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Abstract Objective This study aimed to explore the association between slow‐wave sleep and the progression of motor and nonmotor symptoms in patients with PD. Methods Data were collected from the Parkinson's Progression Markers Initiative study. Slow‐wave sleep, also known as deep non‐rapid eye movement (DNREM) sleep, was objectively assessed using the Verily Study Watch. Motor function was assessed using the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale Part III score, Hoehn and Yahr stage, freezing of gait, motor fluctuations, and dyskinesia severity. Comprehensive assessments were conducted on nonmotor symptoms, including depression, anxiety, global cognitive function, and autonomic dysfunction. Statistical analyses involved repeated‐measures analysis of variance and linear regression. Results A total of 102 patients with PD were included in the study, with a median follow‐up duration of 3.4 years. In the long DNREM sleep duration group (n = 55), better motor function (DNREM × time interaction: F(1,100) = 4.866, p = 0.030), less severe sexual dysfunction (p = 0.026), and improved activities of daily living (p = 0.033) were observed at the last follow‐up visit compared with the short DNREM sleep duration group (n = 47). Reduced DNREM sleep duration is a risk factor for motor progression (β = −0.251, p = 0.021; 95% confidence interval = −0.465 to −0.038). Interpretation The findings suggest an association between longer DNREM sleep duration and slower motor and nonmotor progression in patients with PD.

Abstract Backgrounds Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by synovial hyperplasia. Maintaining a balance between the proliferation and apoptosis of rheumatoid arthritis synovial fibroblasts (RASFs) is crucial for preventing the erosion of bone and cartilage and, ultimately, mitigating the progression of RA. We found that the lncRNA LEF1-AS1 was expressed at low levels in the RASFs and inhibited their abnormal proliferation by targeting PIK3R2 protein and regulating the PI3K/AKT signal pathway through its interaction with miR-30-5p. In this study, we fabricated a nano-drug delivery system for LEF1-AS1 using Zn-Adenine nanoparticles (NPs) as a novel therapeutic strategy against RA. Methods The expression levels of LEF1-AS1, miR-30-5p, PIK3R2, p-PI3K, and p-AKT were detected in the primary RASFs and a human fibroblast-like synovial cell line (HFLS). Zn-Adenine nanoparticles (NPs) were functionalized with anti-CD305 antibody to construct (Zn-Adenine)@Ab. These NPs were then loaded with LEF1-AS1 to form (Zn-Adenine)@Ab@lncRNA LEF1-AS1. Finally, the (Zn-Adenine)@Ab@lncRNA LEF1-AS1 NPs were locally injected into a rat model with collagen-induced arthritis (CIA). The arthritic injuries in each group were evaluated by HE staining and other methods. Results LEF1-AS1 was expressed at low levels in the primary RASFs. High expression levels of LEF1-AS1 were detected in the HFLS cells, which corresponded to a significant downregulation of miR-30-5p. In addition, the expression level of PIK3R2 was significantly increased, and that of p-PI3K and p-AKT were significantly downregulated in these cells. The (Zn-Adenine)@Ab@lncRNA LEF1-AS1 NPs significantly inhibited the proliferation of RASFs and decreased the production of inflammatory cytokines (IL-1β, IL-6, TNF-α). Intra-articular injection (IAI) of (Zn-Adenine)@Ab@lncRNA LEF1-AS1 NPs significantly alleviated cartilage destruction and joint injury in the CIA-modeled rats. Conclusions LEF1-AS1 interacts with miR-30-5p to inhibit the abnormal proliferation of RASFs by regulating the PI3K/AKT signal pathway. The (Zn-Adenine)@Ab NPs achieved targeted delivery of the loaded LEF1-AS1 into the RASFs, which improved the cellular internalization rate and therapeutic effects. Thus, LEF1-AS1 is a potential target for the treatment of RA.

Abstract Background Lung Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive, high‐grade neuroendocrine carcinoma with a poor prognosis, mainly seen in elderly men. To date, we have found no studies on predictive models for LCNEC. Methods We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database of confirmed LCNEC from 2010 to 2018. Univariate and multivariate Cox proportional risk regression analyses were used to identify independent risk factors, and then we constructed a novel nomogram and assessed the predictive effectiveness by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results A total of 2546 patients with LCNEC were included, excluding those diagnosed with autopsy or death certificate, tumor, lymph node, metastasis (TNM) stage, tumor grade deficiency, etc., and finally, a total of 743 cases were included in the study. After univariate and multivariate analyses, we concluded that the independent risk factors were N stage, intrapulmonary metastasis, bone metastasis, brain metastasis, and surgical intervention. The results of ROC curves, calibration curves, and DCA in the training and validation groups confirmed that the nomogram could accurately predict the prognosis. Conclusions The nomogram obtained from our study is expected to be a useful tool for personalized prognostic prediction of LCNEC patients, which may help in clinical decision‐making.

Abstract Primary pulmonary sarcoma (PPS) is a rare and poor prognostic malignancy that results from current clinical studies are lacking. Our study aimed to investigate the prognostic factors of PPS and to construct a predictive nomogram that predict the overall survival (OS) rate. We extracted data on patients diagnosed with PPS from 2010 to 2019 in the SEER database. A total of 169 patients were included after screening by inclusion and exclusion criteria. Univariate and multivariate COX regression analyses showed that age, pathological grade, liver metastasis, surgical intervention, and chemotherapy influenced the prognosis. We constructed the prediction model nomogram based on these factors. Moreover, the results of the internal and external ROC curves, calibration curves, and DCA plots confirmed that the model has good discrimination, accuracy, and clinical practice efficacy. The present study is the first population-based study to explore the factors affecting the prognosis of PPS. We established a novel prognostic nomogram to predict the OS rate, which can help to make proper clinical decisions.

Abstract Although 2D material van der Waals heterostructures (vdWHs) exhibit many novel properties and applications, 2D homojunctions have unique advantages in interface lattice matching, band continuity, and charge transfer efficiency. However, the rectification performances of 2D homojunction diodes are severely limited by the small junction barrier, mainly due to inefficient charge doping. In this work, an ultrahigh‐rectification‐ratio WSe2 homojunction diode achieved by the semi‐floating gate doping of graphdiyne oxide (GDYO) is reported. Utilizing the WSe2/GDYO direct charge trapping mode can free the inhibition of charge capturing efficiency by removing conventional insulating barriers and thus improve the rectification ratio. The C─C(sp) and oxygen‐containing functional groups in the GDYO layer can provide outstanding charge‐trapping ability due to their unsaturation. Furthermore, the oxygen plasma treatment used for oxidizing graphdiyne (GDY) into GDYO can make GDYO a flatter surface, thus creating strong‐coupling WSe2/GDYO interfaces to improve the charge transfer efficiency and enhance the electrostatic doping effect. Besides, the WSe2/GDYO interfaces are confirmed to possess a higher junction barrier than that of the WSe2/GDY interfaces. This research proposes a brand‐new approach to building p–n junctions via charge trapping and the homojunction diode with a record‐highest rectification ratio of up to 106 is obtained.

