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The cytosolic viral nucleic acid-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor interferon (IFN)-regulatory factor 3 (IRF3) to induce type I IFN production and antiviral immune responses. However, the mechanism that triggers the binding of TBK1 and IRF3 after virus infection remains not fully understood. Here, we identified that thousand and one kinase 1 (TAOK1), a Ste20-like kinase, positively regulated virus-induced antiviral immune responses by controlling the TBK1-IRF3 signaling axis. Virus invasion downregulated the expression of TAOK1. TAOK1 deficiency resulted in decreased nucleic acid-mediated type I IFN production and increased susceptibility to virus infection. TAOK1 was constitutively associated with TBK1 independently of the mitochondrial antiviral signaling protein MAVS. TAOK1 promoted IRF3 activation by enhancing TBK1-IRF3 complex formation. TAOK1 enhanced virus-induced type I IFN production in a kinase activity-dependent manner. Viral infection induced TAOK1 to bind with dynein instead of microtubule-associated protein 4 (MAP4), leading to the trafficking of TBK1 to the perinuclear region to bind IRF3. Thus, the depolymerization of microtubule impaired virus-mediated IRF3 activation. Our results revealed that TAOK1 functioned as a new interaction partner and regulated antiviral signaling via trafficking TBK1 along microtubules to bind IRF3. These findings provided novel insights into the function of TAOK1 in the antiviral innate immune response and its related clinical significance.

Objective The adjusted mechanical alignment (aMA) technique is an extension of conventional mechanical alignment (MA), which has rarely been reported. The purpose of this study was to evaluate mid‐term outcomes of navigation‐assisted total knee arthroplasty (TKA) using aMA. Methods This retrospective cohort study enrolled 63 consecutive patients (77 knees) who underwent navigation‐assisted TKA using aMA between September 2017 and October 2019. Fifty‐two consecutive patients (61 knees) who underwent TKA using MA during the same period were assessed as the controlled group. The demographic data and perioperative data were recorded. The parameters of resection and soft tissue balance including tibia resection angle, frontal femoral angle, axial femoral angle, joint line translation, medial and lateral gap in extension and flexion position were recorded. Radiographic parameters and functional scores including the Hospital for Special Surgery (HSS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Forgotten Joint Score‐12 (FJS‐12) were evaluated. Surgery‐related complications were recorded. The average follow‐up was 3.5 years, with a minimum of 2.4 years. Results The frontal femoral angle was 2.55° ± 1.08° in aMA group versus 0.26° ± 0.60° in MA group (p

In the past few years, many convolutional neural networks (CNNs) have been applied to hyperspectral image (HSI) classification. However, many of them have the following drawbacks: they do not fully consider the abundant band spectral information and insufficiently extract the spatial information of HSI; all bands and neighboring pixels are treated equally, so CNNs may learn features from redundant or useless bands/pixels; and a significant amount of hidden semantic information is lost when a single-scale convolution kernel is used in CNNs. To alleviate these problems, we propose a spatial–spectral split attention residual networks (S$^{3}$ARN) for HSI classification. In S$^{3}$ARN, a split attention strategy is used to fuse the features extracted from multireceptive fields, in which both spectral and spatial split attention modules are composed of bottleneck residual blocks. Thanks to the bottleneck structure, the proposed method can effectively prevent overfitting, speeds up the model training, and reduces the network parameters. Moreover, the spectral and spatial attention residual branches aim to generate the attention masks, which can simultaneously emphasize useful bands and neighbor pixels and suppress useless ones. Experimental results on three benchmark datasets demonstrate the effectiveness of the proposed model for HSI classification.

In order to improve the catalytic property of the plate-type De-NOx catalysts, TiO2-montmorillonite and TiO2-acid treated montmorillonite were used as the composite carriers for the preparation of the catalyst. XRF, XRD, N2-adsorption, Raman, H2-TPR and NH3-TPD analysis were carried out to investigate the physical and chemical properties of the catalysts. The result shows that the BET surface area and the attrition strength of the catalysts with the using of composite carriers are higher than that of the traditional V2O5-MoO3/TiO2 catalyst. Alkali metal element (Na, K) contained in the montmorillonite has negative effect on the reducibility and acidity of V2O5-MoO3/TiO2-montmorillonite catalyst, which is unfavorable for the catalytic performance. The acid treatment improves the BET surface area of the montmorillonite, and decreases the alkali metal element content simultaneously. As a result, the catalytic activity of V2O5-MoO3/TiO2-acid treated montmorillonite catalyst is relatively high. Addtionally，this catalyst also exhibits well SO2 and H2O resistance.

Abstract Introduction Although aerobic physical exercise may improve osteoporosis during ageing, the underlying mechanism of the favorable effects remains unclear. The aim of this study was to examine the localized and generalized proinflammatory indicators and the adaptive skeletal responses to treadmill training in aged rats to explore the potential mechanisms by which treadmill training impacts bone deterioration in a natural aged rat model. Materials and methods A total of 24 Sprague Dawley (SD) rats were included in this study. Sixteen of all these animals were twenty-four months natural aged male SD rats, which were distributed into two groups (n = 8/group): AC group with sham treadmill training, and AT group with 8 weeks treadmill training. The remaining 8 were six months male SD rats matched subline and supplier, which were used as the adult control group with sham treadmill training (YC group, n = 8). The serum, bone marrow, fresh femur, tibia, and lumbar spine were harvested for molecular biological analysis, bone mineral density (BMD) testing, and micro-CT analysis after 8 weeks of treadmill training. Results After 8 weeks of intervention, the results showed that treadmill training increased BMD and inhibited deterioration of bone microarchitecture of hind limb bones. Further analysis showed that treadmill training increased serum P1CP concentration and decreased serum CTX-1level. Interestingly, treadmill training down-regulated the protein expressions of proinflammatory indicators, including NLRP3, proCaspase1, cleaved Caspase1, IL-1β, and GSDMD-N, and the mRNA levels of NLRP3, Caspase1, and IL-1β of the bone marrow. In addition, treadmill training also inhibited serum TNF-α and IL-1β concentration. However, 8 weeks of treadmill training did not increase BMD and bone microarchitecture in the lumbar spine. Conclusion Treadmill training mitigates the ageing-induced bone loss and reverses the deterioration of bone microarchitecture in hind limbs probably through inhibiting NLRP3/Caspase1/IL-1β signaling to attenuate low-grade inflammation and improve the inflammatory bone microenvironment.

Abstract Background Acute kidney injury (AKI) is a common and severe complication of cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to establish a model to predict the probability of postoperative AKI in patients undergoing cardiac surgery with CPB. Methods We conducted a retrospective, multicenter study to analyze 1082 patients undergoing cardiac surgery under CPB. The least absolute shrinkage and selection operator regression model was used to optimize feature selection for the AKI model. Multivariable logistic regression analysis was applied to build a prediction model incorporating the feature selected in the previously mentioned model. Finally, we used multiple methods to evaluate the accuracy and clinical applicability of the model. Results Age, gender, hypertension, CPB duration, intraoperative 5% bicarbonate solution and red blood cell transfusion, urine volume were identified as important factors. Then, these risk factors were created into nomogram to predict the incidence of AKI after cardiac surgery under CPB. Conclusion We developed a nomogram to predict the incidence of AKI after cardiac surgery. This model can be used as a reference tool for evaluating early medical intervention to prevent postoperative AKI.

