Search

SummaryClimate change has brought enormous adverse outcomes to biological activities around the world. The main reason is that too much CO2 has been released into the atmosphere. In recent years, storing CO2 in the form of CO2 hydrate is a research hotspot, the main purpose of which is to reduce carbon emissions to mitigate the greenhouse effect. In this work, we use the molecular dynamics simulation method to study the growth of CO2 hydrate in NaCl aqueous solution with the assumption of induction of CO2 sequestration in the ocean. The temperature is 275 K and the pressure is 10 MPa in this work. Under these conditions, stucture I type (sI-type) CO2 hydrate with a density of about 1150 kg/m3 formed within a very short period of time. The simulation results show that during hydrate growth, Na+ and Cl− are “driven” together and the water molecules remain liquid in this region, where they are near Na+ and Cl−. From the independent gradient model (IGM) based on Hirshfeld partition (IGMH) analysis, Na+ does not bond with any ions/molecules, which hinders the formation of water cages and thus inhibits hydrate growth; Cl− forms multiple H-bonds with neighboring H2O molecules and can participate in the formation of water cages. However, it is worth noting that not all Cl– and the nearby water molecules can form either a five-membered ring or a four-membered ring; even some water molecules and Cl− cannot form a closed ring. Therefore, it is impossible to determine whether the water molecules near the Cl− are all in liquid or solid state.

Acute myelogenous leukemia (AML) is a very common hematopoietic malignancy. Hematopoietic stem cell transplantation can improve the therapeutic effect of AML, but the 5-year survival rate is very low. CD123 imbalance, abnormal gene expression, and epigenetics play an important role in the pathogenesis of AML. This research was to explore the differential expression of CD123-related long non-coding RNA (lncRNA) in AML bone marrow mononuclear cells and provide a theoretical basis for targeted therapy of AML. High-throughput sequencing was performed to screen differentially expressed lncRNA in bone marrow mononuclear immunophenotypes of CD123+ and CD123- from patients with primary AML, and real-time quantitative PCR was adopted for screening and validation. There were 933 differentially expressed lncRNAs in the CD123+ group and the CD123- group, 407 lncRNAs were up-regulated and 463 lncRNAs were down-regulated in the CD123+ group. 14 lncRNAs with more than 2 times of difference were screened for identification, and it was found that compared with CD123- group, there was no substantial difference in the expression of JHDM1D-AS1, LINC01355, CASC15, FAM13A-AS1, HSPC324, LOC339803, LINC00877, and MAG12-AS3 in CD123+ group (P0.05). The expressions of LOC101929698, BaALC-AS2, BOLA3-AS1, and FBX19-AS1 were considerably up-regulated (P0.05), while the expressions of LOC100132249 and LINC02085 were considerably down-regulated (P0.05). In summary, differentially expressed lncRNAs in bone marrow samples of CD123+ and CD123- group of newly diagnosed AML patients may be involved in the process of AML and seriously affect the prognosis of patients.

Precise prediction on vacant parking space (VPS) information plays a vital role in intelligent transportation systems for it helps drivers to find the parking space quickly to reduce unnecessary waste of time and excessive environmental pollution. By analyzing the historical zone-wise VPS data, we find that for the number of VPSs, there is not only a solid temporal correlation within each parking lot, but also an obvious spatial correlation among different parking lots. Given this, this paper proposes a hybrid deep learning framework, known as the dConvLSTM-DCN (dual Convolutional Long Short-Term Memory with Dense Convolutional Network), to make short-term (within 30 min) and long-term (over 30 min) predictions on the VPS availability zone-wisely. Specifically, the temporal correlations of different time scales, namely the 5-min and daily-wise temporal correlations of each parking lot, and the spatial correlations among different parking lots can be effectively captured by the two parallel ConvLSTM components, and meanwhile, the dense convolutional network is leveraged to further improve the propagation and reuse of features in the prediction process. Besides, a two-layer linear network is used to extract the meta-info features to promote the prediction accuracy. For long-term predictions, two methods, namely the direct and iterative prediction methods, are developed. The performance of the prediction model is extensively evaluated with practical data collected from nine public parking lots in Santa Monica. The results show that the dConvLSTM-DCN framework can achieve considerably high accuracy in both short-term and long-term predictions.

Oversampling is a promising preprocessing technique for imbalanced datasets which generates new minority instances to balance the dataset. However, improper generated minority instances, i.e., noise instances, may interfere the learning of the classifier and impact it negatively. Given this, in this paper, we propose a simple and effective oversampling approach known as ASN-SMOTE based on the k-nearest neighbors and the synthetic minority oversampling technology (SMOTE). ASN-SMOTE first filters noise in the minority class by determining whether the nearest neighbor of each minority instance belongs to the minority or majority class. After that, ASN-SMOTE uses the nearest majority instance of each minority instance to effectively perceive the decision boundary, inside which the qualified minority instances are selected adaptively for each minority instance by the proposed adaptive neighbor selection scheme to synthesize new minority instance. To substantiate the effectiveness, ASN-SMOTE has been applied to three different classifiers and comprehensive experiments have been conducted on 24 imbalanced benchmark datasets. ASN-SMOTE is also extensively compared with nine notable oversampling algorithms. The results show that ASN-SMOTE achieves the best results in the majority of datasets. The ASN-SMOTE implementation is available at: https://www.github.com/yixinkai123/ASN-SMOTE/.

Magnetic resonance (MR) image enhancement technology can reconstruct high-resolution image from a low-resolution image, which is of great significance for clinical application and scientific research. T1 weighting and T2 weighting are the two common magnetic resonance imaging modes, each of which has its own advantages, but the imaging time of T2 is much longer than that of T1. Related studies have shown that they have very similar anatomical structures in brain images, which can be utilized to enhance the resolution of low-resolution T2 images by using the edge information of high-resolution T1 images that can be rapidly imaged, so as to shorten the imaging time needed for T2 images. In order to overcome the inflexibility of traditional methods using fixed weights for interpolation and the inaccuracy of using gradient threshold to determine edge regions, we propose a new model based on previous studies on multi-contrast MR image enhancement. Our model uses framelet decomposition to finely separate the edge structure of the T2 brain image, and uses the local regression weights calculated from T1 image to construct a global interpolation matrix, so that our model can not only guide the edge reconstruction more accurately where the weights are shared, but also carry out collaborative global optimization for the remaining pixels and their interpolated weights. Experimental results on a set of simulated MR data and two sets of real MR images show that the enhanced images obtained by the proposed method are superior to the compared methods in terms of visual sharpness or qualitative indicators.

Hepatic resection is a potentially curative treatment for patients with hepatocellular carcinoma (HCC). Controversy persists regarding preoperative and intraoperative characteristics related to patient survival in various medical institutes. This study aimed to evaluate the impact of preoperative and intraoperative factors on the long-term survival of patients with HCC who underwent hepatectomy.Data on 455 patients with HCC who underwent hepatectomy over a 20-year period were retrospectively reviewed. Univariate and multivariate Cox regression analyses were performed for preoperative- and intraoperative-related prognostic factors.The 1-, 3-, 5-, and 10-year overall survival rates of patients with HCC who underwent resection were 76.3%, 57.9%, 46.7%, and 27.4%, respectively. Multivariate analyses identified four independent predictors of long-term prognosis-sex (male versus female, hazard ratio [HR] = 2.732, p = 0.026); differentiation (poor versus well, HR = 2.037, p = 0.030); total bilirubin value (μmol/L, HR = 1.056, p = 0.033); and intraoperative blood transfusion (no transfusion versus transfusion, HR = 0.417, p = 0.002). Hepatitis virus B infection (negative versus positive, HR = 0.669, p = 0.232) and resection style (anatomical versus nonanatomical, HR = 0.698, p = 0.181) were not associated with survival.Based on this 20-year study, poor survival of patients with HCC who underwent hepatectomy was correlated with preoperative and intraoperative factors including male sex, poor differentiation, increased total bilirubin levels, and intraoperative blood transfusion.

