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Abstract Background The functional integrity of the anterior cruciate ligament (ACL) influences surgical decision-making in patients with knee osteoarthritis (KOA). This study aimed to compare the diagnostic value of radiography and magnetic resonance imaging (MRI) in determining the functional status of ACL. Methods We analyzed 306 knees retrospectively using preoperative hip-to-ankle anteroposterior standing (APS) radiographs, anteroposterior (AP) and lateral knee radiographs, AP valgus stress (VS) force radiographs, and standard orthogonal MRI. Based on the intraoperative visualization, the knees were grouped into ACL functionally-intact and ACL functionally-deficient (ACLD) groups. The diagnostic validity and reliability were calculated based on the radiograph parameters such as hip-knee-ankle angle (HKA), medial proximal tibial angle (MPTA), lateral distal femoral angle (LDFA), posterior tibial slope (PTS), sagittal tibiofemoral subluxation (STFS), coronal tibiofemoral subluxation (CTFS), joint line convergence angle (JLCA), the maximum wear point of the proximal tibia plateau (MWPPT%), and MRI parameters including ACL grades and MWPPT%. Results HKA, MPTA, PTS, STFS, JLCA, and CTFS on APS and AP radiographs, and MWPPT% on radiographs and MRI showed a significant diagnostic value (P

Abstract Energy poverty, especially in rural areas, has become a central focus of scholarly and policy discussions. However, there is a significant gap in understanding the impact of religious beliefs on this phenomenon. This paper aims to fill this gap by utilizing household survey data from the China Labor-force Dynamics Survey (CLDS) spanning three waves (2012, 2014, and 2016) to examine the causal link between religious beliefs and energy poverty, covering clean energy accessibility and affordability among rural residents. Our analysis unveils a substantial positive influence of religious beliefs on the likelihood of experiencing energy poverty, especially concerning accessibility and affordability. This effect is notably pronounced among males, ethnic minorities, and low-income groups. Low income and education are recognized as pivotal mediating factors through which religious beliefs contribute to energy poverty. The findings of this study offer valuable insights for formulating strategies to mitigate energy poverty in rural China, with a particular emphasis on the role of religious beliefs.

Abstract Background Indigenous chickens were developed through a combination of natural and artificial selection; essentially, changes in genomes led to the formation of these modern breeds via admixture events. However, their confusing genetic backgrounds include a genomic footprint regulating complex traits, which is not conducive to modern animal breeding. Results To better evaluate the candidate regions under domestication in indigenous chickens, we considered both runs of homozygosity (ROHs) and selective signatures in 13 indigenous chickens. The genomes of Silkie feather chickens presented the highest heterozygosity, whereas the highest inbreeding status and ROH number were found in Luhua chickens. Short ROH (

Abstract Voltage-gated sodium (NaV) channels mediate a plethora of electrical activities. NaV channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of NaV channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying NaV channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaVEh (NaVEhΔN) results in a slow-inactivated channel, and present cryo-EM structure of NaVEhΔN in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the NaVEh structure, NaVEhΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into NaV channel slow inactivation.

Abstract Objective Recurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a pro-inflammatory cytokine milieu, which contributes to RPL pathogenesis. The main objective of this study was twofold: first to explore the regulatory effects and mechanisms of villus-derived exosomes (vEXOs) from induced abortion patients or RPL patients at the level of intracellular IFN-γ in dNK cells; second to determine the validity of application of vEXOs in the treatment of unexplained RPL (uRPL) through in vitro experiments and mouse models. Methods Exosomes were isolated from villus explants by ultracentrifugation, co-cultured with dNK cells, and purified by enzymatic digestion and magnetically activated cell sorting. Flow cytometry, enzyme-linked immunosorbent assays, and RT-qPCR were used to determine IFN-γ levels. Comparative miRNA analysis of vEXOs from induced abortion (IA) and uRPL patients was used to screen potential candidates involved in dNK regulation, which was further confirmed by luciferase reporter assays. IA-vEXOs were electroporated with therapeutic miRNAs and encapsulated in a China Food and Drug Administration (CFDA)-approved hyaluronate gel (HA-Gel), which has been used as a clinical biomaterial in cell therapy for > 30 years. In vivo tracking was performed using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyaine iodide (DiR) labelling. Tail-vein and uterine horn injections were used to evaluate therapeutic effects of the engineered exosomes in an abortion-prone mouse model (CBA/J × DBA/2 J). Placental growth was evaluated based on placental weight. IFN-γ mRNA levels in mouse placentas were measured by RT-qPCR. Results IFN-γ levels were significantly higher in dNK cells of uRPL patients than in IA patients. Both uRPL-vEXOs and IA-vEXOs could be efficiently internalized by dNK cells, whereas uRPL-vEXOs could not reduce the expression of IFN-γ by dNK cells as much as IA-vEXOs. Mechanistically, miR-29a-3p was delivered by vEXOs to inhibit IFN-γ production by binding to the 3′ UTR of IFN-γ mRNA in dNK cells. For in vivo treatment, application of the HA-Gel effectively prolonged the residence time of vEXOs in the uterine cavity via sustained release. Engineered vEXOs loaded with miR-29a-3p reduced the embryo resorption rate in RPL mice with no signs of systemic toxicity. Conclusion Our study provides the first evidence that villi can regulate dNK cell production of IFN-γ via exosome-mediated transfer of miR-29a-3p, which deepens our understanding of maternal–fetal immune tolerance for pregnancy maintenance. Based on this, we developed a new strategy to mix engineered vEXOs with HA-Gel, which exhibited good therapeutic effects in mice with uRPL and could be used for potential clinical applications in uRPL treatment. Graphical Abstract

Abstract Background Dysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol efflux and maintaining cellular cholesterol homeostasis. However, further exploration is needed to determine whether it inhibits TNBC metastasis by affecting cholesterol metabolism. Additionally, it is necessary to investigate whether ApoA1-based oncolytic virus therapy can be used to treat TNBC. Methods In vitro experiments and mouse breast cancer models were utilized to evaluate the molecular mechanism of ApoA1 in regulating cholesterol efflux and inhibiting breast cancer progression and metastasis. The gene encoding ApoA1 was inserted into the adenovirus genome to construct a recombinant adenovirus (ADV-ApoA1). Subsequently, the efficacy of ADV-ApoA1 in inhibiting the growth and metastasis of TNBC was evaluated in several mouse models, including orthotopic breast cancer, spontaneous breast cancer, and human xenografts. In addition, a comprehensive safety assessment of Syrian hamsters and rhesus monkeys injected with oncolytic adenovirus was conducted. Results This study found that dysregulation of cholesterol homeostasis is critical for the progression and metastasis of TNBC. In a mouse orthotopic model of TNBC, a high-cholesterol diet promoted lung and liver metastasis, which was associated with keratin 14 (KRT14), a protein responsible for TNBC metastasis. Furthermore, studies have shown that ApoA1, a cholesterol reverse transporter, inhibits TNBC metastasis by regulating the cholesterol/IKBKB/FOXO3a/KRT14 axis. Moreover, ADV-ApoA1 was found to promote cholesterol efflux, inhibit tumor growth, reduce lung metastasis, and prolonged the survival of mice with TNBC. Importantly, high doses of ADV-ApoA1 administered intravenously and subcutaneously were well tolerated in rhesus monkeys and Syrian hamsters. Conclusions This study provides a promising oncolytic virus treatment strategy for TNBC based on targeting dysregulated cholesterol metabolism. It also establishes a basis for subsequent clinical trials of ADV-ApoA1 in the treatment of TNBC.

