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Abstract Richter syndrome (RS), characterized by aggressive lymphoma arising from chronic lymphocytic leukaemia (CLL), presents a poor response to treatment and grim prognosis. To elucidate RS mechanisms, paired samples from a patient with DLBCL-RS were subjected to single-cell RNA sequencing (scRNA-seq) and high-throughput chromosome conformation capture (Hi-C) sequencing. Over 10,000 cells were profiled via scRNA-seq, revealing the comprehensive B cell transformation in RS. Hi-C sequencing exposed a unique chromatin architecture in RS, with increased proximal and decreased distal interactions. At the compartment scale, the interaction between B compartments was strengthened in DLBCL cells, while topologically associating domains (TADs) in DLBCL had elevated intra-TAD and reduced inter-TAD contacts. Differentially expressed genes at TAD borders between CLL and DLBCL cells highlighted an enrichment of cAMP-mediated signalling. To substantiate the functional relevance of ATF1 and CAP1, the genes involve in cAMP-mediated signalling, in the context of cell proliferation, we have performed gain- and loss-of-function experiments in relevant cell lines. Collectively, integrated scRNA-seq and Hi-C data suggest that chromatin reorganization and altered cAMP signalling drive RS transformation.

Abstract This randomized, prospective, multicenter (12 centers in China) phase III trial (Chinese Clinical Trial Registry #ChiCTR2000041170) compared drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with apatinib and DEB-TACE monotherapy for patients with unresectable hepatocellular carcinoma (uHCC). Progression-free survival (PFS) was the primary endpoint. Overall survival (OS), mRECIST-based objective response rates (ORR) and disease control rates (DCR), and treatment-related adverse events (TRAEs) were secondary endpoints. Totally 243 cases were randomized, with 122 and 121 in the DEB-TACE + apatinib and DEB-TACE groups, respectively. Cases administered DEB-TACE + apatinib displayed markedly improved median PFS (7.1 months [95%CI 6.6–8.3] vs. 5.2 months [95%CI 5.0–5.9]) and OS (23.3 months [95%CI 20.7–29.6] vs. 18.9 months [95%CI 17.9–20.1] compared with those treated with DEB-TACE (both p

Abstract Humid heat waves pose significant risks to human health and the ecosystem. Intuitively, rainfall often alleviates extreme humid heat. However, here we show that light rain often accompanies extreme humid heat, exacerbating its frequency and intensity, especially over arid and semi-arid regions compared to no rain and moderate-to-heavy rain cases. This is because light rain does not dramatically reduce solar radiation but increases near-surface humidity through enhanced surface evaporation. The water replenishment from light rain as well as a shallower planetary boundary layer is crucial for consecutive extremes where there are commonly sporadic drizzle days amidst several rain-free days. These extremes last longer than rain-free extremes. Current global climate models (GCMs) overestimate light rain. After reducing this bias in a GCM, underestimations of humid heat waves in energy-limited regions and overestimations in water-limited regions are largely alleviated. These findings underscore the underappreciated impact of light rain on extreme humid heat.

Observation of manta rays exiting water has been rarely reported, as there are various difficulties in observing and obtaining data on their behavior in a marine environment. Therefore, the movement mechanism of manta rays exiting water is still unclear. This paper proposes the idea of using CFD (based on Ansys Fluent, version 2022) to simulate the water-exit process of the manta ray. The study discusses the changes in the mechanical and kinematic parameters of the manta ray over time and obtains the evolution of vortex structures during the underwater movement phase of the manta ray. Time history variations of the mechanical and kinematics parameters in the vertical water-exit motion are discussed. The evolution of vortex structures during the underwater movement of the manta ray is obtained. The direction in which the manta ray approaches the free surface is the X-direction and the direction of its flapping motion is the Z-direction. VX and VZ are the velocities of the manta ray in the X- and Z-directions, respectively. FX and FZ represent the forces acting on the manta ray in the X- and Z-directions, respectively. The results indicate that the vertical water-exit of the manta ray mainly undergoes three stages: underwater acceleration, crossing the free surface, and aerial movement. During the underwater acceleration phase, the force FX of the manta ray fluctuates, but its average value is positive within one cycle. VX also shows a stepwise increase, while FZ and VZ exhibit periodic changes. During the stage of crossing the free liquid surface, FX first increases and then sharply decreases, VX also shows an increase and then decrease, FZ fluctuates greatly, producing a peak, and the swimming speed VZ of the manta ray is negative. During the aerial motion phase, FX is mainly affected by gravity, VX decreases linearly, FZ approaches 0, and VZ remains constant. During the process of swimming underwater, the tail vortex of the manta ray presents a double row staggered structure to generate thrust. Increasing the flapping frequency and decreasing the wave number can improve the swimming speed of the manta ray, and then increase its water-exit height. The findings may provide an important hydrodynamics basis for biomimetic trans-media vehicle designs.

Against the backdrop of achieving the goals of “peak carbon emissions and carbon neutrality”, coal, as the cornerstone of national energy security, plays a crucial role in the green development of our country’s economic construction and social development. However, during the process of coal mining and washing, coal gangue, as the primary associated by-product of coal, has become the foremost bulk solid waste that urgently needs to be addressed in our country. Currently, the comprehensive utilization rate of coal gangue remains at a relatively low level, and a standardized and feasible research system has yet to be established. Therefore, addressing the water, atmospheric, and soil environmental pollution caused by coal mining and coal gangue accumulation, this paper summarizes the relevant research progress on the resource utilization of coal gangue in the production of energy, recovery of valuable metals, production of building materials, and other directions, and also discusses the application of coal gangue in preventing heavy metal pollution, soil remediation, and erosion control. Finally, it proposes the future development direction of coal gangue resource utilization, planning and integrating resources as a whole, not only for conventional purposes but also for the production of high-value-added products. By combining the two, comprehensive and resourceful utilization of coal gangue can be achieved, providing a reference for its “reduction, resource utilization, and recycling” development. In conclusion, the resource utilization of coal gangue is an important direction for the transformation and upgrading of China’s coal industry, and it is also the necessary path to achieve green and sustainable development. Only through unremitting efforts and continuous innovation can we better address the problem of coal gangue accumulation, promote the more efficient, environmentally friendly, and sustainable development of coal gangue resource utilization, and make a greater contribution to the sustainable development of our country’s economy and society.