Summary: Major histocompatibility complex (MHC) class II-reactive CD8+ T cells are found in humans and animals, but little is known about their identity, development, and function. In this study, we discover a group of CD8+ T cells reactive to both MHC class I and II molecules in MHC class II-deficient mice. We clone their T cell receptors (TCRs) and analyze their development and function. In wild-type animals, thymocytes bearing those TCRs are purged by negative selection. In the absence of MHC class II, they develop into mature CD8+ T cells. When encountering MHC class II in the periphery, they undergo robust activation and proliferation, attack self-tissues, and cause lethal autoimmune diseases. In adoptive T cell therapy, those CD8+ T cells are able to efficiently control MHC class II-expressing tumors. This study opens the door to investigation of dual-reactive CD8+ T cells, their development and selection in the thymus, and the perils and promises when their normal development and selection are compromised.

Lung cancer (LC) is one of the leading causes of high cancer-associated mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common type of LC. The mechanisms of NSCLC evolution involve the alterations of multiple complex signaling pathways. Even with advances in biological understanding, early diagnosis, therapy, and mechanisms of drug resistance, many dilemmas still need to face in NSCLC treatments. However, many efforts have been made to explore the pathological changes of tumor cells based on specific molecular signals for drug therapy and targeted delivery. Nano-delivery has great potential in the diagnosis and treatment of tumors. In recent years, many studies have focused on different combinations of drugs and nanoparticles (NPs) to constitute nano-based drug delivery systems (NDDS), which deliver drugs regulating specific molecular signaling pathways in tumor cells, and most of them have positive implications. This review summarized the recent advances of therapeutic targets discovered in signaling pathways in NSCLC as well as the related NDDS, and presented the future prospects and challenges.

Abstract Background The increasing incidence of osteoporosis in recent years has aroused widespread public concern; however, existing effective treatments are limited. Therefore, new osteoporosis treatment methods, including stem cell transplantation and exosome therapy, have been proposed and are gaining momentum. Exosomes are considered to have greater potential for clinical application owing to their immunocompatibility. This study summarises the latest evidence demonstrating the efficacy of exosomes in improving bone loss in the treatment of osteoporosis. Main text This systematic review and meta-analyses searched PubMed, Embase, and Cochrane Library databases from inception to 26 March 2022 for osteoporosis treatment studies using stem cell-derived exosomes. Six endpoints were selected to determine efficacy: bone mineral density, trabecular bone volume/tissue volume fraction, trabecular number, trabecular separation, trabecular thickness, and cortical thickness. The search generated 366 citations. Eventually, 11 articles that included 15 controlled preclinical trials and 242 experimental animals (rats and mice) were included in the meta-analysis. Conclusion The results were relatively robust and reliable despite some publication biases, suggesting that exosome treatment increased bone mass, improved bone microarchitecture, and enhanced bone strength compared with placebo treatments. Moreover, stem cell-derived exosomes may favour anabolism over catabolism, shifting the dynamic balance towards bone regeneration.

Objective Lumbar sympathetic trunk (LST) injury is one of the major complications after oblique lumbar interbody fusion (OLIF). LST injury often manifests as unequal skin temperature in lower limbs after operation, and there may be a large number of missed diagnoses due to the lack of attention and different diagnostic methods. The study aimed to investigate the incidence and clinical characteristics of LST injury after OLIF. Methods The data of patients with lumbar degenerative diseases who underwent OLIF in our hospital from April 2016 to October 2017 were retrospectively analyzed. Finally, a total of 54 patients were included. There were 10 males and 44 females, aged 58.4 ± 10.9 years. The skin temperature of lower limbs was measured before and a day after surgery. The patients were followed up at 1 week, 6 weeks, 6 months, and 2 years after the surgery. Likert five‐point scale was used to evaluate the discomfort caused by LST injury. Injury severity score was introduced to grade injury degree according to the recovery time of postoperative symptoms. The chi‐square test was used to analyze the association of incidence of lumbar sympathetic trunk (LST) injury with contributing factors, such as gender and number of surgical segments. Results The unequal temperature was not found before surgery in all the patients. Postoperatively, 16 cases (29.6%) had difference of skin temperature more than 0.5 °C and were diagnosed with LST injury. Eight patients (14.8%) had self‐perception of skin temperature differences, and 12 patients (22.2%) had other symptoms, such as muscle pain, numbness, and weakness, which were not statistically different between patients with and without lumbar sympathetic trunk injury (p > 0.05). In the 16 patients with LST injury, the difference of skin temperature between the two legs was 0.6 ± 0.1 °C on the first day, and the temperature difference lasted for 1.5–~12 months. According to Likert five‐point scale, two cases (12.5%) were poor, and 14 cases (87.5%) were moderate immediately after surgery. Fifteen cases improved to some extent 6 weeks to 12 months after surgery. Conclusion Postoperative LST injury is mainly manifested by different temperature of lower limbs. The incidence was higher in patients with multi‐segment OLIF than in those with single‐segment OLIF, and the subjective experience of most patients with LST injury was moderate discomfort.

Introduction: Luteolin is a plant-derived flavonoid that exhibits a broad range of pharmacological activities. Studies on luteolin have mainly focused on its use for hyperlipidaemia prevention, whereas the capacity of the flavonoid to hinder hyperglycaemia development remains underexplored. Objectives: To probe the anti-hyperglycemic mechanism of 6,8-guanidyl luteolin quinone-chromium coordination (GLQ.Cr), and to assess its regulatory effect on intestinal microbiota in type 2 diabetes mellitus (T2DM) mice. Methods: High-sucrose/high-fat diet-induced and intraperitoneal injection of streptozotocin was used to develop a T2DM model. Glycometabolism related indicators, histopathology, and gut microbiota composition in caecum samples were evaluated, and RNA sequencing (RNA-seq) of liver samples was conducted. Faecal microbiota transplantation (FMT) was further used to verify the anti-hyperglycemic activity of intestinal microbiota. Results: The administration of GLQ.Cr alleviated hyperglycaemia symptoms by improving liver and pancreatic functions and modulating gut microbe communities (Lactobacillus, Alistipes, Parabacteroides, Lachnoclostridium, and Desulfovibrio). RNA-seq analysis showed that GLQ.Cr mainly affected the peroxisome proliferative activated receptor (PPAR) signalling pathway in order to regulate abnormal glucose metabolism. FMT significantly modulated the abundance of Lactobacillus, Alloprevotella, Alistipes, Bacteroides, Ruminiclostridium, Brevundimonas and Pseudomonas in the caecum to balance blood glucose levels and counteract T2DM mice inflammation. Conclusion: GLQ.Cr improved the abnormal glucose metabolism in T2DM mice by regulating the PPAR signalling pathway and modulating intestinal microbial composition. FMT can improve the intestinal microecology of the recipient and in turn ameliorate the symptoms of T2DM-induced hyperglycaemia.

Alternative splicing crucially affects various biological processes, however, its function in heart development is largely unknown. Here, the authors show an essential role of alternative splicing factor PTBP1 in ventricular chamber development.