Bacterial biofilm-associated infection was one of the most serious threats to human health. However, effective drugs for drug-resistance bacteria or biofilms remain rarely reported. Here, we propose an innovative strategy to develop a multifunctional antimicrobial agent with broad-spectrum antibacterial activity by coupling photosensitizers (PSs) with antimicrobial peptides (AMPs). This strategy capitalizes on the ability of PSs to generate reactive oxygen species (ROS) and the membrane-targeting property of AMPs (KRWWKWIRW, a peptide screened by an artificial neural network), synergistically enhancing the antimicrobial activity. In addition, unlike conventional aggregation-caused quenching (ACQ) photosensitizers, aggregation-induced emission (AIE) PSs show stronger fluorescence emission in the aggregated state to help visualize the antibacterial mechanism. In vitro antibacterial experiments demonstrated the excellent killing effects of the developed agent against both Gram-positive (G+) and Gram-negative (G–) bacteria. The bacterial-aggregations induced ability enhanced the photoactivatable antibacterial activity against G– bacteria. Notably, it exhibited a significant effect on destroying MRSA biofilms. Moreover, it also showed remarkable efficacy in treating wound infections in mice in vivo. This multifunctional antimicrobial agent holds significant potential in addressing the challenges posed by bacterial biofilm-associated infections and drug-resistant bacteria.

Purpose: Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could reduce these parameters. This systematic review and metaanalysis (SRMA) aims to investigate the impact of VR on SDF and seminal malondialdehyde (MDA). Materials and Methods: A literature search was performed in Scopus, PubMed, Ovid, Embase, and Cochrane databases. This SRMA included randomized controlled trials and observational studies reporting the pre- and postoperative levels of SDF and seminal OS in infertile men with clinical varicocele that underwent VR. Subgroup analyses included techniques of VR and SDF testing. The effect size was expressed as standardized mean difference (SMD). Results: Out of 1,632 abstracts assessed for eligibility, 29 studies with 1,491 infertile men were included. The analysis showed a significant reduction in SDF after VR, compared to preoperative values (SMD –1.125, 95% confidence interval [CI] –1.410, –0.840; p

Abstract Background To investigate the role of antimicrobial prophylaxis in laparoscopic nephrectomy for renal cell carcinoma. Methods We retrospectively enrolled 1000 patients who underwent laparoscopic nephrectomy from August 2019 to November 2021 in the Peking Union Medical College Hospital. Patients were divided into group without antimicrobial prophylaxis (n = 444) and group with antimicrobial prophylaxis (n = 556). Outcomes including 30-day postoperative infection rate, the increase rate of pre- and post-operative white blood cell counts and hospital stay were analyzed. Results The overall infection rate was 5.0% (28/556) in the group with antimicrobial prophylaxis, which was similar to 4.1% (18/444) in the group without antimicrobial prophylaxis (P = 0.461). The increase rate of pre- and post-operative white blood cell counts was significantly lower (85.5% versus 97.0%) in the group with antimicrobial prophylaxis (P = 0.004). The postoperative hospital stay was 5 (4, 6) days in both groups (P = 0.483). Logistic regression analyses identified the use of antimicrobial prophylaxis had no influence on the occurrence of infection events (odds ratio = 0.797; 95% confidence interval, 0.435–1.460; P = 0.462). Hemoglobin (odds ratio = 0.430; 95% confidence interval, 0.257–0.719; P = 0.001) and partial nephrectomy (odds ratio = 2.292; 95% confidence interval, 1.724–3.046; P

Abstract Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input‐output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. In this study, a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), is identified as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. PTPRN recruits the NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) to NaV1.2 sodium channels, facilitating NEDD4L‐mediated ubiquitination, and endocytosis of NaV1.2. Knockout of PTPRN in hippocampal granule cells leads to augmented NaV1.2‐mediated sodium currents and higher intrinsic excitability, resulting in increased seizure susceptibility in transgenic mice. Conversely, adeno‐associated virus‐mediated delivery of PTPRN in the dentate gyrus region decreases intrinsic excitability and reduces seizure susceptibility. Moreover, the present findings indicate that PTPRN exerts a selective modulation effect on voltage‐gated sodium channels. Collectively, PTPRN plays a significant role in regulating intrinsic excitability and seizure susceptibility, suggesting a potential strategy for precise modulation of NaV1.2 channels' function.

CD4+ T cells are central mediators of protective immunity to blood-stage malaria, particularly for their capacity in orchestrating germinal center reaction and generating parasite-specific high-affinity antibodies. T follicular helper (Tfh) cells are predominant CD4+ effector T cell subset implicated in these processes, yet the factors and detailed mechanisms that assist Tfh cell development and function during Plasmodium infection are largely undefined. Here we provide evidence that receptor for activated C kinase 1 (RACK1), an adaptor protein of various intracellular signals, is not only important for CD4+ T cell expansion as previously implied but also plays a prominent role in Tfh cell differentiation and function during blood-stage Plasmodium yoelii 17XNL infection. Consequently, RACK1 in CD4+ T cells contributes significantly to germinal center formation, parasite-specific IgG production, and host resistance to the infection. Mechanistic exploration detects specific interaction of RACK1 with STAT3 in P. yoelii 17XNL-responsive CD4+ T cells, ablation of RACK1 leads to defective STAT3 phosphorylation, accompanied by substantially lower amount of STAT3 protein in CD4+ T cells, whereas retroviral overexpression of RACK1 or STAT3 in RACK1-deficient CD4+ T cells greatly restores STAT3 activity and Bcl-6 expression under the Tfh polarization condition. Further analyses suggest RACK1 positively regulates STAT3 stability by inhibiting the ubiquitin-proteasomal degradation process, thus promoting optimal STAT3 activity and Bcl-6 induction during Tfh cell differentiation. These findings uncover a novel mechanism by which RACK1 participates in posttranslational regulation of STAT3, Tfh cell differentiation, and subsequent development of anti-Plasmodium humoral immunity.

Abstract Aims To explore the knowledge, attitudes and practice status of the intrahospital transport (IHT) of critically ill patients among clinical nurses and their influencing factors. Design Cross‐sectional study. Methods A questionnaire determined the nurses' knowledge, attitudes and practice scores. The questionnaire was used for data collection in a tertiary hospital from 10 January to 17 January 2023. Multivariate regression analysis was also used to evaluate the related factors of IHT of critically ill patients in different dimensions. Results Out of 670 distributed questionnaires, 612 nurses returned the completed questionnaire. The scores of KAP were (9.72 ± 1.61), (42.91 ± 4.58) and (82.84 ± 1.61), respectively. Pearson's correlation analysis showed that knowledge, attitude and behaviour scores were positively correlated. Variables that were associated with the scores of transfer knowledge were the scores of transfer practice, different departments and the scores of transfer attitude. The score of practice, number of IHT and received hospital‐level training had statistical significance on the nurses' attitude scores. Furthermore, the score of the attitude and transport knowledge had statistical significance on the nurses' practice. Conclusion The findings indicate a clear need for clinical nurses' knowledge of IHT of critically ill patients, especially in the emergency department (ED) and ICU. In addition, nurses need to be more active in transporting critically ill patients. Managers should enhance nurses' confidence in the IHT of critically ill patients and promote clinical nurses to establish a correct and positive attitude. Impact The findings of this study benefit nursing managers in understanding the current situation of IHT of critically ill patients. Managers should apply new training methods to nursing education and develop a multi‐level training program that is systematic, comprehensive and demand‐oriented. Patient or Public Contribution The participants of this study were nurses and this contribution has been explained in the Data collection section. There was no patient contribution in this study.

