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Background Vascular smooth muscle cell (VSMC) proliferation is involved in many types of arterial diseases, including neointima hyperplasia, in which Ca2+ has been recognized as a key player. However, the physiological role of Ca2+ release via inositol 1,4,5‐trisphosphate receptors (IP3Rs) from endoplasmic reticulum in regulating VSMC proliferation has not been well determined. Methods and Results Both in vitro cell culture models and in vivo mouse models were generated to investigate the role of IP3Rs in regulating VSMC proliferation. Expression of all 3 IP3R subtypes was increased in cultured VSMCs upon platelet‐derived growth factor‐BB and FBS stimulation as well as in the left carotid artery undergoing intimal thickening after vascular occlusion. Genetic ablation of all 3 IP3R subtypes abolished endoplasmic reticulum Ca2+ release in cultured VSMCs, significantly reduced cell proliferation induced by platelet‐derived growth factor‐BB and FBS stimulation, and also decreased cell migration of VSMCs. Furthermore, smooth muscle–specific deletion of all IP3R subtypes in adult mice dramatically attenuated neointima formation induced by left carotid artery ligation, accompanied by significant decreases in cell proliferation and matrix metalloproteinase‐9 expression in injured vessels. Mechanistically, IP3R‐mediated Ca2+ release may activate cAMP response element–binding protein, a key player in controlling VSMC proliferation, via Ca2+/calmodulin‐dependent protein kinase II and Akt. Loss of IP3Rs suppressed cAMP response element–binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca2+ permeable ionophore, ionomycin, can reverse cAMP response element–binding protein phosphorylation in IP3R triple knockout VSMCs. Conclusions Our results demonstrated an essential role of IP3R‐mediated Ca2+ release from endoplasmic reticulum in regulating cAMP response element–binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.

Abstract Nature presents the most beautiful patterns through evolving. Here, a layered porous pattern in golden ratio (0.618) is reported from a type of mushroom ‐Dictyophora Rubrovalvata stipe (DRS). The hierarchical structure shows a mathematical correlation with the golden ratio. This unique structure leads to superior mechanical properties. The gradient porous structure from outside to innermost endows it with asymmetrical hydrophilicity. A mathematical model is then developed to predict and apply to 3D printed structures. The mushroom is then explored to repair gastric perforation because the stomach is a continuous peristaltic organ, and the perforated site is subject to repeated mechanical movements and pressure changes. At present, endoscopic clipping is ineffective in treating ulcerative perforation with fragile surrounding tissues. Although endoscopic implant occlusion provides a new direction for the treatment of gastric ulcers, but the metal or plastic occluder needs to be removed, requiring a second intervention. Decellularized DRS (DDRS) is found with asymmetric water absorption rate, super‐compressive elasticity, shape memory, and biocompatibility, making it a suitable occluder for the gastric perforation. The efficacy in blocking gastric perforation and promoting healing is confirmed by endoscopic observation and tissue analysis during a 2‐month study.

Abstract Background Multiple studies have confirmed that programmed cell death 1 (PD‐1) and programmed cell death ligand 1 (PD‐L1) is widely expressed in gestational trophoblastic neoplasia (GTN) tissues. Therefore, immune checkpoint inhibitors may be an option for the treatment of recurrent and drug‐resistant GTN. Case Four patients with recurrent or drug‐resistant GTN who were treated with PD‐1/PD‐L1 checkpoint inhibitor agents combined with chemotherapy were reported. The mean age of recurrence was 45.8 years (35–56 years), including three cases of choriocarcinoma (CC) and one case of invasive mole (IM). International Federation of Gynecology and Obstetrics (FIGO) prognosis score: ≤6 (low risk) in one case, 7–12 (high risk) in one case, ≥13 (very high risk) in two cases. There were two cases of lung metastasis and one case of vulvar and inguinal lymph node metastasis. One of the four patients underwent total hysterectomy and one patient underwent resection of lung metastases. All the four patients received comprehensive treatment of immunotherapy combined with chemotherapy after relapse, among which one patient achieved complete response (CR), two patients achieved partial response (PR), and one patient developed progressive disease (PD). Three patients who achieved PR or CR were maintained by single agent immunotherapy after combination therapy, and there was no disease recurrence during follow‐up. One patient with PD also achieved CR after using salvage chemotherapy after recurrence, and there was no disease recurrence during follow‐up. During the treatment, four patients had different degrees of immune‐related adverse reactions, all of which were grade I‐II, and no severe adverse reactions were found. Conclusion Immune checkpoint inhibitors combined with chemotherapy has an impressive therapeutic effect on recurrent or drug‐resistant GTN with mild adverse reactions, which can be used as a treatment option for such patients. However, due to the lack of large sample data support, the specific time and treatment course of its use, long‐term use of adverse reactions and whether it affects fertility function remain to be solved.

Ductular reaction (DR) is usually observed in biliary disorders or various liver disorders, including nonalcoholic fatty liver disease. Few studies have focused on interrupting the DR process in the cholestatic environment. Here, we investigated the impact of reversine on DR in rats that had undergone bile duct ligation (BDL). Cholestatic injury was induced in rats 2 weeks following BDL. DR was assessed with biliary markers by immunohistochemistry. Biliary epithelial cells (BECs) were isolated for the analysis of proliferation and biliary factor gene expression. The effects of reversine on DR and fibrosis were analyzed in vivo via intraperitoneal injection in rats for 2 weeks. Chemically‐induced BEC formation was used to investigate the biliary markers affected by reversine in vitro. DR with increased BEC expansion was identified in cholestatic liver injury, as indicated by CK7, CK19, and EpCAM expression around the portal vein in BDL rats. BDL‐induced DR cells showed the increased expression of genes regulating cell proliferation (Ki67, Foxm1, and Pcna) and biliary markers (Krt7, Krt19, Epcam, Sox9, Cftr, and Asbt). Reversine attenuated cholestatic fibrosis and DR in rats. Reversine affected chemically‐induced BEC formation, with the decreased expression of biliary Krt7, Cftr, and Ggt1 genes in vitro. BDL‐induced Notch activation was attenuated upon reversine treatment in vivo, in part via the Notch/Sox9 pathway. In conclusion, reversine attenuated cholestatic ductular reaction and fibrosis in rats and reduced the bile duct formation associated with Dlk1/Notch/Sox9 signaling. Reversine may be regarded as a potential drug for cholangiopathies for preventing a ductular reaction.