Abstract Purpose Retinol-binding protein 4 (RBP4) has been considered to be related to metabolic related diseases, such as hyperuricemia, obesity, and diabetes mellitus. However, whether nonalcoholic fatty liver disease (NAFLD) is related to RBP4 is unclear. Previous studies on the relationship between NAFLD and RBP4 levels have yielded inconsistent results. Hence, this meta-analysis was aimed to clarify whether circulating RBP4 levels are in relation to the risk of NAFLD. Methods A meta-analysis was performed by applying observational studies to evaluate circulating RBP4 levels and NAFLD. Eligible studies published up to September 23, 2022, were searched in Embase, PubMed, and Cochrane databases. Results In this study, 17 cross-sectional studies involving 8423 participants were included. Results from a random effects model showed that circulating RBP4 levels were higher in NAFLD patients than non-NAFLD (standardized mean difference (SMD) 0.28; 95% confidence intervals (CI): 0.11–0.46, I2: 89.8%). This association was confirmed in the Yellow race. However, no significant association was noted in the Caucasian race. After excluding the morbidly obese Population from the weight loss study (n = 2), the results of the comparison remained largely unchanged (SMD 0.28; 95% CI: 0.10–0.47, I2: 90.8%). Remarkable publication bias was not found. Although considerable heterogeneity was observed among the studies, no potential sources of heterogeneity were found in the subgroup analysis. Diagnostic methods for NAFLD were determined to be a potential source of statistical heterogeneity in meta-regression. Conclusion The findings provide evidence that NAFLD patients exhibit higher levels of circulating RBP4 compared with controls, but high heterogeneity was observed. Thus, a high RBP4 level is probably a potential risk factor for NAFLD. To confirm the causal link between NAFLD and RBP4 level of causality, further prospective cohort studies are needed.

Summary: The miR-17∼92 family microRNAs (miRNAs) play a key role in germinal center (GC) reaction through promoting T follicular helper (TFH) cell differentiation. It remains unclear whether they also have intrinsic functions in B cell differentiation and function. Here we show that mice with B cell-specific deletion of the miR-17∼92 family exhibit impaired GC reaction, plasma cell differentiation, and antibody production in response to protein antigen immunization and chronic viral infection. Employing CRISPR-mediated functional screening, we identify Socs3 as a key functional target of miR-17∼92 in regulating plasma cell differentiation. Mechanistically, SOCS3, whose expression is elevated in miR-17∼92 family-deficient B cells, interacts with NIK and promotes its ubiquitination and degradation, thereby impairing NF-κB signaling and plasma cell differentiation. This moderate increase in SOCS3 expression has little effect on IL-21-STAT3 signaling. Our study demonstrates differential sensitivity of two key signaling pathways to alterations in the protein level of an miRNA target gene.

BackgroundAs the most common gastrointestinal malignancy worldwide, liver metastases occur in half colorectal cancer (CRC) patients. Early detection can help treat them early and reduce mortality in patients with colorectal cancer liver metastases (CRLM). Finding useful biomarkers for CRLM is thus essential.MethodsThe TCGA and GEO databases were used to download the expression profiles and clinical data of the patients. Differential analysis screened for genes associated with CRLM, and univariate Cox regression analysis identified genes associated with prognosis. The least absolute shrinkage and selection operator (LASSO) method further preferred genes to construct a prognostic signature. Kaplan-Meier survival curves were used to show patients’ overall survival (OS). Receiver operating characteristic (ROC) curves showed the accuracy of the model. Risk scores and clinical characteristics of patients were included in multivariate Cox regression analysis to identify independent risk factors, and a nomogram was constructed. The proportion of immune cells and infiltration were assessed using the ‘CIBERSORT’ package and the ‘ESTIMATE’ package.ResultsWe constructed a signature consisting of seven CRLM-associated genes, and signature-based risk scores have great potential in estimating the prognosis of CRC patients. Moreover, the poor response to immunotherapy in high-risk patients might contribute to the poor prognosis of individuals. Furthermore, we found that overexpression of Hepcidin antimicrobial peptide (HAMP), the only gene highly expressed in CRC and liver metastatic tissues, promoted CRC development and that it was associated with tumor mutation burden (TMB), DNA mismatch repair (MMR) genes, and microsatellite instability (MSI) in various tumors. Finally, we found that in CRC patients, low expression of HAMP also represented a better immunotherapeutic outcome, reflecting the critical role of HAMP in guiding immunotherapy.ConclusionWe identified a prognostic signature containing 7 CRLM-associated genes, and the signature was specified as an independent predictor and a nomogram containing the risk score was built accordingly. In addition, the derived gene HAMP could help guide the exploration of profitable immunotherapeutic strategies.

The rapid collection of a library of biologically relevant molecules is essential in new drug discovery. Here we show a variety of bioactive 1,3-indanedione-based spirocyclic tetrahydroquinolines that have been concisely and efficiently constructed under the guidance of biology-oriented synthesis (BIOS). Using Pd(PPh3)4 as a catalyst, various 2-arylidene-1,3-indanediones can react with vinyl benzoxazinanones under the mild condition to afford a new class of spirocyclic tetrahydroquinolines in moderate to excellent yields (45%–99%) with high stereocontrol (>95:5 diastereoselectivity). Their structures were unambiguously confirmed by X-ray single crystal analysis. The biological evaluation revealed that two of the 1,3-indanedione-based spirocyclic tetrahydroquinolines show remarkable apoptosis-inducing activities over A549 human lung cancer cells, exceeding that of cisplatin. The antitur activities were triggered by reactive oxygen species, commonly overproduced in cancer cells. The clinical demand for antitumor chemotherapy for lung cancer has encouraged an all-out search for analogues with lower toxcity, improved therapeutic index and increased activity.

BackgroundAluminum (Al) can cause irreversible damage to neurons and synapses function, and the mechanism may be connected to mitochondrial damage caused by glycogen synthase kinase-3β (GSK-3β) regulating dynamin-related protein 1 (DRP1), resulting in inhibition of the growth of neuronal protrusions.ObjectiveTo investigate the role of GSK-3β regulating DRP1 in the inhibition of primary hippocampal neurite growth induced by Al.MethodsNeurons were extracted from the hippocampus of newborn mice (≤24 h old) for primary culture. On day 6, the purity of neurons was detected by immunofluorescence. On day 10, neurons with good growth state were selected for Al exposure and GSK-3β inhibitor SB216763 (SB) intervention. The experiment design included a blank control group, a dimethyl sulfoxide (DMSO) group, an Al (20 μmol·L−1) group, a SB (1 μmol·L−1) group, and a SB (1 μmol·L−1) + Al (20 μmol·L−1) group. After primary hippocampal neurons were treated with Al or SB for 48 h, cell viability was detected by CCK-8 assay, the mitochondrial morphology of primary hippocampal neurons was observed by transmission electron microscopy, the total protrusion length of primary hippocampal neurons was scanned and analyzed by laser confocal imaging, and their complexity was analyzed by Sholl analysis. The expression levels of phospho-GSK-3β, GSK-3β, and DRP1 were detected by Western blotting.ResultsThe immunofluorescent results showed that the purity of primary neurons was higher than 90%. After the Al exposure and the SB intervention for 48 h, compared with the blank control group, there was no obvious difference in cell viability in the DMSO group and the SB group (P>0.05), and the Al group showed reduced cell viability (P=0.006); there was no obvious difference in cell viability between the SB+Al group and the Al group (P>0.05). Compared with the blank control group, there was no obvious difference in the average total length of protrusion in the DMSO group and the SB group (P>0.05), and the Al group showed reduced average total length of neurite (P0.05), and that in the Al group was significantly reduced (P0.05). The mitochondrial structure of the blank control group was complete and the crest was clearly visible; there was no apparent variation in the mitochondrial structure in the DMSO group and the SB group; the mitochondria in the Al group were vacuolated and the crista disappeared; the SB+Al group showed clearer crista than the Al group. The difference in GSK-3β phosphorylation level among groups was statistically significant (F=45.841, P0.05), increased in the SB group (P=0.022), and significantly reduced in the Al group (P0.05), and significantly increased in the Al group (P=0.001); the DRP1 protein level in the SB+Al group was significantly lower than that in the Al group (P=0.029).ConclusionAl may increase the level of DRP1 protein by activating GSK-3β, causing mitochondrial damage and inhibiting neuronal protrusions growth.