Abstract Background It is well-established that biochemical recurrence is detrimental to prostate cancer (PCa). In the present study, we explored the mechanisms underlying PCa progression. Methods Five cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were used to perform gene set variation analysis (GSVA) between nonrecurrent and recurrent PCa patients. We obtained the intersection of pathway enrichment results and extracted the corresponding gene list. LASSO Cox regression analysis was used to identify recurrence-free survival (RFS)-related significant genes and establish an RFS prediction gene signature and nomogram. MTT and colony formation assays were conducted to validate our findings. Results The E2F signaling pathway was activated in recurrent PCa patients compared to nonrecurrent patients. We established an E2F-related gene signature for RFS prediction based on the four identified E2F-related genes (CDKN2C, CDKN3, RACGAP1, and RRM2) using LASSO Cox regression in the Memorial Sloan Kettering Cancer Center (MSKCC) cohort. The risk score of each patient in MSKCC was calculated based on the expression levels of CDKN2C, CDKN3, RACGAP1, and RRM2. PCa patients with low-risk scores exhibited higher RFS than those with high-risk scores. Receiver operating characteristic (ROC) curve analysis validated the good performance and prognostic accuracy of the E2F-related gene signature, which was validated in the TCGA-prostate adenocarcinoma (TCGA-PRAD) cohort. Compared to patients with low Gleason scores and early T stages, PCa patients with high Gleason scores and advanced T stages had high-risk scores. Moreover, the E2F-related gene signature-based nomogram yielded good performance in RFS prediction. Functional experiments further confirmed these results. Conclusions The E2F signaling pathway is associated with biochemical recurrence in PCa. Our established E2F-related gene signature and nomogram yielded good accuracy in predicting the biochemical recurrence in PCa.

Pancreatic cancer is one of the leading causes of cancer-related mortality in both developed and developing countries. The incidence of pancreatic cancer in China accounts for about a quater of the global incidence, and the epidemiological characteristics and therapeutic strategies differ due to social, economic, cultural, environmental, and public health factors. Non-domestic guidelines do not reflect the clinicopathologic characteristics and treatment patterns of Chinese patients. Thus, in 2018, the Chinese Society of Clinical Oncology (CSCO) organized a panel of senior experts from all sub-specialties within the field of pancreatic oncology to compile the Chinese guidelines for the diagnosis and treatment of pancreatic cancer. The guidelines were made based on both the Western and Eastern clinical evidence and updated every one or two years. The experts made consensus judgments and classified evidence-based recommendations into various grades according to the regional differences, the accessibility of diagnostic and treatment resources, and health economic indexes in China. Here we present the latest version of the guidelines, which covers the diagnosis, treatment, and follow-up of pancreatic cancer. The guidelines might standardize the diagnosis and treatment of pancreatic cancer in China and will encourage oncologists to design and conduct more clinical trials about pancreatic cancer.

Abstract A growing body of evidence has indicated an expanding functional network of B‐cell lymphoma 2 (BCL‐2) family proteins beyond regulation of cell death and survival. Here, we examined the role and mechanisms of BH3 interacting‐domain death agonist (BID), a pro‐death BCL‐2 family member, in the development of diet‐induced metabolic dysfunction. Mice deficient in bid (bid−/−) were resistant to high‐fat diet (HFD)–induced obesity, hepatic steatosis, and dyslipidemia with an increased insulin sensitivity. Indirect calorimetry analysis indicated that bid deficiency increased metabolic rate and decreased respiratory exchange ratio, suggesting a larger contribution of lipids to overall energy expenditure. While expression of several genes related to lipid accumulation was only increased in wild‐type livers, metabolomics analysis revealed a consistent reduction in fatty acids but an increase in certain sugars and Krebs cycle intermediates in bid−/− livers. Gut microbiota (GM) analysis indicated that HFD induced gut dysbiosis with differential patterns in wild‐type and in bid−/− mice. Notably, abrogation of GM by antibiotics during HFD feeding eliminated the beneficial effects against obesity and hepatic steatosis conferred by the bid deficiency. Conclusion: These results indicate that the protective role of bid‐deficiency against diet‐induced metabolic dysfunction interacts with the function of GM.

Whether protein samples should be pretreated to remove nonspecific binding proteins in co-immunoprecipitation (CO-IP) is controversial. In this work, nonspecific binding of proteins to agarose beads was found to be greater than that to magnetic beads. The nonspecific binding was increased with the decrease of ion concentrations but reduced by Nonidet P40. Western blot indicated that p65 and β-actin were present as nonspecifically bound protein to the beads. p53 and β-actin were present in the CO-IP precipitates of nuclear proteins but pretreatment cleared the nonspecifically pulled down p53 and β-actin. These data suggest that magnetic beads are better for CO-IP, but preclearing is necessary to minimize false positive regardless of which bead is used, particularly for nuclear proteins.

Antibacterial protein hydrogels are receiving increasing attention in the aspect of bacteria-infected-wound healing. However, bacterial drug resistance and biofilm infections lead to hard healing of wounds, thus the construction of biological agents that can overcome these issues is essential. Here, a simple and universal method to construct antibiotic-free protein hydrogel with excellent biocompatibility and superior antibacterial activity against drug-resistant bacteria and biofilms was developed. The green industrial microbicide tetrakis (hydroxymethyl) phosphonium sulfate (THPS) as cross-linking agent can be quickly cross-linked with model protein bovine serum albumin (BSA) to form antibacterial hydrogel through simple mixing without any other initiators, subsequently promoting drug-resistance bacteria-infected wound healing. This simple gelatinization strategy allows at least ten different proteins to form hydrogels (e.g. BSA, human serum albumin (HSA), egg albumin, chymotrypsin, trypsin, lysozyme, transferrin, myohemoglobin, hemoglobin, and phycocyanin) under the same conditions, showing prominent universality. Furthermore, drug-resistance bacteria and biofilm could be efficiently destroyed by the representative BSA hydrogel (B-Hydrogel) with antibacterial activity, overcoming biofilm-induced bacterial resistance. The in vivo study demonstrated that the B-Hydrogel as wound dressing can promote reepithelization to accelerate the healing of methicillin-resistant staphylococcus aureus (MRSA)-infected skin wounds without inducing significant side-effect. This readily accessible antibiotic-free protein-based hydrogel not only opens an avenue to provide a facile, feasible and general gelation strategy, but also exhibits promising application in hospital and community MRSA disinfection and treatment.

Abstract Hydrogen isotope permeation through structural materials is a key issue for developing nuclear fusion energy, which will cause fuel loss and radioactive pollution. Developing ceramic coatings with high thermal shock and hydrogen resistance is an effective strategy to solve this issue. In this work, a layer-structured Cr/Cr x N coating was successfully fabricated by a facile electroplating-based nitridation technique, which is easy, facile, and applicable to coating complex-shaped substrates. The Cr/Cr x N coating, composed of a bottom Fe/Cr interdiffusion zone, a middle Cr layer, and a top Cr x N layer, exhibits high bonding strength, high anti-thermal-shock ability, and high deuterium permeation resistance. Its bonding strength achieves 43.6 MPa. The Cr/Cr x N coating remains intact even after suffering 300 thermal shock cycles under a 600 °C-water condition. Through optimizing the nitridation temperature, the Cr/Cr x N coating achieves a deuterium permeation reduction factor (PRF) as high as 3599 at 500 °C. Considering its scalable fabrication technique and considerable properties, the developed Cr/Cr x N coating may serve as a novel high-performance hydrogen permeation barrier in various fields.

