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Summary: Many of the advanced technologies, e.g., microprocessors, laser and radar, and power transmitters and amplifiers, are becoming increasingly dependent on the ability to dissipate the enormous amount of waste heat in extremely small areas. Two-phase heat spreaders utilizing the liquid-vapor phase change are appealing due to the high performance and potentially low cost. However, thin film evaporation is limited by the capillary dry-out of wicking structures. We demonstrate here an ultra-high thermal conductance and high flux heat spreader enabled by a capillary-driven liquid film boiling process on a hierarchical mesh wicking structure. By manipulating liquid wicking flow and vapor bubble escape, liquid film boiling is demonstrated to have a heat removal capability of 552 W/cm2 from an area of 25 mm2 with a temperature increase of less than 8 K, corresponding to a heat transfer coefficient of 732.5 kW/m2·K. The effective thermal conductivity of the 1-mm-thick two-phase heat spreader is larger than 104 W/m·K.

Recent studies have identified that long noncoding RNA (lncRNA) might affect the responses to anticancer drug treatment, including colorectal cancer (CRC). However, the association between single-nucleotide polymorphisms (SNPs) in PVT1 and the chemotherapy response in metastatic colorectal cancer has yet to be clarified. In this study, the PVT1 rs2278176 CT/TT genotypes were found to be associated with an increased overall survival (OS) and progression-free survival (PFS) compared with the CC genotype. Furthermore, patients harboring the rs2278176 CT/TT genotypes had a greater chance of achieving clinical benefit from 5-Fluorouracil/leucovorin combined with oxaliplatin (FOLFOX). In vivo nude mice experiments demonstrated that the CRISPR/Cas9 mediated rs2278176 C to T mutation significantly inhibited the tumorigenesis of colorectal cancer cells treated with 5-Fu, but not control DMSO treated cells. Furthermore, the apoptotic rate was significantly enhanced by treatment with 5-Fu in the CRC cells carrying with the CT/TT genotypes. Functional studies demonstrated that the PVT1 rs2278176 C to T mutation altered the binding site for hsa-miR-297, and that hsa-miR-297 downregulated Glutathione S-Transferase Alpha 2(GSTA2), a member of phase II detoxification enzyme, in an Argonaute 2(Ago2)-dependent manner. Moreover, GSTA2 levels were downregulated in the cancer tissues of patients carrying rs2278176 CT/TT genotypes. High GSTA2 expression predicted poor clinical outcome in metastatic colorectal cancer treated with FOLFOX. In conclusion, this study provided that PVT1 with rs2278176 T allele altered the binding affinity with hsa-miR-297, leading to decreased GSTA2 expression and sensitized CRC cells to FOLFOX chemotherapy, suggesting rs2278176 CT/TT genotypes might serve as a predictive biomarker to improve prognosis in patients with metastatic CRC treated with FOLFOX.

BackgroundVisceral adiposity index (VAI) is an indicator of visceral fat accumulation and dysfunction. However, little is known about whether VAI is associated with worsening renal function (WRF) in the elderly. Therefore, our study aimed to explore the association between VAI and WRF among the elderly population.MethodsIn total, 5,583 elderly participants (aged ≥ 65 years) who participated in the annual health checkups at least twice between January 2017 and July 2021 were enrolled and divided into four groups according to the VAI quartiles. The primary endpoint was incident chronic kidney disease (CKD), defined as incident estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The secondary endpoint was rapid kidney function decline (RKFD), defined as decline in eGFR of 40%. To evaluate the association between VAI and WRF, three Cox regression models were conducted, where VAI was treated as a continuous variable and a categorical variable (Q1 as reference), respectively. Subgroup analysis in participants with different baseline characteristics was also performed.ResultsDuring a median of 2.46 year follow-up, 931 (16.68%) participants developed CKD. After fully adjusting for confounding factors, VAI was significantly associated with incident CKD (HR, 1.052; 95% CI: 1.029–1.076, p < 0.001), and RKFD (HR, 1.077; 95% CI: 1.041–1.114, p < 0.001). Moreover, compared to those with the lowest VAI quartiles, subjects with the highest quartiles had a higher risk of incident CKD (HR, 1.286; 95% CI: 1.033–1.601, p = 0.024), and RKFD (HR, 1.895; 95% CI: 1.086–3.307, p = 0.025). The risk of incident CKD also tended to increase with elevated VAI quartiles (all p-values for trend

Mutations in TP53 and hyperactivation of the PI3K/AKT pathway are the two most frequent drivers of cancer progression across multiple human tumour types. Here, the authors identify two TAp63 regulated long non-coding RNAs, TROLL-2 and TROLL-3, that connect these oncogenic pathways, thus promoting tumour and metastasis formation in a wide variety of cancer types.

Background: In some previous studies, serum hepatitis B virus RNA (HBV RNA) was proposed as an HBV viral marker during therapy. However, the dynamic change of HBV RNA, the correlation of HBV RNA with cccDNA, and the combination of HBV RNA with known HBV markers in predicting entecavir (ETV) treatment outcome in the same cohort are rarely reported. Methods: A total of 111 HBeAg-positive patients were enrolled in our study. The dynamic changes of serum HBV RNA and the correlation of HBV RNA with other HBV markers were investigated in the early treatment period of 144-week ETV treatment. Intrahepatic cccDNA was detected at baseline and week 48. Receiver operating characteristic analyses were used to identify HBV RNA levels associated with HBeAg seroconversion. Results: The serum HBV RNA levels decreased more rapidly in patients with HBeAg seroconversion than those without HBeAg seroconversion. The levels of HBV RNA decreased slower compared with the serum HBV DNA, irrespective of whether the patients achieved HBeAg seroconversion or not. Although the serum HBV RNA was positively correlated with cccDNA at baseline among all patients, no significant correlation was observed in the patients with HBeAg seroconversion at week 48 (r = 0.094, P = 0.588). The area under the receiver operating characteristic (AUROC) of HBV RNA and HBeAg at week 24 was 0.754 and 0.800, respectively. The AUROC of the HBV RNA and HBeAg combination had a higher value (AUROC = 0.821). Conclusions: The level of HBV RNA at week 24 was a powerful predictor of HBeAg seroconversion in HBeAg-positive patients after 144-week ETV treatment, while the combination of HBV RNA and HBeAg was superior to HBV RNA alone in predicting HBeAg seroconversion.

Abstract We propose a planar model heterojunction based on α-borophene nanoribbons and study its electronic transport properties. We respectively consider three types of heterojunctions. Each type consists of two zigzag-edge α-borophene nanoribbons (Z αBNR), one is metallic with unpassivated or passivated edges by a hydrogen atom (1H-Z αBNR) and the other is semiconducting with the edge passivated by two hydrogen atoms (2H-Z αBNR) or a single nitrogen atom (N-Z αBNR). Using the first-principles calculations combined with the nonequilibrium Green’s function, we observe that the rectifying performance depends strongly on the atomic structural details of a junction. Specifically, the rectification ratio of the junction is almost unchanged when its left metallic ribbon changes from ZBNR to 1H-Z αBNR. However, its ratio increases from 120 to 240 when the right semiconducting one varies from 2H-Z αBNR to N-Z αBNR. This rectification effect can be explained microscopically by the matching degree the electronic bands between two parts of a junction. Our findings imply that the borophene-based heterojunctions may have potential applications in rectification nano-devices.