Abstract Background Metabolic syndrome (MetS) is a clustering of cardiometabolic components, posing tremendous burdens in the aging society. Retinal age gap has been proposed as a robust biomarker associated with mortality and Parkinson's disease. Although MetS and chronic inflammation could accelerate the aging process and increase the risk of mortality, the association of the retinal age gap with MetS and inflammation has not been examined yet. Methods Retinal age gap (retina‐predicted age minus chronological age) was calculated using a deep learning model. MetS was defined as the presence of three or more of the following: central obesity, hypertension, dyslipidemia, hypertriglyceridemia, and hyperglycemia. Inflammation index was defined as a high‐sensitivity C‐reactive protein level above 3.0 mg/L. Logistic regression models were used to examine the associations of retinal age gaps with MetS and inflammation. Results We found that retinal age gap was significantly associated with MetS and inflammation. Specifically, compared to participants with retinal age gaps in the lowest quartile, the risk of MetS was significantly increased by 10% and 14% for participants with retinal age gaps in the third and fourth quartile (odds ratio [OR]:1.10; 95% confidence interval [CI], 1.01,1.21;, p = .030; OR: 1.14, 95% CI, 1.03,1.26; p = .012, respectively). Similar trends were identified for the risk of inflammation and combined MetS and inflammation. Conclusion We found that retinal age gaps were significantly associated with MetS as well as inflammation. Given the noninvasive and cost‐effective nature and the efficacy of the retinal age gap, it has great potential to be used as a screening tool for MetS in large populations.

Abstract Background Bladder cancer is the most common malignancy of the urinary system, and accounts for 3% of newly diagnosed tumors. Transurethral resection of bladder tumor plays a key role in treating bladder cancer, among which one of the most serious complications is bladder perforation caused by obturator nerve reflex. Obturator nerve reflex can be prevented by inducing obturator nerve block after lumbar anesthesia. However, No study so far has compared the inhibitory effect of different obturator nerve block approaches on intraoperative obturator nerve reflex and bladder perforation. Method In this study, we conducted a network meta‐analysis (NMA) of studies comparing the efficacy of different obturator nerve block approaches performed after lumbar anesthesia in operation. Result The distal obturator nerve block guided by peripheral nerve stimulator is the best approach for preventing obturator reflex. The proximal obturator nerve block guided by ultrasound is the best approach for preventing bladder perforation. Conclusion Spinal anesthesia combined with the distal obturator nerve block guided by peripheral nerve stimulator is the most optimal approach to prevent the obturator nerve reflex. But the doctor should choose the appropriate anesthesia method according to the patient's general condition, tumor location, and doctor's proficiency in puncture techniques.

Abstract Developing a living prosthetic breast to inhibit potential breast cancer recurrence and simultaneously promote breast reconstruction would be a promising strategy for clinical treatment of breast cancer after mastectomy. Here, a living prosthetic breast in the form of injectable gelatin methacryloyl microspheres is prepared, where they encapsulated zeolitic imidazolate framework (ZIF) nanoparticles loaded with small molecules urolithin C (Uro‐C) and adipose‐derived stem cells (ADSCs). Taking advantage of the acidic tumor microenvironment, the ZIF triggered a pH‐sensitive drug release in situ so that Uro‐C can induce tumor cell apoptosis via reactive oxygen species (ROS) generation. Meanwhile, the ADSCs proliferate in situ to promote tissue regeneration. Using such a design, our data showed that the ADSCs maintained viable and proliferate under the inhibitory effect of Uro‐C in vitro. Through ROS generation, Uro‐C also activated a suppressive tumor microenvironment in mice by both re‐polarizing M2 macrophages to M1 macrophages for elevated inflammatory responses, and increasing the ratio between CD8 and CD4 T cells for tumor recurrence inhibition, significantly promoting new adipose tissue formation. Altogether, our results demonstrate that the prepared living prosthetic breast with bifunctional properties can be a promising candidate in clinic involving tumor treatment and tissue engineering in synergy.

Abstract Tube‐to‐tubesheet welding is widely applied in industrial fields. However, the current tubesheet welding robot still mainly relies on manual tubesheet models. Aiming to solve this problem, this paper proposed an improved direct method to automatically establish a tubesheet semi‐dense point cloud model based on a selected monocular camera and a one‐dimension (1D) laser rangefinder. Firstly, a laser filtering method was designed to acquire the distance between the camera and tubesheet through the 1D laser rangefinder. Then, from combing the 1D laser rangefinder data with keyframe data, the scale factor was obtained and proceeded to be processed by the Kalman filter to reduce the error. Then, the computed scale factor and all the keyframes were calculated to construct the tubesheet point cloud model through the graph optimisation algorithm. The experimental results showed that the semi‐dense point cloud model of the tubesheet could be efficiently established by the proposed algorithm with row error and column error both less than 1 mm, satisfying the welding requirements.