Abstract Background Numerous studies have revealed aberrant DNA methylation in esophageal squamous cell carcinoma (ESCC). However, they often focused on the partial genome, which resulted in an inadequate understanding of the shaped methylation features and the lack of available methylation markers for this disease. Methods The current study investigated the methylation profiles between ESCC and paired normal samples using whole-genome bisulfite sequencing (WGBS) data and obtained a group of differentially methylated CpGs (DMC), differentially methylated regions (DMR), and differentially methylated genes (DMG). The DMGs were then verified in independent datasets and Sanger sequencing in our custom samples. Finally, we attempted to evaluate the performance of these genes as methylation markers for the classification of ESCC. Results We obtained 438,558 DMCs, 15,462 DMRs, and 1568 DMGs. The four significantly enriched gene families of DMGs were CD molecules, NKL subclass, HOXL subclass, and Zinc finger C2H2-type. The HOXL subclass homeobox genes were observed extensively hypermethylated in ESCC. The HOXL-score estimated by HOXC10 and HOXD1 methylation, whose methylation status were then confirmed by sanger sequencing in our custom ESCC samples, showed good ability in discriminating ESCC from normal samples. Conclusions We observed widespread hypomethylation events in ESCC, and the hypermethylated HOXL subclass homeobox genes presented promising applications for the early detection of esophageal squamous cell carcinoma.

Abstract Background Palbociclib was the only available cyclin‐dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient‐reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real‐world China. Methods An ambispective cohort study was conducted on patients with advanced HR+HER2− breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 items [EORTC QLQ‐C30] and EuroQoL 5 dimensions [EQ‐5D]) were analyzed. The Kaplan–Meier method was used to visualize and estimate the median progression‐free survival (mPFS). Log‐rank tests, Cox regressions, t tests, and chi‐square tests were performed for comparison. Results A total of 190 patients (median follow‐up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first‐ (n = 83), second‐ (n = 41) and subsequent‐line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p

Abstract Background The incidence of prostate cancer (PCa) increases with age, and age and tumor microenvironment (TME) have important roles in the development of PCa, while the underlying mechanisms have not been fully elucidated. Materials and method The Cancer Genome Atlas‐Prostate Adenocarcinoma (TCGA‐PRAD) RNA‐Seq, the Surveillance, Epidemiology, and End Results (SEER‐PRAD), and ESTIMATE data were downloaded, and the clinical information of PRAD patients in our cohort was collected. The associations among age, TME, and PCa were analyzed. The age‐ and TME‐related risk score (ATRS) of each TCGA‐PRAD sample was calculated based on the identified age‐ and TME‐related differentially expressed genes (DEGs), and the correlation of ATRS with immune‐related characteristics of PCa patients was analyzed, and the ATRS‐based overall survival (OS)‐predicting nomogram was also established. Results Age was correlated with OS, PSA level, tumor stage, T stage, N stage, Gleason score, nerve invasion of PCa, and age was positively correlated with stromal, immune, and ESTIMATE scores. The compositions of immune cells of TCGA‐PRAD patients altered with age. Nine age‐ and TME‐related prognostic DEGs were identified, and the ATRS of each TCGA‐PRAD patient was calculated based on the identified nine DEGs. The ATRS was associated with the expression of immune checkpoints and intratumoral cytolytic activity, and the ATRS‐based nomogram performed well in predicting the outcomes of PCa patients. Conclusions Age and TME had crucial roles in PCa, and the ATRS gene signature was associated with the immune‐related characteristics of PCa patients, which showed good performance in predicting OS of PCa patients.

Supply shortage often occurs during the peak period of gas consumption, which not only decreases the benefits of gas companies, but also reduces the satisfaction of customers. In order to speed up the coordinated development of gas production, supply, storage and marketing, research was performed based on the downstream gas supply shortage resulted from the upstream supplier accident in the gas supply chain, with the influence of different pipeline mechanism considered, to meet the constraints of node capacity, station balance, user demand, and the balance of supply and demand. Meanwhile, two optimization models were established for the purpose of maximizing the benefit and minimizing the shortage index of natural gas, and then CPLEX was used for optimization to obtain the solutions of the mixed integer linear programming model. The gas supply strategies under different pipeline mechanisms were obtained based on a natural gas supply chain, and the accuracy of the new optimization models was verified. The optimized gas purchase and sales decision has guiding significance, and is capable of providing pre-warning and emergency plan for the reasonable gas distribution and supply in the peak period.

Abstract Circular saw blades are widely used in stone processing. The circular saw blade cutting hard rock numerical simulation model based on ANSYS/LS-DYNA was established to investigate the complex dynamic problem in rock cutting. The failure mechanism of the rock and the influence of cutting parameters on the cutting force and rock fragments were studied by numerical simulation. The results demonstrated that the failure modes of the rock were mainly tensile failure with some shear failure and compressive failure. The cutting force and the number of fragments increased with the feed speed. With the increasing circular saw blade rotational speed, the cutting force and the number of fragments decreased and tended to stabilize. With the distance between the circular saw blades increasing, the cutting force and rock fragments number increase and then maintain basic stability, and when the distance between double circular saw blades reaches 25 mm, it will form a completed rock plate and the interaction of circular saw blades will decrease. The numerical simulation can accurately simulate rock breakage and force when a circular saw blade cuts rock.

Abstract Background Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. Methods This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). Results In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4–36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5–73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. Conclusions SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. Trial registration ClinicalTrials.gov , NCT03710265

Abstract Microsecond pulsed electric fields (PEF) have previously been used for various tumour therapies, such as gene therapy, electrochemotherapy and irreversible electroporation (IRE), due to its demonstrated ability. However, recently nanosecond pulsed electric fields (nsPEF) have also been used as a potential tumor therapy via inducing cell apoptosis or immunogenic cell death to prevent recurrence and metastasis by interacting with intracellular organelles. A large proportion of the existing in-vitro studies of nsPEF on cells also suggests cell necrosis and swelling/blebbing can be induced, but the replicability and potential for other effects on cells suggesting a complicated process which requires further investigation. Therefore, this study investigated the effects of pulse width and intensity of nsPEF on the murine melanoma cells (B16) and normal murine fibroblast cells (L929) through electromagnetic simulation and in-vitro experiments. Through examining the evolution patterns of potential difference and electric fields on the intracellular compartments, the simulation has shown a differential effect of nsPEF on normal and cancerous skin cells, which explains well the results observed in the reported experiments. In addition, the modelling has provided a clear evidence that a few hundreds of ns PEF may have caused a mixed mode of effects, i.e. a ‘cocktail effect’, including cell electroporation and IRE due to an over their threshold voltage induced on the plasma membrane, as well as cell apoptosis and other biological effects caused by its interaction with the intracellular compartments. The in-vitro experiments in the pulse range of the hundreds of nanoseconds showed a possible differential cytotoxicity threshold of electric field intensity between B16 cells and L929 cells.

Abstract The demand for emergency department (ED) services is increasing across the globe, particularly during the current COVID-19 pandemic. Clinical triage and risk assessment have become increasingly challenging due to the shortage of medical resources and the strain on hospital infrastructure caused by the pandemic. As a result of the widespread use of electronic health records (EHRs), we now have access to a vast amount of clinical data, which allows us to develop prediction models and decision support systems to address these challenges. To date, there is no widely accepted clinical prediction benchmark related to the ED based on large-scale public EHRs. An open-source benchmark data platform would streamline research workflows by eliminating cumbersome data preprocessing, and facilitate comparisons among different studies and methodologies. Based on the Medical Information Mart for Intensive Care IV Emergency Department (MIMIC-IV-ED) database, we created a benchmark dataset and proposed three clinical prediction benchmarks. This study provides future researchers with insights, suggestions, and protocols for managing data and developing predictive tools for emergency care.