Abstract Although emerging studies showed that certain rhythm genes regulate cancer progression, the expression and roles of the vast majority of rhythm genes in human cancer are largely unknown, and the hallmarks of cancer regulated by rhythm genes have not been detected. In this study, we detected the expression changes of rhythm genes in pan‐cancer and found that almost all rhythm genes mutated in all cancer types, and their expression level was significantly altered partially due to abnormal methylation, and several rhythm genes regulate the expression of other rhythm genes in various cancer types. Furthermore, we revealed that rhythm genes are significantly enriched in genome instability and the expression of certain rhythm genes is correlated with the tumor mutation burden, microsatellite instability, and the expression of DNA damage repair genes in most of the detected cancer types. Moreover, rhythm genes are associated with the infiltration of immune cells and the efficiency of immune blockade therapy. This study provides a comprehensive understanding of the roles of rhythm genes in cancer immunity, which may provide a novel method for the diagnosis and treatment of cancer.

Abstract Background Saccharopolyspora erythraea (S. erythraea) is a Gram-positive bacterium widely used for the production of erythromycin, a potent macrolide antibiotic. However, the mechanism behind erythromycin production is poorly understood. In the high erythromycin-producer strain S. erythraea HL3168 E3, the level of copper ions positively correlates with erythromycin production. To explain this correlation, we performed a genome-based comparison between the wild-type strain NRRL23338 and the mutant strain HL3168 E3, and further characterized the identified gene(s) by targeted genome editing, mRNA transcript analysis, and functional analysis. Results The response regulator of the two-component system (TCS) encoded by the gene SACE_0101 in S. erythraea showed high similarity with CopR of TCS CopRS in Streptomyces coelicolor, which is involved in the regulation of copper metabolism. The deletion of SACE_0101 was beneficial for erythromycin synthesis most likely by causing changes in the intracellular copper homeostasis, leading to enhanced erythromycin production. In addition, Cu2+ supplementation and gene expression analysis suggested that SACE_0101 may be involved in the regulation of copper homeostasis and erythromycin production. Conclusions The mutation of SACE_0101 gene increased the yield of erythromycin, especially upon the addition of copper ions. Therefore, the two-component system gene SACE_0101 plays a crucial role in regulating copper homeostasis and erythromycin synthesis in S. erythraea.

Abstract Background As a novel class of noncoding RNAs, circRNAs have been recently identified to regulate tumorigenesis and aggressiveness. However, the function of circRNAs in colorectal cancer (CRC) metastasis remains unclear. We aimed to identify circRNAs that are upregulated in CRC tissues from patients and study their function in CRC metastasis. Methods We compared six pairs of CRC tissues and their matched adjacent non-tumor tissues by using circRNA microarray. We first evaluated the expression of circPTK2 (hsa_circ_0005273) in fresh tissues from CRC tumors and corresponding adjacent tissues by qPCR analysis. CircPTK2 expression levels in the tissue microarray with 5 years of survival information were determined by RNA-ISH analysis. Meanwhile, the expression levels of circulating circPTK2 were further analyzed according to the patients’ clinical features. We analyzed cell apoptosis, colony formation, migration, and invasion in CRC cells. To further elucidate the effect of circPTK2 in CRC metastasis, we also conducted a colon cancer hepatic and pulmonary metastasis experiment. We used RNA biotin-labeled pull down and mass spectrometry to identify the target of circPTK2. We established a PDTX model to evaluate the effect of shRNA specifically targeting circPTK2 on tumor metastasis. Results We identified a novel circRNA, circPTK2, which is back-spliced of three exons (exons 27, 28 and 29) of PTK2 by using circRNA microarray, bioinformatics and functional studies. CircPTK2 was elevated in CRC tissues and positively associated with tumor growth and metastasis. CRC patients with increased circPTK2 expression were positively correlated with poorer survival rates. Furthermore, our studies showed that circPTK2 could promote EMT of CRC cells in vitro and in vivo by binding to vimentin protein on sites Ser38, Ser55 and Ser82. We further demonstrated the interaction of circPTK2 and vimentin mediated the regulation of CRC by knockdown or overexpression of vimentin. In addition, we revealed that tail vein injection of shRNA specifically targeting circPTK2 blunt tumor metastasis in a patient-derived CRC xenograft model. Conclusions Collectively, these results demonstrate that circPTK2 exerts critical roles in CRC growth and metastasis and may serve as a potential therapeutic target for CRC metastasis, and also a promising biomarker for early diagnosis of metastasis.

With the rapid growth of application demands and the real-time change of environmental situations, the defects of the UAV task network in adaptability, flexibility, and resilience are becoming more and more prominent. The current network architecture that the junction of points and lines is fixed cannot dynamically provide capacity requirements in real-time due to the failure nodes encountered in the Unmanned Aerial Vehicle (UAV) task scheduling process. To address this challenging issue, this paper proposes a flexible network architecture supporting dynamic fault-tolerant task scheduling model (DSM-FNA) for the UAV cluster. To be specific this paper resorts to super network theory, combining the management theory of flexible network and resilience network to carry out the organizational calculation on the model, and also draw upon linear transformation function to weight and stratify the capability value according to the ability requirement required by the task. Then, a flexible network architecture dynamic scheduling algorithm (FDSA) is proposed, and the substitution strategy is designed for the failure point, to realize the capability and dynamically adapt to the task. Finally, compared with the classical Max-Min algorithm and other algorithms, it is verified that the FDSA algorithm performs better dynamic adjustment for quick response in case of UAV cluster emergencies.

The outer consensus between two coupled heterogeneous networked systems with bidirectional actions and nonidentical topologies is addressed in this paper. Based on the adaptive theory, a control protocol is designed for two coupled heterogeneous networked systems, where each system consists of double-integrator and single-integrator nodes with different nonlinear dynamics. In the light of Lyapunov method and LaSalle's invariance principle, we prove that the coupled heterogeneous networked systems can reach outer consensus by using the reported controller. Meanwhile, the adaptive controller is also given for the second-order nonlinear systems under identical and nonidentical topologies. The correctness of the obtained theory is demonstrated by two simulation examples.

An improved Drude-Lorentz model was proposed to describe the effect of annealing on the surface Plasmon resonance (SPR) sensor. In the new model, the grain structure is taken into account to describe theoretically the dispersion of gold films. Then the improved model is used to analyze the performance of SPR sensors before and after annealing. The results indicate that the grain structure of the gold film affect the resonance properties significantly. In our research, a considerable improvement in SPR fiber sensor performance is observed after annealing. The grain size of the gold film rises from 10.8 nm to 34.3 nm, and the absorption spectrum of the SPR fiber sensor becomes deeper and sharper, with the figure of merit increasing from 18.5 to 22.8 after annealing. Comparing with other sensor performance enhancement methods, the annealing progress does not change the sensor structure or add new modified layer. Therefore, most SPR sensors can be further annealed to improve the quality of the sensor after fabrication. This property makes the application of annealing very promising in optical sensing region.

It has been revealed that 2′3′-cyclic-GMP-AMP (cGAMP), a second messenger that activates the antiviral stimulator of IFN genes (STING), elicits an antitumoral immune response. Since cGAMP cannot cross the cell membrane, it is not clear how intracellular STING has been activated by extracellular cGAMP until SLC19A1 was identified as an importer to transport extracellular cGAMP into the cytosol. However, SLC19A1-deficient cells also sense extracellular cGAMP, suggesting the presence of mechanisms other than the facilitating transporters for STING sensing extracellular cGAMP. Here, using immunoprecipitation, immunofluorescence, and flow cytometry, we identified an alternatively spliced STING isoform, plasmatic membrane STING (pmSTING), that localized in the plasma membrane with its C-terminus outside the cell, due to a lack of 1 transmembrane domain in its N-terminus compared with canonical STING. Further studies showed that extracellular cGAMP not only promoted the dimerization of pmSTING and interaction of pmSTING with TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3), but also enhanced the phosphorylation of TBK1 and IRF3 and the production of IFN in pmSTING-transfected cells. Additionally, we also identified similar pmSTING isoforms in other species including human. This study suggests a conserved role for pmSTING in sensing extracellular cGAMP and provides insight into the role of cGAMP as an immunotransmitter.