Background Left ventricular mass index (LVMI) has been extensively studied for its relationship with mortality but has been typically assessed at a single time point. We, therefore, describe the trajectory of LVMI in a population with hypertension over 6 years to study the subsequent risk of mortality. Methods and Results We assessed LVMI that was collected during annual health examinations in round 1 (2010–2012), round 2 (2013–2014), and round 3 (2015–2016) with 2 allometric scalings, height2.7, and body surface area, in a cohort of participants with hypertension to identify 6‐year trajectories of LVMI by latent class trajectory modeling. We followed up with participants for mortality by latent trajectory from the last echocardiographic examination (September 17, 2014–December 8, 2016) to December 31, 2018. We calculated mortality hazard ratios by assigned trajectory using Cox proportional hazards models. We obtained data for LVMI from 2453 participants (mean age, 61.80 [SD, 12.14] years, 1428 [58.2%] female). We identified 3 trajectories of LVM/H2.7, characterized by maintained low stable (1298 [52.9%]); moderate stable (935 [38.1%]); high stable (220 [9.0%]), as well as 3 trajectories by LVM/body surface area. During a median follow‐up of 2.15 years, 167 participants developed all‐cause mortality, and 71 were cardiovascular mortality. Only the high stable trajectory was associated with a higher risk of all‐cause mortality compared with the low stable trajectory by LVM/H2.7 or LVM/body surface area (all P

Abstract With the development of blue laser endoscopy (BLE) technique, it's often used to diagnose early gastric cancer (EGC) by the morphological changes of blood vessels through BLE. However, EGC is still not obvious to identify, resulting in a high rate of missed diagnosis. Molecular imaging can show the changes in early tumors at molecular level, which provides a possibility for diagnosing EGC. Therefore, developing a probe that visually monitors blood vessels of EGC under BLE is particularly necessary. Herein, a bis‐pyrene (BP) based nanoprobe (BP‐FFVLK‐(PEG)‐RGD, M1) is designed, which can target angiogenesis and self‐assemble into fibers in situ, resulting in stable and long‐term retention in tumor. Moreover, M1 probe can emit yellow‐green fluorescence for imaging under BLE. M1 probe is confirmed to steadily remain in tumor for up to 96 hours in mice transplanted subcutaneously. In addition, the M1 probe is able to target angiogenesis for molecular imaging of isolated human gastric cancer tissue under BLE. Finally, M1 probe i.v. injected into primary gastric cancer model rabbits successfully highlighted the tumor site under BLE, which is confirmed by pathological analysis. It's the first time to develop a probe for diagnosing EGC by visualizing angiogenesis under BLE, showing great clinical significance.

Stroke is a disease with high morbidity and disability, and motor impairment is a common sequela of stroke. Transcutaneous auricular vagus nerve stimulation (taVNS) is a type of non-invasive stimulation, which can effectively improve post-stroke motor dysfunction. This review discusses stimulation parameters, intervention timing, and the development of innovative devices for taVNS. We further summarize the application of taVNS in improving post-stroke upper limb motor function to further promote the clinical research and application of taVNS in the rehabilitation of post-stroke upper limb motor dysfunction.

Over the past few years, significant exploration breakthroughs have been made in the sandy conglomerates reservoir of the Triassic Baikouquan Formation in the Mahu Sag, Junggar Basin, China. However, the elasticity and pore characteristics of the tight sandy conglomerates reservoir in this area are still unclear. Through a systematic sonic testing program of the sandy conglomerates sample collected from the Mahu Sag, the regularity behind the variation of the elasticity and pore characteristics of the sample has been analyzed and captured. The Triassic Baikouquan Formation of the slope of Mahu Sag has been through complex burial and diagenetic history. The compaction, cementation, and dissolution are the three types of diagenesis that have the greatest impact on pore characteristics in the study area. In order to quantitatively describe the influence of this complex burial and diagenetic history, we present a rock-physics modeling approach to describe the elastic properties of sandy conglomerate sample. The overall strategy of the modeling is to combine the contact cement theory (CCT), differential effective medium (DEM) and the upper Hashin-Shtrikman bound. The CCT model can well describe the history of cementation, DEM model is suitable for the history of dissolution, and HS upper bound is used to describe the history of compaction. Then, the model is used to describe well log data from sandy conglomerates reservoirs in Mahu Sag and successfully explain the rock porosity, pore shape trends, and the elasticity in the sandy conglomerate reservoirs.

Abstract To investigate the role of the lncRNA growth arrest special 5 (GAS5) in ovarian clear cell carcinoma (OCCC), we measured the expression of GAS5 and miR‐31‐5p in OCCC tissue samples and OCCC cell lines using RT‐qPCR. MTT and colony formation assays were used to measure cell viability and colony formation ability. Cell invasion was determined by Transwell assays. The binding between GAS5 and miR‐31‐5p as well as miR‐31‐5p and ARID1A was determined by dual‐luciferase reporter assays. The ARID1A protein levels were detected using western blotting. Kaplan–Meier curves were used for the analysis of the 5‐year survival rate of patients with OCCC. GAS5 and ARID1A levels were significantly decreased, while miR‐31‐5p levels were strongly elevated in the OCCC tissues and cell lines. Patients with lower GAS5/ARID1A levels had shorter overall survival times. Overexpression of GAS5 or inhibition of miR‐31‐5p suppressed cell viability and invasion of OCCC cells and upregulated the protein levels of ARID1A. Moreover, overexpression of miR‐31‐5p reversed the effects of overexpression of GAS5. Cotransfection with pcDNA3.1‐GAS5 and miR‐31‐5p inhibitor led to the lowest cell viability and cell invasion rates. A dual‐luciferase reporter assay was performed to confirm the target relationship between GAS5 and miR‐31‐5p, as well as between miR‐31‐5p and ARID1A. LncRNA GAS5 inhibited cell viability and invasion of OCCC through activation of ARID1A by sponging miR‐31‐5p.