Background Patients with malignant tumors are more likely to have psychological problems due to their worries about their life expectancy. To understand the psychological status of elderly patients with malignant liver tumor undergoing hepatectomy better, the study was designed to investigate the current situation of anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy and to analyze its related factors. Methods A total of 126 elderly patients with malignant liver tumor undergoing hepatectomy were selected as the research objects. The anxiety and depression of all subjects were evaluated by HADS (Hosptial Anxiety and Depression Scale). The correlation factors affecting the psychological state of elderly patients with malignant liver tumor undergoing hepatectomy were analyzed by linear regression method. Results The HADS-A score of elderly patients with malignant liver tumor undergoing hepatectomy was 8.79 ± 2.56, among which 37 patients were asymptomatic, 60 patients with suspicious symptoms, and 29 patients with definite symptoms. The HADS-D score was 8.40 ± 2.97, among which 61 patients were asymptomatic, 39 patients with suspicious symptoms, and 26 patients with definite symptoms. Multivariate analysis using linear regression method showed that FRAIL score, residence, and complication were significantly associated with anxiety and depression of elderly patients with malignant liver tumor undergoing hepatectomy. Conclusions Anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy were obvious. FRAIL score, regional differences, and the complication were the risk factors for anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy. Improving frailty, reducing regional differences, and preventing complications is beneficial to alleviate the adverse mood of elderly patients with malignant liver tumor undergoing hepatectomy.

Introduction To compare the changes in serum concentrations of vascular endothelial growth factor (VEGF)-A and B after intravitreal injection of ranibizumab (IVR) or conbercept (IVC) for retinopathy of prematurity (ROP). Methods In this prospective study, infants with type 1 ROP in both eyes were recruited in our hospital from September 2021 to February 2022, randomly assigned to the ranibizumab and conbercept groups and administered IVR or IVC (0.25 mg/0.025 mL). Blood samples were collected before the operation and 1 and 4 weeks after the operation to measure the concentrations of serum VEGF-A and B. Results A total of 20 ROP infants were randomly assigned to the ranibizumab (n=10) and conbercept groups (n=10). In the ranibizumab group, the serum VEGF-A concentrations before operation and 1 and 4 weeks after the operation were 73.55±40.78, 11.47±7.00, and 75.36±30.87 pg/mL, respectively (P0.05). In the conbercept group, the serum VEGF-A concentrations before operation and 1 and 4 weeks after the operation were 86.69±55.06,14.68±10.11, and 43.55±57.92 pg/mL, respectively (P0.05). Regarding serum VEGF-B concentrations before the operation and 1 and 4 weeks after the operation, no significant differences were detected in the ranibizumab group (P>0.05), but significant differences were observed in the conbercept group (7.26±2.34, 3.09±2.41, and 4.55±3.37 ng/mL, respectively; P0.05). Conclusions Serum VEGF-A levels in infants with ROP were suppressed after IVR or IVC but returned to preoperative levels at 4 weeks after IVR and remained lower than the preoperative levels at 4 weeks after IVC. Serum VEGF-B was not affected by IVR but was suppressed by IVC for 4 weeks.

CpG island methylator phenotype (CIMP) was closely related to the degree of pathological differentiation of tumors, and it's an important determinant of glioma pathogenicity. However, the molecular and pathological features of CIMP-positive glioma have not been fully elucidated. In addition, CIMP have been reported to be a useful prognostic marker in several human cancers, yet its prognostic value in gliomas is still controversial. Therefore, we aimed to evaluate gene mutations and pathological features of CIMP-positive glioma and explore the prognostic value of CIMP in gliomas.We comprehensively searched PubMed, Embase, and MEDLINE for studies describing gene mutations, pathological features and overall survival of gliomas stratified by CIMP status. Odds ratios (OR), hazard ratios (HR), and their 95% confidence intervals (CI) were used to estimate the correlation between CIMP and the outcome parameters.Twelve studies with 2386 gliomas (1051 CIMP-positive and 1335 CIMP-negative) were included. Our results showed that CIMP was more frequent in isocitrate dehydrogenase 1 (IDH1)-mutated gliomas (OR 229.07; 95% CI 138.72-378.26) and 1p19q loss of heterozygosis (LOH) gliomas (OR 5.65; 95% CI 2.66-12.01). Pathological analysis showed that CIMP was common in low-malignant oligodendroglioma (OR 5.51; 95% CI 3.95-7.70) with molecular features including IDH1 mutations and 1p19q LOH, but rare in glioblastoma (OR 0.14; 95% CI 0.10-0.19). However, CIMP showed no obvious correlation with anaplastic oligoastrocytomas (OR 1.57; 95% CI 1.24-2.00) or oligoastrocytomas (OR 0.79; 95% CI 0.35-1.76). Concerning the prognosis, we found that CIMP-positive gliomas had longer overall survival (HR 0.57; 95% CI 0.97-0.16) than CIMP-negative gliomas.CIMP could be used as a potential independent prognostic indicator for glioma.

Triple-positive breast cancer (TPBC) is a tumor that simultaneously expresses estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Luminal A-like TPBC is a special subtype with a favorable prognosis but benefits less from HER2-targeted therapy. However, little is known about how to identify luminal A-like TPBCs. Therefore, our study aims to explore a clinically feasible method to identify luminal A-like TPBCs using immunohistochemical (IHC) markers.Our cohort enrolled consecutive 190 patients with early-stage TPBCs diagnosed, treated and followed up in our hospital between 2013 and 2019. Patients whose IHC staining displayed ≥ 50% in both ER and PR scores and B-cell lymphoma 2 (BCL2) positivity were classified as cohort A (n = 64), and the rest were enrolled in cohort B (n = 126). Kaplan-Meier plotter and log-rank test were used to compare the survival difference between cohort A and cohort B and the efficacy of trastuzumab therapy in the two cohorts.The disease-free survival (DFS) of patients in cohort A was significantly better than in cohort B (p = 0.031). In cohort A, there was no statistically significant difference in DFS between patients treated with trastuzumab and those without trastuzumab (p = 0.663). While in cohort B, patients treated with trastuzumab had significantly better DFS than those without trastuzumab (p = 0.032). Multivariate survival analysis showed that cohort A was associated with better DFS(95%CI 1.046-11.776, p = 0.042).TPBCs consist of heterogeneous subtypes. Detecting the expression of ER, PR and BCL2 via IHC can help identify luminal A-like TPBCs. This study will enable individualized treatment of TPBCs.

Objective Using a nested, cluster-randomized trial, we tested the hypothesis that a shared decision-making intervention, as part of consent, would improve study-related knowledge. Methods We developed a shared decision-makingintervention then randomized sites in a clinical trial to intervention or control (standard consent). We collected participants’ knowledge (primary outcome) and decisional support data. Other data came from a clinical registry and research coordinator surveys. We compared outcomes between study arms using generalized estimating equation models, accounting for clustering. We used qualitative description to understand variation in intervention use. Results 265 individuals, from 34 sites, enrolled in the parent trial during our study period. Of those, 241 participants completed our survey. There was no knowledge difference between arms (mean difference = 0.56 (95 %CI: -3.8, 4.9)). Both groups had a considerable number of participants with misunderstandings. We also found no difference for decisional support (mean difference = 1.5 (95 %CI: -1.8, 4.8)) or enrollment rate between arms. Clinician use of the intervention varied between sites. Conclusions We found no differences in outcomes but demonstrated the feasibility and acceptability of incorporating a shared decision-making intervention into consent. Practice implications Future work should consider adapting our intervention to other trials and more robust measurement strategies.

