± 1,054.50 ml, p

ABSTRACT Importance Eltrombopag has been recommended for pediatric immune thrombocytopenia (ITP). Response and adverse drug reactions (ADRs) varied widely between individuals, even at the same dose of eltrombopag. The appropriate eltrombopag concentration in ITP has not been reported. Objective This study aims to explore the appropriate eltrombopag concentration in pediatric ITP. Methods This was a single‐center, prospective cohort study. Children diagnosed with refractory persistent/chronic ITP and platelet count < 30×109/L were treated with eltrombopag and followed up for at least 2 months. Concentration was detected by high‐performance liquid chromatography‐mass spectrometry at least 2 weeks after eltrombopag. The clinical characteristics‐concentration, concentration‐response, and concentration‐ADRs were analyzed. Results A total of 30 patients were enrolled, comprising 13 males and 17 females, with a median age of 72 (45‒94) months. The median dose and concentration were 1.39 (1.09‒1.56) mg/kg and 2.70 (2.25‒4.13) mg/L, respectively. Of the enrolled patients, 14 responded to treatment, whereas 16 did not. Additionally, five experienced adverse drug reactions. No linear correlation was observed between eltrombopag concentration and clinical characteristics. The concentration was lower in the response group than in the nonresponse group, but there was no significant difference (t = 0.755, P = 0.457). Patients who experienced ADRs had a higher concentration than those without ADRs (t = 2.538, P = 0.017). The area under the receiver operating characteristic curve of ADRs was 0.78 (95% confidence interval: 0.56‒1.00). Youden's index identified the cutoff point as 4.33 mg/L, with a sensitivity of 88% and a specificity of 60%. Logistic regression analysis demonstrated that a higher platelet count before eltrombopag predicted a favorable response. Interpretation Eltrombopag proves efficacious and well‐tolerated for treating pediatric ITP. However, prolonged and high‐dose administration may increase the likelihood of ADRs. Thus, examining the appropriate eltrombopag concentration assists in directing individualized management of pediatric ITP.

This protocol was developed to conduct population-wide surveillance of the bivalent HPV-16/18-AS04-adjuvanted human papillomavirus (HPV) vaccine in terms of uptake and safety outcomes including potential immune-mediated diseases (pIMDs) and pregnancy-related outcomes in China. The study will use electronic health records from 2010 to 2020 from the Yinzhou Regional Health Information Platform and include a population-based cohort of female permanent residents aged 9–45 years. Baseline and follow-up periods will be defined according to the 2017 introduction of HPV-16/18-AS04 in China. Patients with pIMDs and pregnancy-related outcomes will be identified using primary diagnostic codes from outpatient and inpatient electronic health records. A time trend analysis will be performed to describe the incidence of pIMDs and pregnancy-related outcomes during baseline and follow-up periods by age and overall, per calendar year. Depending on the number of safety outcomes and the size of the study population, incidence in vaccinated and unvaccinated cohorts will be compared using a Poisson regression model for pIMDs and a logistic regression model for pregnancy-related outcomes, adjusting for age and calendar year. Methods and findings from this study will provide valuable experience for designing future real-world studies and complement observations made during clinical trials and post-marketing studies.Study registration: http://www.chinadrugtrials.org.cn/index.html: CTR20210523.

Abstract Background Since the Z0011 trial, the assessment of axillary lymph node status has been redirected from the previous assessment of the occurrence of lymph node metastasis alone to the assessment of the degree of lymph node loading. Our aim was to apply preoperative breast ultrasound and clinicopathological features to predict the diagnostic value of axillary lymph node load in early invasive breast cancer. Methods The 1247 lesions were divided into a high lymph node burden group and a limited lymph node burden group according to axillary lymph node status. Univariate and multifactorial analyses were used to predict the differences in clinicopathological characteristics and breast ultrasound characteristics between the two groups with high and limited lymph node burden. Pathological findings were used as the gold standard. Results Univariate analysis showed significant differences in ki-67, maximum diameter (MD), lesion distance from the nipple, lesion distance from the skin, MS, and some characteristic ultrasound features (P

IntroductionCD8+T cell tolerance plays an important role in tumor escape. Recent studies have shown that CD45+ erythroid progenitor cells (CD45+EPCs) generated through splenic extramedullary erythropoiesis suppress tumor immunity. However, the mechanism underlying how CD45+EPCs mediate CD8+T cell tolerance remains incompletely understood and requires further research.MethodsIn this study, the antigen-processing abilities of CD45+EPCs was verified through both in vitro and in vivo experiments. We have used the method of co-culture in vitro and adoptive transfer experiments in vivo to explore the effects of CD45+EPCs on CD8+T cell tolerance. RNA-sequencing analysis and blocking experiments were used to evaluate the role of ROS in the CD45+EPC mediated tolerance of CD8+T cells. Finally, we incorporated uric acid into the adoptive transfer experiments to rescue the CD45+EPC mediated tumor-promoting effect.Results and discussionWe found that CD45+EPCs take up soluble proteins, present antigenic epitopes on their surface, and induce antigen-specific CD8+T cell anergy. In addition, we found that CD45+EPC directly nitrates tyrosine within the TCR/CD8 complex via the production of reactive oxygen species and peroxynitrite, preventing CD8+ T cells from responding to their specific peptide antigens. Furthermore, uric acid treatment effectively abolished the immunosuppressive effects of CD45+EPCs during CD8+T cell adoptive transfer, thereby enhancing the anti-tumor efficacy. These results demonstrated that CD8+T cell tolerance in tumor-bearing mice is induced by CD45+EPCs. The results of this study have direct implications for tumor immunotherapy.