Abstract The incidence and mortality of hepatocellular carcinoma (HCC) are gradually increasing during the past years. Recently, some studies have reported that malic enzyme (ME) plays an important role in cancer development, while the involvement of ME2 in HCC remains still undetermined. Here, we demonstrated that ME2 played an oncogenic role in HCC. ME2 was overexpressed in HCC tissues. TCGA database showed that the ME2 transcript level was inversely associated with the survival of HCC patients. Loss‐of‐function and gain‐of‐function assays showed that ME2 promoted HCC cell growth and migration. Furthermore, the xenografted tumorigenesis of MHCC97H cells was retarded by ME2 knockdown. ME2 silencing also suppressed the cell cycle process and induced apoptosis. Mechanistically, ME2 potentiated triglyceride synthesis, inhibition of which suppressed the proliferation and migration. We propose that ME2 promotes HCC progression by increasing triglyceride production.

Abstract This paper investigates robust path tracking issue of the four‐wheel independent driven robot (FWIDR) under time‐varying system uncertainties and unavoidable external disturbances. A robust optimal integral sliding mode tracking control (OISMTC) scheme based on double feedback recurrent neural network (DFRNN) is proposed for the FWIDR system. Firstly, the presented OISMTC scheme modifies nominal optimal control part by exploiting an additional integral term to improve the tracking accuracy. Then, the designed DFRNN utilizes a double feedback loops structure to enhance the robustness against large system uncertainties by learning to approximate nonlinear systems. The adaptive law of the DFRNN is presented based on the Lyapunov theory to obtain favourable approximation performance in the presence of the time‐varying operating conditions. Moreover, the asymptotic stability of the resultant FWIDR system is guaranteed by mathematical analysis. Finally, practical experiments are conducted to demonstrate the advantages of the proposed DFRNN‐OISMTC method.

Abstract Atherosclerosis with unstable plaques is the dominant pathological basis of lethal cardio‐cerebrovascular diseases, which can cause acute death due to the rupture of plaques. Plaque‐targeted drug delivery to achieve promoted treatment remains the main challenge because of the systemic occurrence of atheroma. Herein, a rapamycin (RAP) spherical nucleic acid (SNA) structure, capable of specifically accumulating in plaques for synergistic atherosclerosis treatment is constructed. By designing consecutive phosphorothioate (PS) at 3’ terminus of the deoxyribonucleic acid (DNA) strand, multiple hydrophobic RAPs are covalently grafted onto the PS segment to form an amphiphilic drug‐grafted DNA (RAP‐DNA), which successively self‐assembles into micellar SNA (RAP‐SNA). Moreover, the phosphodiester‐DNA segment constitutes the outer shell of RAP‐SNA, enabling further hybridization with functional siRNA (targeting lectin‐like oxidized low‐density lipoprotein receptor‐1, LOX‐1) to obtain the drug codelivered SNA (LOX‐1/RAP‐SNA). With two active ingredients inside, LOX‐1/RAP‐SNA can not only induce robust autophagy and decrease the evil apoptosis of the pathological macrophages, but also simultaneously prohibit the LOX‐1‐mediated formation of damageable foam cells, realizing the effect of synergistic therapy. As a result, the LOX‐1/RAP‐SNA significantly reduces the progression of atheroma and stabilizes the plaques, providing a new strategy for synergistically targeted atherosclerosis treatment.

Background Blood pressure and tissue perfusion are controlled in part by the level of intrinsic (myogenic) arterial tone. However, many of the molecular determinants of this response are unknown. We previously found that mice with targeted disruption of the gene encoding the angiotensin II type 1a receptor (AT1AR) (Agtr1a), the major murine angiotensin II type 1 receptor (AT1R) isoform, showed reduced myogenic tone; however, uncontrolled genetic events (in this case, gene ablation) can lead to phenotypes that are difficult or impossible to interpret. Methods and Results We tested the mechanosensitive function of AT1R using tamoxifen‐inducible smooth muscle‐specific AT1aR knockout (smooth muscle‐Agtr1a−/−) mice and studied downstream signaling cascades mediated by Gq/11 and/or β‐arrestins. FR900359, Sar1Ile4Ile8‐angiotensin II (SII), TRV120027 and TRV120055 were used as selective Gq/11 inhibitor and biased agonists to activate noncanonical β‐arrestin and canonical Gq/11 signaling of the AT1R, respectively. Myogenic and Ang II‐induced constrictions were diminished in the perfused renal vasculature, mesenteric and cerebral arteries of smooth muscle‐Agtr1a−/− mice. Similar effects were observed in arteries of global mutant Agtr1a−/− but not Agtr1b−/− mice. FR900359 decreased myogenic tone and angiotensin II‐induced constrictions whereas selective biased targeting of AT1R‐β‐arrestin signaling pathways had no effects. Conclusions This study demonstrates that myogenic arterial constriction requires Gq/11‐dependent signaling pathways of mechanoactivated AT1R but not G protein‐independent, noncanonical pathways in smooth muscle cells.

In order to investigate energy supply capacity and oil production contribution of near-fracture and fracture-free zone in fractured tight oil reservoirs, a series of CO2 huff-and-puff tests were designed and carried out in different experimental conditions. A fracture-matrix long-core system was established to simulate the near-fracture zone and matrix zone of tight oil reservoirs. The NMR technique was utilized to identify the microscopic remaining oil of certain core samples. The effects of fracture length, soaking time, depressurization method, and asphaltene precipitation on the oil recovery performance of CO2 huff-and-puff process were evaluated, respectively. The results indicated that the dissolution and diffusion range of the injected CO2 can be apparently increased from both macro and micro aspects through increasing the length or density of the fractures and extending the soaking time; and, during puff period, the slow depressurization method has better recovery effect on near-fracture zone, while the step depressurization method has better recovery effect on distal fracture-free matrix. After CO2 huff-and-puff process, the oil recovery of the medium pores near fracture could be close to oil recovery of the large pores, which is higher than 60%. But, in the distal matrix, the oil recovery of the medium pores was only a little higher than depletion development. The remaining oil of medium pores in distal fracture-free matrix still has great potential to be developed after CO2 huff-and-puff process.