The hypoxic microenvironment is an essential characteristic of most malignant tumors. Notably, hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulatory factor of cellular adaptation to hypoxia, and many critical pathways are correlated with the biological activity of organisms via HIF-1α. In the intra-tumoral hypoxic environment, HIF-1α is highly expressed and contributes to the malignant progression of tumors, which in turn results in a poor prognosis in patients. Recently, it has been indicated that HIF-1α involves in various critical processes of life events and tumor development via regulating the expression of HIF-1α target genes, such as cell proliferation and apoptosis, angiogenesis, glucose metabolism, immune response, therapeutic resistance, etc. Apart from solid tumors, accumulating evidence has revealed that HIF-1α is also closely associated with the development and progression of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma. Targeted inhibition of HIF-1α can facilitate an increased sensitivity of patients with malignancies to relevant therapeutic agents. In the review, we elaborated on the basic structure and biological functions of HIF-1α and summarized their current role in various malignancies. It is expected that they will have future potential for targeted therapy.

Due to the resistance of Gram-negative bacteria Pseudomonas aeruginosa PAO1 to most clinically relevant antimicrobials, the use of traditional antibiotic treatments in hospitals is challenging. The formation of biofilms, which is regulated by the quorum-sensing (QS) system of Pseudomonas aeruginosa (PA), is an important cause of drug resistance. There are three main QS systems in P. aeruginosa: the las system, the rhl system, and the pqs system. The inhibitors of the las system are the most studied. Previously, the compound AOZ-1 was found to have a certain inhibitory effect on the las system when screened. In this study, twenty-four compounds were designed and synthesized by modifying the Linker and Rings of AOZ-1. Using C. violaceum CV026 as a reporter strain, this study first assessed the inhibitory effects of new compounds against QS, and their SAR was investigated. Then, based on the SAR analysis of compound AOZ-1 derivatives, the parent core of AOZ-1 was replaced to explore the structural diversity. Then, nine new compounds were designed and synthesized with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one. The compound Y-31 (IC50 = 91.55 ± 3.35 µM) was found to inhibit the QS of C. violaceum CV026. Its inhibitory effect on C. violaceum CV026 was better than that of compound AOZ-1 (IC50 > 200 µM). Furthermore, biofilm formation is one of the important causes of Pseudomonas aeruginosa PAO1 resistance. In this study, it was found that compound Y-31, with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, had the highest biofilm inhibition rate (40.44%). The compound Y-31 has a certain inhibitory effect on the production of PAO1 virulence factors (pyocyanin, rhamnolipid, and elastase) and swarming. When the concentration of compound Y-31 was 162.5 µM, the inhibition rates of pyocyanin, rhamnolipid, and elastase were 22.48%, 6.13%, and 22.67%, respectively. In vivo, the lifetime of wildtype Caenorhabditis elegans N2 infected with P. aeruginosa PAO1 was markedly extended by the new parent nucleus Y-31. This study also performed cytotoxicity experiments and in vivo pharmacokinetics experiments on the compound Y-31. In conclusion, this study identified a compound, Y-31, with a new nucleus core component of 3-amino-tetrahydro-l,3-oxazin-2-one, which is a potential agent for treating P. aeruginosa PAO1 that is resistant to antibiotics and offers a way to discover novel antibacterial medications.

Background & aimsThis multicenter retrospective study evaluated the efficacy and safety of transarterial chemoembolization (TACE) combined with donafenib and a programmed death-1 (PD-1) inhibitor (TACE+DP) and TACE combined with donafenib (TACE+D) for unresectable hepatocellular carcinoma (uHCC).MethodsThe clinical data of 388 patients with uHCC who received TACE+DP or TACE+D as first-line treatment at six Chinese academic centers from July 2021 to July 2022 were collected and analyzed retrospectively. Patients in the TACE+DP group received an intravenous administration of a PD-1 inhibitor every three weeks and oral donafenib (0.2 g) twice daily until intolerable toxicity or disease progression. Patients in the TACE+D group received the same dose of donafenib for 3–5 days after TACE. Overall survival (OS) and progression-free survival (PFS)were analyzed by Kaplan-Meier method and log-rank test. The tumor response was compared between the two groups according to modified RECIST criteria. Adverse events were also analyzed between the two groupsResultsThe TACE+D group included 157 patients and the TACE+DP group included 166 patients. Patients in the TACE+DP group had a longer median OS (18.1 vs. 13.2 months, P

5-methylcytosine modifications play a significant role in carcinogenesis; however, studies exploring 5-methylcytosine-related genes in diffuse large B-cell lymphoma patients are lacking. In this study, we aimed to understand the potential role and clinical prognostic impact of 5-methylcytosine regulators in diffuse large B-cell lymphoma and identify a prognostic biomarker based on 5-methylcytosine-associated genes. Gene expression profiles and corresponding clinical information of diffuse large B-cell lymphoma patients and normal controls were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases. Diffuse large B-cell lymphoma was divided into three clusters according to the 5-methylcytosine regulators, and differentially expressed genes were screened among the three clusters. Univariate Cox and Lasso-Cox regression analyses were used to screen prognostic genes and construct a prognostic risk model. Kaplan-Meier curve analysis, univariate and multivariate Cox regression analyses, and time-dependent receiver operator characteristic curve analysis were used to evaluate prognostic factors. GSVA was used to enrich potential pathways associated with 5-methylcytosine modification patterns. SsGSEA and CIBERSORT were used to assess immune cell infiltration. Six 5-methylcytosine-related genes (TUBB4A, CD3E, ZNF681, HAP1, IL22RA2, and POSTN) were used to construct a prognostic risk model, which was proved to have a good predictive effect. In addition, univariate and multivariate Cox regression risk scores were independent prognostic factors for diffuse large B-cell lymphoma. Further analysis showed that the 5-methylcytosine risk score was significantly correlated with immune cell infiltration and immune checkpoint of diffuse large B-cell lymphoma. Our study reveals for the first time a potential role for 5-methylcytosine modifications in diffuse large B-cell lymphoma, provides novel insights for future studies on diffuse large B-cell lymphoma, and offers potential prognostic biomarkers and therapeutic targets for patients with diffuse large B-cell lymphoma.