ObjectiveThe purpose of this study was to investigate the relationship between lymph node harvest and the prognosis in locally advanced rectal cancer (LARC) patients after neoadjuvant chemoradiotherapy (nCRT).MethodsPatients who were diagnosed with clinical LARC and treated with nCRT and radical surgery between June 2008 and July 2017 were included in this study. The relationship between lymph node retrieval and prognosis was analyzed. Other lymph node-related indicators were explored.ResultsA total of 837 patients with a median follow-up of 61 (7-139) months were included in the study. The five-year DFS and OS rates of all patients were 74.9% and 82.3%, respectively. Multivariate survival analysis suggested that dissection of ≥ 12 lymph nodes did not improve OS or DFS. 7 was selected as the best cutoff value for the total number of lymph nodes retrieved by Cox multivariate analysis (χ2 = 10.072, HR: 0.503, P=0.002). Dissection of ≥ 5 positive lymph nodes (PLNs) was an independent prognostic factor for poorer DFS (HR: 2.104, P=0.004) and OS (HR: 3.471, p

Pancreatitis is the leading cause of hospitalization in gastroenterology, and no medications are available for treating this disease in current clinical practice. FXR plays an anti-inflammatory role in diverse inflammatory diseases, while its function in pancreatitis remains unknown. In this study, we initially observed a marked increase of nuclear FXR in pancreatic tissues of human patients with pancreatitis. Deleting the FXR in pancreatic acinar cells (FXRacinarΔ/Δ) led to more severe pancreatitis in mouse models of caerulein-induced acute and chronic pancreatitis, while the FXR agonist GW4064 significantly attenuated pancreatitis in caerulein or arginine-induced acute pancreatitis and caerulein-induced chronic pancreatitis. FXR deletion impaired the viability and stress responses of pancreatic exocrine organoids (PEOs) in vitro. Utilizing RNA-seq and ChIP-seq of PEOs, we identified Osgin1 as a direct target of FXR in the exocrine pancreas, which was also increasingly expressed in human pancreatitis tissues compared to normal pancreatic tissues. Pancreatic knockdown of Osgin1 by AAV-pan abolished the therapeutic effects of FXR activation on pancreatitis, whereas pancreatic overexpression of Osgin1 effectively alleviated caerulein-induced pancreatitis. Mechanistically, we found that the FXR-OSGIN1 axis stimulated autophagic flux in the pancreatic tissues and cell lines, which was considered as the intrinsic mechanisms through which FXR-OSGIN1 protecting against pancreatitis. Our results highlight the protective role of the FXR-OSGIN1 axis in pancreatitis and provided a new target for the treatment of this disease.

Functional connectivity has been demonstrated to be varying over time during sensory and cognitive processes. Quantitative examinations of such variations can significantly advance our understanding on large-scale functional organizations and their topological dynamics that support normal brain functional connectome and can be altered in individuals with brain disorders. However, toolboxes that integrate the complete functions for analyzing task-related brain functional connectivity, functional network topological properties, and their dynamics, are still lacking. The current study has developed a MATLAB toolbox, the Graph Theoretical Analysis of Task-Related Functional Dynamics (GAT-FD), which consists of four modules for sliding-window analyses, temporal mask generation, estimations of network properties and dynamics, and result display, respectively. All the involved functions have been tested and validated using functional magnetic resonance imaging data collected from human subjects when performing a block-designed task. The results demonstrated that the GAT-FD allows for effective and quantitative evaluations of the functional network properties and their dynamics during the task period. As an open-source and user-friendly package, the GAT-FD and its detailed user manual are freely available at https://www.nitrc.org/projects/gat_fd and https://centers.njit.edu/cnnl/gat_fd/.

Shipping emissions have aroused wide concern in the world. In order to promote the implementation of emission regulations, this study develop a ship based sniffing technique to perform remote measurement of the SO2, NOx and CO2 from ships entering and leaving Shanghai port at the open sea. The ship emission prediction model, Smoke diffusion model and source identification model were developed to automatically analyze the emission data and screen the object ship source based on Automatic Identification System (AIS) system. The fueling documents of the detected ship were obtained from maritime sector and the results precision of the sniffer technique was evaluated by comparing the measured Fuel sulfur content (FSC) with actual value deduced from fueling documents. The influences of wind speed and direction, object ship parameters and monitoring distance on the identification of object ship and accuracy of the calculated FSC were thoroughly investigated and the corresponding correction factors under different conditions were deduced. The modified emission factor ratio of CO2 to NOx were proposed in order to improve the accuracy. It is demonstrated that with wind speed higher than 2 m/s and test distance shorter than 400m, the sniffer technique exhibit high efficiency and accuracy for the remote emissions measurement of ship upwind with detection rate higher than 90% and test error of FSC below 15%. To reduce the influence of the wind direction, at least two sniffer systems were required to guarantee that at least one station is in the downwind of the ship lane. Based on the results and discussion, a novel sniffer monitoring system with two buoy based sniffing stations placed close to each side of the ship lane far off shore was proposed to realize the remote monitoring of ship emissions.

Different from vehicle engines, Diesel Particulate Filter (DPF) inactivation is an unavoidable issue for low-speed marine diesel engines fueled with Heavy Fuel Oil (HFO). This paper introduced a sulfur resisting material in Silicon Carbide (SiC)-DPF to improve DPF performance. The results of bench-scale experiments showed that the Balance Point Temperature of the modified DPF module was 300°C and DPF modules had a good filtration performance, with Particulate Matters (PMs) residual being less than 0.6 g per cycle. In pilot-scale tests, PMs emissions of unit power decreased with engine load going up, filtration efficiency of nucleation mode PMs being only 36% under 100% load, while DPF still had a good performance in accumulation mode PMs control, being 94.2% under the same load. DPF modules showed excellent regeneration durability in the 205h endurance test, with a regeneration period of 1.5-2h under 380°C. There was no obvious degeneration in the DPF module structure, with no cracks or breakage. Besides, the DPF module could also control gaseous emissions, total emissions decreased by 10.53% for NO and 57.19% for CO, respectively. The results suggested that introducing sulfur-resisting material in DPF could greatly improve the DPF performance of low-speed marine diesel engines fueled with HFO.

In order to study the nonlinear characteristics of self-excited aerodynamic forces of bluff body bridge section with the change of motion parameters, a numerical wind tunnel is established by the dynamic mesh technique of computational fluid dynamics (CFD). A state-by-state forced vibration method is used to identify the self-excited aerodynamic forces of single degree-of-freedom (DOF) heaving and pitching motion. Fast Fourier transform (FFT) is adopted to obtain frequency-domain data for analysis. The reliability of the obtained aerodynamic results is verified by wind tunnel tests. The results show that the high-order harmonic components are found in the self-excited aerodynamic forces of semiclosed box deck section, which are more significant in aerodynamic lift than in aerodynamic moment. The proportion of aerodynamic nonlinear components increases with amplitude. The effect of amplitude on the nonlinear components of heaving motion is generally higher than that of pitching motion, and aerodynamic moment is highly sensitive to the increase of vertical amplitude. The variation of the nonlinear components of the deck section with frequency is not a simple monotonic relationship, and there is a stationary point at 10 Hz frequency. The existence of wind attack angle makes the proportion of nonlinear components reach more than 30% and greatly increases the proportion of second harmonic. In addition, the high-order harmonic components, which are not integer multiples, are found at large amplitude and positive angle of attack.