Abstract Gemcitabine (GEM) alone and GEM‐based chemotherapy are the preferred regimens for treating advanced unresectable and metastatic pancreatic cancer (PC). However, these treatments have limited efficacy due to acquired resistance of cancer cells to chemotherapy, the mechanisms of which are not fully understood. In this study, we established two stable multidrug‐resistant cell lines, BxPC‐3‐GR and CFPAC‐1‐GR, from their corresponding parental cells through exposure to GEM following a stepwise incremental dosing strategy. The GEM IC50 values of BxPC‐3‐GR and CFPAC‐1‐GR increased 112‐fold and 210‐fold, respectively, compared to parental cell lines. In vitro and in vivo experiments confirmed that both GEM‐resistant cell subgroups declined in proliferative capacity, but were more resistant to GEM. Unlike CFPAC‐1‐GR, BxPC‐3‐GR exhibited enhanced migratory and invasive properties compared with BxPC‐3 in vitro. We also compared differentially expressed mRNA profiles between parental and GEM‐resistant cells using transcriptome sequencing. RRM1, STIM1, and TRIM21 were significantly upregulated in both GEM‐resistant cell lines and confirmed to be associated with the degree of GEM resistance by quantitative reverse‐transcription polymerase chain reaction and western blot analysis. These three genes were more highly expressed in PC tissues and potentially regarded as prognostic biomarkers through database mining. Thus, our findings provide chemo‐resistant cell models to better understand the underlying mechanisms of chemoresistance, and to explore potential biomarkers for GEM response in PC patients.

Abstract In recent years, some studies suggested that the pretreatment C‐reactive protein to albumin ratio (CAR) may be predictive for prognosis of esophageal cancer (EC), but their results were inconsistent. Therefore, the current meta‐analysis was preformed to better determine the prognostic value of pretreatment CAR in EC. The PubMed, EMBASE, Web of Science, Cochrane Library, and PubMed Central databases were searched up to January 10, 2019 to identify studies evaluating the correlation between CAR and prognosis of EC. The primary outcome was the overall survival (OS) and secondary outcomes were disease‐free survival (DFS) and cancer‐specific survival (CSS). Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were used to estimate the predictive role of CAR for prognosis in EC. Based on the results of this research, a total of 11 studies with 2930 patients diagnosed as EC were included. Pooled results suggested that elevated pretreatment CAR was significantly associated with poor OS (HR = 1.80, 95% CI: 1.31‐2.47, P

Abstract Background The key role of hypoxia‐inducible factor 2alpha (HIF2α) in the process of renal cancer has been confirmed. In the field of tumour research, oxidative stress is also considered to be an important influencing factor. However, the relationship and biological benefits of oxidative stress and HIF2α in ccRCC remain unclear. This research attempts to explore the effect of oxidative stress on the cancer‐promoting effect of HIF2α in ccRCC and reveal its mechanism of action. Methods The bioinformatics analysis for ccRCC is based on whole transcriptome sequencing and TCGA database. The detection of the expression level of related molecules is realised by western blot and PCR. The expression of Nucleoside diphosphate‐linked moiety X‐type motif 1 (NUDT1) was knocked down by lentiviral infection technology. The functional role of NUDT1 were further investigated by CCK8 assays, transwell assays and cell oxidative stress indicator detection. The exploration of related molecular mechanisms is realised by Luciferase assays and Chromatin immunoprecipitation (ChIP) assays. Results Molecular screening based on knockdown HIF2α sequencing data and oxidative stress related data sets showed that NUDT1 is considered to be an important molecule for the interaction of HIF2α with oxidative stress. Subsequent experimental results showed that NUDT1 can cooperate with HIF2α to promote the progression of ccRCC. And this biological effect was found to be caused by the oxidative stress regulated by NUDT1. Mechanistically, HIF2α transcription activates the expression of NUDT1, thereby inhibiting oxidative stress and promoting the progression of ccRCC. Conclusions This research clarified a novel mechanism by which HIF2α stabilises sirtuin 3 (SIRT3) through direct transcriptional activation of NUDT1, thereby inhibiting oxidative stress to promote the development of ccRCC. It provided the possibility for the selection of new therapeutic targets for ccRCC and the study of combination medication regimens.

Background Exploring potential therapeutic target is of great significance for myocardial infarction (MI) and post‐MI heart failure. Transcription factor Yin‐Yang 1 (YY1) is an essential regulator of apoptosis and angiogenesis, but its role in MI is unclear. Methods and Results The expression of YY1 was assessed in the C57BL/6J mouse heart following MI. Overexpression or silencing of YY1 in the mouse heart was achieved by adeno‐associated virus 9 injection. The survival, cardiac function, and scar size, as well as the apoptosis, angiogenesis, cardiac fibrosis, T helper 2 lymphocyte cytokine production, and macrophage polarization were assessed. The effects of YY1 on Akt phosphorylation and vascular endothelial growth factor production were also investigated. The expression of YY1 in heart was significantly stimulated by MI. The survival rate, cardiac function, scar size, and left ventricular volume of mice were improved by YY1 overexpression but worsened by YY1 silencing. YY1 alleviated cardiac apoptosis and fibrosis, promoted angiogenesis, T helper 2 cytokine production, and M2 macrophage polarization in the post‐MI heart, it also enhanced the tube formation and migration ability of endothelial cells. Enhanced Akt phosphorylation, along with the increased vascular endothelial growth factor levels were observed in presence of YY1 overexpression. Conclusions YY1 ameliorates cardiac injury and remodeling after MI by repressing cardiomyocyte apoptosis and boosting angiogenesis, which might be ascribed to the enhancement of Akt phosphorylation and the subsequent vascular endothelial growth factor up‐regulation. Increased T helper 2 cytokine production and M2 macrophage polarization may also be involved in YY1’s cardioprotective effects. These findings supported YY1 as a potential target for therapeutic investigation of MI.