BACKGROUND In an environment without foreign iodine food, the iodine content of water is an important index to measure the iodine intake of the human body, so the accurate determination of iodide content in drinking water has a crucial role in human health. The detection limit of ion chromatography-amperometric detection method is generally lower than that of conductance detection method, and the sensitivity is higher. This method is suitable for the determination of trace iodide in water, but the apparent peak time is later than that of the conductance detection method. Under the same test conditions, for the ion chromatography-hydroxide eluent detection method for the determination of iodide in water, the peak time is obviously better than that of the carbonate body eluent detection method. Using carbonate eluent to analyze iodide requires adding toxic organic improvers, which is complicated, difficult to elute, has a long analysis time, high detection limit and low sensitivity. OBJECTIVES IonPac AS23 column with alkanol-based quaternary ammonium functional group has strong hydrophilicity and can maintain high capacity in a wide pH range (0-14), which is suitable for hydroxide and carbonate leaching systems. Based on this, a method for the determination of iodide in groundwater by suppressed conduction-ion chromatography was developed. METHODS IonPac AS23 (4mm×250mm) anion analysis column and IonPac AS23 anion protection column, Dionex AERS 500(4mm) anion inhibited conductivity detector, HPIC separation method, were used to detect iodide in groundwater with 50mmol/L KOH eluent (hydroxide eluent, the product after conductivity inhibition is zero conductivity water, providing an ideal conductivity baseline) at a flow rate of 1.2mL/min (the concentration and flow rate of the eluent increased, and the retention time was shortened) and a suppressive conductance detector current of 125mA (the current increased, the instrument detection sensitivity increased). The sample volume was 250μL, and the samples were filtered through a 0.45μm water microporous filter membrane. 10mL of initial filtrate was discarded, and about 10mL of subsequent filtrate was collected. After that the iodide in the groundwater samples was detected. RESULTS The chromatographic peak separation was good, peak shape was symmetrical, and no trailing extension. The iodide peak emerged in 8.980min, the detection limit of the method was 0.5μg/L, the correlation coefficient of the calibration curve was 0.9998, and the linear range was wide (0. 01-2mg/L). CONCLUSIONS This method has a lower detection limit than that of the existing standard method for the determination of iodide in water, shorter peak time, and the detection range is better than that of the existing ion chromatography method. The experimental results show that the peak time is faster than that reported by its predecessors. This method is used to determine iodide in groundwater and is not disturbed by seven inorganic anions (F-, Cl-, NO3-, NO2-, SO42-, PO43-, Br-) in water. This method improves the accuracy of the determination of iodide in groundwater by alkanol-based quaternary ammonium functional group column AS23 under the hydroxide eluent system.

How to solve the contradiction between coal mining and soil and water conservation is the key scientific problem to realize the ecological environment protection and high-quality development in the middle reaches of the Yellow River. In this paper, taking the coal mining subsidence area in loess gully of northern Shaanxi as the research object, aiming at the typical geological occurrence characteristics of the main coal seam, and taking the underground mining thickness (9, 7, 5 m), the natural slope shape (straight slope, concave slope, convex slope, compound slope) and slope (5°, 15°, 25°, 35°, 45°) of the surface loess as variables, a total of 60 numerical models are constructed. In this paper, based on FLAC3D numerical simulation software, the evolution process and law of slope morphology under the coupling effect of loess natural slope morphology and mining thickness are studied. Then, based on China soil erosion equation (CSLE model) and empirical model, the soil erosion effect of subsidence slope is calculated and analyzed. The results show that: ① Coal mining subsidence will lead to the increase of the slope of the surface loess slope, and the greater the mining thickness, the greater the slope increase. Significant Amplification Effect of Large Mining Thickness on Slope Gradient Increase of Surface Loess Caused by Coal Mining Subsidence. The concave slope generally has a significant effect on the slope of the subsidence slope, especially under the conditions of “ mining thickness 5 m, natural slope > 5 ° ”, “mining thickness 7 m, arbitrary natural slope ”, “ mining thickness 9 m, natural slope ≤ 35°”. No matter what kind of mining thickness and natural slope shape, the natural slope of ≤ 5 ° has the greatest influence on the increase of subsidence slope. ② Coal mining subsidence will lead to the increase of M1 on the surface loess slope under the scale of “ annual erosion rainfall ”, and the greater the mining thickness, the greater the increase of M1. When the mining thickness increases from 5 m to 9 m, M1 increases by about 1 time. The concave slope of four slope shapes has the greatest influence on the increase of M1 on the subsidence slope. The natural slope of ≤ 15° has a great influence on the increase of M1, which is more than 20% under the condition of “ mining thickness 9 m, concave slope ”. ③ Coal mining subsidence will lead to the increase of M2 of surface loess slope under the scale of “ typical erosion rainfall ”, and the greater the mining thickness, the greater the increase of M2 ; when the mining thickness increases from 5 m to 9 m, the increase of M2 increases by about 1 times. The concave slope of the four slope shapes has the greatest influence on the increase of M2 on the subsidence slope. The natural slope of ≤ 15° has a great influence on the increase of M2, which is more than 17 % under the condition of “ mining thickness 9 m, concave slope ”. The results can provide scientific basis for accurate prevention and control of soil erosion and high-quality development in the mining area of northern Shaanxi and even the middle reaches of the Yellow River Basin.

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) strongly correlated with worse clinical outcomes. However, the role of characteristic pathway-related genes in patients with AITL (e.g., subtype typing and pathogenesis) remains unknown. In this study, we intended to understand the potential role and prognostic value of characteristic pathways in AITL and identified a model for subtype identification based on pathway-related functional status. Transcriptomic (RNA-seq) data were obtained from the Gene Expression Omnibus database for three sets of tumor tissues from AITL patients. AITL was divided into three clusters based on the pathway profile of patients and the best clustering k = 3, and differentially expressed genes (DEGs) in the three clusters were analyzed. The top 45 important variables associated with characteristic pathways, such as Huntington's disease, VEGF signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, purine metabolism, olfactory transduction, etc., were used to construct a subtype identification model. The model was experimentally validated and proved to possess good predictive efficacy. In addition, pathway-related subtype typing was significantly associated with different immune cell infiltration in AITL. Further analysis revealed that the drug IC50 values predicted also differed markedly among the different subtypes, thus further identifying some subtype-specific drugs. Our study indicates a potential role of characteristic pathways in AITL staging for the first time, provides novel insights for future research targeting AITL, and points to potential therapeutic options for patients with different subtypes of AITL.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are class II biopharmaceutics classification system drugs. The poor aqueous solubility of NSAIDs can lead to limited bioavailability after oral administration. Metformin (MET), a small-molecule compound, can be used in crystal engineering to modulate the physicochemical properties of drugs and to improve the bioavailability of orally administered drugs, according to the literature research and preliminary studies. We synthesized two drug–drug molecular salts (ketoprofen–metformin and phenylbutazone–metformin) with NSAIDs and thoroughly characterized them using SCXRD, PXRD, DSC, and IR analysis to improve the poor solubility of NSAIDs. In vitro evaluation studies revealed that the thermal stability and solubility of NSAIDs-MET were substantially enhanced compared with those of NSAIDs alone. Unexpectedly, an additional increase in permeability was observed. Since the structure determines the properties, the structure was analyzed using theoretical calculations to reveal the intermolecular interactions and to explain the reason for the change in properties. The salt formation of NSAIDs with MET could substantially increase the bio-absorption rate of NSAIDs, according to the in vivo pharmacokinetic findings, which provides an experimental basis for developing new antipyretic and analgesic drugs with rapid onset of action.