Abstract Background To investigate the independent risk factors of poor short‐term outcomes in patients with lung cancer‐associated acute ischemic stroke (LCAIS) and use them to develop an index of prognosis LCAIS (pLCAIS) which could help clinicians identify patients at high risk for poor short‐term outcomes. Methods We retrospectively enrolled patients with lung cancer‐associated acute ischemic stroke and employed the 90D modified Rankin cale (mRS) to divide them into two groups: good outcomes (score 0–2) and poor outcomes (score 3–6). Propensity score matching (PSM) was used to remove confounding factors, and multivariable logistic regression analysis was used to analyze the independent risk factors of pLCAIS. The receiver operating characteristic (ROC) and area under the ROC curve (AUC) developed a multiple model combining the independent risk factors of pLCAIS. Results A total of 172 patients were included: 67 (38.9%) with good outcomes and 105 (61.1%) with poor outcomes. After using PSM, there were 33 cases in each group. The results showed that patients with poor short‐term outcomes were significantly higher in D‐dimer (OR = 1.001, 95% CI: 1.000–1.002, p = 0.048), CRP (OR = 1.078, 95% CI: 1.008–1.153, p = 0.028), and neutrophil count (OR = 14.673, 95% CI: 1.802–19.500, p = 0.012). The ROC curve, used to assess the diagnostic ability of binary classifiers, showed that the product of these three independent risk factors showed high sensitivity and specificity. Conclusion In this study, we have identified three independent risk factors associated with poor short‐term outcomes in pLCAIS: higher NC, CRP, and D‐dimer levels. These findings may be helpful for clinicians in identifying poor short‐term outcomes patients.

Due to the high risk of tearing and rupture, vulnerable atherosclerotic plaques would induce serious cardiovascular and cerebrovascular diseases. Despite the available clinical methods can evaluate the vulnerability of plaques and specifically treat vulnerable plaques before a cardiovascular event, but the efficiency is still low and undesirable. Herein, we rationally design and engineer the low-intensity focused ultrasound (LIFU)-responsive FPD@CD nanomedicine for the highly efficient treatment of vulnerable plaques by facilely loading phase transition agent perfluorohexane (PFH) into biocompatible PLGA-PEG-PLGA nanoparticles (PPP NPs) and then attaching dextran sulphate (DS) onto the surface of PPP NPs for targeting delivery. DS, as a typical macrophages-targeted molecule, can achieve the precise vaporization of NPs and subsequently controllable apoptosis of RAW 264.7 macrophages as induced by acoustic droplet vaporization (ADV) effect. In addition, the introduction of DiR and Fe3O4 endows nanomedicine with near-infrared fluorescence (NIRF) and magnetic resonance (MR) imaging capabilities. The engineered FPD@CD nanomedicine that uses macrophages as therapeutic targets achieve the conspicuous therapeutic effect of shrinking vulnerable plaques based on in vivo and in vitro evaluation outcomes. A reduction of 49.4% of vascular stenosis degree in gross pathology specimens were achieved throughout the treatment period. This specific, efficient and biosafe treatment modality potentiates the biomedical application in patients with cardiovascular and cerebrovascular diseases based on the relief of the plaque rupture concerns.

Abstract We report on a monolayer (ML) MoS2 belt-like single crystal directly fabricated on the Rutile-TiO2(001) surface via chemical vapor deposition (CVD). We find that the photoluminescence (PL) behaviors in the ML MoS2 single crystal strongly depend on their shapes and the interface of MoS2/TiO2. Compared with the as-grown triangular ML MoS2, the PL peak position is in a blue shift and the PL intensity is increased for the as-grown ML MoS2 belt. Moreover, the PL peak position is in the blue shift by about 38 meV and the intensity is enhanced by nearly 15 times for the as-grown ML MoS2 belt crystal on TiO2 than those samples transferred onto SiO2/Si substrate. This special PL behavior can be attributed to the in-plane compressive strain that is introduced during the CVD growth of ML MoS2 belts confined by the substrate. The energy band of the strained ML MoS2 belt is changed with an up-shift in the conduction band minimum (VBM) and a down-shift in the valence band maximum (CBM), and the band gap is thus enlarged. This results in the energy band structural realignment in the interface of MoS2/TiO2, thereby weakening the charge transferring from the TiO2 substrate to MoS2 and suppressing the concentration of charged excitons to finally enhance the PL intensity of the ML MoS2 belt. The substrate-confined ML MoS2 belts provide a new route for tailoring light-matter interactions to upgrade their weak quantum yields and low light absorption, which can be utilized in optoelectronic and nanophotonic devices.

Abstract Background The incidence of early‐onset prostate cancer (PCa) has increased significantly over the past few decades. It is necessary to develop a prognostic nomogram for the prediction of overall survival (OS) in early‐onset PCa patients. Methods A total of 23,730 early‐onset PCa patients (younger than 55 years old) between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were enrolled for the current study, and randomly separated into the training cohort and the validation cohort. 361 eligible early‐onset PCa patients from The Cancer Genome Atlas‐Prostate Adenocarcinoma (TCGA‐PRAD) cohort were obtained as the external validation cohort. Independent predictors were selected by univariate and multivariate Cox regression analysis, and a prognostic nomogram was constructed for 1‐, 3‐, and 5‐year OS. The accurate and discriminative abilities of the nomogram were evaluated by the concordance index (C‐index), receiver operating characteristic curve (ROC), calibration plot, net reclassification index (NRI), and integrated discrimination improvement (IDI). Results Multivariate Cox analysis showed that race, marital status, TNM stage, prostate‐specific antigen, Gleason score, and surgery were significantly associated with poor prognosis of PCa. A nomogram consisting of these variables was established, which had higher C‐indexes than the TNM system (training cohort: 0.831 vs. 0.746, validation cohort: 0.817 vs. 0.752). Better AUCs of the nomogram than the TNM system at 1, 3, and 5 years were found in both the training cohort and the validation cohort. The 3‐year and 5‐year AUCs of the nomogram in the TCGA‐PRAD cohort were 0.723 and 0.679, respectively. The calibration diagram, NRI, and IDI also showed promising prognostic value in OS. Conclusions We developed an effective prognostic nomogram for OS prediction in early‐onset PCa patients, which will further assist both the precise clinical treatment and the assessment of long‐term outcomes.

Abstract Background Whether atrial septal aneurysm (ASA) increases the risk of cerebrovascular ischemic events in patients with patent foramen ovale (PFO) remains controversial. Objective We constructed a detailed meta‐analysis to assess the effect of ASA on risk of cerebrovascular ischemic events in patients with PFO. Methods Randomized controlled trials (RCTs) and observational studies (cohort studies and case‐control studies) that compared PFO‐ASA against PFO alone were included. Pooled odds ratios (OR) estimates and 95% CI were calculated using the fixed‐effect and random‐effect models. Results Four RCTs and twelve observational studies (five cohort studies and seven case‐control studies) contributed to the meta‐analysis. The pooled results of case‐control studies showed that ASA increased the risk of cerebrovascular ischemic events in patients with PFO (fixed‐effect model: OR = 3.69; 95% CI: 2.67–5.09; p < 0.01, random‐effect model: OR = 3.63; 95% CI: 2.51–5.24; p < 0.01). However, poole results from RCTs (fixed‐effect model: OR = 1.24; 95% CI: 0.78–1.95; p = 0.36, random‐effect model: OR = 1.27; 95% CI: 0.78–2.08; p = 0.34) and cohort studies (fixed‐effect model: OR = 1.35; 95% CI: 0.81–2.23; p = 0.25, random‐effect model: OR = 1.40; 95% CI: 0.84–2.33; p = 0.20) found no evidence. Overall analysis showed that ASA increased the risk of cerebrovascular ischemic events (fixed‐effect model: OR = 2.30; 95% CI: 1.84–2.87; p < 0.01, random‐effect model: OR = 2.11; 95% CI: 1.48–3.01; p < 0.01). The sensitivity analysis confirmed the stability of all results. Conclusions Although case‐control studies support ASA to increase the risk of cerebrovascular ischemic events in patients with PFO, RCTs and cohort studies challenged the credibility. Further prospective studies are needed to confirm the effect of ASA on patients with PFO.