In recent years, due to the disadvantages of poor overall performance and low safety reserve, there are more and more reinforcement cases for the bridge deck system of long-span arch bridges under the stress of beams. In order to give full play to the effect of adding large longitudinal beam method to strengthen the bridge deck system of long-span arch bridge and improve its stability and seismic performance.Based on the endurance time method (ETM) and the park-ang damage model, a theory for determining the suitable reinforcement section of long-span arch bridge deck system is proposed considering the seismic performance requirements and stability characteristics. Taking a typical flying swallow type CFST Tied Arch Bridge as an example, yield seismic time of three kinds of large longitudinal beams with common sections is compared by numerical simulation. It was indicated by the results that: 1. The bridges strengthened with three types of longitudinal beam sections meet the requirements of structural strength, stiffness and overall stability. It is suggested to adopt box section, which can improve the static and dynamic performance. 2. For the bridge reinforced with three types of large longitudinal beams, the dead load state such as arch axis figure and springing compressive stress has little change. 3. The method for stability and seismic performance evaluation of long-span arch bridge deck system after strengthening of girder can complete scheme selection effectively. The cyclic pushover method with ISO loading protocol was recommended as the most suitable method.

Endothelial dysfunction is an initial and essential step in vascular-remodeling diseases, including atherosclerosis and neointima formation. During vascular remodeling, activated endothelial cells can release pro-inflammatory factors that promote phenotypic switching of vascular smooth muscle cells (VSMCs) to the proliferative phenotype. We previously reported that MEK1/2 inhibitor, U0126, has a protective effect on the development of atherosclerosis and vascular calcification. However, the effect of MEK1/2 inhibitors on neointimal formation and the underlying mechanism is not fully understood. We determined that MEK1/2 inhibitor reduced carotid artery ligation-induced neointimal formation, while increased collagen and elastin levels and vascular integrality. Mechanistically, MEK1/2 inhibitor or ERK1/2 siRNA increased miR-126-3p level in endothelial cells, thereby inhibiting expression of regular of G-protein signaling 16 (RGS16), a miR-126-3p target gene, to activate the C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) signaling pathway. Accordingly, miR-126-3p was also increased by U0126 in serum and carotid artery. RGS16 was inhibited while CXCR4 and CXCL12 was increased by U0126 in neointimal areas, especially in the endothelium. Moreover, similar results were observed in atherosclerotic plaques of high-fat diet-fed apolipoprotein E deficiency (apoE−/−) mice. In addition, vascular cell adhesion molecule 1 (VCAM-1), another miR-126-3p target gene, was reduced by U0126 in the neointimal areas, resulting reduced monocytes/macrophages accumulation. Taken together, our results indicate that MEK1/2 inhibitor can reduce neointima formation by activating endothelial miR-126-3p production to facilitate endothelium repair while reduce monocyte adhesion/infiltration.

BackgroundThe diabetes disease burden in China is heavy, and medical standards such as diabetes guidelines are the core reference guidelines for diabetes management for health care providers and patients. However, patients’ guideline compliance is too low, which correlates with the gap between guidelines and patients’ self-management needs. Incorporating patient needs into the guideline development would reduce this gap. ObjectiveWe sought to capture the needs of patients with diabetes for self-management in everyday situations and to clarify the contradictions and misalignments between medical standards, such as guidelines, and patient needs. MethodsThis study collected crawler-based data from 4 online health communities. We selected 1605 text records collected from Chinese patients with diabetes between March 2020 and July 2020 for analysis. The text analysis applied grounded theory to separate issues that concerned patients into 3 themes, 7 subthemes, and 25 entries. ResultsAltogether, 69.03% (1108/1605) of texts were related to issues concerning disease treatment (theme B) and mainly inquired about medication use (B2 and B3; 686/1108, 61.91%), including medication choice, change in medication administration, side effects, and postmedication effects. In addition, 222 (N=1605, 13.8%) texts (theme A) concerned the explanation of disease etiology and knowledge of diabetes, and 275 (N=1605, 17.1%) texts (theme C) discussed lifestyle changes and various restrictions on life brought about by the disease. ConclusionsOur findings suggest an urgent need to improve diabetes health education and guideline development strategies and to develop health management strategies from a patient perspective to bridge the misalignment between patient needs and current medical standards.

BackgroundTumor grade is associated with the treatment and prognosis of endometrial cancer (EC). The accurate preoperative prediction of the tumor grade is essential for EC risk stratification. Herein, we aimed to assess the performance of a multiparametric magnetic resonance imaging (MRI)-based radiomics nomogram for predicting high-grade EC.MethodsOne hundred and forty-three patients with EC who had undergone preoperative pelvic MRI were retrospectively enrolled and divided into a training set (n =100) and a validation set (n =43). Radiomic features were extracted based on T2-weighted, diffusion-weighted, and dynamic contrast-enhanced T1-weighted images. The minimum absolute contraction selection operator (LASSO) was implemented to obtain optimal radiomics features and build the rad-score. Multivariate logistic regression analysis was used to determine the clinical MRI features and build a clinical model. We developed a radiomics nomogram by combining important clinical MRI features and rad-score. A receiver operating characteristic (ROC) curve was used to evaluate the performance of the three models. The clinical net benefit of the nomogram was assessed using decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination index (IDI).ResultsIn total, 35/143 patients had high-grade EC and 108 had low-grade EC. The areas under the ROC curves of the clinical model, rad-score, and radiomics nomogram were 0.837 (95% confidence interval [CI]: 0.754–0.920), 0.875 (95% CI: 0.797–0.952), and 0.923 (95% CI: 0.869–0.977) for the training set; 0.857 (95% CI: 0.741–0.973), 0.785 (95% CI: 0.592–0.979), and 0.914 (95% CI: 0.827–0.996) for the validation set, respectively. The radiomics nomogram showed a good net benefit according to the DCA. NRIs were 0.637 (0.214–1.061) and 0.657 (0.079–1.394), and IDIs were 0.115 (0.077–0.306) and 0.053 (0.027–0.357) in the training set and validation set, respectively.ConclusionThe radiomics nomogram based on multiparametric MRI can predict the tumor grade of EC before surgery and yield a higher performance than that of dilation and curettage.

Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.

Based on the panel data of 16 cities in Anhui from 2010-2018, this paper measures the index system of fiscal structure and high-quality economic development in Anhui using the entropy weight method, and empirically analyzes the coordinated development level of fiscal structure and high-quality economic development in Anhui using coupled coordination degree model. The study finds that: (1) the overall structure of Anhui's fiscal expenditure is characterized by "service-oriented and investment-oriented", and there is a phenomenon that contradicts "Wagner Principle", and there are also spatial and temporal differences in Anhui's tax structure. (2) The level of high-quality development of Anhui economy shows a steady upward trend, but is still at a low level. (3) The level of coordinated development of fiscal structure and high-quality economic development is still low, and the overall situation is "on the verge of disorder" or "barely coordinated". (4) Regionally, the overall coordination of fiscal expenditure structure, tax structure, and high-quality economic development in southern Anhui shows a decreasing trend, while the overall coordination in central and northern Anhui shows an increasing trend, so that southern Anhui has been or will be surpassed by northern and middle Anhui, and the growth rate of middle Anhui is faster than that of northern Anhui.