Objective Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder. Recent studies report that long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of various diseases. This study explored the molecular mechanism of lncRNA growth arrest specific 5 (GAS5) in regulating the T helper 17 (Th17)/regulatory T (Treg) cell balance in MG. Methods GAS5 and miR-23a expression levels were detected by quantitative reverse transcription polymerase chain reaction. Flow cytometry was performed to examine the proportion of Th17 and Treg cells in CD4+ T cells from MG patients. The interaction between GAS5 and miR-23a was verified by luciferase reporter and RNA immunoprecipitation assays. Levels of Th17 and Treg-related proteins were examined using western blots and enzyme-linked immunosorbent assays. Results GAS5 expression levels were significantly decreased in the CD4+ T cells of MG patients, and GAS5 overexpression restrained Th17 differentiation in CD4+ T cells. Moreover, miR-23a was confirmed as a downstream target of GAS5 and negatively regulated by GAS5 through a direct interaction. Further exploration showed that GAS5 can inhibit Th17 differentiation by downregulating miR-23a. Conclusion Collectively, our results indicate that GAS5 can regulate the Th17/Treg balance by targeting miR-23a expression, providing a scientific basis for clinical therapeutic development for MG.

Purpose RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. Patients and methods This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. Results Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). Conclusion RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status. Clinical trial information NCT02881190.

Alzheimer's disease (AD) is the most common cause of dementia. Increasing evidence shows that mitochondrial DNA (mtDNA) methylation plays an essential role in many diseases related to mitochondrial dysfunction. Since mitochondrial impairment is a key feature of AD, mtDNA methylation may also contribute to AD, but few studies have addressed this issue. Methylation changes of the mitochondrial cytochrome b (CYTB) and cytochrome c oxidase II (COX II) genes in AD have not been reported. We analyzed mtDNA methylation changes of the CYTB and COX II genes in an APP/PS1 transgenic mouse model of AD using pyrosequencing. We examined mtDNA copy numbers and the levels of expression by quantitative real-time PCR. Average methylation levels of different CpG sites were ≤ 4.0%. Methylated mtDNA accounted for only a small part of the total mtDNA. We also observed hypermethylation of mitochondrial CYTB and COX II genes with decreased mtDNA copy numbers and expression in the hippocampi of APP/PS1 transgenic mice. mtDNA methylation may play an important role in AD pathology, which may open a new window for AD therapy.

Developing non-cationic gene carriers and achieving efficient endo/lysosome escape of functional nucleic acids in cytosol are two major challenges faced by the field of gene delivery. Herein, we demonstrate the concept of self-escape spherical nucleic acid (SNA) to achieve light controlled non-cationic gene delivery with sufficient endo/lysosome escape capacity. In this system, Bcl-2 antisense oligonucleotides (OSAs) were conjugated onto the surface of aggregation-induced emission (AIE) photosensitizer (PS) nanoparticles to form core-shell SNA. Once the SNAs were taken up by tumor cells, and upon light irradiation, the accumulative 1 O2 produced by the AIE PSs ruptured the lysosome structure to promote OSA escape. Prominent in vitro and in vivo results revealed that the AIE-based core-shell SNA could downregulate the anti-apoptosis protein (Bcl-2) and induce tumor cell apoptosis without any transfection reagent.

Ubiquitin‐specific peptidase 13 (USP13) has been reported to be involved in the tumorigenesis of several tumors, but its function in tumors is still controversial. In this study, the function of USP13 in hepatocellular carcinoma (HCC) was investigated, and we found that USP13 was significantly upregulated in both of primary HCC tumor tissues and cell lines. And HCC patients with high USP13 expression had a shorter overall survival or relapse‐free survival than patients with low USP13 expression. In HCC cell lines, knockdown of USP13 by shRNAs markedly decreased HCC cell growth, and mechanistic investigations revealed that USP13 knockdown could markedly downregulate the expression levels of c‐Myc. Moreover, overexpression of c‐Myc could significantly attenuate the effects of shUSP13 on HCC cell growth inhibition. In addition, in vivo experiments showed that knockdown of USP13 could significantly inhibit xenograft tumor growth of HCC. Taken together, our present study provided the first evidence that USP13 acted as a novel driver in HCC tumorigenesis by regulating c‐Myc expression, and targeting USP13 could be a promising strategy for HCC therapy.

Ellagic acid (EA) has been reported to have antiproliferative and antioxidant properties, but its function in esophageal squamous cell carcinoma (ESCC) has not been investigated yet. In the current study, EA was found have a significant anti‐tumor activity in ESCC. In specific, EA inhibited ESCC cell survival in both of a concentration‐ and time‐dependent manner. And our results showed that EA promoted ESCC cell apoptosis, including inducing the cleavages of PARP, and inhibiting the expression of anti‐apoptotic proteins. In mechanistic, EA markedly suppressed STAT3‐driven luciferase activity, and inhibited both of the endogenous and cytokines‐induced STAT3 activation in ESCC cells. Further investigations indicated that EA could significantly upregulate SHP‐1 expression, a negative modulator of STAT3 signaling. In contrast, knockdown of SHP‐1 could attenuate the effects of EA on inhibiting ESCC cell survival. Moreover, we found that EA could inhibit RNF6 expression, an E3 of SHP‐1, and overexpressing RNF6 could also significantly attenuate the effects of EA on inhibiting ESCC cell survival, which further revealed that EA could inhibit STAT3 signaling by modulating RNF6/SHP‐1 axis. Our present study indicated that EA could be as a novel STAT3 inhibitor for the treatment of ESCC.

The aim of this study was to investigate potential therapeutic effects of IFN-γ primed human umbilical cord mesenchymal stem cell (IFN-γ-hUCMSCs) transplantation on experimental autoimmune encephalomyelitis (EAE) in mice. In this study, EAE mouse model was established by MOG35-55 immunization method. Outcomes of the EAE mice in terms of body weight and clinical symptoms were analyzed. Electromyography (EMG) was performed to evaluate nerve conduction. ELISA was applied to quantify inflammatory cytokine levels in serum. Our results showed that IFN-γ could up-regulate protein expression of indoleamine 2, 3-dioxygenease 1 (IDO1), an important molecule released by MSCs to exert their immune suppressive activity (p

Purpose Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD). As vascular endothelial growth factor (VEGF) has been shown to be protective in AD, the aim of this study was to investigate the effects of VEGF on mitochondrial function in models of AD. Materials and methods Adeno associated virus (AAV)-VEGF was injected into the hippocampus of APP/PS1 mice. Cognitive function was assessed in these mice with use of the Morris water maze (MWM) and β-amyloid (Aβ) levels in the hippocampus were also measured. Cell viability and reactive oxygen species (ROS) levels were determined in the SH-SY5Y cells treated with Aβ25-35 which served as a cell model of AD. Transmission electron microscopy (TEM) was used to evaluate structural changes in mitochondria and mitochondrial DNA (mtDNA) copy number and mitochondrial membrane potential (MMP) were also recorded. Finally, we investigated the effects of VEGF upon mitochondrial biogenesis, autophagy and mitochondrial autophagy (mitophagy) as determined both in vivo and in vitro with western blots. Results VEGF treated mice showed improvements in spatial learning and memory along with reduced Aβ levels. VEGF protected SH-SY5Y cells against Aβ25-35 induced neurotoxicity as demonstrated by increased cell viability and decreased ROS production. Associated with these effects were improvements in mitochondrial structure and function, and increased numbers of mitochondria resulting from stimulation of mitochondrial biogenesis. Conclusions VEGF alleviates Aβ related patholoy in models of AD. In part, these beneficial effects of VEGF result from protection of mitochondria and stimulation of mitochondrial biogenesis.