Background and AimsCharcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies. The wide phenotypic variability may not be completely explained by a single mutation.Aims and MethodsTo explore the existence of concomitant variants in CMT, we enrolled 189 patients and performed molecular diagnosis by application of next-generation sequencing combined with multiplex ligation-dependent probe amplification. We conducted a retrospective analysis of patients harboring coinherited variants in different genes.ResultsFour families were confirmed to possess variants in two genes, accounting for 2.1% (4/189) of the total in our cohort. One CMT1 patient with PMP22 duplication and MPZ variant (c.286A>C, p.K96Q) exhibited moderate neuropathy with infantile onset, while her father possessing MPZ variant was mildly affected with adolescence onset. A CMT2 patient with heterozygous variants in MFN2 (c.613_622delGTCACCACAG, p.V205Sfs*26) and GDAP1 (c.713G>T, p.W238L) exhibited childhood onset mild phenotype, while his mother with MFN2 variant developed bilateral pes cavus only. A CMT2 patient with heterozygous variants in MFN2 (c.839G>A, p.R280H) and GDAP1 (c.3G>T, p.M1?) presented infantile onset and rapid progression, while her father with MFN2 variant presented with absence of deep tendon reflexes. One sporadic CMT2 patient with early onset was confirmed harboring de novo MFN2 variant (c.1835C>T, p.S612F) and heterozygous GDAP1 variant (c.767A>G, p.H256R).ConclusionOur results suggest that the possibility of concomitant variants was not uncommon and should be considered when significant intrafamilial clinical heterogeneity is observed.

BackgroundNeoadjuvant immunotherapy has preliminarily been effective in multiple resectable cancers. However, its safety is still largely unknown.MethodsA systematic literature search was conducted in PubMed, Embase, Web of Science, and Cochrane Library up to February 28th, 2021. Pooled incidence and risk ratio (RR) of adverse events were calculated using the R software.ResultsTwenty-eight studies involving 2863 patients were included. First, the incidence for all-grade treatment-related adverse events (trAEs) was 94% (95% CI, 81%-98%), with 43% (95% CI, 24%-64%) for high-grade trAEs. For different treatment groups, neoadjuvant immune checkpoint inhibitors (ICIs) plus chemotherapy was associated with a higher incidence of all-grade [99% (95% CI, 98%-99%) vs. 76% (95% CI 47%-92%); P < 0.001] and high-grade [80% (58%-92%) vs. 15% (9%-24%); P < 0.001] trAEs compared with neoadjuvant ICIs alone. The most common high-grade trAEs were lipase increased (5%; 95% CI, 2%-10%), colitis (3%; 95% CI, 0-7%) and transaminitis (3%; 95% CI, 0-7%) for neoadjuvant ICIs, and neutropenia (53%; 95% CI, 31%-74%), anemia (8%; 95% CI, 3%-15%) and AST increased (4%; 95% CI, 2%-7%) for neoadjuvant ICIs plus chemotherapy. Furthermore, the incidence rates of progressive disease while on treatment, treatment-related surgical delays and deaths were 6% (95% CI, 4%-10%), 3.2% (12 of 377 patients) and 0.47% (5 of 1075 patients), respectively.ConclusionCompared with neoadjuvant ICIs alone, neoadjuvant ICIs plus chemotherapy had a higher incidence of trAEs. In addition, neoadjuvant immunotherapy had a low rate of progressive diseases, surgical delays and deaths.

Background & Aims: Loss of Spectrin beta, non-erythrocytic 1 (SPTBN1) plays an important role in the carcinogenesis of hepatocellular carcinoma (HCC); however, the mechanisms underlying its involvement remain poorly understood. Defects in autophagy contribute to hepatic tumor formation. Hence, in this study, we explored the role and mechanism of SPTBN1 in the autophagy of hepatic stem cells (HSCs) and HCC cells. Methods: Expansion, autophagy, and malignant transformation of HSCs were detected in the injured liver of Sptbn1+/- mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment. Hippo pathway and Yes-associated protein (YAP) stabilization were examined in isolated HSCs, Huh-7, and PLC/PRF/5 HCC cells and hepatocytes with or without loss of SPTBN1. Results: We found that heterozygous SPTBN1 knockout accelerated liver tumor development with 3,5-diethoxycarbonyl-1,4-dihydrocollidine induction. Rapamycin promoted autophagy in murine HSCs and reversed the increased malignant transformation induced by heterozygous SPTBN1 deletion. Loss of SPTBN1 also decreased autophagy and increased YAP stability and nuclear localization in human HCC cells and tissues, whereas YAP inhibition attenuated the effects of SPTBN1 deficiency on autophagy. Finally, we found that SPTBN1 positively regulated the expression of suppressor of variegation 3-9-enhancer of zeste-trithorax domain containing lysine methyltransferase 7 to promote YAP methylation, which may lead to YAP degradation and inactivation. Conclusions: Our findings provide the first demonstration that loss of SPTBN1 impairs autophagy of HSCs to promote expansion and malignant transformation during hepatocarcinogenesis. SPTBN1 also cooperates with suppressor of variegation 3-9-enhancer of zeste-trithorax domain containing lysine methyltransferase 7 to inactive YAP, resulting in enhanced autophagy of HCC cells. These results may open new avenues targeting SPTBN1 for the prevention and treatment of HCC.

Knowledge graph (KG) embedding for predicting missing relation facts in incomplete knowledge graphs (KGs) has been widely explored. In addition to the benchmark triple structural information such as head entities, tail entities, and the relations between them, there is a large amount of uncertain and temporal information, which is difficult to be exploited in KG embeddings, and there are some embedding models specifically for uncertain KGs and temporal KGs. However, these models either only utilize uncertain information or only temporal information, without integrating both kinds of information into the underlying model that utilizes triple structural information. In this paper, we propose an embedding model for uncertain temporal KGs called the confidence score, time, and ranking information embedded jointly model (CTRIEJ), which aims to preserve the uncertainty, temporal and structural information of relation facts in the embedding space. To further enhance the precision of the CTRIEJ model, we also introduce a self-adversarial negative sampling technique to generate negative samples. We use the embedding vectors obtained from our model to complete the missing relation facts and predict their corresponding confidence scores. Experiments are conducted on an uncertain temporal KG extracted from Wikidata via three tasks, i.e., confidence prediction, link prediction, and relation fact classification. The CTRIEJ model shows effectiveness in capturing uncertain and temporal knowledge by achieving promising results, and it consistently outperforms baselines on the three downstream experimental tasks.

The preferential sites of Cr in the μ -Co _7 W _6 phase and its influence on electronic properties were studied by first-principles calculations based on density functional theory. The calculation results of the formation energy and defect formation energy show that the stability of the system is enhanced when Cr occupies the Co site, which indicates that Cr tends to occupy the Co site of the system. By calculating the density of states, the Hamilton population of crystal orbital, the electron location function and the Bader charge distribution, the reason why Cr preferentially occupied the Co sites is further explained. This is primarily owing to the hybridization of the d-d orbitals of the Cr atom to its adjacent atoms.