Background and Aims. Previous studies have reported a correlation between vitamin D levels and seasonality in healthy populations. However, there are few studies on the seasonal variation in vitamin D levels and its relationship with glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to investigate seasonal changes in serum 25-hydroxyvitamin D [25(OH)D] levels and the associations between these vitamin D concentrations and HbA1c levels in T2DM patients in Hebei, China. Methods. A cross-sectional study of 1,074 individuals with T2DM was conducted from May 2018 to September 2021. Levels of 25(OH)D in these patients were assessed based on both sex and season, and relevant clinical or laboratory variables that could impact vitamin D status were also considered. Results. In the T2DM patient cohort, the mean blood 25(OH)D levels were 17.05 ng/mL. A total of 698 patients (65.0%) had insufficient serum 25(OH)D levels. The vitamin D deficiency rates were significantly higher in the winter and spring compared to the autumn (P

IntroductionThis study was conducted to evaluate the effects of fermented feed of Pennisetum giganteum (P. giganteum) on growth performance, oxidative stress, immunity and gastrointestinal microflora of Boer goats under thermal stress.MethodsThe study was conducted during 45 days using twenty 2 months Boer goats. The goats were randomly allocated into two groups: NPG (n = 10; normal P. giganteum) and FPG (n = 10; fermented feed of P. giganteum), and the ratio of concentrates to roughage was 3:2. Both groups of animals were kept in sheds and exposed to summer thermal stress from 10:00 h to 18:00 h (temperature and humidity index, THI > 78). At the end of the study, the animals were slaughtered and assessed for various characteristics.ResultsThe findings from the study revealed that FPG-feeding significantly increased (p

Balancing economic development and ecological protection is a dilemma that requires a solution. The construction of ecological industrial parks is expected to be the key to resolving this situation. Based on panel data from 276 prefecture-level cities in China spanning from 2004 to 2019, this paper presents a multi-period difference-in-differences (DID) model to identify the causal relationship between eco-industrial parks and the development of urban green spaces. The research indicates that the creation of eco-industrial parks can significantly promote the sustainable development of urban areas, with a policy promotion effect of approximately 0.0279. The analysis of the mechanism indicates that the implementation of a green industrial policy can enhance the level of sustainable development in cities. This can be accomplished by promoting eco-friendly innovation, facilitating the optimization of industrial structures, and strengthening environmental regulations. A heterogeneity analysis reveals that the impact of eco-industrial parks on promoting green development is more significant in cities located in the eastern and northern regions, as well as those with abundant human capital and financial resources. Conversely, cities situated in the central and western regions, as well as those with low levels of financial resources and non-human capital, tend to experience limited benefits from policies. The conclusions of this study can provide guidance for urban transformation and facilitate sustainable development. Moreover, these parks can function as case studies and provide valuable reference experiences for countries that have not yet established eco-industrial parks.

This paper proposes a modified process analysis method that combines with the input–output method for carbon emissions assessment in slurry shield tunnel construction. The method was applied to analyze the carbon emissions generated during the construction procedures of a slurry shield tunnel. The results indicate that the carbon emissions from building materials account for the majority of the total emissions, while those from the shield machine and construction procedure are relatively small. In addition, BP and CNN-LSTM neural network models were established to validate the accuracy of the calculation results with model error of 0.1031. Finally, recommendations for reducing carbon emissions in the construction course of slurry shield tunnels are provided.

Several tyrosine kinase inhibitors (TKIs) have been developed as targeted therapies to inhibit the oncogenic activity of several tyrosine kinases in chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), gastrointestinal stromal tumor (GIST), and other diseases. TKIs have significantly improved the overall survival of these patients and changed the treatment strategy in the clinic. However, approximately 50% of patients develop resistance or intolerance to imatinib. For second-generation TKIs, approximately 30%–40% of patients need to change therapy by 5 years when they are used as first-line treatment. Clinical study analysis showed that the T315I mutation is highly associated with TKI resistance. Developing new drugs that target the T315I mutation will address the dilemma of treatment failure. Olverembatinib, as a third-generation TKI designed for the T315I mutation, is being researched in China. Preliminary clinical data show the safety and efficacy in treating CML patients harboring the T315I mutation or who are resistant to first- or second-line TKI treatment. Herein, we review the characteristics and clinical trials of olverembatinib. We also discuss its role in the management of CML patients.

Abstract Retinoblastoma is a childhood retinal tumour that is the most common primary malignant intraocular tumour. However, it has been challenging to identify the cell types associated with genetic complexity. Here, we performed single-cell RNA sequencing on 14,739 cells from two retinoblastoma samples to delineate the heterogeneity and the underlying mechanism of retinoblastoma progression. Using a multiresolution network-based analysis, we identified two major cell types in human retinoblastoma. Cell trajectory analysis yielded a total of 5 cell states organized into two main branches, and the cell cycle-associated cone precursors were the cells of origin of retinoblastoma that were required for initiating the differentiation and malignancy process of retinoblastoma. Tumour cells differentiation reprogramming trajectory analysis revealed that cell-type components of multiple tumour-related pathways and predominantly expressed UBE2C were associated with an activation state in the malignant progression of the tumour, providing a potential novel “switch gene” marker during early critical stages in human retinoblastoma development. Thus, our findings improve our current understanding of the mechanism of retinoblastoma progression and are potentially valuable in providing novel prognostic markers for retinoblastoma.

Abstract Background Periodontitis can lead to the destruction of periodontium and adversely influence the overall health, wellbeing, and quality of life. However, studies on the relationship between severe periodontitis and serum 25-hydroxyvitamin D [25(OH)D] are limited. This study is designed to explore the relationship between 25(OH)D and severe periodontitis. Methods A cross-section study of 2928 participants enrolled from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2014 was conducted. The periodontal examination was performed using a total oral periodontal examination program, and probe measurements were collected at six sites per tooth in NHANES. Severe periodontitis was characterized as: ≥ 2 interproximal sites with attachment loss (AL) ≥ 6 mm (not on the same tooth) and ≥ 1 interproximal site with probing depth (PD) ≥ 5 mm. Severe periodontitis and serum 25(OH)D were the dependent and independent variables, respectively. Univariate, multivariate, and subgroup analyses were performed to explore the relationship between severe periodontitis and serum 25(OH)D. Results Among the 2928 participants, the average age of the population was 50 ± 13.71 years old, with 1425 (48.67%) males, 316 (10.79%) exhibited severe periodontitis. Serum 25(OH)D showed a significantly negative association with severe periodontitis after adjusting all variables (OR 0.75, 95% CI 0.63–0.89). In addition, severe periodontitis has a nonlinear relationship with serum 25(OH)D, whoes inflection point was 102 (nmol/L). On the left side of the inflection point (25(OH)D ≤ 102 nmol/L), the effect size was 0.98 and 95%CI was 0.98–0.99 (25(OH)D per 1 nmol/L increments). On the right side of the inflection point (25(OH)D > 102 nmol/L), the effect size was 0.99 and 95% CI was 0.98–1.01. The subgroup analysis showed pronounced changes in non-Hispanic white, alcohol consumption, diabetes, and health insurance. Conclusion Serum 25 (OH) D in relation to severe periodontitis is nonlinear in our study.When serum 25 (OH) D is less than 102 nmol/L, serum 25 (OH) D is negatively associated with severe periodontitis.