Study region: The Yellow River Basin (YRB) in China. Study focus: This study is devoted to simulating flood changes with return periods of 10, 20, 30, 50, 100 and 200 years under three Representative Concentration Pathways (RCPs) using CaMa-Flood models, and examining the drivers. New hydrological insights for the region: In the historical period (1961–2005), the middle and lower YRB and specifically the Wei River Basin (WRB) (a tributary of the middle YRB) are dominated by higher flood risks with once-in-200-year flood magnitude of 9989.63 m3/s. Under climate change scenarios, the relative change in the once-in-100-year flood magnitude increased from 125.0% (RCP2.6) to 204.9% (RCP8.5) during the historical period (1961–2005) to the long-term period (2076–2092). The historical flood-prone regions were more susceptible to increased flood magnitude. Meanwhile, the area with increased flood risks ranged from 73.6% to 95.2% in the YRB. Increased flood magnitude was typically related to lengthened return interval of floods under the RCP2.6 and RCP6.0 scenarios, while decreased flood magnitude was commonly linked to increased return intervals under the RCP8.5 scenarios. Notably, we observed higher correlations between 7-day maximum precipitation and floods compared to those between daily maximum precipitation, soil moisture, and floods. Co-occurrences between flood events and hydrometeorological extremes were higher in the upper and middle YRB.

Abstract Mars lacks a global magnetic field, and instead possesses small-scale crustal magnetic fields, making its magnetic environment fundamentally different from intrinsic magnetospheres like those of Earth or Saturn. Here we report the discovery of magnetospheric ion drift patterns, typical of intrinsic magnetospheres, at Mars using measurements from Mars Atmosphere and Volatile EvolutioN mission. Specifically, we observe wedge-like dispersion structures of hydrogen ions exhibiting butterfly-shaped distributions (pitch angle peaks at 22.5°−45° and 135°−157.5°) within the Martian crustal fields, a feature previously observed only in planetary-scale intrinsic magnetospheres. These dispersed structures are the results of drift motions that fundamentally resemble those observed in intrinsic magnetospheres. Our findings indicate that the Martian magnetosphere embodies an intermediate case where both the unmagnetized and magnetized ion behaviors could be observed because of the wide range of strengths and spatial scales of the crustal magnetic fields around Mars.

Most countries worldwide continue to encounter a pathologist shortage, significantly impeding the timely diagnosis and effective treatment of cancer patients. Deep learning techniques have performed remarkably well in pathology image analysis; however, they require expert pathologists to annotate substantial pathology image data. This study aims to minimize the need for data annotation to analyze pathology images. Active learning (AL) is an iterative approach to search for a few high-quality samples to train a model. We propose our active learning framework, which first learns latent representations of all pathology images by an auto-encoder to train a binary classification model, and then selects samples through a novel ALHS (Active Learning Hybrid Sampling) strategy. This strategy can effectively alleviate the sample redundancy problem and allows for more informative and diverse examples to be selected. We validate the effectiveness of our method by undertaking classification tasks on two cancer pathology image datasets. We achieve the target performance of 90% accuracy using 25% labeled samples in Kather's dataset and reach 88% accuracy using 65% labeled data in BreakHis dataset, which means our method can save 75% and 35% of the annotation budget in the two datasets, respectively.

To explore the risk factors for venous thromboembolism (VTE) in inpatients with colorectal cancer. The demographic factors, comorbidities, and hematological indices of patients with colorectal cancer treated in our hospital from 2016 to 2021 were collected and recorded. Venous thromboembolism events, including deep venous thrombosis and/or pulmonary embolism, were recorded and the patients were divided into the VTE group and the non-VTE group. We compared clinical data between the two groups and explored risk factors for VTE. Comparing the clinical data of 293 cases of non-VTE group and 235 cases of VTE group, we found significant differences in age, smoking, temperature, amount of blood loss, differentiation degree, peripherally inserted central catheter (PICC), radiotherapy, anemia, infection, white blood cell count, prothrombin time (PT), PT%, prothrombin ratio, international normalized ratio, thrombin time, CA199 and CEA between the two groups ( P < 0.05). Logistic regression analysis showed that age ( P = 0.0444), temperature ( P = 0.0317), amount of blood loss ( P = 0.0067), PICC ( P < 0.0001), chemotherapy ( P = 0.0459), anemia ( P = 0.0007), international normalized ratio ( P = 0.003) and CA199 ( p = 0.0234) were independent risk factors for VTE. Receiver operating characteristic curve analysis showed that the amount of blood loss predicted thrombosis better (AUC = 0.778, P < 0.001), when the cutoff value was 20 mL, the sensitivity was 76.17%, and the specificity was 79.18%, respectively. And PICC predicted thrombosis better (AUC = 0.808, P < 0.001), the sensitivity was 70.21%, and the specificity was 91.47%, respectively. Clinical parameters are associated with VTE in inpatients with colorectal cancer, which will help to guide clinicians to take effective measures to improve the patients' prognosis.

