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Abstract This study evaluated the ability of the triglyceride (TG) to high-density lipoprotein cholesterol (TG/HDL-C) ratio to identify individuals at risk of type 2 diabetes mellitus (T2DM) in the non-alcoholic fatty liver disease (NAFLD) population. We retrospectively studied 4,769 patients with NAFLD from the Affiliated Hospital of Hangzhou Normal University (2020–2023). Binary logistic regression models were used to evaluate the association between the TG/HDL-C ratio and lipid parameters with T2DM. TG/HDL-C ratio was positively associated with T2DM in patients with NAFLD, with an odds ratio (OR) of 2.72 (95% confidence interval, 2.23–3.31, p

Abstract This study aimed to assess the effectiveness and safety of 5-Fluorouracil (5-Fu) combined with conventional transarterial chemoembolization (cTACE) compared to 5-Fu combined with drug-eluting bead transarterial chemoembolization (DEB-TACE) using CalliSpheres for the treatment of unresectable hepatocellular carcinoma (HCC) using propensity score weighting methods. This retrospective analysis included 131 patients with HCC treated with 5-Fu combined with cTACE (5-Fu-cTACE group, n = 65) or DEB-TACE (5-Fu-DEB-TACE group, n = 66) at the Affiliated Hospital of North Sichuan Medical College from January 2019 to December 2022. Based on the baseline data and laboratory indicators, propensity score weighting was used to reduce confounding bias. Modified response evaluation criteria in solid tumors (mRECIST) were used to evaluate clinical efficacy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the disease control rate (DCR), objective response rate (ORR) and adverse events (AEs). PFS was assessed using Kaplan‒Meier analysis and Cox proportional hazards models. The ORRs at 1 month (M1) after treatment in the 5-Fu-DEB-TACE group and 5-Fu-cTACE group were 90.9% and 76.9%, respectively (P = 0.029), while at this time, the DCRs were 93.9% in the 5-Fu-DEB-TACE group and 90.8% in the 5-Fu-cTACE group (P = 0.494). At 3 months (M3) after treatment, the 5-Fu-DEB-TACE group had a higher ORR (84.8% vs. 56.9%, P

ObjectivesThis study aimed to evaluate the effectiveness of combining hepatic arterial infusion chemotherapy (HAIC) with lenvatinib and programmed cell death protein 1 (PD-1) inhibitors in the treatment of advanced, unresectable hepatocellular carcinoma (HCC).MethodsA comprehensive search across multiple databases was conducted to identify relevant studies published up to May 2024. This search focused on clinical trials investigating the combination of HAIC with lenvatinib and PD-1 inhibitors for the treatment of advanced HCC. Data from these trials were analyzed using either fixed-effects or random-effects models, with results reported as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs). To evaluate the robustness of the findings, trial sequential analysis was employed.ResultsA total of 8 cohort studies encompassing 1073 patients with unresectable HCC were included. Compared with other treatment regimens, the combined use of HAIC, lenvatinib, and PD-1 inhibitors significantly improved overall survival (OS) (HR=0.53 [95% CI 0.45, 0.63], P

Abstract The soil environment plays an important role in urban ecosystems. To study the heavy metal contamination of soil in Beilun District, Ningbo, we collected soil samples from 60 points in urban and peri-urban areas of Beilun District and analyzed the spatiotemporal variation and sources of heavy metal pollution in various land-use types. The results shown that the heavy metal contents in 2015 and 2022 were higher than the background soil values of Ningbo city, and there was an accumulation of heavy metals over these 7 years. The contents of heavy metals in green belts and woodland in 2022 were higher than those in 2015, while there was no significant change in agricultural land. The heavy metal contents in both years were mainly in the order green belts > agricultural land > woodland. The spatiotemporal distribution of heavy metal content showed that heavy metal pollution in Beilun District was concentrated in five industrial areas, and there was a trend toward the disappearance of highly polluted points. But the single-factor pollution index, pollution load index (PLI), and geoaccumulation index (Igeo) indicated that there was no significant heavy metal pollution in Beilun District, and individual elements at specific points showed slight pollution. The source analysis results showed that the main source of Hg is chemical, As is mainly derived from agricultural, Cr, Ni and Cu are mainly derived from natural, the main sources of Zn and Cd are electroplating and machinery activities, and the main source of Pb is traffic. These results specify a reference for future investigation on urban soil heavy metals, and the source apportionment results provide a scientific foundation for subsequent soil heavy metal pollution treatment.