Abstract Aging is a critical factor affecting physical health and disease in mammals. Emerging evidence indicates that aging may affect the gut bacteriome in cynomolgus macaques, but little is known about whether or how the gut virome changes with age. Here, we compared the DNA gut viral composition of 16 female cynomolgus monkeys (Macaca fascicularis) at three life stages (young, adult, and old) using the shotgun metagenome sequencing method. We found that the DNA gut virome from these monkeys differed substantially among the three groups. The gut viruses were dominated by bacteriophages, the most abundant of which was the Caudovirales order (i.e., Siphoviridae, Myoviridae, and Podoviridae families). Additionally, the co‐occurrence analysis revealed that the age‐related bacteriophages were correlated in an extensive and complex manner with the main intestinal bacteria (i.e., Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria phyla). Furthermore, the age‐related DNA gut viral functions were enriched for genetic information processing, nucleotide, and folate metabolism. Our gut virome analysis provides new insight into how aging influences the gut virome of non‐human primates.

Abstract Paris polyphylla var. yunnanensis is one of the original plants used to make the traditional medicine Paridis Rhizoma. Wild individuals have been excessively collected in recent decades, and thus, it has become increasingly endangered. Cultivation is a major method for the conservation and sustainable utilization of its wild resources. In this study, amplified fragment length polymorphism markers were used in the genetic analysis of 15 wild and 17 cultivated populations of P. polyphylla var. yunnanensis. This study revealed that cultivated populations possessed higher genetic diversity than wild ones at the species level (H = 0.2636 vs. 0.2616, respectively). However, most of the genetic variation was found within populations for both of these groups (ΦST = 18.83% vs. 19.39%). In the dendrogram produced using UPGMA, the 32 populations were divided into three groups (I, II, and III). In group II, both wild and cultivated populations were included, but remained in distinct clusters within this group, which showed the significant separation between the cultivated and wild populations. Furthermore, wild populations were also clustered into three subgroups (W‐I, W‐II, and W‐III), with an obvious geographic structure. In contrast, although cultivated populations were similarly placed in three subgroups (C‐I, C‐II, and C‐III), the latter two of these were not separated based on geography. Finally, the wild populations in Guizhou, China (W‐I), possessed higher genetic diversity than those in Yunnan (W‐II and W‐III). As P. polyphylla var. yunnanensis is an endangered medicinal plant, the fact that it showed richer genetic diversity in its wild populations in Guizhou means that these should be regarded as priority areas for protection and used for provenance selection. Moreover, cultivated populations also showed high genetic variation, which might be attributed to them having originated from mixed provenances, indicating that screening for superior provenances should be carried out as soon as possible.

Background The neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR) are reported to show a strong correlation with prognosis in patients with non‐small cell lung cancer (NSCLC). We aimed to describe a novel scoring system combining these ratios, termed the inflammatory response biomarker (IRB) score, and test its prognostic value in NSCLC. Methods The data of 261 NSCLC patients who underwent thoracoscopic radical resection in a single center were retrospectively reviewed. The IRB score was defined as follows: a high NLR (> 2.12), a high PLR (92.9), and a low LMR (< 4.57) were each scored as 1; the opposite values were scored as 0. The individual scores were added to produce the IRB score (range: 0–3). Results Multivariate analyses indicated that high tumor node metastasis (TNM) stage (hazard ratio [HR] 2.721, 95% confidence interval [CI] 1.597–4.989; P

Abstract Inspired by nature, scientists and researchers have studied the wetting behaviors on various creatures and mimicked their structures to fabricate diverse functional superwetting materials. As one kind of emerging application, the bioinspired superwettable surfaces used for biosensing have been aroused wide interests. In this review, we summarized the recent developments of bioinspired superwettable surfaces in the field of biosensing. In the first part, superwettable creatures in nature, namely, superhydrophobic self‐cleaning lotus leaf, high‐adhesion superhydrophobic rose petal, amphiphobic springtail, patterned wetting desert beetles, slippery pitcher plant, were introduced. In sequence, we successively described the special wetting models of superhydrophobicity, superamphiphobicity, responsive wettability, patterned wettability, and slipperiness. Then, biosensing applications based on the respective patterned wettable, superhydrophobic, responsive wettable, and slippery substrates that were combined with the common detection approaches (colorimetry, fluorescence, surface‐enhanced Raman scattering (SERS), electrochemistry) were shown in detailed. At last, an insight of remaining challenges and future development for bioinspired superwetting materials applied in biosensing was provided.

Estuarine zones are regarded as the ecotones connecting the rivers and lakes. Sediment dredging is a conventional treatment technology that is widely used to remove the internal loading in estuarine zones worldwide. However, what is the characteristic of nutrient release in the gate-controlled estuary and how long this practice is effective are still unclear. Hence, sediment and water samples were collected from dredged and undredged regions around the gate-controlled estuary of northern Taihu Lake for laboratory experiments, in which they were subjected to different temperatures, depths, and disturbance levels. The total nitrogen (TN) and total phosphorus (TP) concentrations of the dredged region were lower than those from the undredged region under stable hydrodynamic conditions. A high dynamic release rate (R) of nutrients in the dredged sediments (RTN = 164.75 mg/m2·d and RTP = 5.83 mg/m2·d) existed under dynamic release conditions (stirring speeds: 90 and 120 r/min). The effect of disturbance and temperature on release rate and nutrient form was completely different for the static and dynamic release cases. The nutrient loads from dynamic release were 4–17 times greater than those from static release. For unstable hydrodynamic conditions, the release rate from the bottom sediment exceeded that from the surface sediment in the undredged region. These results indicated that, under stable hydrodynamic conditions, dredging improves long-term water quality. However, dredging alone in unstable hydrodynamic conditions may not remove the potential risk of internal release in the long term. Specific ecological and engineering measures should be combined with dredging practice to restore estuary habitats and minimize the release of internal pollutants.