Series of experiments were performed to simulate the invasion of formation sand into and the plugging process of gravel-pack at different viscosities and flowing rates of fluid. Two types of formation sands with the medium size of 0.10 mm and 0.16 mm and the quartz sand and ceramsite of 0.6—1.2 mm were used in the experiments. A new viscosity-velocity index (the product of fluid viscosity and velocity) was put forward to characterize the influencing mechanism and law of physical property and flow condition of formation fluid on gravel-pack plugging, and a new method to optimize the production rate of wells controlling sand production with gravel-packing was proposed. The results show that the permeability of formation sand invaded zone and final permeability of plugged gravel-pack have negative correlations with viscosity and flow velocity of fluid, the higher the flow velocity and viscosity, the lower the permeability of formation sand invaded zone and final permeability of plugged gravel-pack will be. The flow velocity and viscosity of fluid are key factors affecting plugging degree of the gravel zone. The viscosity-velocity index (v-v index) can reflect the flow characteristics of fluid very well and make it easier to analyze the plugging mechanism of gravel zone. For different combinations of fluid viscosity and flow velocity, if the v-v index is the same or close, their impact on the final gravel permeability would be the same or close. With the increase of the v-v index, the permeability of plugged gravel zone decreases first, then the reduction rate slows down till the permeability stabilizes. By optimizing production and increasing production step by step, the optimal working scheme for sand-control well can reduce the damage to gravel-pack zone permeability caused by sand-carrying fluid effectively, and increase well productivity and extend the sand control life. Key words: gravel-pack, sand retention experiment, plugging law, viscosity-velocity index, working scheme, optimization method, plugging simulation

Objectives: We investigated the influence of coronary disease characteristics on prognostic implications of residual ischemia after coronary stent implantation.Methods: This study included 1,476 patients with drug-eluting stent implantation and available pre- and post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) measurements. Residual ischemia was defined as post-PCI FFR ≤ 0.80. Coronary disease characteristics with significant interaction hazard ratios (HRs) for clinical outcomes with residual ischemia were defined as interaction characteristics with residual ischemia (ICwRI). The primary outcome was target vessel failure (TVF)—a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization—at 2 years.Results: The mean pre- and post-PCI FFR were 0.68 ± 0.11 and 0.87 ± 0.07, respectively. During the median follow-up duration of 2.0 years, the cumulative incidence of TVF was 6.1%. The 203 vessels (13.8%) with residual ischemia had higher risks of TVF compared to that for post-PCI FFR >0.80 (P < 0.001). ICwRI with a significant interaction HR with residual ischemia included pre-PCI SYNTAX score >17 and pre-PCI FFR ≤ 0.62. Each ICwRI had a direct prognostic effect not mediated by residual ischemia. The association between an increased TVF risk and residual ischemia was significant in patients with 0 or 1 ICwRI [hazard ratio (HR) 3.25, 95% confidence interval (CI) 1.90–5.57, P < 0.001] but not in those with 2 ICwRI (HR 0.47, 95% CI 0.14–1.64, P = 0.24). Among patients with post-PCI FFR >0.80, those with 2 ICwRI showed similar TVF risks to those with residual ischemia (HR 1.55, 95% CI 0.79–3.02, P = 0.20).Conclusions: Coronary disease characteristics including pre-PCI SYNTAX score and pre-PCI FFR affected the prognostic implications of residual ischemia. The prognostic relevance of residual ischemia was attenuated in patients with multiple interacting characteristics.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent, inheritable, and heterogeneous neurodevelopmental disorder. Children with a family history of ADHD are at elevated risk of having ADHD and persisting its symptoms into adulthood. The objective of this study was to investigate the influence of having or not having positive family risk factor in the neuroanatomy of the brain in children with ADHD. Cortical thickness-, surface area-, and volume-based measures were extracted and compared in a total of 606 participants, including 132, 165, and 309 in groups of familial ADHD (ADHD-F), non-familial ADHD (ADHD-NF), and typically developed children, respectively. Compared to controls, ADHD probands showed significantly reduced gray matter surface area in the left cuneus. Among the ADHD subgroups, ADHD-F showed significantly increased gray matter volume in the right thalamus and significantly thinner cortical thickness in the right pars orbitalis. Among ADHD-F, an increased volume of the right thalamus was significantly correlated with a reduced DSM-oriented t-score for ADHD problems. The findings of this study may suggest that a positive family history of ADHD is associated with the structural abnormalities in the thalamus and inferior frontal gyrus; these anatomical abnormalities may significantly contribute to the emergence of ADHD symptoms.

Large nitrous oxide (N2O) emissions pulses have been observed after rewetting dry soil. However, few studies have uncoupled the effects of drought severity from the degree to which the soil is saturated. In this study, we conducted three aerobic incubation experiments to investigate the effects of soil rewetting on N2O emissions from a dryland soil. The results showed that, at constant soil moisture, total N2O emissions in soil with 90% water-holding capacity (WHC) were significantly higher than those in 30%, 45%, 60% and 75% WHC treatments. In the dry–wet group, the soil moisture content was adjusted from 30%, 45% and 60% WHC to the end content of 75% and 90% WHC, respectively; the cumulative N2O emissions in the 30–90%, 45–90% and 60–90% WHC nitrogen (N) treatments were significantly higher than those in the 30–75%, 45–75% and 60–75% WHC N treatments. Regarding fertilizer N types, there was no significant difference in N2O emissions from soil at 90% WHC when (NH4)2SO4 or urea was applied. Nitrification inhibitor significantly reduced N2O emissions in soil applied with NH4+-N fertilizer, indicating that nitrification played a major role in N2O emissions from soils. The contribution of denitrification was negligible, according to the low emission rate of soils with only NO3− additions. High N2O emissions occurred in soil treated with NO2−, accounting for about 83.6% of those of the NH4+ treatment. Therefore, in this study we concluded that the end water content of soil was more important than the role of drought severity in the dry-wet process and that nitrifier denitrification was probably the main pathway of N2O production under the condition of 90% WHC moisture after rewetting soil.

It is well known that chicken CD8+ T cell response is vital to clearing viral infections. However, the differences between T cell subsets expressing CD8 receptors in chicken peripheral blood mononuclear cells (PBMCs) have not been compared. Herein, we used Smart-Seq2 scRNA-seq technology to characterize the difference of chicken CD8high+, CD8high αα+, CD8high αβ+, CD8medium+, and CD4+CD8low+ T cell subsets from PBMCs of avian leukosis virus subgroup J (ALV-J)-infected chickens. Weighted gene co-expression network analysis (WGCNA) and Trend analysis revealed that genes enriched in the “Cytokine–cytokine receptor interaction” pathway were most highly expressed in the CD8high αα+ T cell population, especially T cell activation or response-related genes including CD40LG, IL2RA, IL2RB, IL17A, IL1R1, TNFRSF25, and TNFRSF11, suggesting that CD8high αα+ T cells rather than other CD8 subpopulations were more responsive to ALV-J infections. On the other hand, genes involved in the “FoxO signaling pathway” and “TGF-beta signaling pathway” were most highly expressed in the CD4+CD8low+ (CD8low+) T cell population and the function of CD4+CD8low+ T cells may play roles in negatively regulating the functions of T cells based on the high expression of CCND1, ROCK1, FOXO1, FOXO3, TNFRSF18, and TNFRSF21. The selected gene expressions in CD8+ T cells and CD4+CD8low+ double-positive T cells confirmed by qRT-PCR matched the Smart-Seq2 data, indicating the reliability of the smart-seq results. The high expressions of Granzyme K, Granzyme A, and CCL5 indicated the positive response of CD8+ T cells. Conversely, CD4+CD8+ T cells may have the suppressor activity based on the low expression of activation molecules but high expression of T cell activity suppressor genes. These findings verified the heterogeneity and transcriptional differences of T cells expressing CD8 receptors in chicken PBMCs.

Radiotherapy at the temporomandibular joint (TMJ) area often results in trismus, however, post radiation ankylosis is extremely rare and has not been previously reported in literature. Radiation is known to impact the vasculature of bony structures leading to bone necrosis with certain risk factors including surgical intervention, even teeth extraction, that could lead to osteoradionecrosis. Accordingly, gap arthroplasty for such case seemed rather challenging. In this report, we introduce for the first time, a rare case of temporomandibular joint ankylosis post radiotherapy for management of rhabdomyosarcoma in a 12 years-old boy. A modified gap arthroplasty technique combined simultaneously with pterygo-masseteric muscle flap was applied to lower the risk of osteoradionecrosis due surgical trauma at irradiated area. Computed tomographic scan on the head indicated that the TMJ architecture was completely replaced by bone, with fusion of the condyle, sigmoid notch, and coronoid process to the zygomatic arch and glenoid fossa. The patient’s problem was totally solved with no osteoradionecrosis or relapse of ankylosis observed at follow up visits. Herein, the modified gap arthroplasty combined with pterygo-masseteric muscle flap could be recommended to be applied on other cases of ankylosis especially after receiving radiotherapy.