Microbial communities play crucial roles in the biogeochemical cycling of many important soil elements. Pesticides are known to affect non-targeted soil microorganisms. Glyphosate (GP) and diquat (DQ), two commonly used non-selective herbicides, often co-exist in lateritic paddy soil rich in iron/aluminum oxides. However, there is limited information on their co-impact on microbial community structure and diversity in this type of soil. Here, the short-term effects of combined exposure to GP and DQ on microbial diversity and community structure shifts were investigated in lateritic paddy soil from a tropical agricultural region (Hainan, China). The combined utilization dosages of two herbicides were set in three concentrations: low concentration (1 fold of the recommended dosage), medium concentration (10 fold of the recommended dosage) and high concentration (100 fold of the recommended dosage). The structure and diversity of microbial communities were determined via 16S rRNA and ITS gene high-throughput sequencing. The results revealed that Actinobacteria and Proteobacteria were the most sensitive microbial phyla to the combined exposure of GP and DQ in lateritic paddy soil. The combined exposure to GP and DQ increased the abundance of Actinobacteria but significantly inhibited that of Proteobacteria, especially at low and medium concentrations. Compared with CK, mixed herbicide (GP + DQ) had no adverse effects on the richness of bacteria and fungi communities as well as on the diversity of bacteria communities, but it significantly decreased the diversity of fungi communities at high concentrations within 28 days. However, the effects of combined exposure to GP and DQ on soil microbial richness and diversity were not significantly different from those of separate exposure of the two herbicides. In conclusion, the combined application of GP and DQ had no more adverse effects on soil microorganisms. Therefore, these two herbicides can be used reasonably in actual agricultural production.

Few-shot semantic segmentation has attracted much attention because it requires only a few labeled samples to achieve good segmentation performance. However, existing methods still suffer from insufficient contextual information and unsatisfactory edge segmentation results. To overcome these two issues, this paper proposes a multi-scale context enhancement and edge-assisted network (called MCEENet) for few-shot semantic segmentation. First, rich support and query image features were extracted, respectively, using two weight-shared feature extraction networks, each consisting of a ResNet and a Vision Transformer. Subsequently, a multi-scale context enhancement (MCE) module was proposed to fuse the features of ResNet and Vision Transformer, and further mine the contextual information of the image by using cross-scale feature fusion and multi-scale dilated convolutions. Furthermore, we designed an Edge-Assisted Segmentation (EAS) module, which fuses the shallow ResNet features of the query image and the edge features computed by the Sobel operator to assist in the final segmentation task. We experimented on the PASCAL-5i dataset to demonstrate the effectiveness of MCEENet; the results of the 1-shot setting and 5-shot setting on the PASCAL-5i dataset are 63.5% and 64.7%, which surpasses the state-of-the-art results by 1.4% and 0.6%, respectively.

BackgroundRetinoblastoma (Rb) is a common ocular malignant tumor in children. Intra-arterial chemotherapy (IAC) has been widely used in children with Rb and has achieved an ideal therapeutic effect. However, IAC has side effects, including anemia and bone marrow suppression, for which explicit evidence on the risk factors is lacking. This study aimed to evaluate the covariates that may affect the occurrence of anemia and bone marrow suppression in children with Rb after IAC.MethodsChildren with Rb admitted between May 2019 and January 2021 were included into the study. The differences in the number of children with anemia and bone marrow suppression before and after IAC according to different covariates were recorded. All potential impact factors were included into the univariate and multivariate regression models to identify the related covariates of post-IAC anemia and bone marrow suppression.ResultsData of 282 children with Rb were retrospectively collected. After IAC, children with Rb had increased severities of anemia (p

TP53 is the most frequently mutated gene in lung adenocarcinoma (LUAD). The tumor immune microenvironment (TIM) is considered a vital factor that influences tumor progression and survival rate. The influence of TP53 mutation on TIM in LUAD has not been fully studied. Here we systematically investigated the relationship and potential mechanisms between TP53 mutation status and immune response in LUAD. We constructed an immune prognostic model (IPM) using immune associated genes, which were expressed differentially between the TP53 mutant and wild type LUAD patients. We discovered that TP53 mutations were significantly associated with 5 immune related biological processes. Thirty-six immune genes were expressed differentially between TP53 mutant and wild type LUAD patients. An IPM was constructed using 3 immune genes to differentiate the prognostic survival in LUAD. The high-risk LUAD group displayed significantly higher proportions of dendritic cell resting, T cell CD4 memory resting and mast cell resting, and significantly low proportions of dendritic cell activated, T cell CD4 memory activated, and mast cell activated. Moreover, IPM was found to be an independent clinical feature and can be used to predict immunotherapy responses. In summary, we constructed and validated an IPM using 3 immune related genes, which provides a better understanding of the mechanism from an immunological perspectives.

Abstract As the electronic technology becomes increasingly integrated and miniaturized, thermal management has become a major challenge for electronic device applications. A heat pipe is a highly efficient two-phase heat transfer device. Due to its simple structure, high thermal conductivity and good temperature uniformity, it has been used in many different industrial fields. A novel aluminum flat heat pipe, with micro-grooves, has in the present work been designed and fabricated by using a 3D printing technology. Aluminum powder was used as a raw material, which was selectively melted and solidified to form the shape of the heat pipe. The sintered aluminum powder increased the roughness of the inner surface of the heat pipe, and the designed micro-grooves further enhanced the capillary forces induced by the wick structure. The wettability, for the working fluid (acetone), was excellent and the capillary forces were sufficient for the working fluid to flow back in the pipe. The effects of working fluid filling ratio, on the heat transfer performance of the heat pipe, was also investigated. It was shown that a filling ratio of 10% gave the best heat transfer performance with the lowest thermal resistance. The 3D-printed flat heat pipe was, therefore, also tested for the thermal management of a LED. The temperature of the LED could be kept within 40 °C and its service life became prolonged.

An investigation into the mechanical properties of K55, N80, and P110 steels commonly used for casing drilling was carried out together with microstructural and fractographic analysis. The results show that P110 steel consisted of almost fully tempered martensite and exhibited a synergy combination of static tensile, dynamic impact, and fatigue crack propagation properties among the three steels, possessing a higher fatigue limit and deeper crack tolerance before failure occurred. The K55 steel consisted of the pearlite and network structure of ferrite and possessed a high strain hardening exponent and low impact property, which led to the more suitable application under incidental large overload and temperature change, but it was unsuitable under the condition of higher impact force. The properties of N80 steel were moderate, and its fatigue property was higher than that of K55 and lower than that of P110; its incidental overload resistance was also higher than that of P110. The casing drilling steel can be selected according to the environment.

A controlled-not (cnot) circuit is the key gadget for entangling qubits in quantum computing systems. However, the qubit connectivity of noisy intermediate-scale quantum (NISQ) devices is constrained by their limited-connectivity architecture. To improve the performance of cnot circuits on NISQ devices, we investigate the optimization of the size/depth of cnot circuits under the limited-connectivity architecture. We present a method that can optimize the size of any n-qubit cnot circuit O(n^{2}/logδ) on any connected graph with minimum degree δ, and prove this bound is optimal for the regular graph. For the near-term sparsely connected structure, we additionally present a method that can optimize the size of any n-qubit cnot circuit to below 2n^{2}. The numerical experiment shows that our method performs better than state-of-the-art results. Specifically, we present an example to illustrate the applicability of our algorithm. For the grid structure, which is commonly used in current quantum devices, we demonstrate that the depth of any n-qubit cnot circuit can be optimized to be linear in n with certain ancillary qubits (ancillas). Experimental results indicate that this method has significant improvements compared with all of the existing methods. We additionally test our algorithms on the five-qubit IBMQ devices, and the experiments show that the measurement results of the optimized circuit with our algorithm are more robust to noise compared with the IBM mapping method.