The manta ray, exemplifying an agile swimming mode identified as the median and paired fin (MPF) mode, inspired the development of underwater robots. Robotic manta typically comprises a central rigid body and flexible pectoral fins. Flexible fins provide excellent maneuverability. However, due to the complexity of material mechanics and hydrodynamics, its dynamics are rarely studied, which is crucial for the advanced control of robotic manta (such as trajectory tracking, obstacle avoidance, etc.). In this paper, we develop a multibody dynamic model for our novel manta robot by introducing a pseudo-rigid body (PRB) model to consider passive deformation in the spanwise direction of the pectoral fins while avoiding intricate modeling. In addressing the rigid-flexible coupling dynamics between flexible fins and the actuation mechanism, we employ a sequential coupling technique commonly used in fluid-structure interaction (FSI) problems. Numerical examples are provided to validate the MPF mode and demonstrate the effectiveness of the dynamic model. We show that our model performs well in the rigid-flexible coupling analysis of the manta robot. In addition to the straight-swimming scenario, we elucidate the viability of tailoring turning gaits through systematic variations in input parameters. Moreover, compared with finite element and CFD methods, the PRB method has high computational efficiency in rigid-flexible coupling problems. Its potential for real-time computation opens up possibilities for future model-based control.

Anthocyanins, which belong to the flavonoid group, are commonly found in the organs of plants native to South and Central America. However, these pigments are unstable under conditions of varying pH, heat, etc., which limits their potential applications. One method for preserving the stability of anthocyanins is through encapsulation using proteins or peptides. Nevertheless, the complex and diverse structure of these molecules, as well as the limitation of experimental technologies, have hindered a comprehensive understanding of the encapsulation processes and the mechanisms by which stability is enhanced. To address these challenges, computational methods, such as molecular docking and molecular dynamics simulation have been used to study the binding affinity and dynamics of interactions between proteins/peptides and anthocyanins. This review summarizes the mechanisms of interaction between these systems, based on computational approaches, and highlights the role of proteins and peptides in the stability enhancement of anthocyanins. It also discusses the current limitations of these methods and suggests possible solutions.

Abstract We aimed to comprehensively investigate the proteomic profile and underlying biological function of exosomal proteins associated with B-cell acute lymphoblastic leukemia. Exosomes were isolated from plasma samples collected from five patients with B-ALL and five healthy individuals, and their protein content was quantitatively analyzed by liquid chromatography with tandem mass spectrometry. A total of 342 differentially expressed proteins were identified in patients with B-ALL. The DEPs were mainly associated with protein metabolic processes and protein activity regulation and were significantly enriched in the Notch and autophagy pathways. Furthermore, we found that ADAM17 and ATG3 were upregulated in patients with B-ALL and enriched in the Notch and autophagy pathways, respectively. Further western blot analysis of exosomes collected from additional 18 patients with B-ALL and 10 healthy controls confirmed that both ADAM17 and ATG3 were overexpressed in exosomes derived from patients with B-ALL (p

Abstract Targeting immune checkpoints has achieved great therapeutic effects in the treatment of early-stage tumors. However, most patients develop adaptive resistance to this therapy. The latest evidence demonstrates that tumor-derived exosomes may play a key role in systemic immune suppression and tumor progression. In this article, we highlight the role of exosomal immune checkpoint proteins in tumor immunity, with an emphasis on programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as emerging evidence on roles of T cell immunoglobulin-3 (TIM-3), arginase 1 (ARG1), and estrogen receptor binding fragment-associated antigen 9 (EBAG9) expressed by exosomes.

BackgroundThe prognostic performance of four lymph node classifications, the 8th American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) N stage, lymph node ratio (LNR), log odds of positive lymph nodes (LODDS), and examined lymph nodes (ELN) in early-onset pancreatic cancer (EOPC) remains unclear.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was searched for patients with EOPC from 2004 to 2016. 1048 patients were randomly divided into training (n = 733) and validation sets (n = 315). The predictive abilities of the four lymph node staging systems were compared using the Akaike information criteria (AIC), receiver operating characteristic area under the curve (AUC), and C-index. Multivariate Cox analysis was performed to identify independent risk factors. A nomogram based on lymph node classification with the strongest predictive ability was established. The nomogram’s precision was verified by the C-index, calibration curves, and AUC. Kaplan–Meier analysis and log-rank tests were used to compare differences in survival at each stage of the nomogram.ResultsCompared with the 8th N stage, LODDS, and ELN, LNR had the highest C-index and AUC and the lowest AIC. Multivariate analysis showed that N stage, LODDS, LNR were independent risk factors associated with cancer specific survival (CSS), but not ELN. In the training set, the AUC values for the 1-, 3-, and 5-year CSS of the nomogram were 0.663, 0.728, and 0.760, respectively and similar results were observed in the validation set. In addition, Kaplan–Meier survival analysis showed that the nomogram was also an important factor in the risk stratification of EOPC.ConclusionWe analyzed the predictive power of the four lymph node staging systems and found that LNR had the strongest predictive ability. Furthermore, the novel nomogram prognostic staging mode based on LNR was also an important factor in the risk stratification of EOPC.