Abstract Background Drug-induced hearing loss (DIHL) is very common, and seriously affects people's happiness in life. RG108 is a small molecule inhibitor. RG108 is protective against DIHL. Our purpose is to probe the incidence of RG108 on cisplatin-induced ototoxicity. Materials and methods In our research, the ototoxicity of RG108 was investigated in HEI-OC1. We observed under the microscope whether RG108 had an effect on cisplatin-induced cochlear hair cells. RNA-seq experiments were further performed to explore possible gene ontology (GO) and pathways. ROS assay was applied to supervisory the effect of RG108 on oxidative harm of auditory cells. In auditory cells, RG108 was tested for its effects on apoptosis-related proteins by Western blotting (WB). Results GO analysis showed that RG108 associated with apoptosis. KEGG analysis shows RG108 may act on PI3K-AKT signaling pathway (PASP) in hearing loss. BIOCARTA analysis showed that RG108 may affect oxidative stress by activating NRF2 pathway. ROS ascerted that RG108 could rescue oxidative harm in HEI-OC1. RG108 rescued cisplatin-induced significant increase in Bax and significant decrease in BCL2. RG108 attenuates cisplatin-induced cochlear apoptosis through upregulated phosphorylated PI3K and phosphorylated AKT and down-regulated caspase3. MTT experiments showed that both PI3K and AKT inhibitors could significantly rescue the damage caused by cisplatin to HEI-OC1. RG108 significantly increases the level of NRF2/HO-1/NQO1 in cisplatin-induced cells. Conclusion Overall, these results provide evidence that NRF2/PI3K-AKT axis may mediate RG108 in the treatment of DIHL, which provide a broader outlook on drug-induced deafness treatment.

Introduction Stroke remains the second leading cause of death worldwide, a common cause of which is intracranial atherosclerotic stenosis (ICAS). Medical treatment is recommended as first-line therapy for treating ICAS, but the recurrence rate remains high. Drug-coated balloon (DCB) angioplasty has been designed to lower the risk of recurrent stenosis, holding therapeutic promise in the treatment of ICAS. However, the benefits of DCB require further evaluation.Methods and analysis The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols was followed to develop this protocol. We will systematically search online databases including Cochrane Central Register of Controlled Trials, PubMed, Web of Science, EMBASE, China Biological Medicine Database, ClinicalTrials.gov and WHO ICTRP from 1 January 2011 to the date of search. This will be supplemented by a manual search of unpublished and ongoing trials to manually select articles for inclusion. Inclusion criteria are randomised or quasi-randomised clinical trials and observational studies that investigated DCB or medical treatment for patients with a symptomatic ICAS of 50%–99%. The primary outcome is short-term composite safety including death of any cause, or non-fatal stroke. Secondary outcomes include long-term death or stroke, restenosis, neurological rehabilitation, quality of life and other complications. The available data will be analysed using meta-analysis, if appropriate. The evaluation of heterogeneity and biases will be guided by the Cochrane Handbook for Systematic Reviews of Interventions.Ethics and dissemination This systematic review does not require ethical approval as all available data from eligible studies will be anonymous with no concerns regarding privacy. Our findings will be disseminated through international conferences and peer-reviewed publications. Additional data from the study are available on request to corresponding authors via email.PROSPERO registration number CRD42022341607.

Cervical cancer is the fourth most common cancer in women, with a high disease burden worldwide. Human papillomavirus (HPV) vaccination reduces HPV-related infection and associated cervical lesions and cancers. Few studies have explored HPV vaccination impact in real-world settings in China. This study aims to monitor HPV vaccine uptake and its effects on HPV-related diseases, evaluating vaccine effectiveness in a real-world context and complementing clinical trial results. Electronic health records (EHRs) from 2010 to 2020 from the Yinzhou Regional Health Information Platform (YRHIP) will be queried/extracted to identify and monitor HPV vaccine uptake in females aged 9–45 years, and HPV-related screening and prevalence (i.e., cervical HPV infection, cervical intraepithelial neoplasia [CIN] grades 1–3, and cervical cancer) in a cohort of females aged 9–70 years. Cervical cancer screening guidelines and expert consultation will be used for intra-database validation, to determine the best algorithm for identifying HPV-related disease. Pre-launch (2010–2016) and post-launch (2018–2020) periods are predefined. A time trend analysis will be performed to describe the vaccination impact on disease prevalence and, if prerequisite conditions are met, vaccine effectiveness will be computed using logistic regression, adjusting for age, calendar year, history of screening and HPV infection. Cohort study design, outcomes validation, data linkage, and multi-step statistical analyses could provide valuable experience for designing other real-world studies in the future. The study outcomes can help inform policy-makers about uptake and HPV vaccination policy in girls and women in Yinzhou District, and provide insights on progress toward achieving goals set by the World Health Organization.