Climatic changes and environmental pollution caused by traditional urban development models have increased due to accelerated urbanisation and industrialisation. As a new model of urban development, smart city construction relies on digital technology reform to achieve intelligent urban governance, which is crucial for reducing carbon emission intensity and achieving regional green development. This paper constructs a multi-period DID model based on panel data from 283 cities from 2007 to 2019 to explore the impact of smart city construction on urban carbon emission intensity. This study found that smart city construction decreased urban carbon emissions intensity significantly and decreased carbon emissions per unit GDP in pilot areas by 0.1987 tonnes/10,000 CNY compared to that in non-pilot areas. According to a heterogeneity analysis, the integration of smart city developments could decrease carbon emission intensity in northern China’s cities and resource-based cities significantly but had an insignificant influence on carbon emission intensity in southern China’s cities and non-resource-based cities. The reason for this finding is that northern cities and resource-based cities have a higher carbon emission intensity and enjoy more marginal benefits from smart city construction. Based on an analysis of the influencing mechanisms, smart city construction can decrease urban carbon emission intensity by stimulating green innovation vitality, upgrading industrial structures, and decreasing energy consumption. These research conclusions can provide directions for urban transformation and low-carbon development, as well as a case study and experience for countries that have not yet established smart city construction.

Background. Esophageal cancer (EC), a common malignant tumor of digestive tract, is also one of the most deadly cancers. Accumulating studies have shown that the initiating and progressing multiple human diseases were closely related to the expression of MAIP. However, the specific roles and mechanisms of MAIP1 in EC remain incompletely defined. Purpose. This study aims to determine the clinical significance of MAIP1 in EC and explores its potential molecular mechanisms regulating tumor immune infiltration. Methods. We obtained RNA-seq datasets and corresponding clinical data for EC patients from the Cancer Genome Atlas (TCGA) database via the UCSC Xena browser to extract MAIP1 expression and plot survival curves to determine their prognosis. Based on the differential expression of MAIP1, EC patients were divided into high and low group to investigate the mechanism of MAIP1 in EC. In addition, the single sample gene set enrichment analysis (ssGSEA) quantified the expression of various immune cell signature marker genes and assessed the degree of immune infiltration in EC. Results. In the TCGA-EC cohort, the overexpression of MAIP1 was observed in tumor tissues compared to normal tissues (p=0.0038). Overall survival analysis showed that EC patients with the overexpression of MAIP1 presented a lower overall survival and worse prognosis (p=0.004). Enrichment analysis revealed that the differential genes (DEGs) between high and low group are involved in biological functions such as extracellular matrix and organization extracellular structure. The results of ssGSEA showed that DCs, iDCs, macrophages, mast cells, and NK cells were significantly different in MAIP1high and MAIP1low groups, and all showed high expression in the MAIP1low group. Conclusion. We proposed that MAIP1 overexpression was associated with poor prognosis and tumor immune infiltration in EC. At present, there are few MAIP1-related tumor immune infiltration studies in EC, and further investigation is needed.

Background. Thyroid cancer (TC) is a rapidly increasing incidence of endocrine malignancies, occupying 3% of new cancer incidence, of which 10% has a heterogeneous prognosis. Ferroptosis is a form of cell death distinct from apoptosis, which involves antitumor drug-related research. Long noncoding RNAs (lncRNAs) could affect cancer prognosis by regulating the ferroptosis; thus, ferroptosis-associated lncRNAs are emerging as prospective biomarkers for cancer therapy and prognosis. However, the prognostic factors of ferroptosis-associated lncRNAs in this solid tumor and their mechanisms remain unknown. Methods. The TC lncRNA data were extracted from RNA sequencing files of The Cancer Genome Atlas (TCGA). Then, we performed a two-cluster analysis and grouped 502 patients with TC in a 7 : 3 ratio. Both the least absolute shrinkage and selection operator (LASSO) regression and Cox regression analysis were conducted to create and validate the ferroptosis-associated lncRNA prognostic model (Ferr-LPM). Based on the median Ferr-LPM-based risk score (LPM_score) of the training cohort, we categorized patients into high and low LPM_score groups, which were then subjected to prognostic correlation and difference analysis. We also created a nomogram and assessed its predictive ability. Furthermore, immune-related mechanisms were investigated by analyzing the tumor immune microenvironment (TIME) and applying algorithms such as CIBERSROT. Results. We built a highly accurate nomogram to promote the clinical applicability of Ferr-LPM. The area under the receiver operating characteristic curve (AUC-ROC) reached above 0.9. Survival analysis suggested that when the Ferr-LPM score was higher, the overall survival (OS) of patients within this group was shorter. Meanwhile, we found a strong association between Ferr-LPM and TIME. Interestingly, the LPM_score was inversely proportional to the tumor purity but positively related to immune checkpoint blockade (ICB) response. Conclusion. We constructed a novel ferroptosis-associated lncRNA nomogram that could highly predict the prognosis of TC patients. Ferroptosis-associated lncRNAs might possess potential functions in regulating TIME, and lncRNAs provide TC patients with new prognostic biomarkers and therapeutic targets.

Abstract Background Long non-coding RNAs (lncRNAs) have been identified as important epigenetic regulators that play critical roles in human cancers. However, the regulatory functions of lncRNAs in tumorigenesis remains to be elucidated. Here, we aimed to investigate the molecular mechanisms and potential clinical application of a novel lncRNA, retinoblastoma associated transcript-1 (RBAT1), in tumorigenesis. Methods RBAT1 expression was determined by real-time PCR in both retinoblastoma (Rb) and bladder cancer (BCa) cell lines and clinical tissues. Chromatin isolation using RNA purification (ChIRP) assays were performed to identify RBAT1-interacting proteins. Patient-derived xenograft (PDX) retinoblastoma models were established to test the therapeutic potential of RBAT1-targeting GapmeRs. Results Here, we found that RBAT1 expression was significantly higher in Rb and BCa tissues than that in adjacent tissues. Functional assays revealed that RBAT1 accelerated tumorigenesis both in vitro and in vivo. Mechanistically, RBAT1 recruited HNRNPL protein to E2F3 promoter, thereby activating E2F3 transcription. Therapeutically, GapmeR-mediated RBAT1 silencing significantly inhibited tumorigenesis in orthotopic xenograft retinoblastoma models derived from Rb cell lines and Rb primary cells. Conclusions RBAT1 overexpression upregulates a known oncogene, E2F3, via directly recruiting HNPNPL to its promoter and cis-activating its expression. Our finding provides a novel mechanism of lncRNA biology and provides potential targets for diagnosis and treatment of Rb and BCa.