Background Hepatic resection is a potentially curative treatment for patients with hepatocellular carcinoma (HCC). The treatment of elderly patients with HCC has always been difficult. With the development of geriatrics and geriatric surgery, the number of elderly patients with HCC undergoing hepatectomy has gradually increased. To further improve the long-term prognosis of elderly patients with hepatocellular carcinoma undergoing surgery, it is necessary to study the related perioperative factors. Our aim was to study the impact of preoperative and intraoperative factors on the long-term survival of elderly patients with HCC who underwent hepatectomy. Methods A total of 151 elderly patients with HCC who underwent hepatectomy were retrospectively studied. Univariate and multivariate Cox regression analyses were performed for preoperative- and intraoperative-related prognostic factors. Results The 1-, 3-, 5- and 10-year overall survival rates of elderly patients with HCC who underwent resection were 79.5%, 60.8%, 46.6%, and 25.4%, respectively. Multivariate analyses identified four independent predictors of long-term prognosis: Child–Pugh grade (B/C versus A: HR[hazard ratio] = 2.318, P = 0.019), alpha-fetoprotein value (> 20 ng/ml versus ≤ 20 ng/ml: HR = 1.972, P = 0.005), resection style (anatomical versus no anatomical: HR = 1.976, P = 0.006), and intraoperative blood loss (> 400 ml versus ≤ 400 ml: HR = 2.008, P = 0.003). Conclusions Poor survival of elderly patients with HCC who underwent hepatectomy was correlated with the preoperative and intraoperative factors of Child–Pugh grade, Alpha-fetoprotein value, resection style, and intraoperative blood loss.

This paper analyzes the present situation of cooperative education in China’s art disciplines, points out the deficiencies during the development and puts forward some countermeasures and suggestions based on its approach of “introduction, integration and innovation” while studying the case of the Birmingham Institute of Fashion and Creative Art. It aims to cultivate a group of new design talents with design creativity, practical ability and international vision by inheriting Chinese excellent traditional culture to strengthen cultural self-confidence.

Organophosphate esters (OPEs) are developmental toxicants in experimental studies of animals, but limited evidence is available in humans. We included 340 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, Ohio, USA) for the analysis. We evaluated gestational exposure to OPEs with gestation age at birth and newborn anthropometric measures. We quantified four OPE urinary metabolites at 16 weeks and 26 weeks of gestation. We extracted gestational age at birth, newborn weight, length, and head circumference from the chart review. We calculated z-scores for these anthropometric measures and the ponderal index. We used multiple informant models to examine the associations between repeated OPE measurements and the outcomes. We used modified Poisson regression to estimate the association of gestational exposure to OPEs with preterm birth. We also explored effect modification by infant sex and the potential mediation effect by the highest maternal blood pressure and glucose levels. We found that bis(2-chloroethyl) phosphate (BCEP) at 16 weeks and diphenyl phosphate at 26 weeks of pregnancy were positively associated with gestational age and inversely associated with preterm birth. In female newborns, BCEP at 16 weeks was inversely related to birth weight and length z-scores. In male newborns, we observed negative associations of 26-week di-n-butyl phosphate with the ponderal index at birth. No mediation by the highest maternal blood pressure or glucose levels during pregnancy was identified. In this cohort, gestational exposure to some OPEs was associated with gestational age, preterm birth, and neonatal anthropometric measures. Certain associations tended to be window- and infant sex-specific.

Introduction: Ki67 value and its variation before and after neoadjuvant chemotherapy are commonly tested in relation to breast cancer patient prognosis. This study aims to quantify the extent of changes in Ki67 proliferation pre- and post-neoadjuvant chemotherapy, confirm an optimal cut-off point, and evaluate its potential value for predicting survival outcomes in patients with different molecular subtypes of breast cancer.Methods: This retrospective real-world study recruited 828 patients at the Department of Breast Surgery of the First Affiliated Hospital of China Medical University and the Cancer Hospital of China Medical University from Jan 2014 to Nov 2020. Patient demographic features and disease pathology characteristics were recorded, and biomarkers were verified through immunohistochemistry. Various statistical methods were used to validate the relationships between different characteristics and survival outcomes irrespective of disease-free and overall survival.Results: Among 828 patients, statistically significant effects between pathological complete response and survival outcome were found in both HER2-enriched and triple-negative breast cancer (p < 0.05) but not in Luminal breast cancer (p > 0.05). Evident decrease of Ki67 was confirmed after neoadjuvant chemotherapy. To quantify the extent of Ki67 changes between pre- and post-NAC timepoints, we adopted a computational equation termed ΔKi67% for research. We found the optimal cut-off value to be “ΔKi67% = −63%” via the operating characteristic curve, defining ΔKi67% ≤ −63% as positive status and ΔKi67% > −63% as negative status. Patients with positive ΔKi67% status were 37.1% of the entire cohort. Additionally, 4.7, 39.9, 34.5 and 39.6% of patients with Luminal A, Luminal B, HER2-enriched and triple negative breast cancer were also validated with positive ΔKi67% status. The statistically significant differences between ΔKi67% status and prognostic outcomes were confirmed by univariate and multivariate analysis in Luminal B (univariate and multivariate analysis: p < 0.05) and triple negative breast cancer (univariate and multivariate analysis: p < 0.05). We proved ΔKi67% as a statistically significant independent prognostic factor irrespective of disease-free or overall survival among patients with Luminal B and triple-negative breast cancer.Conclusions:ΔKi67% can aid in predicting patient prognostic outcome, provide a measurement of NAC efficacy, and assist in further clinical decisions, especially for patients with Luminal B breast cancer.

Baker's yeast industries generate highly polluted effluents, especially the cell free broth (i.e., vinasse) characterized by high chemical oxygen demand, nitrogen, and salts. In this work, it was found that the residual by-products (i.e., ethanol and acetic acid) and salts in the vinasse severely inhibited the cell growth, which hindered the reuse of the vinasse for the production of Saccharomyces cerevisiae. Through optimizing a suitable control strategy, the productions of ethanol and acetic acid were eliminated. Then, a nanofiltration membrane (i.e., NF5) was preferred for preliminarily and simultaneously separating and concentrating valuable molecules (i.e., invertase, food grade proteins and pigments) in the vinasse, and the main fouling mechanism was cake layer formation. Subsequently, a reverse osmosis membrane (RO) was suitable to separate and concentrate salts in the NF5 permeate, where the membrane fouling was negligible. Finally, the RO permeate was successfully reused for the production of S. cerevisiae. In addition, without calculating the benefit from the recovery of the valuable molecules, the cost of the integrated process can be decreased by 59.8% compared with the sole triple effect evaporation. Meanwhile, the volume of the fresh water used in the fermentation process can be decreased by 68.8%. Thus, it is a sustainable process for the cleaner production of baker's yeast using the integrated fermentation and membrane separation process.

With the rapid development of remote sensing technology, change detection (CD) methods based on remote sensing images have been widely used in land resource planning, disaster monitoring, and urban expansion, among other fields. The purpose of CD is to accurately identify changes on the Earth’s surface. However, most CD methods focus on changes between the pixels of multitemporal remote sensing image pairs while ignoring the coupled relationships between them. This often leads to uncertainty about edge pixels with regard to changing objects and misclassification of small objects. To solve these problems, we propose a CD method for remote sensing images that uses a coupled dictionary and deep learning. The proposed method realizes the spatial-temporal modeling and correlation of multitemporal remote sensing images through a coupled dictionary learning module and ensures the transferability of reconstruction coefficients between multisource image blocks. In addition, we constructed a differential feature discriminant network to calculate the dissimilarity probability for the change area. A new loss function that considers true/false discrimination loss, classification loss, and cross-entropy loss is proposed. The most discriminating features can be extracted and used for CD. The performance of the proposed method was verified on two well-known CD datasets. Extensive experimental results show that the proposed method is superior to other methods in terms of precision, recall, F1-score, IoU , and OA .