Objectives. Diabetic wound inflammation deficiencies lead to ulcer development and eventual amputation and disability. Our previous research demonstrates that myeloid-derived suppressor cells (MDSCs) accumulate during inflammation and promote chronic wound healing via the regulation of Kruppel-like factor 4 (KLF4). In this study, we aimed to investigate the potential roles of MDSCs and KLF4 in diabetic wound healing. Methods. An ob/ob mouse pressure ulcer (PU) model was used to evaluate the process of wound healing. The expression levels of KLF4 and IL-17A were measured by real-time PCR, and the population of MDSCs and Th17 cells was measured by flow cytometry. The levels of cytokines were determined by an immunosuppression assay. Results. KLF4 deficiency in the diabetic PU model resulted in decreased accumulation of MDSCs, increased expansion of Th17 cells, and significantly delayed wound healing. Conversely, KLF4 activation by APTO-253 accelerated wound healing accompanied by increased MDSC populations and decreased numbers of Th17 cells. MDSCs have been proven to mediate Th17 differentiation via cytokines, and our in vitro data showed that elevated KLF4 expression in MDSCs resulted in reduced Th17 cell numbers and, thus, decreased levels of cytokines indispensable for Th17 differentiation. Conclusions. Our study revealed a previously unreported function of KLF4-regulated MDSCs in diabetic wound healing and identified APTO-253 as a potential agent to improve the healing of pressure ulcers.

In order to grasp the timing of sun calibration in advance, this paper introduces a high-precision method to predict the solar angle by using the current broadcast time and orbital instantaneous root of the satellite platform. By calculating the sun’s apparent right ascension and apparent declination, the conversion matrix from the geocentric inertial coordinate system to the orbital coordinate system, and the satellite attitude correction matrix, the sun vector in the satellite body coordinate system is obtained. This method is used to predict the sun angle of a sun synchronous orbit in the satellite coordinate system, and the prediction results are compared with the STK simulation results. The results show that the sun angle prediction error of this method is less than ±0.003°. It can meet the requirements of on-orbit solar calibration. The main error sources in the prediction method are analysed.

In order to improve the capability of dealing with software common cause failure (CCF) of digital reactor protection and monitoring system (RPMS), the diverse actuation system (DAS) is introduced for ACPR1000 nuclear power plants. From economic and feasibility point of view, the solution of DAS sharing with RPMS sensors and actuators is suggested; after capturing the function requirement of DAS, the automatic functions and manual functions assigned to it are determined based on transient analysis of design basic accidents concurrent with software CCF of RPMS. The independent verification proves that the reactor can be fallen back to and maintained at safety shutdown state, thanks to these DAS functions. Insight into probabilistic safety assessment proves significant reductions of risks are contributed. The critical technical issues while implementing DAS, such as measures to ensure its diversity from RPMS, precautions for preventing from its spurious actuation, isolation and independency from RPMS, and its testability and maintainability, are deliberately settled to improve its engineering reliability and alleviate the impact on RPMS as far as possible. Field programmable gate array technology that is diversified from RPMS is chosen to build DAS of ACPR1000 nuclear power plant, and the commissioning test verifies that it is capable of performing its designed functions. At last, a set of DAS-specific, paper-based, and event-oriented emergency operating procedure is developed, verified, and validated. Until now, the DAS system has always been successfully operating in all ACPR1000 nuclear power plants for several years.

Abstract Discriminating depressive episodes of bipolar disorder (BD) from major depressive disorder (MDD) is a major clinical challenge. Recently, gut microbiome alterations are implicated in these two mood disorders; however, little is known about the shared and distinct microbial characteristics in MDD versus BD. Here, using 16S ribosomal RNA (rRNA) gene sequencing, the microbial compositions of 165 subjects with MDD are compared with 217 BD, and 217 healthy controls (HCs). It is found that the microbial compositions are different between the three groups. Compared to HCs, MDD is characterized by altered covarying operational taxonomic units (OTUs) assigned to the Bacteroidaceae family, and BD shows disturbed covarying OTUs belonging to Lachnospiraceae, Prevotellaceae, and Ruminococcaceae families. Furthermore, a signature of 26 OTUs is identified that can distinguish patients with MDD from those with BD or HCs, with area under the curve (AUC) values ranging from 0.961 to 0.986 in discovery sets, and 0.702 to 0.741 in validation sets. Moreover, 4 of 26 microbial markers correlate with disease severity in MDD or BD. Together, distinct gut microbial compositions are identified in MDD compared to BD and HCs, and a novel marker panel is provided for distinguishing MDD from BD based on gut microbiome signatures.

Many real infrastructure systems such as power grids and communication networks across cities not only depend on each other but also have community structures. This observation derives a new research subject of the interdependent community networks (ICNs). Recent works showed that the ICNs are extremely vulnerable to the failure of interconnected nodes between communities. Such vulnerability is prone to cause avalanche breakdown of the ICNs. How to improve the robustness of ICNs remains a challenge. In this paper, we propose a new target recovery strategy in the self-awareness recovery model, called recovery strategy based on community structures (RCS). The self-awareness recovery model repairs and reactivates the original pair of failed nodes that belong to mutual boundary of networks during cascading failures. The key insight is that the RCS explicitly considers both intercommunity links and intracommunity links. In this paper, we compare RCS with the state-of-the-art approaches based on randomness, degree centrality, and local centrality. We find that the RCS outperforms the other three strategies on the size of giant component, the existence probability of giant component, the number of iterative cascade steps, and the average degree of the remaining network. Moreover, RCS is robust against a given noise, and the optimal parameter of RCS remains stable even if the recovery ratio varies.