The ground-based Synthetic Aperture Radar (GB-SAR) technique can be applied to the safety monitoring and early warning of geo-hazards, especially for monitoring displacement of various types of landslide masses. One of the key techniques of processing GB-SAR monitoring data is phase unwrapping, which can be dramatically affected by atmospheric humidity, atmospheric pressure, sampling interval, etc. In high mountains and valleys where environmental change is drastic, GB-SAR monitoring data is vulnerable to incoherence both spatially and temporally. Therefore, an improved phase unwrapping method of GB-SAR data for landslide monitoring is proposed in this paper, which can realize three-dimensional phase unwrapping in time and space. The method adopts the idea of sparse data processing and realizes phase unwrapping of monitoring data in two steps. Firstly, taking full advantage of the high temporal resolution of GB-SAR monitoring data, the one-dimensional phase unwrapping method in the spatial domain is applied to the time domain, and the interference phases of PS points are unwrapped in the time domain. Then, the PS network is constructed based on the time-phase unwrapping results, the double-difference phases of the network baselines are obtained and the spatial consistency adjustment is applied to them, and the spatial phase unwrapping can be realized by the indirect least square adjustment method. This method successfully solves the problem of path dependence, island isolation and large computation of the common method of space-borne SAR phase unwrapping, which can process GB-SAR data with high accuracy and efficiency.

Forests cover approximately one-third of the Earth’s land surface and constitute the core region of the carbon cycle on Earth. The paramount importance and multi-purpose applications of forest monitoring have gained widespread recognition over recent decades. Polarimetric synthetic aperture radar interferometry (PolInSAR) has been demonstrated as a promising technique to retrieve the forest height over large areas with a limited cost. This paper presents an overview of forest height inversion (FHI) techniques based on PolInSAR data. Firstly, we introduce the basic theories of PolInSAR and FHI procedures. Next, we review the established data-based algorithms for single-baseline data and describe innovative techniques related to multi-baseline data. Then, the model-based algorithms are also introduced with their corresponding forest scattering models under multiple data acquisition modes. Subsequently, a case study is presented to demonstrate the applicable scenarios and advantages of different algorithms. Model-based algorithms can provide accurate results when the scene and forest properties are well understood and the model assumptions are valid. Data-based algorithms, on the other hand, can handle complex scattering scenarios and are generally more robust to uncertainties in the input parameters. Finally, the prospect of forest height inversion was analyzed. It is our hope that this review will provide guidelines to future researchers to enhance further FHI algorithmic developments.

To reduce the impact of series battery pack inconsistency on energy utilization, an active state of charge (SOC) balancing method based on an inductor and capacitor is proposed. Only one inductor and one capacitor can achieve a direct transfer of balanced energy between the highest power cell and the lowest power cell. This method has the characteristics of a simple structure, small size, simple control, fast balancing speed, and low topology cost. First, the topology, working principle, parameter design, and control strategy of the proposed balancing method are explained. Second, the characteristics of the speed and efficiency are analyzed through the simulation models, and the advantages of its low topology cost and simple control are explained. Finally, by building an experimental platform for a four-cell series battery pack, the effectiveness of the new balancing method in the charging/discharging process and the dynamic process of the battery pack is verified. After the end of the balancing, the SOC difference is less than 4%.

C19H25N5O, monoclinic, P21 (no. 4), a = 16.0600(2) Å, b = 5.3992(1) Å, c = 19.8514(2) Å, β = 94.260(1)°, V = 1716.58(4) Å3, Z = 4, Rgt (F) = 0.0350, wRref(F2) = 0.0908, T = 100.00(10) K.

It is challenging to measure, analyze, and control the deformation and space attitude of antennas in narrow radomes through geometric measurement to ensure the accuracy of phased array radar application. In this manuscript, a method for rapid measurement of antennas by adopting the combination of photogrammetry system, laser tracker and total station was proposed. The photogrammetric method was used with a homemade auxiliary tool to measure and calculate the antenna’s deformation under different temperatures and pitch angles. Mapping relations between the instrumental coordinate systems of photogrammetry system, laser tracker and total station were established through common points, including target balls and reflectors. Coordinates of mark points on antenna surface were converted from photogrammetric coordinate system to laser tracker’s and total station’s coordinate system. Thus, antenna’s pitch angles relative to the local horizontal plane and deflection angles relative to the north of the engineering coordinate system were calculated. Planar fitting, coordinate transformation and space attitude calculation were all carried out in the Spatial Analyzer (SA) software. The photogrammetric method detected the antenna’s gravitational deformation sensitively, the maximum Root Mean Square Residual (RMSR) of the reference length was $54~\mu \text{m}$ , and that of the mark points was $59~\mu \text{m}$ , which was stably in line with its nominal accuracy. Deviations caused by coordinate transformation had no significant effect on the calculation of antenna’s spatial attitude, for the maximum deviation between the converted and measured coordinates in laser tracker’s coordinate system was 0.139 mm, and that in total station’s coordinate system was 1.037 mm, both of which were within reasonable limits of the derived theoretical maximum deviations between different instruments. As a result, the maximum deviation between the calculated value and servo system’s nominal value of antenna’s pitch angle was $59.4''$ , and that of antenna’s deflection angle was $91.87''$ . This method’s efficiency was greatly improved by about ten times compared with traditional methods through statistics and estimates.

Abstract A cocrystal of diosgenin with piperazine in 2:1 stoichiometry was successfully synthesized. The solid form was prepared by liquid assisted grinding, slurry and crystallization methods. The cocrystal was characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and structure determined by single crystal X-ray diffraction, the hydrogen bonds formed into fish bone structure along the [010] direction and all the molecules packed into 3D layer structure along a axis. After formation of cocrystal, the solubility of diosgenin was improved, and the solubility value in 0.2% SDS solution was approximately 1.5 times as large as that of the parent material. Graphic Abstract

Abstract. Objectives:. Timing of drain removal and its effects on complications after major pancreatectomy remain controversial. We designed this study to assess whether early drain removal after major pancreatectomy influences the incidence of complications in the patients with low risk of postoperative pancreatic fistula (POPF). Methods:. This is a single-center randomized controlled trial (RCT). A total of 144 patients undergoing pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) who met the criteria, including drain amylase on postoperative day (POD) 1 and 3 less than 5000 U/L and drain output within POD 3 less than 300 mL/d, were randomly assigned to early drain removal (POD 3) or standard drain removal (≥POD 5). The primary outcome was major complications (Clavien-Dindo grades 2–4), and the secondary outcome was POPF, reintervention treatment, readmission, and total medical expense within 3 months after surgery. Results:. A total of 5 patients in early drain removal group had at least 1 major complications (grades 2–4), compared to 15 patients in standard drain removal group (P = .028). The incidence of grade B/C pancreatic fistula was not significantly different (2.8% vs 0%). Multivariate analysis demonstrated that early drain removal was an independent factor associated with a reduced risk of major complications (P = .039, odds ratio = 0.314). Majority of major complications occurred in PD patients, and only very few cases occurred in DP patients. Stratified analysis showed that early drain removal significantly reduced the major complications only in the patients undergoing PD. Conclusion:. This single-center RCT shows early drain removal on POD 3 is safe for both DP and PD patients, under our criteria. Early drain removal could reduce the incidence of major complications in patients undergoing PD.