Background: Machine learning has shown to be an effective method for early prediction and intervention of Gestational diabetes mellitus (GDM), which greatly decreases GDM incidence, reduces maternal and infant complications and improves the prognosis. However, there is still much room for improvement in data quality, feature dimension, and accuracy. The contributions and mechanism explanations of clinical data at different pregnancy stages to the prediction accuracy are still lacking. More importantly, current models still face notable obstacles in practical applications due to the complex and diverse input features and difficulties in redeployment. As a result, a simple, practical but accurate enough model is urgently needed. Design and methods: In this study, 2309 samples from two public hospitals in Shenzhen, China were collected for analysis. Different algorithms were systematically compared to build a robust and stepwise prediction system (level A to C) based on advanced machine learning, and models under different levels were interpreted. Results: XGBoost reported the best performance with ACC of 0.922, 0.859 and 0.850, AUC of 0.974, 0.924 and 0.913 for the selected level A to C models in the test set, respectively. Tree-based feature importance and SHAP method successfully identified the commonly recognized risk factors, while indicated new inconsistent impact trends for GDM in different stages of pregnancy. Conclusion: A stepwise prediction system was successfully established. A practical tool that enables a quick prediction of GDM was released at https://github.com/ifyoungnet/MedGDM.This study is expected to provide a more detailed profiling of GDM risk and lay the foundation for the application of the model in practice.

Summary: Background: Contrast-enhanced CT scans provide a means to detect unsuspected colorectal cancer. However, colorectal cancers in contrast-enhanced CT without bowel preparation may elude detection by radiologists. We aimed to develop a deep learning (DL) model for accurate detection of colorectal cancer, and evaluate whether it could improve the detection performance of radiologists. Methods: We developed a DL model using a manually annotated dataset (1196 cancer vs 1034 normal). The DL model was tested using an internal test set (98 vs 115), two external test sets (202 vs 265 in 1, and 252 vs 481 in 2), and a real-world test set (53 vs 1524). We compared the detection performance of the DL model with radiologists, and evaluated its capacity to enhance radiologists’ detection performance. Findings: In the four test sets, the DL model had the area under the receiver operating characteristic curves (AUCs) ranging between 0.957 and 0.994. In both the internal test set and external test set 1, the DL model yielded higher accuracy than that of radiologists (97.2% vs 86.0%, p 0.99), and it detected 2 cases that had been missed by radiologists. Interpretation: The developed DL model can accurately detect colorectal cancer and improve radiologists’ detection performance, showing its potential as an effective computer-aided detection tool. Funding: This study was supported by National Science Fund for Distinguished Young Scholars of China (No. 81925023); Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20345); National Natural Science Foundation of China (No. 82072090 and No. 82371954); Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No. 2022B1212010011); High-level Hospital Construction Project (No. DFJHBF202105).

Excess copper (Cu) imparts negative effects on plant growth and productivity in soil. To develop the ability of O. biennis to govern pollution soil containing excessive Cu, we investigated seed germination, seedling growth, and seed yield. Furthermore, Cu content and the expression levels of Cu transport related genes in different tissues were measured under exogenous high concentration Cu. O. biennis seeds were sensitive to excess Cu, with an observed reduction in the germination rate, primary root length, fresh weight, and number of seeds germinated daily. Consecutive Cu stress did not cause fatal damage to evening primrose, yet it slowed down plant growth slightly by reducing the leaf water, chlorophyll, plant yield, and seed oil contents while increasing the soluble sugar, proline, malondialdehyde, and H2O2 contents. The Cu content in different organs of O. biennis was disrupted by excess Cu. In particular, the Cu content in O. biennis seeds and seed oil increased and subsequently decreased with the increase of exogenous Cu, reaching a peak under 600 mg·kg−1 consecutive Cu. Furthermore, the 4-month 900 mg·kg−1 Cu treatment did not induce the excessive accumulation of Cu in peels, seeds, and seed oil, maintaining the Cu content within the range required by the Chinese National Food Safety Standards. The treatment also resulted in an upregulation of Cu-uptake (ObCOPT5, ObZIP4, and ObYSL2) and vigorous efflux (ObHMA1) of transport genes, of which expression levels were significant positive correlation (p < 0.05) with the Cu content. Among all organs, the stem replaced the root as the organ exhibited the greatest ability to absorb and store Cu, and even the Cu transport genes could still function continuously in stem under excess Cu. This work identified a species that can tolerate high Cu content in soil while maintaining a high yield. Furthermore, the results revealed the enrichment of Cu to occur primarily in the O. biennis stem rather than the seeds and peel under excess Cu.

Abstract Compared to commercial chickens, local breeds exhibit better in meat quality and flavour, but the productivity (e.g., growth rate, body weight) of local chicken breeds is rather low. Genetic analysis based on whole-genome sequencing contributes to elucidating the genetic markers or putative candidate genes related to some economic traits, facilitating the improvement of production performance, the acceleration of breeding progress, and the conservation of genetic resources. Here, a total of 209 local chickens from 13 breeds were investigated, and the observation of approximately 91.4% high-quality sequences (Q30 > 90%) and a mapping rate over 99% for each individual indicated good results of this study, as confirmed by a genome coverage of 97.6%. Over 19 million single nucleotide polymorphisms (SNPs) and 1.98 million insertion-deletions (InDels) were identified using the reference genome (GRCg7b), further contributing to the public database. This dataset provides valuable resources for studying genetic diversity and adaptation and for the cultivation of new chicken breeds/lines.

Abstract Background Ovarian stimulation (OS) during assisted reproductive technology (ART) appears to be an independent factor influencing the risk of low birth weight (LBW). Previous studies identified the association between LBW and placenta deterioration, potentially resulting from disturbed genomic DNA methylation in oocytes caused by OS. However, the mechanisms by which OS leads to aberrant DNA methylation patterns in oocytes remains unclear. Methods Mouse oocytes and mouse parthenogenetic embryonic stem cells (pESCs) were used to investigate the roles of OS in oocyte DNA methylation. Global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels were evaluated using immunofluorescence or colorimetry. Genome-wide DNA methylation was quantified using an Agilent SureSelectXT mouse Methyl-Seq. The DNA methylation status of mesoderm-specific transcript homologue (Mest) promoter region was analyzed using bisulfite sequencing polymerase chain reaction (BSP). The regulatory network between estrogen receptor alpha (ERα, ESR1) and DNA methylation status of Mest promoter region was further detected following the knockdown of ERα or ten-eleven translocation 2 (Tet2). Results OS resulted in a significant decrease in global 5mC levels and an increase in global 5hmC levels in oocytes. Further investigation revealed that supraphysiological β-estradiol (E2) during OS induced a notable decrease in DNA 5mC and an increase in 5hmC in both oocytes and pESCs of mice, whereas inhibition of estrogen signaling abolished such induction. Moreover, Tet2 may be a direct transcriptional target gene of ERα, and through the ERα-TET2 axis, supraphysiological E2 resulted in the reduced global levels of DNA 5mC. Furthermore, we identified that MEST, a maternal imprinted gene essential for placental development, lost its imprinted methylation in parthenogenetic placentas originating from OS, and ERα and TET2 combined together to form a protein complex that may promote Mest demethylation. Conclusions In this study, a possible mechanism of loss of DNA methylation in oocyte caused by OS was revealed, which may help increase safety and reduce epigenetic abnormalities in ART procedures.