Aims To develop a nomogram for incident chronic kidney disease (CKD) risk evaluation among community residents with high cardiovascular disease (CVD) risk.Methods In this retrospective cohort study, 5730 non-CKD residents with high CVD risk participating the National Basic Public Health Service between January 2015 and December 2020 in Guangzhou were included. Endpoint was incident CKD defined as an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 during the follow-up period. The entire cohorts were randomly (2:1) assigned to a development cohort and a validation cohort. Predictors of incident CKD were selected by multivariable Cox regression and stepwise approach. A nomogram based on these predictors was developed and evaluated with concordance index (C-index) and area under curve (AUC).Results During the median follow-up period of 4.22 years, the incidence of CKD was 19.09% (n=1094) in the entire cohort, 19.03% (727 patients) in the development cohort and 19.21% (367 patients) in the validation cohort. Age, body mass index, eGFR 60–89 mL/min/1.73 m2, diabetes and hypertension were selected as predictors. The nomogram demonstrated a good discriminative power with C-index of 0.778 and 0.785 in the development and validation cohort. The 3-year, 4-year and 5-year AUCs were 0.817, 0.814 and 0.834 in the development cohort, and 0.830, 0.847 and 0.839 in the validation cohort.Conclusion Our nomogram based on five readily available predictors is a reliable tool to identify high-CVD risk patients at risk of incident CKD. This prediction model may help improving the healthcare strategies in primary care.

Many multi-agent systems (MASs) can be regarded as hybrid systems that contain continuous variables and discrete events exhibiting both continuous and discrete behavior. An MAS can accomplish complex tasks through communication, coordination, and cooperation among different agents. The complex, adaptive and dynamic characteristics of MASs can affect their stability that is critical for MAS performance. In order to analyze the stability of MASs, we propose a stability analysis method based on invariant sets and Lyapunov’s stability theory. As a typical MAS, an unmanned ground vehicle formation is used to evaluate the proposed method. We design discrete modes and control polices for the MAS composed of unmanned ground vehicles to guarantee that the agents can cooperate with each other to reliably achieve a final assignment. Meanwhile, the stability analysis is given according to the definition of MAS stability. Simulation results illustrate the feasibility and effectiveness of the proposed method.

Recent studies report that inhibiting TNF-α might be a novel therapeutic strategy for managing brain ischemia. Our previous study reported that mesenchymal stem cell (MSC) transplantation could suppress TNF-α level in both serum and brain. However, the cell type(s) that contribute to the production of TNF-α during ischemia following MSC transplantation has not been well studied. In the present study, we found by fluorescent immunohistochemistry, that 7.95 ± 6.17% of TNF-α+ cells co-expressed Iba-1 in the infarct area of dMCAO rats, a majority of which were found to be CD68+ (activated microglia), suggesting that resident microglial population were not the major source of TNF-α expression. 68.49 ± 5.12% of the TNF-α+ cells in the infarct area could be labeled by GFAP, a specific marker for astrocytes, indicating that resident GFAP+ astrocytes might be the major source of TNF-α expression in the infarct area. In addition to the infarct area, the GFAP+/TNF-α+ double-positive astrocytes accounted for 73.68 ± 7.48% of the TNF-α+ cells in striatum and corpus callosum. The infiltrating cells, including monocytes and lymphocytes, were not the main source of TNF-α either. In response to MSC transplantation, the total TNF-α+ cells as well as the percentage of TNF-α-expressing astrocytes were significantly reduced in the infarct area, suggesting that MSC transplantation could suppress the expression of TNF-α by astrocytes. Taken together, the results demonstrated that resident astrocytes, but not microglia, were the major source of TNF-α expression and could be suppressed by MSC infusion.

Background and PurposeThis study aimed to quantify the differences between pre- and post-contrast agent (CA) CT for CyberKnife brain SRS plans.Materials and MethodsTwenty-five patients were retrospectively analyzed. They were divided into two categories, inhomogeneous cases (13 patients) and homogeneous cases (12 patients), according to whether the tumor was close to the cavity and inhomogeneous tissues or not. The pre-CA and post-CA plans were designed and calculated using the same monitor unit and paths as those in the ray-tracing algorithm, respectively.ResultsThe CT number difference of tumor between pre- and post-CA was significant (on average, 24.78 ± 18.56 HU, P-value < 0.01). The deviation value of the target was the largest at approximately 37 HU (inhomo-) and 13 HU (homo-) (P < 0.01), and the values of the organs at risk (OARs) were not statistically significant (P-value > 0.05). However, it was not statistically significant for the dose difference between the two groups with the injection of CA (P-value > 0.05). The absolute effective depth difference generally remained at a level of 1 mm, but the dose difference was quitely fluctuated sometimes more than 20%. The absolute effective depth difference of the inhomo-case (0.62 mm) was larger than that of the homo-case (0.37 mm) on median, as well as the variation amplitude (P-value < 0.05). Moreover, the relative dose differences between the two cases were 0.38% (inhomo-) and 0.2% (homo-), respectively (P-value < 0.05). At the criterion of 1 mm/1%, the gamma pass rate of the homo-case (95.89%) was larger than that of the inhomo-case (93.79%). For the OARs, except for the cochlea, the two cases were almost the same (>98.85%). The tumor control probability of the target was over 99.99% before and after injection of a CA, as well as the results for the homo-case and inhomo-case.ConclusionsConsidering the difference of evaluation indexes between pre- and post-CA images, we recommended plain CT to be employed as the primary image for improving the CK treatment accuracy of brain SRS, especially when the target was close to CA-sensitive OARs and cavity.

Excess soluble salts in saline soils are harmful to most plants. Understanding the biochemical responses to salts in plants and studying the salt tolerance-associated genetic resources in nature will contribute to the improvement of salt tolerance in crops. As an emerging model crop, foxtail millet (Setaria italica L.) has been regarded as a novel species for stress resistance investigation. Here, the dynamic proteomic and phosphoproteomic profiling of two foxtail millet varieties of An04 and Yugu2 with contrasting salt tolerance characteristics were investigated under salt stress. In total, 10,366 sites representing to 2,862 proteins were detected and quantified. There were 759 and 990 sites corresponding to 484 and 633 proteins identified under salinity in An04 and Yugu2, respectively, and 1,264 and 1,131 phosphorylation sites corresponding to 789 and 731 proteins were identified between these two varieties before and after salt stress, respectively. The differentially-regulated phosphoproteins (DRPPs) were mainly involved in signal transduction, regulation of gene expression, translation, ion transport, and metabolism processes. Yugu2 possessed signal perception and transduction capabilities more rapidly and had a more intense response compared with An04 upon salinity. The sucrose metabolism pathway, in particularly, might play a vital role in salt response in foxtail millet, which not only provides UDP-glucose for the cellulose synthesis and energy production, but also promotes flavonoid related synthesis to enhance the salt tolerance ability. Over-expressing the phospho-mimic sucrose synthase (SuS) (SuSS10D) in soybean roots enhanced salt tolerance compared with over-expressing SuS lines. The knowledge of this research will shed light on elucidating the mechanisms of salt response, and pave the way for crop varieties innovation and cultivation under salinity and stresses.