Montmorillonite modified lime-ceramic sand-lake sediment (LC-sediments) was synthesized and its algae removal efficiency was investigated in this study. Montmorillonite not only improved the morphology and surface area of original LC-sediments, but also promoted the algal removal rate due to its inherent properties such as accumulating an electric charge, acting as a flocculant, and displaying a local bridging effect. Based on parameter optimization including the ratio of raw materials, agent dosage, initial algae density, pH and a determination of overlying water, the effect of hydrodynamic conditions on the algal removal process was researched. Under the optimal condition, the removal rates of turbidity, algae density and chlorophyll a could reach 86, 88 and 68%, respectively. As verified with a response surface model, it was shown that low disturbance (stirring) of the algae could promote algal removal by montmorillonite modified LC-sediment. Furthermore, a water column was utilized to approximatively simulate the flocculation and algae control in shallow lakes. This study solved the problem of reducing the dosage of lake sediment and improving the removal efficiency of algae without causing secondary pollution to the environment. It was expected to provide a certain theoretical basis for clay flocculation-based algae control in a real environment. HIGHLIGHTS Hydrodynamic conditions on algal removal process were studied.; Montmorillonite improved algal control efficiency of modified lake sediment.; Water column was utilized to simulate the state of natural lakes.; The removal rates of turbidity and algae reached 86 and 88%, respectively.;

Abstract Background Endometriosis is one of the most common gynecological diseases, and seriously reduces the quality of life of patients. However, the pathogenesis of this disease is unclear. Therefore, more studies are needed to elucidate its pathogenesis. Our previous publication found that the Sonic Hedgehog (SHH) signaling pathway was activated in endometriosis. This study tested whether SHH signaling in endometrial stromal cells (ESCs) was critical for the pathogenesis of endometriosis. Methods To examine the effect of inhibiting the SHH signaling pathway on endometriosis, we first isolated ESCs from eutopic endometrial tissues of patients with or without endometriosis and identified the extracted cells by morphological observation and immunofluorescence. Then, we treated ESCs with the GLI inhibitor GANT61 and used CCK-8, wound healing and invasion assays to detect cell activities, such as proliferation, invasion and metastasis. Furthermore, we detected the expression of key proteins and proliferation markers of the SHH signaling pathway in the lesions of nude mice using immunochemistry. Results We demonstrated that higher concentrations of GANT61 decreased the proliferation rate and migration distance of ESCs. We observed that GANT61 inhibited the invasion of ESCs. In addition, blockage of the SHH signaling pathway significantly reduced cell proliferation in vitro. Conclusions Our study suggested that inhibition of the SHH pathway is involved in cell proliferation and invasive growth in the pathogenesis of endometriosis.

Abstract Deep learning (DL) has indeed emerged as a powerful tool for rapidly and accurately predicting materials properties from big data, such as the design of current commercial Li-ion batteries. However, its practical utility for multivalent metal-ion batteries (MIBs), the most promising future solution of large-scale energy storage, is limited due to scarce MIB data availability and poor DL model interpretability. Here, we develop an interpretable DL model as an effective and accurate method for learning electrode voltages of multivalent MIBs (divalent magnesium, calcium, zinc, and trivalent aluminum) at small dataset limits (150–500). Using the experimental results as validation, our model is much more accurate than machine-learning models, which usually are better than DL in the small dataset regime. Besides the high accuracy, our feature-engineering-free DL model is explainable, which automatically extracts the atom covalent radius as the most important feature for the voltage learning by visualizing vectors from the layers of the neural network. The presented model potentially accelerates the design and optimization of multivalent MIB materials with fewer data and less domain-knowledge restriction and is implemented into a publicly available online tool kit in http://batteries.2dmatpedia.org/ for the battery community.

Abstract Objective To describe a new alignment technique of adjusted restricted kinematic alignment (arKA) for the treatment of severe varus deformity in total knee arthroplasty. Methods Three female patients (three severe varus knees) who underwent navigation‐assisted total knee arthroplasty (TKA) using arKA from April 2020 to September 2020 were included in this study, with an average age of 71.33 years (range, 61 to 80 years). General anesthesia was given to all patients. Intraoperative observations including tibia resection angle, frontal femoral angle, axial femoral angle, medial and lateral gap in the extension and flexion positions and joint line translation were recorded. Also, operation duration and drainage volume were recorded. Radiographic parameters including the mechanical axis (α), coronal femoral component angle (β), coronal tibial component angle (γ), sagittal femoral component angle (δ), tibial posterior slope angle (ε), femoral‐patella angle (θ), and femoral notching were assessed. Clinical evaluation was performed using the Hospital for Special Surgery (HSS) Score and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Score. Both individual and mean measurement data were displayed. Results The mean tibial resection was 4.00° varus (range, 3° to 5°), and the mean frontal femoral angle was 3.67° varus (range, 3° to 4°) in extension. The flexion lateral gap was wider than the medial gap with a mean laxity of 1.34 mm. Moreover, the mean axial femoral angle was 2.67° external (range, 0° to 6°) in flexion, and the mean joint line translation was 1.00 mm proximal (range, 0 to 3 mm). In addition, the mean preoperative mechanical axis was 156.22° (range, 153.65° to 158.90°) and the mean postoperative mechanical axis was 174.04° (range, 173.83° to 174.17°) with a mean correction of 17.82°. The mean femoral angle was 92.60° (range, 91.29° to 93.30°) and the mean tibial angle was 86.95° (range, 86.83° to 87.04°) in coronal plane. The HSS score improved from an average of 46.67 points (range, 42 to 51) preoperatively to 83.67 points (range, 81 to 86) at 3 months postoperatively. The mean WOMAC score was 16.33 points at 3 months postoperatively. Conclusions The new alignment technique of arKA aims to balance the flexion and extension gap without extensive releases of soft tissue and restore the native pre‐arthritic alignment, may be a promising alignment strategy for treating severe varus deformity. However, further study and comparison with other alignment techniques is needed.

Abstract Introduction A portable spirometer is a promising alternative to a traditional pulmonary function test (PFT) spirometer for respiratory function evaluation. Objectives This study aimed to investigate the accuracy of automated interpretation of the PFT measured by a portable Yue Cloud spirometer in Chinese adults. Methods The PFT was performed to evaluate subjects prospectively enrolled at Ruijin Hospital (n = 220). A Yue Cloud spirometer and a conventional Jaeger MasterScreen device were applied to each patient with a 20‐min quiescent period between each measurement. Pulmonary function parameters, including forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF), maximal expiratory flow at 25%, 50%, and 75% of the FVC (MEF25, MEF50, and MEF75, respectively), and maximal mid‐expiratory flow (MMEF), were compared by correlation analyses and Bland–Altman methods. The Yue Cloud spirometer automatically interpreted the PFT results, and a conventional strategy was performed to interpret the PFT results obtained by the Jaeger machine. Concordance of the categorization of pulmonary dysfunction, small airway dysfunction, and severity was analyzed by the kappa (κ) statistic. Results Significantly similar correlations of all variables measured with the two spirometers were observed (all p 0.80). Conclusion The portable Yue Cloud spirometer not only yields reliable measurements of pulmonary function but also can automatically interpret the PFT results.