Abstract Cancer survivors are vulnerable to frailty. While few studies have focused on the association of frailty with mortality risk among cancer survivors, the current study aimed to reveal this association. In this cohort study, 4723 cancer survivors were enrolled from the National Health and Nutrition Examination Surveys (NHANES, 1999–2018). Frailty status was quantified using the 53-item frailty index. Death outcomes were linked to National Death Index mortality data (as of December 31, 2019). Cox proportional hazard models were used to estimate HRs (95% CIs). The median (IQR) frailty score was 0.190 (0.132, 0.277). During the median follow-up of 6.7 years, 1775 all-cause deaths (including 581 cancer deaths and 385 cardiac deaths) were documented. Compared to the lowest tertile of frailty scores, the adjusted HRs (95% CIs) for the highest tertile were 2.698 (2.224, 3.272) for all-cause mortality (P trend

On July 20, 2021, the northern Henan Province was hit by a historically rare, exceptionally heavy rainstorm (“7.20” Rainstorm Event), accompanied by severe urban flooding, flash floods, landslides, and other multiple disasters, resulting in significant casualties and property losses. On the other hand, the long-term overexploitation of groundwater since the last century has led to severe ground subsidence in the same area. We apply the intensity information of Sentinel-1 SAR images to extract the large-scale flood inundation area and their phase information to measure the ground deformation. Since heavy precipitations can recharge groundwater, the relationship between flood inundation, groundwater level change, and ground deformation is analyzed. The results show that the flood inundation areas are mainly distributed along the major rivers due to river overflowing, while heavy precipitation led to the rise of groundwater levels, and there was a significant amount of subsidence mitigation and surface uplift across the region due to the groundwater recovery. This study demonstrates the contribution of radar remote sensing to analyze the mechanism of groundwater recharge and subsidence mitigation benefited by rainstorm events and provides a technical reference to similar circumstances.

Abstract Background Programmed cell death protein 1 (PD-1) checkpoint inhibitors such as pembrolizumab are novel therapeutics used to treat various advanced malignancies. Immune-related adverse events are common, among the most serious of these toxicities is hemophagocytic lymphohistiocytosis (HLH), which is a life-threatening disorder of unbridled immune activation but has not been properly established. Methods We have procured the first case of hemophagocytic lymphohistiocytosis as an aftermath of treatment with pembrolizumab from the Sir Run Run Shaw Hospital, Zhejiang University, China. In a pursuit to enhance the understanding of this condition, a comprehensive systematic review was performed encompassing all reported instances of ICI-associated Hemophagocytic lymphohistiocytosis within the realms of PubMed and Embase databases. Results We detail the recovery of a cervical cancer patient with a history of psoriasis who developed HLH after combined pembrolizumab and bevacizumab treatment. Remarkably, tumor lesions exhibited substantial and sustained regression. From an analysis of 52 identified Immune Checkpoint Inhibitor (ICI)-related HLH cases, we discovered that HLH often occurred within the first two treatment cycles and approximately 20% of these patients had a history of autoimmune-related diseases. Despite a 15% mortality rate, the majority of patients experienced positive outcomes. Notably, in instances of recovery from HLH, 80% showed positive tumor outcomes. Even after discontinuation of ICI treatment, tumor control persisted in some cases. Conclusion We identified the first case of HLH caused by ICI treatment in cervical cancer and summarized the possible occurrence factors of these cases, the treatment outcomes of HLH, and the impact on tumor outcomes.

Abstract Chinese torreya nut (Torreya grandis cv. Merrillii) is a unique edible nut that grows in China, which is known for its ability to reduce blood lipids, prevent blood sclerosis, and coronary heart disease. However, its effect on reproduction is not well understood. In this study, the comprehensive effects of Chinese torreya nut on the sex hormones and endometrium in female mice and their uterine expression profiles were investigated. Here, feeding of mice with Chinese torreya nut resulted in a decrease in uterine coefficients and serum progesterone levels, thickening of the endometrium, and an increase in estrogen levels. The enrichment analyses indicated that the differentially expressed genes between the Chinese torreya nut addition and control mice were enriched in NOD‐like receptor signaling pathway, complement and coagulation cascades and p53 pathway. Quantitative real time PCR and western blot results showed that there were significant differences in the transcripts and protein expression of estrogen receptor alpha and progestogen receptor associated with G protein coupled estrogen receptor. These findings suggest that Chinese torreya nut may have a potentially beneficial effect on coordinating uterine contractions in mice, rendering it a promising functional food.

Abstract Background We created discriminative models of different regions of interest (ROIs) using radiomic texture features of neurite orientation dispersion and density imaging (NODDI) and evaluated the feasibility of each model in differentiating glioblastoma multiforme (GBM) from solitary brain metastasis (SBM). Methods We conducted a retrospective study of 204 patients with GBM (n = 146) or SBM (n = 58). Radiomic texture features were extracted from five ROIs based on three metric maps (intracellular volume fraction, orientation dispersion index, and isotropic volume fraction of NODDI), including necrosis, solid tumors, peritumoral edema, tumor bulk volume (TBV), and abnormal bulk volume. Four feature selection methods and eight classifiers were used for the radiomic texture feature selection and model construction. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of the models. Routine magnetic resonance imaging (MRI) radiomic texture feature models generated in the same manner were used for the horizontal comparison. Results NODDI-radiomic texture analysis based on TBV subregions exhibited the highest accuracy (although nonsignificant) in differentiating GBM from SBM, with area under the ROC curve (AUC) values of 0.918 and 0.882 in the training and test datasets, respectively, compared to necrosis (AUCtraining:0.845, AUCtest:0.714), solid tumor (AUCtraining:0.852, AUCtest:0.821), peritumoral edema (AUCtraining:0.817, AUCtest:0.762), and ABV (AUCtraining:0.834, AUCtest:0.779). The performance of the five ROI radiomic texture models in routine MRI was inferior to that of the NODDI-radiomic texture model. Conclusion Preoperative NODDI-radiomic texture analysis based on TBV subregions shows great potential for distinguishing GBM from SBM.

In order to clarify the characteristic compounds and establish the authenticity evaluation method of heptapleurum honey, high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (HPLC-Q/TOF-MS/MS) was used to qualitative and quantitative analysis of characteristic compounds in heptapleurum honey. Five compounds were identified including 4-(1'-cyclodiethyl ether-3'-butanediol)-3,5,5-trimethyl-2-cyclohexenone (Unedone B), 3,4,5-trimethoxy cinnamyl alcohol, 4-(1'2'-dihydroxy-3'epoxypropane) -3,5,5-2-cyclohexenone (Unedone C), trans, trans abscisic acid, and cis, trans abscisic acid. Notably, 3,4,5-trimethoxy cinnamyl alcohol was first found in honey, and it could be a marker of heptapleurum honey. Moreover, 10 raw heptapleurum honey samples with different geographic origins were collected to establish HPLC fingerprint. The authenticity of six commercial heptapleurum honey samples were evaluated by combining characteristic compound with HPLC fingerprint. The results demonstrated that three brands of sample were genuine pure heptapleurum honey, two brands of sample might be mixed with other honeys. A brand sample did not contain characteristic compound and were significantly different with the standard fingerprints of heptapleurum honey. It was inferred that the sample was not heptapleurum honey. This study provides theoretical reference for the authenticity evaluation of heptapleurum honey.