Future changes in climate and socioeconomic systems will exacerbate water scarcity. Previous studies on China’s water footprint and scarcity often consider only climate change or socioeconomic factors in isolation. Here, we address these issues by coupling an integrated assessment model, the Global Change Analysis Model, with a global hydrological model to project China’s future water footprints and water scarcity, considering both climate change and socioeconomic factors. We simulated China’s water footprints under 52 scenarios, which include four global climate models (GCMs) and 13 combinations of Shared Socioeconomic Pathway (SSP)–Representative Concentration Pathway (RCPs) scenarios. We then projected the intensity of water stress (WSI), defined as a ratio of water footprint to renewable water volume, based on the simulations of the SSP2-RCP6.0 scenario. Our results align well with statistical data on water footprint variations between 2005 and 2020. China’s water footprints are likely to peak around 2030 and then decrease. We find through a scenario matrix analysis that emission-mitigation measures will significantly impact the water footprint, particularly in the electricity sector, which will become the largest water use sector in the future. This means that the low carbon energy option on China’s path to carbon neutrality may aggravate water scarcity. Water stress in China is projected to be greatest in 2025–2035, and all northern basins will experience water scarcity. Projections based on all GCMs consistently show a decline in WSI in China after 2050.

Abstract Background PTEN is one of the most frequently mutated genes in human cancer. Although the roles of canonical PTEN protein and PTEN isoforms have been extensively explored, the current understanding of PTEN family members cannot fully illustrate the diversity of their roles in biological processes and tumor development. Notably, the function of noncoding RNAs arising from PTEN has been less elucidated. Methods We searched circBase and circInteractome to analyze the potential of PTEN for generating circRNAs. Then, Sanger sequencing, RNase R and Actinomycin D assays were used to verify the ring structure of circPTEN1. In situ hybridization and qRT-PCR were used to determine the level of circPTEN1 in peritumor and tumor tissues of colorectal cancer (CRC). Furthermore, functional experiments, including Transwell assay, 3D multicellular tumor spheroid invasion assay and metastasis models, were performed using circPTEN1 knockdown and overexpression cell lines in vitro and in vivo to investigate the effects of circPTEN1 on tumor metastasis in CRC. Mechanistically, luciferase reporter assay, fluorescence in situ hybridization, electrophoretic mobility shift assay, RNA immunoprecipitation, RNA pull-down and mass spectrometry were executed. Results We identified a circular RNA generated from the PTEN gene, designated circPTEN1, that is frequently downregulated in colorectal cancer, and decreased expression of circPTEN1 predicts poor survival. Low expression of circPTEN1 promotes metastasis in PDX models in vivo and accelerates cancer cell invasion in vitro, whereas overexpression of circPTEN1 reveals opposite roles. Mechanically, we found that circPTEN1 is capable of binding the MH2 domain of Smad4 to disrupt its physical interaction with Smad2/3, which reduces the formation and subsequent nucleus translocation of Smad complexes and consequently suppresses the expression of its downstream genes associated with epithelial-mesenchymal transition upon TGF-β stimulation. Furthermore, we found that eIF4A3 suppresses the cyclization of circPTEN1 by directly binding to the circPTEN1 flanking region. Conclusions Our study uncovered a novel PTEN gene-generated circRNA with a tumor suppression function, and further revealed the mechanism of circPTEN1 in CRC metastasis mediated by TGF-β. The identification of circPTEN1 provides a new direction for PTEN investigation, and elucidation of circPTEN1/TGF-β/Smad signaling may pave the way for the development of a potential therapeutic strategy for the suppression of cancer progression.

Planetary science is the science of studying planets, moons, and planetary systems. The scale of the research objects ranges from small meteoroids to large gas giant planets, and the research purpose is to determine their composition, dynamics, formation, evolution, mutual relationship, and history. With the development of human space technology, planetary exploration has become one of the most important space exploration activities of mankind. According to statistics from the Spacecraft Encyclopedia website, as of December 2021, a total of 252 planetary probes have been launched around the world. The missions reveal the deep space to humankind. In this paper, we review some advances in planetary science made by these missions in the past years. The topics involve interior structures, geological features, atmospheres, magnetospheres, and so on, not every aspect but as much as possible. Although there are still many extraordinary scientific results that have not been included, we believe that this review can already help people learn about the scientific results of planetary exploration and hopefully inspire the next generation of planetary missions.