The purpose of this experiment was to investigate the effects of Litsea cubeba essential oil (LCO) on the growth performance, blood antioxidation, immune function, apparent digestibility of nutrients, and fecal microflora in fattening pigs. A total of 120 pigs were randomly assigned to five groups, with six replicate pens per treatment and four pigs per pen, and they were fed basal diet, chlortetracycline (CTC), and low-, medium-, and high-concentration LCO. The results of the study showed that compared with the control treatment and CTC addition treatment of the basic diet, the catalase level in the serum of the pigs treated with 500 mg/kg LCO in the diet of finishing pigs was significantly increased (p < 0.05). The apparent digestibility of crude protein, crude ash, and calcium in pigs with different levels of LCO was significantly increased compared with the control treatments fed the basal diet (p < 0.05). In addition, compared with the control treatment fed the basal diet and the treatment with CTC, the apparent digestibility of ether extract in pigs treated with medium-dose LCO was significantly increased (p < 0.05), and the apparent digestibility of pigs was significantly increased after the addition of low-dose LCO (p < 0.05). Among the genera, the percentage abundance of SMB53 (p < 0.05) was decreased in the feces of the CTC group when compared to that in the medium-LCO group. At the same time, the relative abundance of L7A_E11 was markedly decreased in the feces of the control and medium- and high-concentration LCO group than that in the CTC group (p < 0.05). In conclusion, adding the level of 250 mg/kg LCO in the diet of pig could improve the growth performance and blood physiological and biochemical indicators of pigs, improve the antioxidant level of body and the efficiency of digestion and absorption of nutrients, and show the potential to replace CTC.

Hydraulic fracturing technology is an important means to efficiently exploit unconventional oil and gas reservoirs. As the development of oil and gas fields continues at a high rate, the life cycle of oil and gas wells has been significantly shortened. Fracture sealing is often used to transform oil and gas reservoirs, maintaining long-term economic development benefits. Multiple high-conductivity channels were created between the borehole and the reservoir through temporary sealing of fractures near the contaminated zone. This extended the recovery range and further improved the recovery of oil and gas. A mathematical model was developed to predict the distribution of stress around the artificial fracture prior to the rupture of the seal. Finite element software was used to model the stress distribution around a reservoir containing natural and artificial fractures. We discuss the mechanical conditions for the initiation of a new fracture and the optimal timing for fracture sealing. The prediction of the propagation and propagation trajectories of the new fracture is revealed, and the behavior rules for the initiation and steering propagation of the new fracture are clarified. These results can facilitate theoretical studies and on-site technical optimization of fracture sealing.

BackgroundPreoperative cognitive impairment (PCI) may increase the incidence of postoperative delirium (POD), yet screening for cognitive impairment is rarely performed. This study hypothesized that Mini-Cog for preoperative cognitive impairment screening predicts postoperative delirium.MethodsThe prospective observational study recruited 153 elderly patients presenting for elective thoracic surgery. Cognitive function of these patients was screened using Mini-Cog preoperatively. We considered that patients with Mini-Cog scores ≤ 3 had cognitive impairment. Delirium was assessed using the Short CAM scale on postoperative days 1–5.ResultsOf the 153 participants, 54 (35.3%) were assigned to the PCI group, and 99 (64.7%) were assigned to the Normal group. Place of residence, education level, and history of hypertension were significantly different between the two groups (P < 0.05). 51 (33.3%) patients developed POD. Multifactorial analysis revealed that PCI (OR = 2.37, P = 0.028), older age (OR = 1.13, P = 0.009), ASA grade III (OR = 2.75, P = 0.012), and longer duration of anesthesia (OR = 1.01, P = 0.007) were associated with POD.ConclusionPreoperative cognitive impairment is strongly associated with POD. Mini-Cog could be recommended for screening PCI.Clinical trial registrationClinicalTrials.gov, identifier NCT05798767.

The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and lead to ciliopathies, notably Bardet-Biedl syndrome. Over the past few years, there has been significant progress in elucidating the molecular organization and functions of the BBSome complex. An improved understanding of BBSome-mediated biological events and molecular mechanisms is expected to help advance the development of diagnostic and therapeutic approaches for BBSome-related diseases. Here, we review the current literature on the structural assembly, transport regulation, and molecular functions of the BBSome, emphasizing its roles in cilium-related processes. We also provide perspectives on the pathological role of the BBSome in ciliopathies as well as how these can be exploited for therapeutic benefit.

Action recognition is an important component of human-computer interaction, and multimodal feature representation and learning methods can be used to improve recognition performance due to the interrelation and complementarity between different modalities. However, due to the lack of large-scale labeled samples, the performance of existing ConvNets-based methods are severely constrained. In this paper, a novel and effective multi-modal feature representation and contrastive self-supervised learning framework is proposed to improve the action recognition performance of models and the generalization ability of application scenarios. The proposed recognition framework employs weight sharing between two branches and does not require negative samples, which could effectively learn useful feature representations by using multimodal unlabeled data, e.g., skeleton sequence and inertial measurement unit signal (IMU). The extensive experiments are conducted on two benchmarks: UTD-MHAD and MMAct, and the results show that our proposed recognition framework outperforms both unimodal and multimodal baselines in action retrieval, semi-supervised learning, and zero-shot learning scenarios.

IntroductionLipid metabolic reprogramming is gaining attention as a hallmark of cancers. Recent mounting evidence indicates that the malignant behavior of breast cancer (BC) is closely related to lipid metabolism. Here, we focus on the estrogen receptor-positive (ER+) subtype, the most common subgroup of BC, to explore immunometabolism landscapes and prognostic significance according to lipid metabolism-related genes (LMRGs).MethodsSamples from The Cancer Genome Atlas (TCGA) database were used as training cohort, and samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), Gene Expression Omnibus (GEO) datasets and our cohort were applied for external validation. The survival-related LMRG molecular pattern and signature were constructed by unsupervised consensus clustering and least absolute shrinkage and selection operator (LASSO) analysis. A lipid metabolism-related clinicopathologic nomogram was established. Gene enrichment and pathway analysis were performed to explore the underlying mechanism. Immune landscapes, immunotherapy and chemotherapy response were further explored. Moreover, the relationship between gene expression and clinicopathological features was assessed by immunohistochemistry.ResultsTwo LMRG molecular patterns were identified and associated with distinct prognoses and immune cell infiltration. Next, a prognostic signature based on nine survival-related LMRGs was established and validated. The signature was confirmed to be an independent prognostic factor and an optimal nomogram incorporating age and T stage (AUC of 5-year overall survival: 0.778). Pathway enrichment analysis revealed differences in immune activities, lipid biosynthesis and drug metabolism by comparing groups with low- and high-risk scores. Further exploration verified different immune microenvironment profiles, immune checkpoint expression, and sensitivity to immunotherapy and chemotherapy between the two groups. Finally, arachidonate 15-lipoxygenase (ALOX15) was selected as the most prominent differentially expressed gene between the two groups. Its expression was positively related to larger tumor size, more advanced tumor stage and vascular invasion in our cohort (n = 149).DiscussionThis is the first lipid metabolism-based signature with value for prognosis prediction and immunotherapy or chemotherapy guidance for ER+ BC.