AbstractLigand-based drug design methods are thought to require large experimental datasets to become useful for virtual screening. In this work, we propose a computational strategy to design novel inhibitors of coronavirus main protease, Mpro. The pipeline integrates publicly available screening and binding affinity data in a two-stage machine-learning model using the recent MACAW embeddings. Once trained, the model can be deployed to rapidly screen large libraries of molecules in silico. Several hundred thousand compounds were virtually screened and 10 of them were selected for experimental testing. From these 10 compounds, 8 showed a clear inhibitory effect on recombinant Mpro, with half-maximal inhibitory concentration values (IC50) in the range 0.18–18.82 μM. Cellular assays were also conducted to evaluate cytotoxic, haemolytic, and antiviral properties. A promising lead compound against coronavirus Mpro was identified with dose-dependent inhibition of virus infectivity and minimal toxicity on human MRC-5 cells.

BackgroundWhen employing the transcription-mediated amplification method for screening blood donors, there are some non-discriminatory reactive results which are screening assay reactive but HBV-DNA discriminatory assay negative. This raises concerns regarding the possibility of false positives among donors, which may lead to permanent deferral of blood donors and affect blood supply. This study aimed to elucidate the infection status of these non-discriminatory reactive blood donors and develop and validate a model to predict individualized hepatitis B status to establish an optimal screening strategy.MethodsSupplementary tests were conducted on initial non-discriminating reactive donations to determine their HBV infection status, including repeat testing, viral load, serological marker detection, and follow-up. Primary clinical variables of the donors were recorded. Based on the Akaike information criterion, a stepwise forward algorithm was used to identify the predictive factors for information and construct a predictive model. The optimal screening strategy was determined through cost-effectiveness analysis.ResultsAt the Blood Center of Zhejiang Province, 435 cases of initial non-discriminatory reactive donations were collected over two successive periods and sub-categorized through repeated testing into the following three groups: non-repeated positive group, non-discriminated positive group, and non-repeated HBV-DNA positive group. The HBV discriminatory rate increased after repeated testing (110/435, 25.29%). According to supplementary tests, the HBV-DNA positivity rate was 65.52% (285/435), and occult HBV infection was a significantly different among groups (χ2 = 93.22, p

Multiple cancers have been associated with MYB-related protein B (MYBL2), its involvement in clear cell renal cell carcinoma (ccRCC) has yet to be demonstrated. Our study revealed a significant upregulation of MYBL2 in ccRCC tissues, correlating with clinicopathological features and patient prognosis. Increased MYBL2 expression promoted cell proliferation and suppressed apoptosis. RNA-seq analysis unveiled a reduction in smoothened (SMO) expression upon MYBL2 silencing. However, luciferase and chromatin immunoprecipitation (ChIP) assays demonstrated MYBL2's positive regulation of SMO expression by directly targeting the SMO promoter. Reintroduction of SMO expression in MYBL2-knocked down cells partially restored cell proliferation and mitigated apoptosis inhibition. Overall, these results indicate that MYBL2 facilitates ccRCC progression by enhancing SMO expression, suggesting its potential as an intriguing drug target for ccRCC therapy.

Background: The TLC Domain Containing 1 (TLCD1) protein, a key regulator of phosphatidylethanolamine (PE) composition, is distributed across several cellular membranes, including mitochondrial plasma membranes. Existing research has revealed the impact of TLCD1 on the development of non-alcoholic fatty liver disease. However, there remains a gap in comprehensive pan-cancer analyses of TLCD1, and the precise role of TLCD1 in cancer patient prognosis and immunological responses remains elusive. This study aims to provide a comprehensive visualization of the prognostic landscape associated with TLCD1 across a spectrum of cancers, while shedding light on the potential links between TLCD1 expression within the tumor microenvironment and immune infiltration characteristics.Methods: TLCD1 expression data were obtained from GTEx, TCGA, and HPA data repositories. Multiple databases including TIMER, HPA, TISIDB, cBioPortal, GEPIA2, STRING, KEGG, GO, and CancerSEA were used to investigate the expression pattern, diagnostic and prognostic significance, mutation status, functional analysis, and functional status of TLCD1. In addition, we evaluated the relationship between TLCD1 expression and immune infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and immune-related genes in pan-cancer. Furthermore, the association of TLCD1 with drug sensitivity was analyzed using the CellMiner database.Results: We found that TLCD1 is generally highly expressed in pan-cancers and is significantly associated with the staging and prognosis of various cancers. Furthermore, our results also showed that TLCD1 was significantly associated with immune cell infiltration and immune regulatory factor expression. Using CellMiner database analysis, we then found a strong correlation between TLCD1 expression and sensitivity to anticancer drugs, indicating its potential as a therapeutic target. The most exciting finding is that high TLCD1 expression is associated with worse survival and prognosis in GBM and SKCM patients receiving anti-PD1 therapy. These findings highlight the potential of TLCD1 as a predictive biomarker for response to immunotherapy.Conclusion: TLCD1 plays a role in the regulation of immune infiltration and affects the prognosis of patients with various cancers. It serves as both a prognostic and immunologic biomarker in human cancer.

Objectives Peritoneal dialysis (PD) allows patients increased autonomy and flexibility; however, both infectious and non-infectious complications may lead to technique failure, which shortens treatment longevity. Maintaining patients on PD remains a major challenge for nephrologists. This study aims to describe nephrologists’ perspectives on technique survival in PD.Design Qualitative semistructured interview study. Transcripts were thematically analysed.Setting and participants 30 nephrologists across 11 countries including Australia, the USA, the UK, Hong Kong, Canada, Singapore, Japan, New Zealand, Thailand, Colombia and Uruguay were interviewed from April 2017 to November 2019.Results We identified four themes: defining patient suitability (confidence in capacity for self-management, ensuring clinical stability and expected resilience), building endurance (facilitating access to practical support, improving mental well-being, optimising quality of care and training to reduce risk of complications), establishing rapport through effective communications (managing expectations to enhance trust, individualising care and harnessing a multidisciplinary approach) and confronting fear and acknowledging barriers to haemodialysis (preventing crash landing to haemodialysis, facing concerns of losing independence and positive framing of haemodialysis).Conclusion Nephrologists reported that technique survival in PD is influenced by patients’ medical circumstances, psychological motivation and positively influenced by the education and support provided by treating clinicians and families. Strategies to enhance patients’ knowledge on PD and communication with patients about technique survival in PD are needed to build trust, set patient expectations of treatment and improve the process of transition off PD.

Background The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies.Methods We constructed a recombinant oncolytic vaccinia virus encoding the hyaluronidase, and investigated its function in remodeling the ECM of the TME, the antitumor efficacy both in vitro and in several murine solid tumors either alone, or in combination with chemo drugs including doxorubicin and gemcitabine, with polypeptide liraglutide, with immune therapeutics such as PD-L1/PD-1 blockade, CD47 antibody, and with CAR-T cells.Results Compared with control OVV, intratumoral injection of OVV-Hyal1 showed superior antitumor efficacies in a series of mouse subcutaneous tumor models. Moreover, HA degradation by OVV-Hyal1 resulted in increased intratumoral dissemination of chemo drugs, infiltration of T cells, NK cells, macrophages, and activation of CD8+ T cells. When OVV-Hyal1 was combined with some antitumor therapeutics, for example, doxorubicin, gemcitabine, liraglutide, anti-PD-1, anti-CD47 blockade, or CAR-T cells, more profound therapeutic outcomes were obtained.Conclusions OVV-Hyal1 effectively degrades HA to reshape the TME, therefore overcoming some major hurdles in current cancer therapy, such as limited OVs spread, unfavored dissemination of chemo drugs, polypeptides, antibodies, and insufficient infiltration of effector immune cells. OVV-Hyal1 holds the promise to improve the antitumor outcomes of current cancer therapeutics.