Cordyceps extract and withaferin A (Wi-A) are natural compounds that have therapeutic effects on non-alcoholic fatty liver disease (NAFLD). However, their efficacy is limited and a long treatment duration is usually required. To enhance their efficiency, the synergistic effects of nanobubble water (NBW) derived from nitrogen, hydrogen, and oxygen gases were investigated. Results showed that the physical properties of all three NBWs, including nanobubble density (108 particles/mL) and zeta potential (below −22 mV), were stable during 48 h of storage. Hydrogen and nitrogen NBWs did not reduce, but instead promoted, free fatty acid-induced lipid accumulation in HepG2 cells. In contrast, oxygen NBW synergistically enhanced the effects of cordyceps extract and Wi-A. The lipid content decreased by 29% and 33% in the oxygen NBW + cordyceps extract and oxygen NBW + Wi-A groups, respectively, compared to reductions of 22% and 16% by aqueous extracts without NB. This study found that NBW may enhance the lipid-reducing effects of natural compounds, such as cordyceps extract and withaferin A, in hepatic cells. Further studies in animal experiments are needed to determine whether NBW has a potential application in NAFLD.

Previous studies indicate that, in the Jovian magnetosphere, the long-term trend of the radial profile of relativistic electron intensities is primarily shaped by slow radial diffusion. However, measurements by the Galileo spacecraft reveal the existence of transient increases in MeV electron intensities well above the ambient distribution. It is unclear how common such transient enhancements are, and to which dynamic processes in Jupiter's magnetosphere their occurrence is linked. We investigate the radial distributions of \begin{document}$>$\end{document}11 MeV and \begin{document}$>$\end{document}1 MeV electron intensities from \begin{document}$9R_{J}$\end{document} to \begin{document}$40R_{J}$\end{document} (\begin{document}$R_{J}=71492\;{\rm{km}}$\end{document} denotes the Jovian radius), measured by the Galileo spacecraft from 1996 to 2002. We find transient enhancements of MeV electrons during seven Galileo crossings, mostly occurring around ~20RJ. An apparent dawn-dusk asymmetry of their occurrence is resolved, with a majority of events discovered at dawn. This dawn-dusk asymmetry, as well as the average recurrence time scale of a few days, implies a potential relationship between the MeV electron transients and the storm-like dynamics in the middle and outer magnetosphere detected using a variety of Galileo, Juno and remote sensing aurora observations. We suggest that the observations of some of these transients in the inner magnetosphere may result from a synergy between the convective transport by a large-scale dawn-dusk electric field and the sources provided by injections in the middle magnetosphere.

Clams are commercially important species and are a vital component of the offshore ecosystem. Investigations on microplastics (MPs) in clams have attracted public attention recently, for its ecological and food safety risks. However, knowledge gaps still exist regarding MPs in commercial clams from the intertidal zone of the South Yellow Sea (SYS), China, an important clam habitat. In this study, to investigate the distribution of MPs in clams of the SYS, four species of clams were collected from nine sites in different tide zones (high, middle, and low tides) in three coastal areas (Nantong, Yancheng and Lianyungang). The abundance and characteristics of MPs, including size, shape, color and composition, were determined using microscope and micro-Fourier transform infrared (FTIR) spectroscopy. Furthermore, to evaluate the MPs purification ability of clams, the abundance of MPs in various tissues was examined by microscopic observation after being purified in filtered seawater for 72 h. The results showed that there were significant differences in the abundance of MPs in clams from different regions, with the most serious pollution in the high-tide zone. Moreover, the lowest MPs abundance was found in Yancheng (5.07 ± 2.73 items/individual, 1.16 ± 0.78 items/g), while Lianyungang was found with the most abundant MPs (7.52 ± 2.68 items/individual, 3.94 ± 3.00 items/g). The size of MPs in Ruditapes philippinarum (1,329.99 μm) was significantly higher than in other species. The MPs in clams were characterized by fiber in shape, black-grey, blue-green and white-transparent in color and rayon in composition. Moreover, it was found that the MPs originally present in various tissues tended to migrate and accumulate into the mantle of the clam during depuration, and after 72 h of depuration, removing the mantle could reduce nearly half amount of microplastics in clams. Overall, our study revealed the microplastic distribution in commercial clams from the intertidal zone of the SYS and provided suggestions for the safety of aquatic production.

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs, thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery. In particular, intestinal carnitine/organic cation transporter 2 (OCTN2) and mono-carboxylate transporter protein 1 (MCT1) possess high transport capacities and complementary distributions. Therefore, we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review. First, basic information of the two transporters is reviewed, including their topological structures, characteristics and functions, expression and key features of their substrates. Furthermore, progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed, including improvements in the oral absorption of anti-inflammatory drugs, antiepileptic drugs and anticancer drugs. Finally, the potential of a dual transporter-targeting strategy is discussed. Keywords: Carnitine/organic cation transporter 2 (OCTN2), Monocarboxylate transporter protein 1 (MCT1), Transporter-targeting, Nanoparticle, Prodrug

For weakly basic drugs, the sharp decrease of drug solubility and the following drug precipitation after drugs transferring from the gastric fluid to the intestinal fluid in the gastrointestinal (GI) tract is a main reason for the poor oral bioavailability of drugs. Here, an anticoagulant dabigatran etexilate (DE) was used as a model drug, and a composite nanocarrier system of DE was developed to improve the drug dissolution by decreasing the drug leakage in the stomach and inhibiting the drug precipitation in the intestinal tract. With the encapsulation of drugs in nanocarriers, the precipitation percentage of DE in composite nanocarriers was 22.25 ± 3.88% in simulated intestinal fluid, which was far below that of the commercial formulation. Moreover, the relative bioavailability of DE-loaded composite nanocarriers (456.58%) was greatly enhanced and the peak of its activated partial thromboplastin time was also significantly prolonged (p