Summary: Although microbe-associated molecular pattern (MAMP) molecules can promote cholesterol accumulation in macrophages, the existence of a host-derived MAMP inactivation mechanism that prevents foam cell formation has not been described. Here, we tested the ability of acyloxyacyl hydrolase (AOAH), the host lipase that inactivates gram-negative bacterial lipopolysaccharides (LPSs), to prevent foam cell formation in mice. Following exposure to small intraperitoneal dose(s) of LPSs, Aoah−/− macrophages produced more low-density lipoprotein receptor and less apolipoprotein E and accumulated more cholesterol than did Aoah+/+ macrophages. The Aoah−/− macrophages also maintained several pro-inflammatory features. Using a perivascular collar placement model, we found that Aoah−/− mice developed more carotid artery foam cells than did Aoah+/+ mice after they had been fed a high fat, high cholesterol diet, and received small doses of LPSs. This is the first demonstration that an enzyme that inactivates a stimulatory MAMP in vivo can reduce cholesterol accumulation and inflammation in arterial macrophages.

With the rapid development of intelligent unmanned technology, unmanned combat swarms are faced with a highly aggressive, highly uncertain, and highly dynamic battlefield environment, and the operation mode of unmanned combat has gradually shifted from single-platform operations to swarm networking collaboration combat development. Aiming at the typical characteristics of the unmanned swarm combat system, this paper proposes a role assignment model for organizational reconfiguration at the swarm layer and builds an unmanned swarm organization reconfiguration role-assignment mechanism model (SORAM) based on the fourth-order directed motif. The method starts from the organizational domain of the swarm system and takes the task as the the dependent variable of the role assignment of the swarm organization, quantifies the importance of the motif from a statistical point of view, and establishes a multi-objective model considering the similarity of the structure. The swarm reconfiguration role optimization method of SR-NSGA-2 provides a reference for the online adaptation of the swarm links. Finally, combined with a simulated combat simulation case, the usability and effectiveness of the method are tested.

Up-to-date in vitro and in vivo preclinical models expressing the patient-specific cancer lineage responsible for CRC and its metastatic behavior and responsiveness to therapy are needed. Exosomes’ role in tumorigenesis and the metastatic process was demonstrated, and the material content and size of the exosomes are associated with a poor prognosis of CRC. Exosomes are generally imagined after their recovery from blood serum as isolated entities, and our work aims to investigate them “in situ” in their native environment by scanning and transmission electron microscopy to understand their secretion modalities. We studied CRC stem cells in patient-derived multicellular tumor spheroids (MTSs) and in their mouse xenograft to find possible differences in terms of exosome amount, size, and secretion site between in vitro and in vivo models. We observed that MTSs’ exosome secretion patterns depend on their structural complexity: few-layer MTSs show a lesser exosome secretion, limited to the apical domain of cancer cells, secretion increases in multilayered MTSs, and it develops from apical and basolateral cancer cells domains. In xenograft models, exosome secretion occurs from all cancer cell domains, and it is quantitatively greater than that observed in MTSs. This difference in exosome secretion pattern between MTSs and xenografts may be due to the influence of surrounding non-tumor cells.

The connecting rod assembly of a high-power low-speed diesel engine has high quality and high cost. If the connecting rod component is damaged, the whole machine may be paralyzed, resulting in serious economic losses and safety problems, so it is necessary to carry out strength analysis and structure optimization, reduce the failure rate, and increase its life. This paper takes the connecting rod of a low-speed diesel engine as the research object, builds the crank connecting rod mechanism model, and carries on the strength simulation analysis through professional simulation software. During this period, the accurate S-N curve of connecting rod material is obtained through a fatigue test, and the static strength test of the connecting rod assembly is carried out by an electro-hydraulic servo universal testing machine. The numerical modeling is validated based on the test results. Therefore, the influence of the structural parameters of the cross-section and the large end transition fillet on the stress of the connecting rod is analyzed. The results show that optimizing matching between the large end fillet of the connecting rod and the long diameter of the rod section not only reduces the mass but also improves the safety factor. After optimizing the structure of the connecting rod, the mass of the connecting rod is reduced by 5.85%, the maximum stress is reduced by 13.7%, and the safety factor is increased by 16.0%. In addition, due to the low-speed diesel engine connecting rod assembly weight is big, and the simulation computation efficiency is low, this paper by studying the influence of the cross-section parameters of the rod body and the large end transition fillet on the stress of the connecting rod, fitted the empirical formula calculating the maximum stress of connecting rod, for this model and similar type in the conceptual design, technology design provides a new analysis method, improved the efficiency of structural optimization and strength analysis of connecting rod assembly, filled the research gap of strength analysis and structural optimization of low-speed diesel engine connecting rod.

This paper studies the event-triggered adaptive tracking control problem of a class of pure-feedback systems. Via the backstepping method and the neural network approximation with the central symmetric distribution, an event-triggered adaptive neural network controller is designed. In particular, a dynamic gain driven by the tracking error is introduced into the event-triggering mechanism. Then, by using the Lyapunov stability theory, the boundedness of all the closed-loop signals is proved, and the tracking error falls into a prespecified ϵ-neighbourhood of zero. Meanwhile, the Zeno behaviour is avoided. Finally, two simulations verify the effectiveness of the proposed control scheme.

Motivated by some practical applications of post-disaster supply delivery, we study a multi-trip time-dependent vehicle routing problem with split delivery (MTTDVRP-SD) with an unmanned aerial vehicle (UAV). This is a variant of the VRP that allows the UAV to travel multiple times; the task nodes’ demands are splittable, and the information is time-dependent. We propose a mathematical formulation of the MTTDVRP-SD and analyze the pattern of the solution, including the delivery routing and delivery quantity. We developed an algorithm based on the simulation anneal (SA) framework. First, the initial solution is generated by an improved intelligent auction algorithm; then, the stochastic neighborhood of the delivery route is generated based on the SA algorithm. Based on this, the model is simplified to a mixed-integer linear programming model (MILP), and the CPLEX optimizer is used to solve for the delivery quantity. The proposed algorithm is compared with random–simulation anneal–CPLEX (R-SA-CPLEX), auction–genetic algorithm–CPLEX (A-GA-CPLEX), and auction–simulation anneal–CPLEX (A-SA) on 30 instances at three scales, and its effectiveness and efficiency are statistically verified. The proposed algorithm significantly differs from R-SA-CPLEX at a 99% confidence level and outperforms R-SA-CPLEX by about 30%. In the large-scale case, the computation time of the proposed algorithm is about 30 min shorter than that of A-SA. Compared to the A-GA-CPLEX algorithm, the performance and efficiency of the proposed algorithm are improved. Furthermore, compared to a model that does not allow split delivery, the objective function values of the solution of the MTTDVRP-SD model are reduced by 52.67%, 48.22%, and 34.11% for the three scaled instances, respectively.

With the rapid development of interferometric synthetic aperture radar (InSAR) measurement technology, its measurement accuracy requirements are increasing. Atmospheric delay errors must be corrected, especially in the case of crustal deformation monitoring, the 20% variation of tropospheric water vapor among InSAR pairs generally produces range from 10 cm to 14 cm deformation errors. Such errors can be of the same magnitude as the annual changes in crustal deformation, or even greater, masking crustal deformation information and seriously affecting the results of crustal deformation monitoring. Therefore, in order to obtain a more accurate InSAR atmospheric delay correction model, this paper calculated and integrated atmospheric delays that were estimated by different sources, including the 37 pressure levels of the fifth generation of the European Centre for Medium-Range Weather Forecasts (ECMWF)) numerical weather prediction model, ECMWF Reanalysis v5 (ERA5), and Global Navigation Satellite System (GNSS) measurement data from the crustal movement observation network of China, based on the variance component estimation (VCE) weighting method. The results showed that the integrated model, based on the VCE method, is better than the generic atmospheric correction online service (GACOS) model for InSAR measuring of crustal deformation. The precision in monitoring crustal deformations was improved by approximately 5 mm, the correlation coefficient of atmospheric delay errors and crustal deformations improved from 0.287 to 0.347, and accuracy improved by approximately 25%. However, the improvement in accuracy was limited because of system error decoherence that was induced by atmospheric noise caused by abundant vegetation or snow cover. Therefore, in order to achieve more accurate results, we recommend the adoption of the multi-source integrated atmospheric delay correction model, based on the VCE method, for InSAR high-precision measuring of crustal deformation and seismic activities.