Purpose: To determine whether using robots in spine surgery results in more clinical advantages and fewer adverse consequences. Methods: Between October 1990 and October 2022, a computer-based search was conducted through the databases of PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, China Biology Medicine, VIP databases, and WAN FANG. The study only included randomized controlled trials (RCTs) comparing the clinical efficacy and safety of robot-assisted surgery with those of conventional spine surgery. The review was conducted following PRISMA 2020, and AMSTAR-2 was used to evaluate the methodological quality. R version 4.2.1 was used in the meta-analysis. The Cochrane Collaboration Tool was used for evaluating the risk of bias. Results: This study analyzed 954 participants from 20 RCTs involving cervical spondylosis, lumbar degenerative disease, scoliosis, etc. The robot-assisted group outperformed the freehand group in terms of intraoperative blood loss, number of screws in grade A position, grade A + B position, radiation dose, and hospital stay. Operation duration, visual analog scale scores of low back pain, Oswestry disability index, and radiation exposure time did not significantly differ between the two groups. Conclusions: Although robotic spine surgery is more accurate in pedicle screw placement than conventional methods, the robot group did not demonstrate an advantage in terms of clinical efficacy. Studies of complications and cost-effectiveness are still very rare.

Abstract Aneuploidy seriously compromises female fertility and increases incidence of birth defects. Rates of aneuploidy in human eggs from even young women are significantly higher than those in other mammals. However, intrinsic genetic factors underlying this high incidence of aneuploidy in human eggs remain largely unknown. Here, we found that ectopic expression of human TUBB8 in mouse oocytes increases rates of aneuploidy by causing kinetochore–microtubule (K–MT) attachment defects. Stretched bivalents in mouse oocytes expressing TUBB8 are under less tension, resulting in continuous phosphorylation status of HEC1 by AURKB/C at late metaphase I that impairs the established correct K–MT attachments. This reduced tension in stretched bivalents likely correlates with decreased recruitment of KIF11 on meiotic spindles. We also found that ectopic expression of TUBB8 without its C-terminal tail decreases aneuploidy rates by reducing erroneous K–MT attachments. Importantly, variants in the C-terminal tail of TUBB8 were identified in patients with recurrent miscarriages. Ectopic expression of an identified TUBB8 variant in mouse oocytes also compromises K–MT attachments and increases aneuploidy rates. In conclusion, our study provides novel understanding for physiological mechanisms of aneuploidy in human eggs as well as for pathophysiological mechanisms involved in recurrent miscarriages.

Abstract China is the world’s second-largest maize producer, contributing 23% to global production and playing a crucial role in stabilizing the global maize supply. Therefore, accurately mapping the maize distribution in China is of great significance for regional and global food security and international cereals trade. However, it still lacks a long-term maize distribution dataset with fine spatial resolution, because the existing high spatial resolution satellite datasets suffer from data gaps caused by cloud cover, especially in humid and cloudy regions. This study aimed to produce a long-term, high-resolution maize distribution map for China (China Crop Dataset–Maize, CCD-Maize) identifying maize in 22 provinces and municipalities from 2001 to 2020. The map was produced using a high spatiotemporal resolution fused dataset and a phenology-based method called Time-Weighted Dynamic Time Warping. A validation based on 54,281 field survey samples with a 30-m resolution showed that the average user’s accuracy and producer’s accuracy of CCD-Maize were 77.32% and 80.98%, respectively, and the overall accuracy was 80.06% over all 22 provinces.

Objective: The adenosine triphosphate-sensitive potassium channel opener diazoxide mimics ischemic preconditioning and is cardioprotective. Clarification of diazoxide's site and mechanism of action could lead to targeted pharmacologic therapies for patients undergoing cardiac surgery. Several mitochondrial candidate proteins have been investigated as potential adenosine triphosphate-sensitive potassium channel components. Renal outer medullary potassium (Kir1.1) and sulfonylurea sensitive regulatory subunit 1 have been suggested as subunits of a mitochondrial adenosine triphosphate-sensitive potassium channel. We hypothesized that pharmacologic blockade or genetic deletion (knockout) of renal outer medullary potassium and sensitive regulatory subunit 1 would result in loss of diazoxide cardioprotection in models of global ischemia with cardioplegia. Methods: Myocyte volume and contractility were compared after Tyrode's physiologic solution (20 minutes), stress (hyperkalemic cardioplegia ± diazoxide, ± VU591 (Kir1.1 inhibitor), N = 9 to 23 each, 20 min), and Tyrode's (20 minutes). Isolated mouse (wild-type, sensitive regulatory subunit 1 [−/−], and cardiac knockout renal outer medullary potassium) hearts were given cardioplegia ± diazoxide (N = 9-16 each) before global ischemia (90 minutes) and 30 minutes reperfusion. Left ventricular pressures were compared before and after ischemia. Results: Stress (cardioplegia) was associated with reduced myocyte contractility that was prevented by diazoxide. Isolated myocytes were not responsive to diazoxide in the presence of VU591. In isolated hearts, diazoxide improved left ventricular function after prolonged ischemia compared with cardioplegia alone in wild-type and knockout (sensitive regulatory subunit 1 [−/−] and cardiac knockout renal outer medullary potassium) mice. Conclusions: Isolated myocyte and heart models may measure independent and separate actions of diazoxide. By definitive genetic deletion, these data indicate that sensitive regulatory subunit 1 and renal outer medullary potassium are not implicated in cardioprotection by diazoxide.

This work provides a facile route to synthesize the homogeneous hierarchical nanosheets of nickel phyllosilicate (HN-NiPS), which are imparted into epoxy resin (EP) to yield the composites. Various measurements are adopted to examine the structure and compositions of HN-NiPS and the structure-property relationships of EP composites. Results show that HN-NiPS is composed of multi-scaled nanosheets, of which the tiny nanopetals of nickel phyllosilicate grow in situ perpendicularly to a relatively large metal-organic-framework-derived plane. Adequate HN-NiPS disperses well in the EP matrix, not only moderately elevating the tensile strength and elastic modulus, but also improving the tribological properties significantly under starved lubrication. The lowest wear rate of 1.94 × 10−5 mm3/Nm is achieved with 3% HN-NiPS and ca. 72.1% lower than pure EP. The introduced HN-NiPS suppresses the weight loss rate and changes the reaction order insignificantly based on Carrasco whereas activation energies decline gradually with increased filler content. This study contributes robust, thermal stable and wear-resistant polymeric composites strengthened involving the homogeneous hierarchical nanosheets.

At present, the back-propagation (BP) network algorithm widely used in the short-term output prediction of photovoltaic power stations has the disadvantage of ignoring meteorological factors and weather conditions in the input. The existing traditional BP prediction model lacks a variety of numerical optimization algorithms, such that the prediction error is large. The back-propagation (BP) neural network is easy to fall into local optimization thus reducing the prediction accuracy in photovoltaic power prediction. In order to solve this problem, an improved grey wolf optimization (GWO) algorithm is proposed to optimize the photovoltaic power prediction model of the BP neural network. So, an improved grey wolf optimization algorithm optimized BP neural network for a photovoltaic (PV) power prediction model is proposed. Dynamic weight strategy, tent mapping and particle swarm optimization (PSO) are introduced in the standard grey wolf optimization (GWO) to construct the PSO–GWO model. The relative error of the PSO–GWO–BP model predicted data is less than that of the BP model predicted data. The average relative error of PSO–GWO–BP and GWO–BP models is smaller, the average relative error of PSO–GWO–BP model is the smallest, and the prediction stability of the PSO–GWO–BP model is the best. The model stability and prediction accuracy of PSO–GWO–BP are better than those of GWO–BP and BP.