Abstract The decision‐making and risk assessment of electricity purchase and sales is the key to adapt to the electricity market for independent electricity retailers in China. This research carried out the purchase and sales risks of electricity for electricity retailers and constructed the multi‐level market purchase and sales combination optimization model. Based on the portfolio optimization theory, the conditional value at risk theory (CVaR) was proposed. Based on the evaluation index about the conditional risk profit and CVaR, electricity retailers purchase and sales combined optimization model has been constructed to explore the impact of purchase and sales risks by different factors in multi‐level electricity market. The example analysis was carried out by the fixed spread mode and the linkage spread mode. The results showed that the mathematical mean and variance of market spread had great influence on the electricity purchase and sales combination. Especially in the mature electricity market, the mathematical mean of spread and risk in medium‐ and long‐term market was smaller than that in spot market, and the best point of the electricity purchase and sales combination was shown on the smallest value of CVaR, while the electricity purchase and sales combination was optimal under limited conditions.

Perioperative venous thromboembolism (VTE) of patients after thoracic cancer surgery has proved to be a serious or even fatal postoperative complication, which calls for great attention. China National Research Collaborative Group released the first edition of Chinese experts consensus on the perioperative VTE prophylaxis in 2018. This article is to interpret it on the aspect of epidemiological characteristics of perioperative venous thromboembolism and the current status of prophylaxis in China and other countries, in order to provide a better understanding of Chinese experts consensus for readers.

Monocarboxylate transporter 1 (MCT1) is responsible for oral absorption of short-chain monocarboxylic acids from small intestine, hence, it's likely to serve as an ideal design target for the development of oral prodrugs. However, potential application of MCT1 to facilitate the oral delivery is still unclear. Irregular oral absorption, poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil (5-FU). Herein, we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages. Interestingly, due to high MCT1 affinity and good gastrointestinal stability, 5-FU-octanedioic acid monoester prodrug exhibited significant improvement in membrane permeability (13.1-fold) and oral bioavailability (4.1-fold) compared to 5-FU. More surprisingly, stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells, which provides an ideal foundation for the improvement of oral bioavailability. In summary, good gastrointestinal stability, high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs, and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters. Keywords: 5-Fluorouracil, Prodrugs, Monocarboxylate transporter 1, Permeability, Oral bioavailability

This study aimed at investigating the tumor stiffness of hepatocellular carcinoma (HCC) bearing mice model in vivo to evaluate the therapeutic efficacy of targeting nanobubbles (TNBS) conjugated with NET-1 siRNA (NET-1 siRNA-TNBS). Also tested whether shear wave elastography (SWE) could demonstrate the pathological tumor changes and used to monitor therapeutic efficacy as a noninvasive method. The HCC bearing mice model was established by injecting human HCC cell line (HepG2). The mice were then divided into three groups randomly, and were treated with TNBS conjugated with NET-1 siRNA, TNBS conjugated with negative control gene, and saline as control. US-SWE was performed for three times. SWE values of all the tumors in three groups were increased with tumor growth. Emax was correlated with tumor size (p

Osteoarthritis (OA) is characterized by progressive cartilage degeneration with increasing prevalence and unsatisfactory treatment efficacy. Exosomes derived from mesenchymal stem cells play an important role in alleviating OA by promoting cartilage regeneration, inhibiting synovial inflammation and mediating subchondral bone remodeling without the risk of immune rejection and tumorigenesis. However, low yield, weak activity, inefficient targeting ability and unpredictable side effects of natural exosomes have limited their clinical application. At present, various approaches have been applied in exosome engineering to regulate their production and function, such as pretreatment of parental cells, drug loading, genetic engineering and surface modification. Biomaterials have also been proved to facilitate efficient delivery of exosomes and enhance treatment effectiveness. Here, we summarize the current understanding of the biogenesis, isolation and characterization of natural exosomes, and focus on the large-scale production and preparation of engineered exosomes, as well as their therapeutic potential in OA, thus providing novel insights into exploring advanced MSC-derived exosome-based cell-free therapy for the treatment of OA.

Estimation of rice plant height distribution plays a significant role in keeping the feed rate of rice combine harvesters stable. This is an effective way to guarantee the working stability of the whole machine, as a consequence, improving threshing and cleaning efficiency and reducing loss and damage rates. However, dense growth and leafy and bent branches of mature rice make it difficult to detect the lowest point of aggregated growing plants in three dimensional (3D) point cloud data. Therefore, the objective of this study was to put forward a method to estimate plant height distribution on the basis of a moving surface and 3D point cloud elevation. The statistical outlier removal (SOR) algorithm was used to reduce noise points far away from target point cloud body, and then moving surface fitting elevation was applied to achieve accurate classification of ground and crop point cloud data for plant height estimation. Experiments showed that, compared with the actual value, the average square root error (RMSE) of the estimation results was 8.29, the average absolute percentage error (MAPE) was 9.28%, and the average accuracy was 90%. The proposed method could accurately estimate the height of mature rice and is beneficial to calculating the feed rate in advance, which can provide a reference for further investigation in automatic and intelligent harvesting.