Summary: The terahertz (THz) radiation refers to electromagnetic waves between infrared and millimeter waves. THz technology has shown a significant potential for medical diagnosis and biomedical applications over the past three decades. Therefore, exploring the biological effects of THz waves has become an important new field in life sciences. Specifically, THz radiation has been proved to be able to diagnose and treat several head and neck diseases. In this review, we primarily discuss the biological characteristics of THz waves and clinical applications of THz technology, focusing on the research progress of THz technology in head and neck diseases (brain cancer, hypopharyngeal cancer, oral diseases, thyroid nodules, Alzheimer’s disease, eyes diseases, and otitis). The future application perspectives of THz technologies in head and neck diseases are also highlighted and proposed.

Abstract Chinese jujube (Ziziphus jujuba Mill.) is a globally popular and economically important fruit that is rich in bioactive compounds with strong anti‐cancer effects. Rain‐proof cultivation is widely used to cultivate Chinese jujube, as it helps avoid rainfall damage during fruit harvest. Although the sugar content of jujube fruits differs between rain‐proof and open‐field cultivation, the underlying molecular mechanisms are unknown. Here, we analyzed the levels of sugar content, sugar accumulation pattern, and transcriptome profiles of jujube fruits at five developmental stages grown under rain‐proof and open‐field cultivation modes. The sugar content of jujube fruits was significantly higher under rain‐proof cultivation than under open‐field cultivation, although the sugar composition and sugar accumulation patterns were comparable. Comparative analysis of transcriptomic profiles showed that rain‐proof cultivation enhanced the intrinsic metabolic activity of fruit development. Gene expression and correlation analyses suggested that ZjSPS, ZjSS, ZjHXK, and ZjINV regulate the development‐related changes in sugar content in jujube fruits grown under rain‐proof cultivation. Temperature, humidity, and moisture conditions were key climatic factors affecting sugar accumulation. Our results provide insights into the molecular mechanisms regulating sugar content and sugar accumulation in Chinese jujube fruits grown under rain‐proof cultivation, and we provide genetic resources for studying the development mechanism of Chinese jujube fruit.

Abstract PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin‐proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano‐PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano‐PROTACs are developed by encapsulating PROTACs in glutathione (GSH)‐responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano‐PROTAC, nanoengineered BRD4 degrader ARV‐771, improves BRD4 protein degradation and decreases the downstream oncogene c‐Myc expression. Benefiting from the GSH‐scavenging ability to amply the c‐Myc‐related ferroptosis and cell cycle arrest, this ARV@PDSA Nano‐PROTACs strategy shows superior anti‐tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano‐PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.

BackgroundExtrathyroidal extension is a major risk factor for poor prognosis in papillary thyroid cancer. However, the effect of different degrees of extrathyroidal extension on prognosis remains controversial. We performed a retrospective study to elucidate how the extent of extrathyroidal extension in papillary thyroid cancer affected the clinical prognosis of patients and its covariates.MethodsThe study included 108,426 patients with papillary thyroid cancer. We categorized the extent of extension into none, capsule, strap muscles, and other organs. Three causal inference methods for retrospective studies, namely, inverse probability of treatment weighting, standardized mortality ratio weighting, and propensity score matching analysis, were used to minimize potential selection bias. Kaplan–Meier analysis and univariate Cox regression analyses were applied to analyze the precise effect of ETE on survival in papillary thyroid cancer patients.ResultsIn the Kaplan–Meier survival analysis, only extrathyroidal extension into or beyond the strap muscles was statistically significant for both overall survival (OS) and thyroid cancer-specific survival (TCSS). In univariate Cox regression analyses before and after matching or weighting based on causal inference, extrathyroidal extension into soft tissues or other organs is a high-risk factor for both overall survival and thyroid cancer-specific survival. Sensitivity analysis revealed that lower overall survival was observed in patients with older age (≥55) and larger tumor size (>2 cm) of papillary thyroid cancer with extrathyroidal extension into or beyond the strap muscles.ConclusionsOur study indicates that extrathyroidal extension into soft tissues or other organs is a high-risk factor in all papillary thyroid cancer. Even though invasion into the strap muscles did not seem to be a marker for poor prognosis, it still impaired the overall survival of patients with older age (≥55 years old) or larger tumor size (>2 cm). Further investigation is needed to confirm our results and to clarify further risk factors independent of extrathyroidal extension.

Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes and is characterized by abundant infiltrating immune cells within the microenvironment. As standard care, chemotherapy remains the fundamental neoadjuvant treatment in TNBC, and there is increasing evidence that supplementation with immune checkpoint inhibitors may potentiate the therapeutic efficiency of neoadjuvant chemotherapy (NAC). However, 20-60% of TNBC patients still have residual tumor burden after NAC and require additional chemotherapy; therefore, it is critical to understand the dynamic change in the tumor microenvironment (TME) during treatment to help improve the rate of complete pathological response and long-term prognosis. Traditional methods, including immunohistochemistry, bulk tumor sequencing, and flow cytometry, have been applied to elucidate the TME of breast cancer, but the low resolution and throughput may overlook key information. With the development of diverse high-throughput technologies, recent reports have provided new insights into TME alterations during NAC in four fields, including tissue imaging, cytometry, next-generation sequencing, and spatial omics. In this review, we discuss the traditional methods and the latest advances in high-throughput techniques to decipher the TME of TNBC and the prospect of translating these techniques to clinical practice.

The performance of the temporary plug is a key factor in determining the success of loss-circulation control and temporary plug diversion fracturing. Due to the complexity of geomechanics and working conditions, current commonly used temporary plug agents face problems such as low plug strength and efficiency, large filtration losses due to failure to form filter cakes, and slow degradation affecting the recovery of fracture conductivity. A novel idea for the development of a novel water-soluble polymer plug for fracking is proposed, namely, low-to middle-molecule weight + reinforced chain rigidity + supramolecular aggregation. Using sodium bisulfite and potassium sulfate as initiators, AA, AM, and AMPS as grafting monomers, and SM as hydrophobic functional monomers, the AM-AA-AMPS-SM copolymer was prepared by polymerization. The developed new temporary plugging agent was completely degraded at 70°C for 5–8 h by carrying out experimental evaluation tests, such as water absorption expansion rate, swelling kinetics, density, post-dissolution viscosity, strength of the temporary plugging agent and post-degradation conductivity. After degradation, the viscosity of the solution is 2.5–3.6 mPa s with good fluidity and no gel remnants. The density of the temporary plug material is about 1.14 g/cm3. The absorption expansion rate was 25.8 g/g. The pressure is 60.1 MPa when the thickness of the granular temporary plug is 0.4 cm. Under experimental conditions, the fracture conductivity was found to be 69–123 D*cm at a closing pressure of 30 MPa after degradation of the temporary plug. The test results demonstrate that the new temporary plug agent, with its high plug strength, temperature-controlled degradation, reflux stability and effective self-support after degradation, can meet the requirements of drilling plug and temporary plug fracturing technologies.