Stress‐related illnesses are linked to the onset and progression of renal diseases and depressive disorders. To investigate stress‐induced changes in the renal transcriptome associated with the development of depressive behaviors, we generated here a chronic social defeat stress (CSDS) model of C57 BL/6 male mice and then performed RNA sequencing of the kidneys to obtain an inflammation‐related transcriptome. Administration of the antidepressant drug fluoxetine (10 mg·kg−1·day−1) during CSDS induction could partially alleviate renal inflammation and reverse CSDS‐induced depression‐like behaviors. Moreover, fluoxetine also modulated gene expression of stress‐related hormone receptors, including prolactin and melanin‐concentrating hormone. These results suggest that CSDS can induce gene expression changes associated with inflammation in the kidney of C57 BL/6 male mice, and this inflammation can be treated effectively by fluoxetine.

The main type of saponins occurring in the root of Platycodon grandiflorus (Jacq.) A. DC. are oleanolic acid glycosides. The CYP716 gene family plays a major role in catalyzing the conversion of β-amyrin into oleanolic acid. However, studies on the CYP716 genes in P. grandiflorus are limited, and its evolutionary history remains poorly understood. In this study, 22 PgCYP716 genes were identified, distributed among seven subfamilies. Cis-acting elements of the PgCYP716 promoters were mainly involved in plant hormone regulation and responses to abiotic stresses. PgCYP716A264, PgCYP716A391, PgCYP716A291, and PgCYP716BWv3 genes were upregulated in the root and during saponin accumulation, as shown by RNA-seq analysis, suggesting that these four genes play an important role in saponin synthesis. The results of subcellular localization indicated that these four genes encoded membrane proteins. Furthermore, the catalytic activity of these four genes was proved in the yeast, which catalyzed the conversion of β-amyrin into oleanolic acid. We found that the content of β-amyrin, platycodin D, platycoside E, platycodin D3, and total saponins increased significantly when either of the four genes was over expressed in the transgenic hair root. In addition, the expression of PgSS, PgGPPS2, PgHMGS, and PgSE was also upregulated while these four genes were overexpressed. These data support that these four PgCYP716 enzymes oxidize β-amyrin to produce oleanolic acid, ultimately promoting saponin accumulation by activating the expression of upstream pathway genes. Our results enhanced the understanding of the functional variation among the PgCYP716 gene family involved in triterpenoid biosynthesis and provided a theoretical foundation for improving saponin content and enriching the saponin biosynthetic pathway in P. grandiflorus.

This study used a static bidirectional multifunctional loading system. The system conducted bidirectional compression tests on scaled specimens of slurry masonry schist under freeze–thaw cycling conditions. This study aimed to investigate the influence of bidirectional stress coupling with freeze–thaw cycles on the mechanical properties of slurry masonry schist. The results indicate that lateral pressure can increase the peak stress of slurry masonry schist, while freeze–thaw cycles have an adverse effect on the material’s internal pore structure, counteracting the gain effect of lateral pressure. This study also employed acoustic emission (AE) technology to analyze the evolution of slurry masonry schist failure characteristics. The findings reveal that freeze–thaw cycles accelerate the failure of slurry masonry schist during loading, and lateral pressure to some extent mitigates the damage development of slurry masonry schist. The synergistic effect of lateral pressure and freeze–thaw cycles alters the fracture mode of slurry masonry schist. Acoustic emission signal localization demonstrates numerous AE localization points in the interface transition zone, forming a coherent signal band where cracks propagate toward complete interface penetration. The crack extension process of the slurry masonry schist was investigated using the digital image correlation (DIC) method. The results indicated that macroscopic cracks formed in the strain localization zone, resulting in fracture damage to the specimens, with interfacial debonding identified as the primary failure mode for slurry masonry schist structures.

Capillary barriers are widely used as a cover system to enhance the upper-soil-layer water storage capacity and reduce water infiltrate into the lower soil layer. In this paper, the effects of the median soil–particle size ratio on the water storage capacity of capillary barriers were studied using a series of indoor one-dimensional soil column infiltration tests. The results show that the water storage capacity rises with an increase in the median soil–particle size ratio until it exceeds 10. The variation in the total water storage capacity is related to not only the median soil–particle size ratio but also the particle size of coarse-grained soil or fine-grained soil. When the fine-grained soil-layer particle size is constant, the total water storage first increases, then decreases, and finally remains constant after increasing the median soil–particle size ratio. In contrast, when the coarse-grained soil layer particle size is constant, the relationship between the capillary barrier’s total water storage and median soil–particle size ratio can be defined as a power function. Using the capillary barrier can increase coarse-grained sand by 90% in water storage capacity and can only increase fine-grained sand by 7% in water storage capacity. The breakthrough time increases with the increase in the median soil–particle size ratio. The presence of the coarse and fine-grained soil layer interface in the capillary barrier can affect the fine-grained soil layer infiltration rate.

Sandy soil in the north of Hebei region of China is widely distributed, the temperature difference between day and night is large, the phenomenon of freezing and thawing is obvious, and the soil body before and after the freezing and thawing cycle of sandy soil slopes is affected by the changes. This paper takes the stability of a sandy soil anchorage interface under a freeze-thaw cycle as the research background and, based on the self-developed anchor-soil interface shear device, analyses the influence of changing sand rate, confining pressure, and the number of freeze-thaw cycles on the shear characteristics of an anchor-soil interface in anchorage specimens. The research findings indicate that, at 50–60% sand contents, the shear strength increases with a higher sand content and is positively correlated with confining pressure within a higher range. A higher sand content stabilises the anchoring body, but an excessively high sand content can lead to failure. Increasing the sand content, confining pressure, and freeze-thaw cycle number all result in a reduction in the shear displacement at the peak strength. After 11 freeze-thaw cycles, the shear strength of the anchoring body stabilises, with a reduction in strength of approximately 32%, and a higher sand content effectively reduces the reduction in strength.

Gestational diabetes mellitus (GDM) is a gestational disorder characterized by hyperglycemia, that can lead to dysfunction of diverse cells in the body, especially the immune cells. It has been reported that immune cells, specifically natural killer (NK) cells, play a crucial role in normal pregnancy. However, it remains unknown how hyperglycemia affects NK cell dysfunction thus participates in the development of GDM. In this experiment, GDM mice were induced by an intraperitoneal injection of streptozotocin (STZ) after pregnancy and it has been found that the intrauterine growth restriction occurred in mice with STZ-induced GDM, accompanied by the changed proportion and function of NK cells. The percentage of cytotoxic CD27-CD11b+ NK cells was significantly increased, while the proportion of nourished CD27-CD11b- NK cells was significantly reduced in the decidua of GDM mice. Likewise, the same trend appeared in the peripheral blood NK cell subsets of GDM patients. What’s more, after intrauterine reinfusion of NK cells to GDM mice, the fetal growth restriction was alleviated and the proportion of NK cells was restored. Our findings provide a theoretical and experimental basis for further exploring the pathogenesis of GDM.

Background. Robot-assisted nephroureterectomy (RANU) has been more and more applied since 21st century. However, the high cost limits the widespread use of robot system. A relatively low-cost new robotic surgical system (KD-SR-01™) has recently been developed in China. Objective. To assess the safety and efficacy of the KD-SR-01™ Surgical System in RANU. Methods. Patients with upper-tract urothelial tumor and undergoing RANU with the KD-SR-01™ Robotic System were prospectively included. Surgeries were all performed by a single surgeon. Patients’ demographic and clinical characteristics, perioperative data, pathology findings, and follow-up data were collected. Key Findings. 9 patients were enrolled in this study, and the surgeries went smoothly with no conversion to open. The 1st docking time, the 2nd docking time, and the operation time were 222 s, 169 s, and 202 min respectively. No equipment-related adverse events occurred. All patients were followed up for at least 3 months, and one patient experienced bladder recurrences. Conclusions and Clinical Implications. This study is the first to verify that the KD-SR-01™ robot system is effective and safe in RANU and has advantages in terms of its rotation boom during redocking and its price. This trial is registered with ChiCTR2200056672.