Body tilt is typically unavoidable for agricultural vehicles or platforms when operated over tough terrain in agricultural production, and, therefore, it is not possible to guarantee the operation performance. Current leveling methods mainly focus on wheeled vehicles or adjustment for single working parts rather than the vehicle body, and few of them could be applied to crawler vehicles. The objective of this research was to put forward an adaptive leveling system for combine harvesters based on the development of a new four-point lifting adjustable crawler chassis. The working principle of the proposed adjustable mechanism was studied on the basis of the analysis of adjustment characteristics under multiple posture adjustment conditions in a RecurDyn environment. The design relies on the combination of the attitude detection of the leveling system and adjustment calculation of driving hydraulic cylinders according to the established mathematical models. Within the designed adjustable extent (including adjustment range of vehicle height 0–87.8 mm, lateral inclination ±3.98° and longitudinal inclination −2.9–5.2°), the leveling performance of lateral and longitudinal inclination was then tested separately. The experiment showed that the leveling system could achieve automatic leveling with an accuracy of ±0.4° and could provide technical support for the development of crawler vehicles.

Bottled water is a rapidly growing yet relatively understudied source of drinking water globally. In addition to concerns about the safety of bottled water, the adverse environmental health and social impacts associated with bottled water production, distribution, consumption, and reliance are considerable. Our objective was to comprehensively review, analyze, and synthesize ∼20 years of publicly available data on bottled water quality and associated health outcomes in China. We conducted a systematic review and meta-analysis of publicly available studies of bottled water quality and associated health outcomes in China published between 1995 and early 2016 (in Chinese and English). We pre-specified and registered our study protocol, independently replicated key analyses, and followed standardized reporting guidelines. Our search identified 7059 potentially eligible records. Following screening, after full-text review of 476 publications, 216 (reporting results from 625 studies) met our eligibility criteria. Among many findings, 93.7% (SD = 10.1) of 24 585 samples tested for total coliforms ( n = 241 studies), and 92.6% (SD = 12.7) of 7261 samples tested for nitrites ( n = 85 studies), were in compliance with China’s relevant bottled water standards. Of the studies reporting concentration data for lead ( n = 8), arsenic ( n = 5), cadmium ( n = 3), and mercury ( n = 3), median concentrations were within China’s standards for all but one study of cadmium. Only nine publications reported health outcome data, eight of which were outbreak investigations. Overall, we observed evidence of stable or increasing trends in the proportions of samples in compliance over the ∼20 year period; after controlling for other variables via meta-regression, the association was significant for microbiological but not chemical outcomes ( p = 0.017 and p = 0.115, respectively). Bottled water is typically marketed as being safe, yet in most countries it is less well-regulated than utility-supplied drinking water. Given the trend of increasing bottled water use in China and globally—and the associated environmental health impacts—we hope this work will help to inform policies and regulations for improving bottled water safety, while further highlighting the need for substantially expanding the provision of safe and affordable utility-supplied drinking water globally.

Accurately identifying the key nodes of the road network and focusing on its management and control is an important means to improve the robustness and invulnerability of the road network. In this paper, a classification and identification method of key nodes in urban road networks based on multi-attribute evaluation and modification was proposed. Firstly, the emergency function guarantee grade of road network nodes was divided by comprehensively considering the importance of road network nodes, the consequences of failure, and the degree of difficulty of recovery. The evaluation indexes were selected according to the local attributes, global attributes, and functional attributes of the road network topology. The spatial distribution patterns of the evaluation indexes of the nodes were analyzed. The dynamic classification method was used to cluster the attributes of the road network nodes, and the TOPSIS method was used to comprehensively evaluate the importance ranking of the road network nodes. Attribute clustering of road network nodes by dynamic classification method (DT) and the TOPSIS method was used to comprehensively evaluate the ranking of the importance of road network nodes. Then, combined with the modification of the comprehensive evaluation and ranking of the importance of the road network nodes, the emergency function support classification results of the road network nodes were obtained. Finally, the method was applied to the road network within the second Ring Road of Beijing. It was compared with the clustering method of self-organizing competitive neural networks. The results show that this method can identify the key nodes of the road network more accurately. The first-grade key nodes are all located at the more important intersections on expressways and trunk roads. The spatial distribution pattern shows a “center-edge” pattern, and the important traffic corridors of the road network show a “five vertical and five horizontal” pattern.