Abstract The equilibrium use of energy is very important for wireless sensor networks (WSN) with limited energy in order to avoid premature network collapse. The existing methods either need too complex calculations for precise clustering, or are too simple to overburden a few cluster heads. In order to solve these problems, we proposed energy balanced clustering routing (EBCR) in this paper. It could maximize the WSN life in energy non-harvesting scenario or improve energy utilization efficiency in energy harvesting scenario without increasing the amount of calculations. It gives a complete solution to the process of cluster head election, clustering, and intercluster routing algorithm. Firstly, a light weight cluster head election and a distributed cluttering method are proposed by introducing dynamic cluster radius and intersection region node division schemes with new principles. Thus, lightweight distributed clustering achieves the advantages of balancing the burden of cluster heads and alleviating hot zone problem. Then we optimized the cluster cooperative routing algorithm by analyzing cooperation and competition among cluster heads. The intercluster cooperative routing algorithm greatly improves the transmission efficiency between cluster heads. Moreover, this paper analyzes the reasons why the algorithm achieves more balanced energy usage, higher energy efficiency, and fewer calculations compared to the existing mainstream algorithms. At last, simulation results show that EBCR algorithm has advantages in terms of network energy consumption, number of surviving nodes in energy non-harvesting scenario compared with the delay-constrained energy-efficient cluster-based multi-hop routing (DCEM) method. Simulation also gives EBCR algorithm performance under various energy harvesting scenarios, which is quite satisfactory in energy utilization efficiency comparing with DCEM method. EBCR algorithm has superior performance in terms of balanced energy usage, low computation complexity, and high energy efficiency.

Atherosclerosis is a major pathology for cardiovascular diseases (CVDs). Clinically, the intermittent fasting (IF) has been observed to reduce the risk of CVDs. However, the effect of IF on the development of atherosclerosis has not been fully elucidated. Herein, we determined the protection of IF against high-fat diet–induced atherosclerosis in pro-atherogenic low-density lipoprotein receptor deficient (LDLR-/-) mice and the potentially involved mechanisms. The LDLR-/- mice were scheduled intermittent fasting cycles of 3-day HFD feeding ad libitum and 1 day fasting, while the mice in the control group were continuously fed HFD. The treatment was lasted for 7 weeks (∼12 cycles) or 14 weeks (∼24 cycles). Associated with the reduced total HFD intake, IF substantially reduced lesions in the en face aorta and aortic root sinus. It also increased plaque stability by increasing the smooth muscle cell (SMC)/collagen content and fibrotic cap thickness while reducing macrophage accumulation and necrotic core areas. Mechanistically, IF reduced serum total and LDL cholesterol levels by inhibiting cholesterol synthesis in the liver. Meanwhile, HFD-induced hepatic lipid accumulation was attenuated by IF. Interestingly, circulating Ly6Chigh monocytes but not T cells and serum c-c motif chemokine ligand 2 levels were significantly reduced by IF. Functionally, adhesion of monocytes to the aortic endothelium was decreased by IF via inhibiting VCAM-1 and ICAM-1 expression. Taken together, our study indicates that IF reduces atherosclerosis in LDLR-/- mice by reducing monocyte chemoattraction/adhesion and ameliorating hypercholesterolemia and suggests its potential application for atherosclerosis treatment.

Two Cd(II) coordination polymers namely, [Cd(L)(phen)(H2O)]n (1) and [Cd(L)(bpe)0.5]n (2) (H2L is 4,4′-{[1,2-phenylenebis-(methylene)]}bis(oxy)dibenzoic acid, bpe is 1,2-bis(-4-pyridyl)ethane and phen is 1,10-phenanthroline), have been created by the mixed-ligand self-assembly strategy. Moreover, the two compounds’ luminescent and photocatalytic performances were also studied. The treatment activity and nursing application values on children bronchopneumonia was explored and specific mechanism was investigated simultaneously. First of all, the ELISA detection kit was implemented to detect the TNF-α and IL-6 levels released into the respiratory secretions after treatment of compound. Furthermore, the real time RT-PCR was conducted to determine the activation levels of NF-κb signaling pathway in the airway epithelial cells. Finally, the cytotoxicity of the coordination polymers on normal airway epithelial cells was assessed through the CCK-8 assay.

Next-generation sequencing (NGS) has drastically enhanced human cancer research, but diverse sequencing strategies, complicated open-source software, and the identification of massive numbers of mutations have limited the clinical application of NGS. Here, we first presented GPyFlow, a lightweight tool that flexibly customizes, executes, and shares workflows. We then introduced DIVIS, a customizable pipeline based on GPyFlow that integrates read preprocessing, alignment, variant detection, and annotation of whole-genome sequencing, whole-exome sequencing, and gene-panel sequencing. By default, DIVIS screens variants from multiple callers and generates a standard variant-detection format list containing caller evidence for each sample, which is compatible with advanced analyses. Lastly, DIVIS generates a statistical report, including command lines, parameters, quality-control indicators, and mutation summary. DIVIS substantially facilitates complex cancer genome sequencing analyses by means of a single powerful and easy-to-use command. The DIVIS code is freely available at https://github.com/niu-lab/DIVIS, and the docker image can be downloaded from https://hub.docker.com/repository/docker/sunshinerain/divis.

Purpose: To evaluate the efficacy of an external carotid artery (ECA) alternative route in intra-arterial chemotherapy (IAC) for treatment of retinoblastoma.Methods: In this retrospective, single-centre, case-control study, 98 retinoblastoma patients who received successful IAC were included. The drug delivery routes were the primary ophthalmic artery (OA) route and the ECA route when OA catheterization was not feasible.Results: A total of 337 successful IAC procedures were performed in our study, of which 32 (9.5%) procedures were performed through the ECA route. Eighteen eyes (18.4%) accepted at least one IAC through branches of the ECA. Statistical analysis showed that there was no significant difference in ocular clinical results (enucleation, death, recurrence and event-free) between the ECA and OA routes. No significant association was found between the route of drug delivery and the ocular survival time (p = 0.69). The use of ECA catheterization in at least one IAC cycle was not a predictor of enucleation (HR: 1.58; 95% CI: 0.56–4.46, p = 0.39). The increasing number of procedures through the ECA route did not increase the risk of enucleation (HR: 1.64; 95% CI: 0.42–6.39, p = 0.48).Conclusion: The ECA alternative route did not affect the efficacy of IAC in retinoblastoma. When the standard OA approach is not feasible, ECA system catheterization should be considered.

The accelerating growth of the public microbial genomic data imposes substantial burden on the research community that uses such resources. Building databases for non-redundant reference sequences from massive microbial genomic data based on clustering analysis is essential. However, existing clustering algorithms perform poorly on long genomic sequences. In this article, we present Gclust, a parallel program for clustering complete or draft genomic sequences, where clustering is accelerated with a novel parallelization strategy and a fast sequence comparison algorithm using sparse suffix arrays (SSAs). Moreover, genome identity measures between two sequences are calculated based on their maximal exact matches (MEMs). In this paper, we demonstrate the high speed and clustering quality of Gclust by examining four genome sequence datasets. Gclust is freely available for non-commercial use at https://github.com/niu-lab/gclust. We also introduce a web server for clustering user-uploaded genomes at http://niulab.scgrid.cn/gclust. Keywords: Microbial genome clustering, Parallelization, Sparse suffix array, Maximal exact match, Segment extension

Brain science accelerates the study of intelligence and behavior, contributes fundamental insights into human cognition, and offers prospective treatments for brain disease. Faced with the challenges posed by imaging technologies and deep learning computational models, big data and high-performance computing (HPC) play essential roles in studying brain function, brain diseases, and large-scale brain models or connectomes. We review the driving forces behind big data and HPC methods applied to brain science, including deep learning, powerful data analysis capabilities, and computational performance solutions, each of which can be used to improve diagnostic accuracy and research output. This work reinforces predictions that big data and HPC will continue to improve brain science by making ultrahigh-performance analysis possible, by improving data standardization and sharing, and by providing new neuromorphic insights. Keywords: Brain science, Big data, High-performance computing, Brain connectomes, Deep learning