Chitinase-3 like-protein-1 (CHI3L1) has been found to be overexpressed in many cancers and increased CHI3L1 level in serum seems to correlate with a poor prognosis in patients with metastatic cancer. However, the expression of CHI3L1 and its potential role in esophageal cancer remains unclear. We retrieved publicly available RNA-seq datasets of esophageal cancer tissues and normal esophageal tissues. We analyzed the correlation between CHI3L1 expression with different clinical parameters (such as T stages, N stage, response to treatment and tumor residues after treatment), the relationship between CHI3L1 expression level and prognosis, and the relationship between CHI3L1 expression and different immune cell signatures in esophageal cancer tissues. A transgenic mouse model of esophageal carcinoma was used to validate CHI3L1 expression and its association with macrophage signature gene expression. The effect of recombinant CHI3L1 on macrophage polarization was assessed in cell model. We showed the upregulation of CHI3L1 in esophageal cancer tissues in comparison to normal esophageal tissues, and its upregulation was positively associated with tumor size. The analysis of immunological signatures and CHI3L1 expression indicated that CHI3L1 level was highly correlated with increased expression of macrophage signature genes in esophageal tumor tissues. CHI3L1 was also upregulated in the esophagus dysplasia tissues in a transgenic mouse model. Recombinant CHI3L1 treatment favored M2 gene expression in LPS-stimulated RAW 264.7 macrophage cell line. CHI3L1 overexpression may favor macrophage recruitment in esophageal tumor tissues. Future studies are needed to delineate the mechanisms of CHI3L1-mediated macrophage recruitment and polarization in tumor tissues.

ImportanceOutreach messages to patients overdue for well child care (WCC) can be delivered different ways (ie, telephone calls and text messages). Use of electronic health record patient portals is increasingly common but their effectiveness is uncertain.ObjectiveTo determine the effectiveness of patient portal outreach messages, with and without the date of the last WCC, on the scheduling and completion of WCC visits and completion of vaccinations.Design, Setting, and ParticipantsAn intention-to-treat, multigroup, randomized clinical trial was conducted at 3 academic primary care practices from July 30 to October 4, 2021. The population included predominantly non-Hispanic Black, low-income children (age, 6-17 years) whose parent had an active portal account.InterventionsParticipants were randomized to the standard message, tailored message, or no message (control) group. Two messages were delivered to those in the message groups.Main Outcomes and MeasuresOutcomes included WCC visit scheduled within 2 weeks of the first intervention message, WCC visit completed within 8 weeks (primary outcome), and receipt of COVID-19 vaccine within 8 weeks.ResultsNine hundred forty-five patients participated (mean [SD] age, 9.9 [3.3] years, 493 [52.2%] girls, 590 [62.4%] non-Hispanic Black, 807 [85.4%] publicly insured). Scheduling rates were 18.4% in the standard message group (adjusted risk ratio [aRR], 1.97; 95% CI, 1.32-2.84) and 14.9% in the tailored message group (aRR, 1.57; 95% CI, 1.02-2.34) compared with the control group (9.5%). Well child care visit completion rates were 24.1% in the standard message group (aRR, 1.92; 95% CI, 1.38-2.60) and 19.4% in the tailored message group (aRR, 1.52; 95% CI, 1.06-2.13) compared with the control group (12.7%). Among eligible children, rates of receiving the COVID-19 vaccine were 16.7% in the standard message group compared with 4.8% in the tailored message (aRR, 3.41; 95% CI, 1.14-9.58) and 3.7% in the control groups (aRR, 4.84; 95% CI, 1.44-15.12).Conclusions and RelevanceIn this randomized clinical trial, outreach messages delivered via electronic health record patient portals increased the rates of scheduling and completing WCC visits and receiving the COVID-19 vaccine, providing a useful tool to help restore WCC in populations whose care was delayed during the pandemic.Trial RegistrationClinicalTrials.gov Identifier: NCT04994691

Yingying Xu,1 Huanyu Zhao,2 Yusuo Tong,1 Wanwei Wang,1 Jing Huang,1 Weiguo Zhu1 1Department of Radiation Oncology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, 223300, People’s Republic of China; 2Department of Pathology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, 223300, People’s Republic of ChinaCorrespondence: Weiguo Zhu Email zhuweiguo_1270@126.comBackground: Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma (SCC) of the esophagus. This study aimed to assess the discrepancy in clinicopathological characteristics and protein expression between esophageal BSCC and typical esophageal SCC.Study Design: We reviewed 40 cases of esophageal BSCC. As controls, 63 well-differentiated SCC (WSCC) patients, 70 moderately differentiated SCC (MSCC) patients, and 51 poorly differentiated SCC (PSCC) patients were selected. The clinicopathologic characteristics and immunoreactivity of Ki-67, p53, p63, and epidermal growth factor receptor (EGFR) were then evaluated in the BSCC and typical SCC patients.Results: The 5-year survival rates for the BSCC patients were 27.5%. The prognostic outcomes of the BSCC group were similar to those of the PSCC and MSCC groups but worse than that of the WSCC group, with a significant difference (P=0.045). Ki-67 expression was significantly higher in the BSCC group than that in the WSCC group (P < 0.05). Meanwhile, there were no significant differences in the expression of the other molecular markers (p53, p63, and EGFR) between the typical SCC and BSCC groups (P > 0.05). The median survival time of esophageal the BSCC patients with low p53 expression was significantly longer than that of the patients with high p53 expression (P=0.026). Further, the median survival time of the esophageal BSCC patients with high p63 expression was significantly longer than that of the patients with low p63 expression (P=0.041). Meanwhile, Ki-67 and EGFR expressions were not correlated with OS in the BSCC group.Conclusion: Esophageal BSCC has a more clinically virulent course. Notably, p53 and p63 expression are associated with prognosis in BSCC. These findings conject that evaluation of multiple cancer biomarkers might be a promising auxiliary diagnostic indicator in BSCC.Keywords: basaloid squamous cell carcinoma, Ki-67, p53, p63, EGFR

Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC50 = 5.3 nM, SI > 4000), superior to CBD (IC50 = 0.67 μM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (Kd = 13 nM, k2 = 0.26 min−1), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Aβ1−42 (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.

Expression and short-term prognostic value of miR-126 and miR-182 in patients with acute stroke were investigated. In total, 153 patients with acute stroke admitted to the Second Affiliated Hospital of Soochow University from February 2016 to February 2018 were enrolled into the observation group as group A [88 patients with acute cerebral infarction (AIS)] or group B [65 patients with cerebral hemorrhage (ICH)]. Furthermore, 69 healthy people receiving physical examinations in the hospital were enrolled into the control group. The relative expression of miR-126 and miR-182 in all subjects were measured and their correlation with the National Institute of Health stroke scale (NIHSS) and activities of daily living (ADL) scores was analyzed. After 3 months of follow-up, the correlation of miR-126 and miR-182 with the Modified Rankin Scale (MRS) score of patients was investigated. The receiver operating characteristic (ROC) curve was employed to explore the value of miR-126 and miR-182, alone or in combination, in predicting the prognosis of acute stroke patients. Subjects in the control group had markedly higher miR-126 expression and lower miR-182 expression than those in group A and group B in the observation group (P

Objectives In this study, we investigated the possible analgesic effects of Botulinum toxin type A (BoNT/A) on trigeminal neuralgia (TN). A modified TN mouse model was established by chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) in mice, and the possible roles of microglia toll-like receptor 2 (TLR2) and neuroinflammation was investigated. Methods Male C57BL/6 mice were divided into 3 groups, including sham group, vehicle-treated TN group and BoNT/A-treated TN group. Bilateral mechanical pain hypersensitivity, anxiety-like and depressive-like behaviors were evaluated by using von Frey test, open field, elevated plus-maze testing, and forced swimming test in mice, respectively. The mRNA or protein expression levels of toll-like receptors (TLRs), glia activation markers and proinflammatory factors in the trigeminal nucleus caudalis (TNC) were tested by RT-qPCR, immunofluorescence and Western blotting. We also tested the pain behaviors of TN in Tlr2−/− mice. Results We found that unilateral subcutaneous injection of BoNT/A into the whisker pad on the ipsilateral side of dIoN-CCI mice significantly attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors induced by dIoN-CCI surgery in mice. The dIoN-CCI surgery significantly up-regulated the expression of TLR2, MyD88, CD11b (a microglia marker), IL-1β, TNF-α and IL-6 in the ipsilateral TNC in mice, and BoNT/A injection significantly inhibited the expression of these factors. Immunostaining results confirmed that BoNT/A injection significantly inhibited the microglia activation in the ipsilateral TNC in dIoN-CCI mice. TLR2 deficiency also alleviated bilateral mechanical pain hypersensitivity and the up-regulation of MyD88 expression in the TNC of dIoN-CCI mice. Conclusion These results indicate that unilateral injection of BoNT/A attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors in dIoN-CCI mice, and the analgesic effects of BoNT/A may be associated with the inhibition of TLR2-mediated neuroinflammation in the TNC.