In this study, the complete mitochondrial genome of orange swift, Triodia sylvina, was recovered through Illumina sequencing data. This complete mitochondrial genome of T. sylvina is 15,040 bp in length and has a base composition of A (41.0%), T (41.2%), C (10.4%), G (7.5%), demonstrating an extreme bias of high AT content (82.2%). The mitochondrial genome contains a typically conserved structure among moth mitogenomes, encoding 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA (12S rRNA and 16S rRNA) genes and a control region (D-loop region). Seven PCGs were located on the H-strand, others were located on the L-strand. ATP8 gene and ATP6 gene were overlapped by 6 bp. ND4 gene and ND4L gene were overlapped by 9 bp. The whole mt genome of T. sylvina and other moth and butterfly mitogenomes (100 species, in total) were used for phylogenetic analysis. The result indicated T. sylvina represents a distinct genus, which separated far from genus Hepialus.

Background and objective Primary lung cancer has been common malignant tumors. Accurate preoperative N staging can avoid unnecessary surgical operations, and patients with N3 has non-surgical treatment of indications. The aim of this study is to investigate the clinical value of ultrasound in the diagnosis of supraclavicular lymph node metastasis and staging of primary lung cancer. Methods We retrospectively analyzed 131 patients who were pathologically diagnosed with lung cancer from October 2012 to November 2013. All patients received ultrasound and contrast-enhanced computed tomograohy (CT) examination of the supraclavicular area, and those who were with positive results underwent ultrasound-guided biopsy. The accuracy of the two methods was compared according to their consistency with the pathological results. The pathological diagnosis was used as the diagnosis standard of lymph node metastasis. Results There were 50 cases of patients who were confirmed supraclavicular lymph node metastasis pathologically in a total of 131 cases of patients with lung cancer. Fifty-four cases were tested positive by ultrasound, and 50 cases were pathologically proven to be with lymph node metastasis. For comparison, the ratio was 36 out of 41 for contrast-enhanced CT. The sensitivity, specificity, You den's index, the positive predictive value and the negative predictive value of ultrasound (100%, 95.06%, 95.06%, 92.59%, 100%) was significantly higher than that of contrast-enhanced CT (72%, 93.83%, 65.83%, 87.80%, 84.44%). The differences of accuracy of the two methods in TNM staging of lung cancer had statistically significance (P

Background: Recently, microbotulinum, a new technique that involves injecting botulinum toxin type A (BoNTA) microdroplets into superficial cutaneous tissue, has gained popularity. The precise distribution of BoNTA in the targeted area profoundly affects outcomes. Many factors may influence the effective area of BoNTA in the dermis. This study aimed to determine the dermal distribution properties of BoNTA to guide microbotulinum injection. Methods: Ten healthy males aged 18--65 years without BoNTA treatment in the previous year were recruited to receive intradermal injections in the chest and back. Ultrasound was used to ensure the intradermal delivery of injections and measure the dermal thickness. The minor iodine starch test was performed at baseline and 3 days, 7 days, 21 days, 1 month, and 2 months after treatment. Results: All participants received intradermal injections. The dermis was thinner on the chest (thickness, 0.20±0.03 cm) than on the back (thickness, 0.39 ± 0.07 cm) (P<0.05). An injection in the thicker dermis had a significantly smaller effective area at every follow-up visit. The drug concentration did not affect the effective area except at 3 days after treatment. Injection speed did not influence the effective area at any follow-up visits. Conclusion: An injection in a thicker dermis leads to a smaller effective area for intradermal injections. When the BoNTA dose is the same, the drug concentration and injection speed do not matter. [ABSTRACT FROM AUTHOR]

This study aimed to provide comprehensive clinical screening data for anal intraepithelial neoplasia (AIN). This study included 312 patients who underwent high‐resolution anoscopy (HRA) examinations between January 1, 2020 and April 15, 2024. Clinical data, including demographic information, clinical history, cytology/high‐risk human papilloma virus (hrHPV) results, and HRA records, were analyzed. The median age of all patients was 42 years (interquartile range: 33–52 years). Approximately 26.3% reported a history of VIN2/3+, 13.5% had a history of VaIN2/3+, 29.8% had a history of CIN2/3+, 44.6% had persistent cervical HPV16 infection, and 12.5% had immune suppression. Among the 312 patients, 14.4% were diagnosed with AIN2/3, 25.0% with AIN1 and 60.6% were normal. Anal cytological abnormalities were found in 41.3% of all patients, with a significantly higher rate in AIN2/3 patients than in ≤AIN1, 71.1% versus 36.3%, p < 0.001. The hrHPV positivity rate was 89.7%, with HPV16 being the most prevalent. The complete agreement rate for HRA impressions was 79.5%. Multi‐variable analysis revealed immune suppression (odds ratio [OR]: 3.47, 95% confidence interval [CI]: 1.42–8.5) and VIN2/3+ (OR: 2.82, 95% CI: 1.27–6.28) were independent risk factors for AIN2/3. Abnormal cytology results (OR: 3.3, 95% CI: 1.52–7.17) and anal HPV16 infection (OR: 3.2, 95% CI: 1.26–8.12) demonstrated similar ORs for AIN2/3. Early screening for AIN2/3+ is crucial in Chinese women with lower genital tract precancerous and cancerous lesions, particularly in those with VIN2/3+ and immune suppression. [ABSTRACT FROM AUTHOR]