Objective: This meta-analysis aimed to systematically assess the therapeutic efficacy and safety of Qinghao Biejia decoction combined with conventional chemical medicine in patients with systemic lupus erythematosus (SLE), and to provide reference for clinical medication.Methods: Multiple databases were retrieved by computer for randomized controlled trials (RCTs) of treating SLE with Qinghao Biejia decoction combining chemical medicine, from the establishment of the database to January 2021. Study screening, data collection, and quality assessment were performed independently by two reviewers. RevMan 5.4 and Stata 15.1 software were used for Meta-analysis.Results: Nine eligible studies, involving 655 SLE participants, were included. Meta-analysis showed that the additional use of Qinghao Biejia decoction superior to chemical medicine alone in people with SLE in improving the overall response rate (RR = 1.30, 95% CI [1.19, 1.41], p < 0.00001, heterogeneity p = 0.61, I2 = 0%), and can decrease SLE Disease Activity Index (SLEDAI) and TCM symptom scores, improve immunological indexes (C3, C4, IgG, IgA, IFN-γ, IL-4, Th1/Th2), reduce the occurrence of adverse events in treatment (P ≤ 0.05).Conclusion: Based on this meta-analysis, the additional use of Qinghao Biejia decoction has more advantages in the treatment of SLE than conventional chemical medication alone, which could enhance the efficacy and reduce adverse reactions, and is worthy of clinical promotion. However, more and higher quality RCTs are still need to confirm our findings.

Containment of the AIDS pandemic requires reducing HIV transmission. HIV infection is initiated by the fusion of the membrane between the virus and the cell membrane of the host. 2P23 is an effective HIV membrane fusion inhibitor that may be a good entry inhibitor microbicide candidate. This study evaluated the potential of using gel-formulated 2P23 as a topical microbicide to prevent sexual transmission of HIV in the rectum and vagina. Our data revealed that 2P23 formulated in gel is effective against HIV. There was no change in antiviral activity at 25°C for 4 months or 60°C for 1 week. In addition, we demonstrated that the 2P23 gel was stable and fully functional at pH 4.0–8.0 and under different concentrations of H2O2. Finally, the 2P23 gel exhibited no cytotoxicity or antimicrobial activity and did not induce inflammatory changes in the rectal or vaginal mucosal epithelium in New Zealand rabbits after 20 mg/day daily rectovaginal application for 14 consecutive days. Despite repeated tissue sampling and 2P23 gel treatment, the inflammatory cytokines and microbiota of the rectum and vagina remained stable. These results add to general knowledge on the in vivo evaluation of anti-HIV microbicide application concerning inflammatory cytokines and microbiota changes in the rectum and vagina. These findings suggest that the 2P23 gel is an excellent candidate for further development as a safe and effective pre-exposure prophylactic microbicide for the prevention of HIV transmission.

Exposure to fine particulate matter (PM2.5) in outdoor air is carcinogenic and associated with the development of lung cancer; however, the underlying mechanism remains unclear. In the present study, the profiles of lncRNA, microRNA and mRNA expression profiles in human bronchial epithelia (HBE) following exposure to PM2.5, diesel exhaust particles (DEPs), or aluminum oxide nanoparticles (Al2O3 NPs) were explored by microarray to reveal the lncRNA-microRNA-mRNA network participating in the malignant transformation of HBE cells following long-term PM2.5 exposure. The results showed that lncRNA SOX2 overlapping transcript (SOX2-OT) was significantly induced in HBE cells exposed to PM2.5, DEPs, or Al2O3 NPs, acting as a sponge to microRNA-345-5p, which subsequently increased the expression levels of epidermal growth factor receptor (EGFR). EGFR is a therapeutic target in non-small cell lung cancer. Here, we found that SOX2-OT is an upstream trigger of EGFR in HBE cells during long-term PM2.5 exposure. Importantly, SOX2-OT knockdown effectively reduced the colony formation and migration capacities of HBE cells, compared to the wild type control. Collectively, SOX2-OT/microRNA-345-5p/EGFR is a ceRNA mechanism underlying the malignant transformation of bronchial epithelia exposed to PM2.5, which improves our understanding of the association between ambient PM2.5 exposure and the development of lung cancer.

Breast cancer is a heterogeneous malignant disease with different prognoses and has been divided into four molecular subtypes. It is believed that molecular events occurring in breast stem/progenitor cells contribute to the carcinogenesis and development of different breast cancer subtypes. However, these subtype-specific molecular characteristics are largely unknown. In this study, we employed 1217 breast cancer samples from The Cancer Genome Atlas (TCGA) database for a multiomics analysis of the molecular characteristics of different breast cancer subtypes based on PAM50 algorithms. We detected the expression changes of subtype-specific genes and revealed that the expression of particular subtype-specific genes significantly affected prognosis. We also investigated the mutations and copy number variations (CNVs) of breast cancer driver genes and the representative genes of ten signaling pathways in different subtypes and revealed several subtype-specifically altered genes. Moreover, we detected the infiltration of various immune cells in different subtypes of breast cancer and showed that the infiltration levels of major immune cell types are different among these subtypes. Additionally, we investigated the factors affecting the immune infiltration level and the immune cytolytic activity in different breast cancer subtypes, namely, the mutation burden, genome instability and cancer-associated fibroblast (CAF) infiltration. This study may shed light on the molecular events contributing to carcinogenesis and development and provide potential markers and targets for the clinical diagnosis and treatment of different breast cancer subtypes.

Recently, machine learning techniques have been widely applied in discriminative studies of schizophrenia (SZ) patients with multimodal magnetic resonance imaging (MRI); however, the effects of brain atlases and machine learning methods remain largely unknown. In this study, we collected MRI data for 61 first-episode SZ patients (FESZ), 79 chronic SZ patients (CSZ) and 205 normal controls (NC) and calculated 4 MRI measurements, including regional gray matter volume (GMV), regional homogeneity (ReHo), amplitude of low-frequency fluctuation and degree centrality. We systematically analyzed the performance of two classifications (SZ vs NC; FESZ vs CSZ) based on the combinations of three brain atlases, five classifiers, two cross validation methods and 3 dimensionality reduction algorithms. Our results showed that the groupwise whole-brain atlas with 268 ROIs outperformed the other two brain atlases. In addition, the leave-one-out cross validation was the best cross validation method to select the best hyperparameter set, but the classification performances by different classifiers and dimensionality reduction algorithms were quite similar. Importantly, the contributions of input features to both classifications were higher with the GMV and ReHo features of brain regions in the prefrontal and temporal gyri. Furthermore, an ensemble learning method was performed to establish an integrated model, in which classification performance was improved. Taken together, these findings indicated the effects of these factors in constructing effective classifiers for psychiatric diseases and showed that the integrated model has the potential to improve the clinical diagnosis and treatment evaluation of SZ.

ABSTRACTSARS-CoV-2 caused a major outbreak of severe pneumonia (COVID-19) in humans. Viral RNA was detected in multiple organs in COVID-19 patients. However, infectious SARS-CoV-2 was only isolated from respiratory specimens. Here, infectious SARS-CoV-2 was successfully isolated from urine of a COVID-19 patient. The virus isolated could infect new susceptible cells and was recognized by its’ own patient sera. Appropriate precautions should be taken to avoid transmission from urine.

Abstract The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.