The Cassegrain telescope, made of a concave primary mirror and a convex secondary mirror, is widely utilized for modern astronomical observation. However, the existence of curved mirrors inevitably results in bulky configurations. Here, we propose a new design of the miniaturized Cassegrain telescope by replacing the curved mirrors with planar reflective metasurfaces. The focusing and imaging properties of the Cassegrain metasurface telescopes are experimentally verified for circularly polarized incident light at near infrared wavelengths. The concept of the metasurface telescopes can be employed for applications in telescopes working at infrared, Terahertz, and microwave and even radio frequencies.

China unanimously believed that Emei Martial Arts has the essence of self-improvement. It is a spiritual force that actively promotes human progress. It should be protected and continuously innovated to make it a spiritual pillar of people. However, its promotion faces huge challenges. In recent years, neural networks have made great progress in various fields, such as speech recognition, computer vision, and natural language understanding. On this basis, the combination of neural networks and traditional recommendation methods is helpful for the better development of Emei Martial Arts promotion. Neural networks have a direct analog interaction function and perform coordinated filtering directly through interactive data. Due to the effectiveness of the structure, the neural network can mine nonlinear implicit relationships from the data and find the martial arts items that users want to promote. In order to enhance the effectiveness of the standard recommendation algorithm, a deep neural network-based recommendation algorithm is paired with a neural network-based recommendation algorithm that is proposed in this article. The recall rate of the upgraded deep neural network recommendation model is up to 80%, whereas the recall rate of the model without enhancement is up to 40%, according to the experimental results of this article. The upgraded deep neural network’s recommendation model has a recall rate that is 4% greater than the baseline model. It showed that the recommendation algorithm combined with a neural network has a better recommendation effect so as to achieve a better effect of Emei Martial Arts promotion so that Emei Martial Arts culture can be carried forward and economic development can be promoted at the same time.

Background: Total pancreatectomy (TP) seems to be experiencing a renaissance in recent years. In this study, we aimed to determine the long-term survival of pancreatic ductal adenocarcinoma (PDAC) patients who underwent TP by comparing with pancreaticoduodenectomy (PD), and formulate a nomogram to predict overall survival (OS) for PDAC individuals following TP.Methods: Patients who were diagnosed with PDAC and received PD (n = 5,619) or TP (n = 1,248) between 2004 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. OS and cancer-specific survival (CSS) of the PD and TP groups were compared using Kaplan-Meier method and log-rank test. Furthermore, Patients receiving TP were randomly divided into the training and validation cohorts. Univariate and multivariate Cox regression were applied to identify the independent factors affecting OS to construct the nomogram. The performance of the nomogram was measured according to concordance index (C-index), calibration plots, and decision curve analysis (DCA).Results: There were no significant differences in OS and CSS between TP and PD groups. Age, differentiation, AJCC T stage, radiotherapy, chemotherapy, and lymph node ratio (LNR) were identified as independent prognostic indicators to construct the nomogram. The C-indexes were 0.67 and 0.69 in the training and validation cohorts, while 0.59 and 0.60 of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system. The calibration curves showed good uniformity between the nomogram prediction and actual observation. DCA curves indicated the nomogram was preferable to the AJCC staging system in terms of the clinical utility. A new risk stratification system was constructed which could distinguish patients with different survival risks.Conclusions: For PDAC patients following TP, the OS and CSS are similar to those who following PD. We developed a practical nomogram to predict the prognosis of PDAC patients treated with TP, which showed superiority over the conventional AJCC staging system.

Abstract Automatic registration of multi‐source remote sensing data is a challenging task due to the high non‐linearity of radiometric differences among various data. Feature extraction is a key enabling technique in registration algorithm design. In this letter, we prove the feasibility of using extracted regional features for multi‐source image registration. In particular, regional features can be extracted through pixel‐level image classification, and existing off‐the‐shelf algorithms can be directly adopted. Experiment results demonstrate the robustness of the regional‐feature‐based registration method.

Henry Gas Solubility Optimization Algorithm (HGSO) is a physical-based algorithm based on Henry's Law and simulates the process that the solubility of gas in liquid changes with temperature. The search strategy of the HGSO is very simple, which results in the algorithm having poor exploitation ability and unable to find a more accurate optimal solution. The Harris Hawk optimization algorithm (HHO) has strong exploitation because of its diverse exploitation strategies. In order to make up for the shortcomings of HGSO algorithm, this article proposes an improved Henry gas solubility optimization algorithm (HHO-HGSO) based on the Harris Hawk optimization. During the iteration, taking the escaping energy function of the HHO algorithm as an indicator and determining a threshold, when the escaping energy function value is greater than the threshold, the algorithm conducts the search strategy of the HGSO algorithm, when less than the threshold, executes four exploitation strategies of Harris Hawk. In order to verify the performance of the proposed algorithm, HHO-HGSO is used to optimize CEC2005 and CEC2017 benchmark test functions and solve 4 real engineering design problems. Marine predators algorithm (MPA), Whale optimization algorithm (WOA), Lightning search algorithm (LSA), Water cycle algorithm (WCA), HGSO, and HHO were used to conduct comparative experiments. The simulation results show that the proposed HHO-HGSO algorithm has strong optimization ability. The core code of the paper has been uploaded in https://github.com/xwaiyy123/HHO-HGSO.