Abstract The difference in the survival of obese patients and normal-weight/lean patients with diabetic MAFLD remains unclear. Therefore, we aimed to describe the long-term survival of individuals with diabetic MAFLD and overweight/obesity (OT2M), diabetic MAFLD with lean/normal weight (LT2M), MAFLD with overweight/obesity and without T2DM (OM), and MAFLD with lean/normal weight and without T2DM (LM). Using the NHANESIII database, participants with MAFLD were divided into four groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular disease (CVD)-related, and cancer-related mortalities for different MAFLD subtypes were evaluated using Cox proportional hazards models. Of the 3539 participants, 1618 participants (42.61%) died during a mean follow-up period of 274.41 ± 2.35 months. LT2M and OT2M had higher risks of all-cause mortality (adjusted HR, 2.14; 95% CI 1.82–2.51; p

Abstract Food consumption can alter the biochemistry and redox status of human saliva, and the serving temperature of food may also play a role. The study aimed to explore the immediate (3 min) and delayed (30 min) effects of hot tea (57 ± 0.5 °C) ingestion and cold tea (8 ± 0.5 °C) ingestion on the salivary flow rate and salivary redox-relevant attributes. The saliva was collected from 20 healthy adults before, 3-min after and 30-min after the tea ingestion. The hot or cold deionised water at the same temperatures were used as control. The salivary flow rate and redox markers in hot tea (HBT), cold tea (CBT), hot water (HW) and cold water (CW) group were analysed and compared. The results demonstrated that neither the black tea nor the water altered the salivary flow rate; the black tea immediately increased the salivary thiol (SH) and malondialdehyde (MDA) content while reduced salivary uric acid (UA) significantly. The tea ingestion showed a tendency to elevate the ferric reducing antioxidant power (FRAP) in saliva, although not significantly. The water ingestion decreased the MDA content immediately and increased the UA level significantly. Cold water was found to induce a greater delayed increase in total salivary total protein (TPC) than the hot water. In conclusion, the black tea ingestion affects the redox attributes of human saliva acutely and significantly, while the temperature of drink makes the secondary contribution.

ABSTRACT: The economic losses incurred due to reduced muscle pigmentation highlight the crucial role of melanin-based coloration in the meat of black-bone chickens. Melanogenesis in the breast muscle of black-bone chickens is currently poorly understood in terms of molecular mechanisms. This study employed whole-transcriptome sequencing to analyze black and white breast muscle samples from black-bone chickens, leading to the identification of 367 differentially expressed (DE) mRNAs, 48 DElncRNAs, 104 DEcircRNAs, and 112 DEmiRNAs involved in melanin deposition. Based on these findings, a competitive endogenous RNA (ceRNA) network was developed to better understand the complex mechanisms of melanin deposition. Furthermore, our analysis revealed key DEmRNAs (TYR, DCT, EDNRB, MLPH and OCA2) regulated by DEmiRNAs (gga-miR-140-5p, gga-miR-1682, gga-miR-3529, gga-miR-499-3p, novel-m0012-3p, gga-miR-200b-5p, gga-miR-203a, gga-miR-6651-5p, gga-miR-7455-3p, gga-miR-31-5p, miR-140-x, miR-455-x, novel-m0065-3p, gga-miR-29b-1-5p, miR-455-y, novel-m0085-3p, and gga-miR-196-1-3p). These DEmiRNAs competitively interacted with DElncRNAs including MSTRG.2609.2, MSTRG.4185.1, LOC112530666, LOC112533366, LOC771030, LOC107054724, LOC121107411, LOC100859072, LOC101750037, LOC121108550, LOC121109224, LOC121110876, and LOC101749016, as well as DEcircRNAs, such as novel_circ_000158, novel_circ_000623, novel_001518, and novel_circ_003596. The findings from this study provide insight into the mechanisms that regulate lncRNA, circRNA, miRNA, and mRNA expression in chicken melanin deposition.