Highlights • A human embryonic stem cell line (WAe001-A-58) with inducible expression of the SARS-CoV-2 nucleocapsid protein was generated by piggyBac transposon system. • This single cell-derived cell line maintained its pluripotency, differentiation potentials, normal morphology and karyotype. • SARS-CoV-2 nucleocapsid protein in this cell line is inducible in a doxycycline dose-dependent manner., Excessive prostaglandin E2 (PGE2) is the key pathological basis for COVID-19 and a Celebrex treatment of hospitalized COVID-19 patients with comorbidities led to 100% discharged rate and zero death (Hong et al. 2020). It is also suggested that SARS-CoV-2 infected multiple organs and the SARS-CoV nucleocapsid (N) protein transcriptionally drives the expression of the host COX-2 gene. In order to test whether SARS-CoV-2 N protein activates COX-2 transcription in multiple human relevant cell types, an expression inducible human embryonic stem cell line was generated by piggyBac transposon system. This cell line maintained its pluripotency, differentiation potentials, normal morphology and karyotype.

In this paper, we propose a phase attention residual network (PA-ResSeg) to model multi-phase features for accurate liver tumor segmentation, in which a phase attention (PA) is newly proposed to additionally exploit the images of arterial (ART) phase to facilitate the segmentation of portal venous (PV) phase. The PA block consists of an intra-phase attention (Intra-PA) module and an inter-phase attention (Inter-PA) module to capture channel-wise self-dependencies and cross-phase interdependencies, respectively. Thus it enables the network to learn more representative multi-phase features by refining the PV features according to the channel dependencies and recalibrating the ART features based on the learned interdependencies between phases. We propose a PA-based multi-scale fusion (MSF) architecture to embed the PA blocks in the network at multiple levels along the encoding path to fuse multi-scale features from multi-phase images. Moreover, a 3D boundary-enhanced loss (BE-loss) is proposed for training to make the network more sensitive to boundaries. To evaluate the performance of our proposed PA-ResSeg, we conducted experiments on a multi-phase CT dataset of focal liver lesions (MPCT-FLLs). Experimental results show the effectiveness of the proposed method by achieving a dice per case (DPC) of 0.77.87, a dice global (DG) of 0.8682, a volumetric overlap error (VOE) of 0.3328 and a relative volume difference (RVD) of 0.0443 on the MPCT-FLLs. Furthermore, to validate the effectiveness and robustness of PA-ResSeg, we conducted extra experiments on another multi-phase liver tumor dataset and obtained a DPC of 0.8290, a DG of 0.9132, a VOE of 0.2637 and a RVD of 0.0163. The proposed method shows its robustness and generalization capability in different datasets and different backbones., Comment: A self-archive version to be published in Medical Physics, awaiting minor revision

Obesity is a chronic and recurrent disease with potential risks. Traditional weight-loss methods (like exercises, surgeries, oral drugs, etc.) have shown different side effects. In this experiment, the microneedle (MN) patch was selected as the drug carrier of the weight-loss drug Rosiglitazone (Rosi). Besides, melanin was added to enhance the photo-thermal effect and accelerate the release of drugs to the target fat region under near-infrared (NIR) light. Afterwards, with exterior cold stimulation, the significant and accurate effect of body slimming could be achieved. This combination of soluble MN patches and variable temperatures provides an attractive nonsurgical method for future accurate body slimming management.

A population genetic study identified that the asialoglycoprotein receptor 1 (ASGR1) mutation carriers had substantially lower non-HDL-cholesterol (non-HDL-c) levels and reduced risks of cardiovascular diseases. However, the mechanism behind this phenomenon remained unclear. Here, we established Asgr1-knockout mice that represented a plasma lipid profile with significantly lower non-HDL-c and triglyceride (TG) caused by decreased secretion and increased uptake of VLDL/LDL. These 2 phenotypes were linked with the decreased expression of microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9, 2 key targeted genes of sterol regulatory element-binding proteins (SREBPs). Furthermore, there were fewer nuclear SREBPs (nSREBPs) on account of more SREBPs being trapped in endoplasmic reticulum, which was caused by an increased expression of insulin-induced gene 1 (INSIG1), an anchor of SREBPs. Overexpression and gene knockdown interventions, in different models, were conducted to rescue the ASGR1-deficient phenotypes, and we found that INSIG1 knockdown independently reversed the ASGR1-mutated phenotypes with increased serum total cholesterol, LDL-c, TG, and liver cholesterol content accompanied by restored SREBP signaling. ASGR1 rescue experiments reduced INSIG1 and restored the SREBP network defect as manifested by improved apolipoprotein B secretion and reduced LDL uptake. Our observation demonstrated that increased INSIG1 is a critical factor responsible for ASGR1 deficiency-associated lipid profile changes and nSREBP suppression. This finding of an ASGR1/INSIG1/SREBP axis regulating lipid hemostasis may provide multiple potential targets for lipid-lowering drug development.

Gastric cancer (GC) has been identified as one of the most common malignancies. It was found that microRNAs can be used as potential biomarkers for GC diagnosis. The aim of this study was to estimate the diagnostic value of 4 potential microRNAs in GC.PubMed, Embase, Cochrane Library, and Web of Science were used to search published studies. The quality of the studies was scored with the Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity and specificity, diagnostic odds ratio (DOR) and area under the curve (AUC) were calculated. The heterogeneity was evaluated using Cochrane Q statistics and the inconsistency index.A total of 22 studies reporting the diagnostic value of miR-21 (n = 9), miR-106 (n = 10), miR-421 (n = 5) and miR-223 (n = 3) were included. Quality Assessment of Diagnostic Accuracy Studies scores showed the high quality of the selected 22 articles. The random effects model was adopted by evaluating the heterogeneity between articles. The DOR, AUC, and Q value of miRNA-21 were 12.37 (95% confidence interval [CI]: 5.36-28.54), 0.86 and 0.79, respectively. The DOR, AUC and Q value of miRNA-106 were 12.98 [95% CI: 7.14-23.61], 0.85 and 0.78, respectively. The DOR, AUC and Q value of miRNA-421 were 27.86 [95% CI: 6.04-128.48], 0.92 and 0.86, respectively. The DOR, AUC and Q value of miRNA-223 were 18.50 [95% CI: 7.80-43.86], 0.87 and 0.80, respectively. These results indicate that miRNA-421 has the highest diagnostic accuracy, followed by miR-223, miRNA-21, and miRNA-106 among the 4 microRNAs in GC.miR-21, miR-106, miR-421, and miR-223 have good diagnostic efficacy, especially miR-421, could be used as auxiliary diagnostic indicator for GC.