Abstract Myasthenia gravis (MG) is a devastating acquired autoimmune disease. Emerging evidence indicates that the gut microbiome plays a key role in maintaining immune system homeostasis. This work reports that MG is characterized by decreased α‐phylogenetic diversity, and significantly disturbed gut microbiome and fecal metabolome. The altered gut microbial composition is associated with fecal metabolome changes, with 38.75% of altered bacterial operational taxonomic units showing significant correlations with a range of metabolite biomarkers. Some microbes are particularly linked with MG severity. Moreover, a combination of microbial makers and their correlated metabolites enable discriminating MG from healthy controls (HCs) with 100% accuracy. To investigate whether disturbed gut mcirobiome might contribute to the onset of MG, germ‐free (GF) mice are initially colonized with MG microbiota (MMb) or healthy microbiota (HMb), and then immunized in a classic mouse model of MG. The MMb mice demonstrate substantially impaired locomotion ability compared with the HMb mice. This effect could be reversed by cocolonizing GF mice with both MMb and HMb. The MMb mice also exhibit similar disturbances of fecal metabolic pathways as found in MG. Together these data demonstrate disturbances in microbiome composition and activity that are likely to be relevant to the pathogenesis of MG.

Background Hypertension is the major risk factor for cardiovascular disease, the most common cause of death worldwide. Resistance arteries are capable of adapting their diameter independently in response to pressure and flow‐associated shear stress. Ryanodine receptors (RyRs) are major Ca2+‐release channels in the sarcoplasmic reticulum membrane of myocytes that contribute to the regulation of contractility. Vascular smooth muscle cells exhibit 3 different RyR isoforms (RyR1, RyR2, and RyR3), but the impact of individual RyR isoforms on adaptive vascular responses is largely unknown. Herein, we generated tamoxifen‐inducible smooth muscle cell–specific RyR2‐deficient mice and tested the hypothesis that vascular smooth muscle cell RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow. Methods and Results Targeted deletion of the Ryr2 gene resulted in a complete loss of sarcoplasmic reticulum–mediated Ca2+‐release events and associated Ca2+‐activated, large‐conductance K+ channel currents in peripheral arteries, leading to increased myogenic tone and systemic blood pressure. In the absence of RyR2, the pulmonary artery pressure response to sustained hypoxia was enhanced, but flow‐dependent effects, including blood flow recovery in ischemic hind limbs, were unaffected. Conclusions Our results establish that RyR2‐mediated Ca2+‐release events in VSCMs specifically regulate myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. They further suggest that vascular smooth muscle cell–expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.

With the rapid growth of microgrids, many regional multi-microgrids systems emerge gradually with microgrids being integrated to the certain distribution network. By connecting each microgrid using cables and coordinating interaction power among microgrids, the total operation cost of multi-microgrids system can be decreased. On the basis of modeling a variety of energy supply and storage devices, this paper proposes an energy supply infrastructure for combined cooling, heating and power (CCHP) microgrid on centralized and interconnected energy exchange network, and energy loads are subdivided into cooling load, thermal load and power load. Then the optimal economic dispatch model considering interaction power among microgrids is proposed in this study for CCHP type multi-microgrids, and energy balance constraints are established according to load types. This model not only takes into account the power interaction between microgrid and the distribution network, but also considers the power interaction among microgrids. The objective is the minimal total operation cost of CCHP type multi-microgrids system. In case studies of Sino-Singapore district, Tianjin, China, the output power of pre-defined equipment and the total operation cost are compared under two different operation mode, coordination mode and independence mode, which verifies the effectiveness and economy of the proposed model.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPARγ agonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence of L-NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increased ETBR but decreased ETAR level in pulmonary arteries from PAH rats. ETBR antagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPARγ agonists in PAH.

A novel La (III) complex, [LaL(H2O)3]NO3·3H2O, with Schiff base ligand L derived from kaempferol and diethylenetriamine, has been synthesized and characterized by elemental analysis, IR, UV-visible, 1H NMR, thermogravimetric analysis, and molar conductance measurements. The fluorescence spectra, circular dichroism spectra, and viscosity measurements and gel electrophoresis experiments indicated that the ligand L and La (III) complex could bind to CT-DNA presumably via intercalative mode and the La (III) complex showed a stronger ability to bind and cleave DNA than the ligand L alone. The binding constants (Kb) were evaluated from fluorescence data and the values ranged from 0.454 to 0.659 × 105 L mol−1 and 1.71 to 17.3 × 105 L mol−1 for the ligand L and La (III) complex, respectively, in the temperature range of 298–310 K. It was also found that the fluorescence quenching mechanism of EB-DNA by ligand L and La (III) complex was a static quenching process. In comparison to free ligand L, La (III) complex exhibited enhanced cytotoxic activities against tested tumor cell lines HL-60 and HepG-2, which may correlate with the enhanced DNA binding and cleaving abilities of the La (III) complex.

This paper presents and puts forward an optimal automatic distributing of physical cell identity (ADPCI) scheme for the self-organizing network (SON). Considering the high number and the layered structure of the evolved node B (eNodeB, eNB) in the initial rollout phase, the assigning of PCI for cells would be quite complex. The PCI self-distributing problem is mapped to the well-known minimum spanning tree (MST) problem in order to optimize the PCI reuse distance and decrease the multiplexing interference. The correlation property of PCI is analyzed and taken into consideration in the assigning phase. Moreover, a suboptimal algorithm (SADPCI) is presented as it performs approximately to ADPCI but the computational complexity is lower. To demonstrate the proposal validity, performances of ADPCI and SADPCI are evaluated. Simulation results illustrate that these schemes can achieve significantly higher performance even under the condition of severe PCI deficiency.