Abstract Background and aim Repetitive transcranial magnetic stimulation (rTMS) has been found to attenuate cerebral ischemia/reperfusion (I/R) injury. However, its effects and mechanism of action have not yet been clarified. It has been reported that cerebral I/R injury is closely associated not only with ferroptosis but also with inflammation. Hence, the current study aimed to investigate whether high‐frequency rTMS attenuates middle cerebral artery occlusion (MCAO)‐induced cerebral I/R injury and further to elucidate the mediatory role of ferroptosis and inflammation. Methods The protective effects of rTMS on experimental cerebral I/R injury were investigated using transient MCAO model rats. Neurological scores and pathological changes of cerebral ischemic cortex were assessed to evaluate the effects of rTMS on cerebral I/R injury. The involvement of ferroptosis and that of inflammation were examined to investigate the mechanism underlying the effects of rTMS. Results High‐frequency rTMS remarkably rescued the MCAO‐induced neurological deficits and morphological damage. rTMS treatment also increased the mRNA and protein expression of glutathione‐dependent peroxidase 4, decreased the mRNA and protein levels of acyl‐CoA synthetase long‐chain family member 4 and transferrin receptor in the cortex. Moreover, rTMS administration reduced the cerebrospinal fluid IL‐1β, IL‐6, and TNF‐α concentrations. Conclusion These findings implicated that high‐frequency rTMS alleviates MCAO‐induced cerebral I/R injury, and the underlying mechanism could involve the inhibition of ferroptosis and inflammation. Our study identifies rTMS as a promising therapeutic agent for the treatment of cerebral I/R injury. Moreover, the mechanistic insights into ferroptosis and inflammation advance our understanding of it as a potential therapeutic target for diseases beyond cerebral ischemia stroke.

Summary: Background: Approximately 3–4% of patients with non-small-cell lung cancer (NSCLC) have MET exon 14 (METex14) skipping mutations. We report primary results from the phase 2 stage of a phase 1b/2 study of gumarontinib, a selective, potent, oral MET inhibitor, in patients with METex14 skipping mutation-positive (METex14-positive) NSCLC. Methods: The single-arm, multicentre, open-label, phase 2 stage of the GLORY study was conducted at 42 centres across China and Japan. Adults with locally advanced or metastatic METex14-positive NSCLC received oral gumarontinib 300 mg once daily in continuous 21-day cycles until disease progression, intolerable toxicity, or withdrawal of consent. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor), were ineligible for/refused chemotherapy, and had no genetic alterations targetable with standard therapies. The primary endpoint was objective response rate in patients with a valid baseline tumour assessment, by blinded independent review. The study was registered at ClinicalTrials.gov (NCT04270591). Findings: Between Aug 2, 2019 and Apr 28, 2021, 84 patients were enrolled and received gumarontinib (median follow-up 13.5 months [IQR 8.7–17.1]), at data cut-off (Apr 28, 2022) five patients whose METex14 status could not be confirmed by a central laboratory were excluded from the efficacy analysis. The objective response rate was 66% (95% CI 54–76) overall (n = 79), 71% (95% CI 55–83) in treatment-naïve patients (n = 44), and 60% (95% CI 42–76) in previously-treated patients (n = 35). The most common treatment-related adverse events (any grade) were oedema (67/84 patients, 80%) and hypoalbuminuria (32/84, 38%). Grade ≥3 treatment-emergent adverse events occurred in 45 (54%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8% (7/84) of patients. Interpretation: Gumarontinib monotherapy had durable antitumour activity with manageable toxicity in patients with locally advanced or metastatic METex14-positive NSCLC when used in first line or later. Funding: Haihe Biopharma Co., Ltd. Supported in part by grants from the National Science and Technology Major Project of China for “Clinical Research of Gumarontinib, a highly selective MET inhibitor” (2018ZX09711002-011-003); the National Natural Science Foundation of China (82030045 to S.L. and 82172633 to YF.Y); Shanghai Municipal Science & Technology Commission Research Project (19411950500 to S.L.); Shanghai Shenkang Action Plan (16CR3005A to S.L.) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190105 to S.L.).

The plant communities and wild animals in the Gobi desert outside the oases in the west of Hexi Corridor are an indispensable and important part of the human living environment. Affected by global warming, the spatial and temporal distribution patterns of precipitation have changed significantly. This article uses daily precipitation data from 6 hydro-logical stations in the middle and lower reaches of the Shule River Basin from 1957 to 2018, and daily precipitation data from 3 meteorological stations from 1980 to 2018. Through research on annual scale precipitation anomaly percentage, effective precipitation days and annual distribution, and drought station frequency ratio and other parameters, it is shown that there is a significant change in precipitation distribution within the year. The distribution of effective precipitation is not conducive to the survival of ecosystems, and seasonal drought is on the rise. The trend of continuous drought in two seasons and three seasons is on the rise, and the evolution of drought has a significant impact on the natural ecological environment. Effective rainfall is a key element in the rise and fall, distribution, and change of natural ecosystems. Studying the impact of changes in drought characteristics on natural ecology is of great significance for actively responding to drought disasters and maintaining basic ecology.

The intermetallic PtBi/MgO/Mg monolithic catalyst was first prepared using non-equilibrium plasma electrolytic oxidation (PEO) technology. Spherical aberration-corrected transmission electron microscope (ACTEM) observation confirms the successful synthesis of the PtBi intermetallic structure. The efficiency of PtBi/Mg/MgO catalysts in catalyzing the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) in the presence of NaBH4 was demonstrated. The activity factor for the catalyst is 31.8 s−1 g−1, which is much higher than reported values. In addition, the resultant catalyst also exhibits excellent catalytic activity in the organic pollutant reaction of p-nitrobenzoic acid (p-NBA) and methyl orange (MO). Moreover, benefiting from ordered atomic structures and the half-embedded PtBi nanoparticles (NPs), the catalyst demonstrates excellent stability and reproducibility in the degradation of 4-NP. This study provides an example of a simple method for the preparation of intermetallic structures as catalysts for organic pollutant degradation.

Glaciers play a vital role in the Asian mountain water towers and have significant downstream impacts on domestic, agricultural, and industrial water usage. The rate of glacier mass loss in the Southeastern Tibetan Plateau (SETP) is among the highest in Asia and has intensified in recent decades. However, a comprehensive quantification that considers both spatial and temporal aspects of glacier mass loss across the entire SETP is still insufficient. This study aimed to address this gap by utilizing geodetic datasets specific to each glacier by calibrating the Open Global Glacier Model (OGGM) driven by HAR v2 and reconstructing the glacier mass balance of 7756 glaciers in the SETP from 1980 to 2019 while examining their spatial variability. The findings reveal that the average mass balance during this period was −0.50 ± 0.28 m w.e. a−1, with an accelerated loss observed in the 2000s (average: 0.62 ± 0.24 m w.e. a−1). Notably, central glaciers in the SETP exhibited relatively smaller mass loss, indicating a gradient effect of increased loss from the central region toward the eastern and western sides. By the end of this century, the area, length, and volume of glaciers in the entire SETP region are projected to decrease by 83.57 ± 4.91%, 90.25 ± 4.23%, and 88.04 ± 4.52%, respectively. Moreover, the SETP glacier melt runoff is estimated to decrease by 62.63 ± 6.16% toward the end of the century, with the “peak water” point of glacier melt runoff predicted to occur in 2023 under the SSP585 scenario. Sensitivity experiments demonstrated that the SETP glaciers are more than three times more sensitive to temperature changes than to precipitation variations, and the observed decrease in monsoon precipitation indicates the weakening magnitude of the Indian summer monsoon in recent years. The spatially refined and high-temporal-resolution characteristics of glacier mass loss presented in this study contribute to a better understanding of specific glacier changes in the SETP. Additionally, the prediction results provide valuable references for future water resources management and policy formulation in the SETP region.