Abstract Background Papillomaviruses (PVs) and polyomaviruses (PyVs) infect diverse vertebrates including human and cause a broad spectrum of outcomes from asymptomatic infection to severe disease. There has been no PV and only one PyV detected in tree shrews, though the genomic properties of tree shrews are highly similar to those of the primates. Methods Swab and organ samples of tree shrews collected in the Yunnan Province of China, were tested by viral metagenomic analysis and random PCR to detect the presence of PVs and PyVs. By PCR amplification using specific primers, cloning, sequencing and assembling, genomes of two PVs and one PyV were identified in the samples. Results Two novel PVs and a novel PyV, named tree shrew papillomavirus 1 and 2 (TbelPV1 and TbelPV2) and polyomavirus 1 (TbelPyV1) were characterized in the Chinese tree shrew (Tupaia belangeri chinensis). The genomes of TbelPV1, TbelPV2, and TbelPyV1 are 7410 bp, 7526 bp, and 4982 bp in size, respectively. The TbelPV1 genome contains 7 putative open-reading frames (ORFs) coding for viral proteins E1, E2, E4, E6, E7, L1, and L2; the TbelPV2 genome contains 6 ORFs coding for viral proteins E1, E2, E6, E7, L1, and L2; and the TbelPyV1 genome codes for the typical small and large T antigens of PyV, as well as the VP1, VP2, and VP3 capsid proteins. Genomic comparison and phylogenetic analysis indicated that TbelPV1 and TbelPV2 represented 2 novel PV genera of Papillomaviridae, and TbelPyV1 represented a new species of genus Alphapolyomavirus. Our epidemiologic study indicated that TbelPV1 and TbelPV2 were both detected in oral swabs, while TbelPyV1 was detected in oral swabs and spleens. Conclusion Two novel PVs (TbelPV1 and TbelPV2) and a novel PyV (TbelPyV) were discovered in tree shrews and their genomes were characterized. TbelPV1, TbelPV2, and TbelPyV1 have the highest similarity to Human papillomavirus type 63, Ursus maritimus papillomavirus 1, and Human polyomavirus 9, respectively. TbelPV1 and TbelPV2 only showed oral tropism, while TbelPyV1 showed oral and spleen tropism.

Deep learning methods have been widely studied for Polarimetric synthetic aperture radar (PolSAR) land cover classification. The scarcity of PolSAR labeled samples and the small receptive field of the model limit the performance of deep learning methods for land cover classification. In this paper, a vision Transformer (ViT)-based classification method is proposed. The ViT structure can extract features from the global range of images based on a self-attention block. The powerful feature representation capability of the model is equivalent to a flexible receptive field, which is suitable for PolSAR image classification at different resolutions. In addition, because of the lack of labeled data, the Mask Autoencoder method is used to pre-train the proposed model with unlabeled data. Experiments are carried out on the Flevoland dataset acquired by NASA/JPL AIRSAR and the Hainan dataset acquired by the Aerial Remote Sensing System of the Chinese Academy of Sciences. The experimental results on both datasets demonstrate the superiority of the proposed method.

Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL.

Two novel co-crystals of naproxen (NPX) were designed and prepared at a stoichiometric ratio of 1:1, namely, naproxen–caprolactam (NPX–CPL) and naproxen–oxymatrine (NPX–OMT). The characteristics of the co-crystals were evaluated in terms of stability and solubility studies. In terms of solubility, in four kinds of solvent systems with different pH, the solubility of NPX–OMT was significantly improved compared with that of NPX, whereas the NPX–CPL showed advantages in acidic solvent systems, indicating that the co-crystals can be applied to concoct preparations depending on therapeutic purposes. Furthermore, the experimental results of the thermal analysis showed that the co-crystal NPX–OMT had better thermal stability than the co-crystal NPX–CPL. Finally, as a complement to the single crystal X-ray diffraction (SC XRD) method, the theoretical calculation based on density functional theory (DFT) was also used to reveal the intermolecular interaction of the co-crystals at the molecular level and visually display the difference between them.

Introduction Several previous studies have reported the incidence of new-onset diabetes mellitus (NODM) after pancreatectomy. Nevertheless, the results were inconsistent. The true rate of NODM after distal pancreatectomy (DP) is still unknown.Research design and methods The aim of this study was to investigate the incidence of and the risk factors for NODM after DP. This study enrolled patients who underwent DP between January 2004 and February 2016 at Peking Union Medical College Hospital. Patients with preoperative diabetes mellitus or diagnosed with pancreatic cancer were excluded. The primary outcome was NODM.Results A total of 485 patients were enrolled. The median (IQR) of follow-up duration was 30.95 (9.26–180.30) months. The accumulative incidence of NODM was 8.9% at postoperative 6 months, 14.0% at postoperative year one, 22.3% at year three, 27.1% at year five, and 35.5% at year ten. Multivariate analysis showed that the risk of postoperative NODM was positively correlated with age (HR 1.029 (1.013–1.045), p

Summary: Here we demonstrate a novel and robust mechanism, termed as “current-induced Joule heating activated thermal tunneling excitation,” to achieve electroluminescence (EL) by the hot electron-hole-pair recombination in a single highly compensated semiconductor microrod. The radiative luminescence is electrically excited under ambient conditions. The current-induced Joule heating reduces the thermal tunneling excitation threshold of voltage down to 8 V and increases the EL efficiency ~4.4-fold at 723 K. We interpret this novel phenomenon by a thermal tunneling excitation model corrected by electric-induced Joule heating effect. The mechanism is confirmed via theoretical calculation and experimental demonstration, for the first time. The color-tunable EL emission is also achieved by regulation of donor concentration. This work opens up new opportunities for design of novel multi-color light-emitting devices by homogeneous defect-engineered semiconductors in future.

With the popularity and development of network technology and the Internet, intrusion detection systems (IDSs), which can identify attacks, have been developed. Traditional intrusion detection algorithms typically employ mining association rules to identify intrusion behaviors. However, they fail to fully extract the characteristic information of user behaviors and encounter various problems, such as high false alarm rate (FAR), poor generalization capability, and poor timeliness. In this paper, we propose a network intrusion detection model based on a convolutional neural network-IDS (CNN-IDS). Redundant and irrelevant features in the network traffic data are first removed using different dimensionality reduction methods. Features of the dimensionality reduction data are automatically extracted using the CNN, and more effective information for identifying intrusion is extracted by supervised learning. To reduce the computational cost, we convert the original traffic vector format into an image format and use a standard KDD-CUP99 dataset to evaluate the performance of the proposed CNN model. The experimental results indicate that the AC, FAR, and timeliness of the CNN-IDS model are higher than those of traditional algorithms. Therefore, the model we propose has not only research significance but also practical value.