Aim This study aimed to reveal the effects of icaritin (ICT) on lipotoxicity induced by palmitate (PA) in hepatic cells and steatosis in high-fat diet (HFD)-fed mice as well as exploring the potential mechanisms. Main methods Primary mouse hepatocytes and human hepatoma Huh7 cells were used to evaluate ICT effect in vitro. HFD-fed mice were used to evaluate the ICT effect in vivo. Results In vitro study indicated that ICT significantly rescued PA-induced steatosis, mainly through a combination of robust increased mitochondrial respiration, fatty acid oxidation and mildly decreased synthesis of fatty acid. An HFD-fed mouse model with 8 weeks HFD-fed showed metabolic disorders, while ICT application significantly reduced the weight, serum glucose levels, insulin resistance, hepatic steatosis level and adipose contents. In consistent with the observations in cell lines, ICT rescued the HFD-impaired functions and contents of key factors related to fatty acid β-oxidation through elevated expression of peroxisome proliferator-activated receptor α (PPARα). Meanwhile, it also reversed the decreased phosphoryl levels of AKT and glucogen synthase kinase 3 (GSK3β), leading to the improvement of insulin resistance. Significance ICT administration had a therapeutic effect on PA- or HFD-induced hepatic steatosis and metabolic disorders. It may provide a novel strategy to construct preventive and therapeutic means for hepatic steatosis.

PurposeEnvironmental chemical exposures may adversely affect an array of adolescent health outcomes. Thus, we used the Health Outcomes and Measures of the Environment (HOME) study, a prospective cohort that recruited pregnant women and conducted longitudinal follow-up on children over the first 12 years of life, to determine if and when chemical exposures affect adolescent health.ParticipantsWe recruited 468 pregnant women (age range: 18–45 years) from the Cincinnati, Ohio region to participate in a cohort study between March 2003 and January 2006. Follow-up included two clinic and one home visits during pregnancy, a delivery hospital visit, and four home and six clinic visits when children were aged 4 weeks and 1, 2, 3, 4, 5 and 8 years. Of 441 children available for follow-up, 396 (90%) completed at least one follow-up and 256 (58%) completed the most recent follow-up at 12 years of age (range: 11–14).Findings to dateOur new measures include maternal/child report of internalising symptoms, neuroimaging, dual-energy X-ray absorptiometry-derived estimates of lean/adipose tissue and bone mineral density, and cardiometabolic risk biomarkers. We assessed adolescent exposure to perfluoroalkyl substances, phenols, phthalates and flame retardants. Participants completing follow-up at 12 years of age were similar to the original cohort in terms of baseline factors. Most children had typical and expected values for this age on measures of internalising symptoms, body composition, bone density and cardiometabolic risk markers. Notably, 36% and 11% of children had scores indicative of potential anxiety and depressive disorders, respectively. Approximately 35% of children were overweight or obese, with higher prevalence among girls. Thirty-three per cent of children had borderline or high triglyceride concentrations (>90 mg/dL).Future plansWe will examine associations of early life environmental chemical exposures with adolescent health measures while considering potential periods of heightened susceptibility and mixture effects.Trial registration numberNCT00129324.

BACKGROUND: The discordance of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 cell nuclear proliferation antigen status in patients with locally advanced breast cancer pre- and post-neoadjuvant chemotherapy (NAC) is quite common. This study aimed to assess the frequency of changes in receptor status after NAC in patients with invasive ductal breast cancer and the prognostic impact of such changes. METHODS: The study comprised 670 patients who were diagnosed with invasive ductal breast carcinoma and treated with both NAC and surgery from 2012–2017. Hormone receptor (HR; including ER and PR), HER2, and Ki-67 status was assessed before NAC and in residual invasive tumor cells of the surgical specimens. The prognostic impact of receptor conversions in breast cancer patients treated with NAC was evaluated in this retrospective study. RESULTS: The conversion of ER was related to overall survival (OS; P=0.008) and disease-free survival (DFS; P=0.004). Patients whose ER status was always positive had the best prognosis, and those who were always negative had the worst prognosis. Similar results were also found for PR status, as the conversion of PR status was also related to OS (P20% after NAC had the worst survival. Nevertheless, there was no statistical significance in the conversion of HER2 status. In multivariate Cox regression analyses, PR conversion and post-neoadjuvant pathological lymph node stage (ypN) were independent prognostic factors for DFS (P=0.008

The human GLI3 protein has a dual function as a transcriptional activator or repressor of hedgehog signaling, depending on the proteolytic processing forms of GLI3. In this study, we established a compound heterozygous GLI3 mutant human embryonic stem cell line (WAe001-A-20) through CRISPR/Cas9 editing. The WAe001-A-20 cells carried two deletions on two different alleles of exon 2 of GLI3, respectively, which resulted in a frame shift and early termination in the translation of GLI3. Moreover, WAe001-A-20 maintains a normal karyotype, parental cell morphology, pluripotent phenotype and the ability to differentiate into three germ layers.Resource tableUnlabelled TableUnique stem cell line identifierWAe001-A-20Alternative name(s) of stem cell lineH1-GLI3-KOInstitutionGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesContact information of distributorYin-xiong Li, li_yinxiong@gibh.ac.cnType of cell lineEmbryonic stem cell lineOriginWAe001-AAdditional origin infoAge: blastocyst stageSex: male, 46, XYCell SourceN/AClonalityClonalMethod of reprogrammingN/AGenetic ModificationYESType of ModificationDeletionAssociated diseaseGreig Cephalopolysyndactyly Syndrome, Pallister-Hall Syndrome, Postaxial PolydactylyGene/locusGLI3/7p14.1Method of modificationCRISPR/Cas9Name of transgene or resistanceN/AInducible/constitutive systemN/ADate archived/stock dateApril 20, 2018Cell line repository/bankN/AEthical approvalCell line was used according to institutional ethical guidelines of GIBH

This study aims to evaluate the practical potential of using constructed wetlands (CWs) for treating saline wastewater containing various heavy metals. The results demonstrated that CWs growing Canna indica with porous slag as substrate could efficiently remove heavy metals (Cu, Zn, Cd, and Pb) from saline wastewater at an electrical conductivity (EC) of 7 mS/cm, especially under low influent load. Salts with salinity level (characterized as EC) of 30 mS/cm suppressed the removal of some heavy metals, dependent on heavy metal species and their influent concentrations. The presence of salts in CWs can improve the accumulation of Cu, Zn, and Pb in plant tissues as compared to control treatment, irrespective of metal concentrations in solution. The influence of salts on Cd accumulation depended on both salinity levels and Cd concentrations in solution. Although more heavy metals were accumulated in roots than in shoots, the harvesting of aboveground plant materials is still efficient addition for heavy metal removal due to the greater biomass and growth rate of aboveground plant material. Furthermore, replacing all plants instead of preserving roots from harvested plants in CWs over a period of time is essential for heavy metal removal, because the continued accumulation by roots can be inhibited by the increasing accumulated heavy metals from saline wastewater.

The aim of this study was to assess the diagnostic performance of fluorine-18-fluorodeoxyglucose (F-FDG) PET/MRI for suspected recurrence of pelvis malignancies of female patients using a meta-analysis. We performed a systematical literature search for relevant studies in PubMed, Cochrane Library, Google Scholar, and several Chinese databases. Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the quality of all included studies. Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were calculated per patient and per lesion. Summary receiver operating characteristic curves were also constructed. All procedures involving human participants in this study were performed in conformity with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Finally, seven articles comprising 257 patients and 695 lesions were included in this meta-analysis. On patient-based analysis, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of F-FDG PET/MRI in detecting recurrence of pelvis malignancies were 0.96 [95% confidence interval (CI): 0.93-0.99], 0.95 (95% CI: 0.87-0.99), 9.85 (95% CI: 4.62-21.00), 0.07 (95% CI: 0.04-0.13), and 201.41 (95% CI: 62.89-645.03), respectively. On lesion-based analysis, the corresponding estimates were 0.99 (95% CI: 0.97-1.00), 0.94 (95% CI: 0.89-0.97), 17.11 (95% CI: 4.46-65.60), 0.02 (95% CI: 0.01-0.05), and 1125.24 (95% CI: 211.46-5987.79), respectively. The results of our meta-analysis indicate that F-FDG PET/MRI has excellent diagnostic performance in restaging female patients with suspected recurrence of gynecological pelvic malignancies.