Summary: Functions of the SKP1-CUL1-F box (SCF) ubiquitin E3 ligases are essential in plants. The F box proteins (FBPs) are substrate receptors that recruit substrates and assemble an active SCF complex, but the regulatory mechanism underlying the FBPs binding to CUL1 to activate the SCF cycle is not fully understood. We show that Arabidopsis csn1-10 is defective in SCFEBF1-mediated PIF3 degradation during de-etiolation, due to impaired association of EBF1 with CUL1 in csn1-10. EBF1 preferentially associates with un-neddylated CUL1 that is deficient in csn1-10 and the EBF1-CUL1 binding is rescued by the neddylation inhibitor MLN4924. Furthermore, we identify a subset of FBPs with impaired binding to CUL1 in csn1-10, indicating their assembly to form SCF complexes may depend on COP9 signalosome (CSN)-mediated deneddylation of CUL1. This study reports that a key role of CSN-mediated CULLIN deneddylation is to gate the binding of the FBP-substrate module to CUL1, thus initiating the SCF cycle of substrate ubiquitination.

Background. Blood safety levels have been significantly improved since the implementation of nucleic acid amplification technology (NAT) testing for blood donors. However, there remains a residual risk of transfusion transmission infections. This study aimed to evaluate the prevalence of HIV and its residual risk transmission among volunteer blood donors of Zhejiang Province, China, for five years after NAT implementation. Materials and Methods. All specimens and information were collected from voluntary unpaid donors at all blood services in Zhejiang Province, China, from January 2018 to December 2022. The HIV antibody or antigen and HIV RNA were detected using enzyme-linked immunosorbent assay and NAT, respectively. The HIV residual risk transmission was calculated using the incidence or window period model. Results. A total of 3,375,678 voluntary blood donors were detected, revealing an HIV prevalence of 9.92/100000. The HIV prevalence of blood donors in 12 blood services in Zhejiang Province was 6.11, 6.98, 7.45, 8.21, 8.36, 8.94, 9.04, 9.66, 9.73, 10.22, 11.80, and 12.47 per 100000 donors, without statistically significant difference observed among the services (p>0.05). The HIV prevalence of males (15.49/100000) was significantly higher compared to females (1.95/100000; p0.05), but the HIV prevalence in the 26–35 age group and 18–25 age group was significantly higher compared to the 36–45 age group (p

BackgroundThe COVID-19 pandemic has resulted in a greater workload in the health care system. Therefore, health care professionals (HCPs) continue to experience high levels of stress, resulting in mental health disorders. From a preventive perspective, building resilience has been associated with reduced stress and mental health disorders and promotes HCPs’ intent to stay. Despite the benefits of resilience training, few studies provided an in-depth understanding of the contextual factors, implementation, and mechanisms of impact that influences the sustainability of resilience programs. Therefore, examining target users’ experiences of the resilience program is important. This will provide meaningful information to refine and improve future resilience programs. ObjectiveThis qualitative study aims to explore HCPs’ experiences of participating in the web-based Building Resilience At Work (BRAW) program. In particular, this study aims to explore the contextual and implementational factors that would influence participants’ interaction and outcome from the program. MethodsA descriptive qualitative approach using individual semistructured Zoom interviews was conducted with participants of the web-based resilience program. A framework analysis was conducted, and it is guided by the process evaluation framework. ResultsA total of 33 HCPs participated in this qualitative study. Three themes depicting participants’ experiences, interactions, and impacts from the BRAW program were elucidated from the framework analysis: learning from web-based tools, interacting with the BRAW program, and promoting participants’ workforce readiness. ConclusionsFindings show that a web-based asynchronous and self-paced resilience program is an acceptable and feasible approach for HCPs. The program also led to encouraging findings on participants’ resilience, intent to stay, and employability. However, continued refinements in the components of the web-based resilience program should be carried out to ensure the sustainability of this intervention. Trial RegistrationClinicalTrials.gov NCT05130879; https://clinicaltrials.gov/ct2/show/NCT05130879

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6’s N- and C-termini binding to Slack’s C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of ‘Slack as an isolated target’ for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.

Introduction: Drug-induced QT prolongation and (or) Torsade de Pointes (TdP) is a well-known serious adverse reaction (ADR) for some drugs, but the widely recognized comprehensive landscape of culprit-drug of QT prolongation and TdP is currently lacking.Aim: To identify the top drugs reported in association with QT prolongation and TdP and provide information for clinical practice.Method: We reviewed the reports related to QT prolongation and TdP in the FDA Adverse Event Reporting System (FAERS) database from January 1, 2004 to December 31, 2022, and summarized a potential causative drug list accordingly. Based on this drug list, the most frequently reported causative drugs and drug classes of QT prolongation and TdP were counted, and the disproportionality analysis for all the drugs was conducted to in detect ADR signal. Furthermore, according to the positive–negative distribution of ADR signal, we integrated the risk characteristic of QT prolongation and TdP in different drugs and drug class.Results: A total of 42,713 reports in FAERS database were considered to be associated with QT prolongation and TdP from 2004 to 2022, in which 1,088 drugs were reported as potential culprit-drugs, and the largest number of drugs belonged to antineoplastics. On the whole, furosemide was the most frequently reported drugs followed by acetylsalicylic acid, quetiapine, citalopram, metoprolol. In terms of drug classes, psycholeptics was the most frequently reported drug classes followed by psychoanaleptics, analgesics, beta blocking agents, drugs for acid related disorders. In disproportionality analysis, 612 drugs showed at least one positive ADR signals, while citalopram, ondansetron, escitalopram, loperamide, and promethazine were the drug with the maximum number of positive ADR signals. However, the positive-negative distribution of ADR signals between different drug classes showed great differences, representing the overall risk difference of different drug classes.Conclusion: Our study provided a real-world overview of QT prolongation and TdP to drugs, and the presentation of the potential culprit-drug list, the proportion of reports, the detection results of ADR signals, and the distribution characteristics of ADR signals may help understand the safety profile of drugs and optimize clinical practice.

Haploid males of hymenopteran species produce gametes through an abortive meiosis I followed by meiosis II that can either be symmetric or asymmetric in different species. Thus, one spermatocyte could give rise to two spermatids with either equal or unequal amounts of cytoplasm. It is currently unknown what molecular features accompany these postmeiotic sperm cells especially in species with asymmetric meiosis II such as bees. Here we present testis single-cell RNA sequencing datasets from the honeybee (Apis mellifera) drones of 3 and 14 days after emergence (3d and 14d). We show that, while 3d testes exhibit active, ongoing spermatogenesis, 14d testes only have late-stage spermatids. We identify a postmeiotic bifurcation in the transcriptional roadmap during spermatogenesis, with cells progressing toward the annotated spermatids (SPT) and small spermatids (sSPT), respectively. Despite an overall similarity in their transcriptomic profiles, sSPTs express the fewest genes and the least RNA content among all the sperm cell types. Intriguingly, sSPTs exhibit a relatively high expression level for Hymenoptera-restricted genes and a high mutation load, suggesting that the special meiosis II during spermatogenesis in the honeybee is accompanied by phylogenetically young gene activities.