Objective Serum chloride disorders have been gaining increased attention. We aimed to assess the impact of serum chloride on all-cause mortality in critically ill patients in coronary care units (CCUs). Methods We extracted clinical data from the Multiparameter Intelligent Monitoring in Intensive Care III database. We used data for the first CCU admission of each patient; baseline data were extracted within 24 hours after CCU admission. Statistical methods included the Lowess smoothing technique, Cox proportional hazards model, and subgroup analyses. Results A total 5616 patients who met the inclusion criteria were included. We observed a U-shaped relationship between admission chloride levels and 30-day all-cause mortality. In multivariate analysis adjusted for age, ethnicity, and sex, both hyper- and hypochloremia were significant predictors of risk of 30-day, 90-day, and 365-day all-cause mortality. After adjusting additional clinical characteristics, hypochloremia remained a significant predictor of risk of 30-day all-cause mortality (hazard ratio, 1.47; 95% confidence interval, 1.19–1.83). For 90-day and 365-day all-cause mortality, similar significant robust associations were found. Conclusions We observed a U-shaped relationship between admission chloride levels and 30-day all-cause mortality among patients in the CCU. Hypochloremia was associated with increased risk of all-cause mortality in these patients.

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

This research proposes a novel bionic pectoral fin and experimentally studied the effects of the oscillation parameters on the hydrodynamic performance of a bionic experimental prototype. Inspired by manta rays, the bionic pectoral fin was simplified and modeled based on the natural pectoral fin skeleton structure and oscillation morphology of this underwater creature. A dual-degree-of-freedom bionic pectoral fin was designed. The active spatial motion was realized by the space six-link mechanism driven by two motors, and the passive deformation was achieved by carbon fiber. The motion analysis of the bionic pectoral fin proves that the pectoral fin can realize an “8”-shaped spatial trajectory. An experimental prototype was developed accordingly. The experimental prototype could flap between 0.1 Hz and 0.6 Hz and produce a maximum thrust of 20 N. The hydrodynamic performance under different oscillation parameters was studied experimentally in a water pool. The experimental results indicate that the hydrodynamic performance of the pectoral fin oscillation is closely related to the motion equation parameters including the amplitude, frequency, phase difference, and initial bias. In addition to considering the impact of parameters on thrust and lift, the influences of asymmetrical oscillation on the position of the equivalent point were also studied. The results show that the pectoral fin proposed in this research exhibited the expected spatial deformation and outstanding hydrodynamic performance. The obtained results shed light on the updated design and control of a bionic robot fish.

Monopolar spindle 1 (Mps1), a dual-specific kinase, is related to the proper execution of chromosome biorientation and mitotic checkpoint signaling. The overexpression of Mps1 promotes the occurrence of cancer or the survival of aneuploid cancer cells, in other words, the reduction of Mps1 will severely reduce the viability of human cancer cells. Therefore, Mps1 is a potential target for cancer treatment. Recently, a series of novel pyrido [3,4-d] pyrimidine derivatives targeting Mps1 with high biological activity were synthesized. The crystal structure of Mps1 in complex with pyrido [3,4-d] pyrimidine derivatives was also reported, but there were no specific mechanism studies for this series of small molecule inhibitors. In this study, complexes binding modes were probed by molecular docking and further validated by molecular dynamics simulations and the molecular mechanics/generalized Born surface area (MM/GBSA) method. The results indicated that the van der Waals interactions and the nonpolar solvation energies were responsible to the basis for favorable binding free energies, all inhibitors interacted with residues I531, V539, M602, C604, N606, I607, L654, I663, and P673 of Mps1. By analyzing the hydrogen bonds, we found the residues G605 and K529 in Mps1 formed stable hydrogen bonds with compounds, it was more conducive to activities of Mps1 inhibitors. According to the above analysis, we further designed five new compounds. We found that compounds IV and V were better potential Mps1 inhibitors through docking and ADMET prediction. The obtained new insights not only were helpful in understanding the binding mode of inhibitors in Mps1, but also provided important references for further rational design of Mps1 inhibitors.

The traditional measurement theory interprets the variance as the dispersion of a measured value, which is actually contrary to a general mathematical concept that the variance of a constant is 0. This paper will fully demonstrate that the variance in measurement theory is actually the evaluation of probability interval of an error instead of the dispersion of a measured value, point out the key point of mistake in the traditional interpretation, and fully interpret a series of changes in conceptual logic and processing method brought about by this new concept.

Soft-sensor technology plays a vital role in tracking and monitoring the key production indicators of the grinding and classifying process. Least squares support vector machine (LSSVM), as a soft-sensor model with strong generalization ability, can be used to predict key production indicators in complex grinding processes. The traditional crossvalidation method cannot obtain the ideal structure parameters of LSSVM. In order to improve the prediction accuracy of LSSVM, a golden sine Harris Hawk optimization (GSHHO) algorithm was proposed to optimize the structure parameters of LSSVM models with linear kernel, sigmoid kernel, polynomial kernel, and radial basis kernel, and the influences of GSHHO algorithm on the prediction accuracy under these LSSVM models were studied. In order to deal with the problem that the prediction accuracy of the model decreases due to changes of industrial status, this paper adopts moving window (MW) strategy to adaptively revise the LSSVM (MW-LSSVM), which greatly improves the prediction accuracy of the LSSVM. The prediction accuracy of the regularized extreme learning machine with MW strategy (MW-RELM) is higher than that of MW-LSSVM at some moments. Based on the training errors of LSSVM and RELM within the window, this paper proposes an adaptive hybrid soft-sensing model that switches between LSSVM and RELM. Compared with the previous MW-LSSVM, MW-neural network trained with extended Kalman filter(MW-KNN), and MW-RELM, the prediction accuracy of the hybrid model is further improved. Simulation results show that the proposed hybrid adaptive soft-sensor model has good generalization ability and prediction accuracy.

C20H34N4O, triclinic, P1 (no. 1), a = 7.8545(6) Å, b = 10.8802(9) Å, c = 12.3714(9) Å, α = 73.200(7)°, β = 75.372(6)°, γ = 71.091(7)°, V = 942.65(13) Å3, Z = 2, Rgt(F) = 0.0591, wRref(F2) = 0.1641, T = 293(2) K.