The ASS1 gene encodes argininosuccinate synthetase-1, a cytosolic enzyme with a critical role in the urea cycle. Mutations are found in all ASS1 exons and cause the autosomal recessive disorder citrullinemia. Using CRISPR/Cas9-editing, we established the WAe001-A-13 cell line, which was heterozygous for an ASS1 mutation, from the human embryonic stem cell line H1. The WAe001-A-13 cell line maintained the pluripotent phenotype, the ability to differentiate into all three germ layers and a normal karyotype.

Background Coronavirus disease 2019 (COVID-19) has evolved into a worldwide pandemic, and has been found to be closely associated with mental and neurological disorders. We aimed to comprehensively quantify the association between mental and neurological disorders, both pre-existing and subsequent, and the risk of susceptibility, severity and mortality of COVID-19. Methods In this systematic review and meta-analysis, we searched PubMed, Web of Science, Embase, PsycINFO, and Cochrane library databases for studies published from the inception up to January 16, 2021 and updated at July 7, 2021. Observational studies including cohort and case-control, cross-sectional studies and case series that reported risk estimates of the association between mental or neurological disorders and COVID-19 susceptibility, illness severity and mortality were included. Two researchers independently extracted data and conducted the quality assessment. Based on I2 heterogeneity, we used a random effects model to calculate pooled odds ratios (OR) and 95% confidence intervals (95% CI). Subgroup analyses and meta-regression analysis were also performed. This study was registered on PROSPERO (registration number: CRD 42021230832). Finding A total of 149 studies (227,351,954 participants, 89,235,737 COVID-19 patients) were included in this analysis, in which 27 reported morbidity (132,727,798), 56 reported illness severity (83,097,968) and 115 reported mortality (88,878,662). Overall, mental and neurological disorders were associated with a significant high risk of infection (pre-existing mental: OR 1·67, 95% CI 1·12-2·49; and pre-existing neurological: 2·05, 1·58-2·67), illness severity (mental: pre-existing, 1·40, 1·25-1·57; sequelae, 4·85, 2·53-9·32; neurological: pre-existing, 1·43, 1·09-1·88; sequelae, 2·17, 1·45-3·24), and mortality (mental: pre-existing, 1·47, 1·26-1·72; neurological: pre-existing, 2·08, 1·61-2·69; sequelae, 2·03, 1·66-2·49) from COVID-19. Subgroup analysis revealed that association with illness severity was stronger among younger COVID-19 patients, and those with subsequent mental disorders, living in low- and middle-income regions. Younger patients with mental and neurological disorders were associated with higher mortality than elders. For type-specific mental disorders, susceptibility to contracting COVID-19 was associated with pre-existing mood disorders, anxiety, and attention-deficit hyperactivity disorder (ADHD); illness severity was associated with both pre-existing and subsequent mood disorders as well as sleep disturbance; and mortality was associated with pre-existing schizophrenia. For neurological disorders, susceptibility was associated with pre-existing dementia; both severity and mortality were associated with subsequent delirium and altered mental status; besides, mortality was associated with pre-existing and subsequent dementia and multiple specific neurological diseases. Heterogeneities were substantial across studies in most analysis. Interpretation The findings show an important role of mental and neurological disorders in the context of COVID-19 and provide clues and directions for identifying and protecting vulnerable populations in the pandemic. Early detection and intervention for neurological and mental disorders are urgently needed to control morbidity and mortality induced by the COVID-19 pandemic. However, there was substantial heterogeneity among the included studies, and the results should be interpreted with caution. More studies are needed to explore long-term mental and neurological sequela, as well as the underlying brain mechanisms for the sake of elucidating the causal pathways for these associations. Funding This study is supported by grants from the National Key Research and Development Program of China, the National Natural Science Foundation of China, Special Research Fund of PKUHSC for Prevention and Control of COVID-19, and the Fundamental Research Funds for the Central Universities.

Many clinical studies have demonstrated that the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and Onodera's prognostic nutritional index (OPNI) are visibly involved in the prognosis of a variety of tumors. In our research, we aim to determin the prognostic impact of NLR, PLR, and OPNI for hepatocellular carcinoma (HCC). Data of hepatocellular carcinoma patients undergoing treatment in Changzhi People's Hospital between 2011 and 2017 were reviewed. 270 patients with HCC were under inclusion criteria. The optimal cut-off points of OPNI, NLR and PLR were determined by using the X-tile program. The overall survival (OS) was analyzed by Kaplan–Meier method. Multivariate analysis was performed using Cox Proportional Hazard Regression model to determine independent prognostic indicators for HCC. As revealed by Univariate and multivariate analysis, OPNI, Treatment, PLR, and BCLC Stage can be used as independent prognostic indicators for HCC. Comparing the P values and hazard ratios, we found out that the OPNI has greatest influence on prognosis in these indexes. The appropriate cut-off points of NLR, PLR, and OPNI were 2.5, 133.3, and 39.5, respectively. High score OPNI group had a better OS. In the analysis between OPNI and clinicopathological characteristics, there were differences in treatment, postoperative therapy, AST, ALBI grade, NLR and PLR between the high OPNI group and the low OPNI group, while others did not. OPNI is a straightforward and effective independent prognostic indicator for HCC.

The gene asialoglycoprotein receptor 1 (ASGR1) encodes a subunit of the asialoglycoprotein receptor. Here we report the generation of a human embryonic stem cell line WAe001-A-6 harbouring homozygous ASGR1 mutations using CRISPR/Cas9. The mutation involves a 37 bp deletion, resulting in a frame shift. The homozygous knockout WA01 cell line maintains a normal karyotype, typical stem cell morphology, pluripotency and differentiation potential in vitro.

Lignocellulosic biomass from various types of wood has become a renewable resource for production of biofuels and biobased chemicals. Because xylan is the major component of wood hemicelluloses, highly efficient enzymes to enhance xylan hydrolysis can improve the use of lignocellulosic biomass. In this study, a xylanolytic gene cluster was identified from the crude oil-degrading thermophilic strain Geobacillus thermodenitrificans NG80-2. The enzymes involved in xylan hydrolysis, which include two xylanases (XynA1, XynA2), three β-xylosidases (XynB1, XynB2, XynB3), and one α-L-arabinofuranosidase (AbfA), have many unique features, such as high pH tolerance, high thermostability, and a broad substrate range. The three β-xylosidases were highly resistant to inhibition by product (xylose) accumulation. Moreover, the combination of xylanase, β-xylosidase, and α-L-arabinofuranosidase exhibited the largest synergistic action on xylan degradation (XynA2, XynB1, and AbfA on oat spelt or beechwood xylan; XynA2, XynB3, and AbfA on birchwood xylan). We have demonstrated that the proposed enzymatic cocktail almost completely converts complex xylan to xylose and arabinofuranose and has great potential for use in the conversion of plant biomass into biofuels and biochemicals.

Inhibition of α-glucosidase has attracted the attention of researchers due to its connection to type-2 diabetes. Hydroxysafflor yellow A (HSYA) extracted from Carthamus tinctorius L. is a natural antioxidant used in traditional Chinese medicine. In this study, the effect of HSYA on α-glucosidase was evaluated using inhibitory kinetics based on the antioxidant properties of HSYA and by performing computational simulation integration methods. HSYA reversibly inhibited α-glucosidase in a competitive inhibition manner and the evaluated kinetic parameters were IC50 = 1.1 ± 0.22 mM and Ki = 1.04 ± 0.23 mM, respectively. The results of spectrofluorimetry showed that the inner hydrophobic regions of α-glucosidase, which are mostly in the active site, were exposed to the surface with increasing HSYA concentrations, indicating that the inactivation of α-glucosidase by HSYA was accompanied by regional unfolding. The molecular dynamics simulations indicated that the four rings of HSYA interact with four residues such...