Abstract Purpose The onset of OA is affected by a variety of factors, which eventually lead to the loss of cartilage in the joints, the formation of osteophytes, the loss of normal knee mobility, and pain and discomfort, which seriously affects the quality of life. HUC-MSCs can promote cartilage production and have been widely used in research in the past decade. This article systematically summarizes that it is well used in basic research and clinical studies to promote inflammatory chondrogenesis in the treatment of OA. Provide a theoretical basis for clinical treatment. Patients and methods This study collected CNKI, Wanfang, PubMed, and articles related to the treatment of OA with HUC-MSCs since their publication, excluding non-basic and clinical studies such as reviews and meta-analysis. A total of 31 basic experimental studies and 12 clinical studies were included. Systematically analyze the effects of HUC-MSCs on inhibiting inflammatory factors, promoting chondrocyte production, and current clinical treatment. Results HUC-MSCs can reduce inflammatory factors such as MMP-13, ADAMTS-5, IL-1β, IL-1, IL-6, TNF-α, induced conversion from M1 to M2 in OA to protect cartilage damage and reduce OA inflammation. Synthesize ColII, SOX9, and aggrecan at the same time to promote cartilage synthesis. Conclusion HUC-MSCs not only have typical stem cell biological characteristics, but also have rich sources and convenient material extraction. Compared with stem cells from other sources, HUC-MSCs have stronger proliferation, differentiation, and immune regulation abilities. Furthermore, there are no ethical issues associated with their use. Safety: Primarily attributed to pain, the majority of individuals experience recovery within 24 h following injection. HUC-MSCs possess the ability to alleviate pain, enhance knee joint function, and potentially postpone the need for surgical intervention in both non-surgical and other cases, making them highly deserving of clinical promotion and application.

In this work, a novel functionalized graphene oxide nucleating agent (GITP) was successfully synthesized using a silane coupling agent (IPTES), and polymer block (ITP) to efficiently improve the crystallization and mechanical performance of PET. To comprehensively investigate the effect of functionalized GO on PET properties, PET/GITP nanocomposites were prepared by introducing GITP into the PET matrix using the melt blending method. The results indicate that PET/GITP exhibits better thermal stability and crystallization properties compared with pure PET, increasing the melting temperature from 244.1 °C to 257.1 °C as well as reducing its crystallization half-time from 595 s to 201 s. Moreover, the crystallization temperature of PET/GITP nanocomposites was increased from 185.1 °C to 207.5 °C and the tensile strength was increased from 50.69 MPa to 66.8 MPa. This study provides an effective strategy for functionalized GO as a nucleating agent with which to improve the crystalline and mechanical properties of PET polyester.

Ecological water replenishment (EWR) has been widely implemented for the restoration of the groundwater resources in the North China Plain since 2018, and the Hutuo River is one of the typical rivers. Recovering the groundwater storage capacity while ensuring the safety of the existing land use is essential for groundwater management. To simulate the groundwater response to different recharge schemes, and to determine the optimal recharge strategy that has the maximum amount of water recharged into the aquifers under specific constraints, an optimization framework, which integrates a 3D transient groundwater flow model with a genetic algorithm (GA), was realized in a Python programming environment in this study. The optimization results show that the optimal amount of water recharged into aquifers is 5.36 × 109 m3 from January 2020 to December 2029, and the upper river reaches are the main recharge area, accounting for 67.58% of the total. Compared with constant recharge, optimal results indicate that the total amount of water recharged into aquifers will increase without exceeding the upper limits of the groundwater levels. However, as groundwater exploitation reduces (18.44%), the river's optimal amount of water recharged also decreases (17.23%). Therefore, the developed model can identify the optimal groundwater recharge strategy and eventually facilitate decision-making in the case of EWR. HIGHLIGHTS Optimal groundwater replenishment strategy from the Hutuo River in the case of ecological water replenishment.; An optimization framework was developed relying on a groundwater flow model and GA.; Existing land use limits the restoration of the groundwater resources.; Nonlinear programming problem in groundwater management was solved by GA.;

In this paper, the commonly used pore structure models were summarized. The concept, construction method, and application of pore structure reconstruction model, pore network model, and equivalent pore network model were introduced. From pore structure reconstruction model to pore network model and then to equivalent pore network model, the description of pore structure develops from authenticity to equivalence, and the computational efficiency is significantly improved. A large number of studies have been carried out on seepage process on the basis of the pore structure model. Previous research shows that the pore structure model can reflect the influence of the pore structure of porous media on seepage process, and reveal the pore-scale mechanism of seepage and mass transfer process. The pore structure model has a good application prospect in many fields such as geo-environmental engineering and energy geotechnics. The future study about the pore structure model lies on the establishment of macro/micro-behavior relationship according to pore structure model simulation and more universal model based on the equivalence of statistical parameters.

Accurate investigation of adrenal hormone levels plays a vital role in pediatric endocrinology for the detection of steroid-related disorders. This study aims to develop a straightforward, sensitive UHPLC-MS/MS method to quantify 17 endogenous adrenal corticosteroid hormones in human plasma. These hormones are the main ingredients in the synthetic and metabolic pathways of adrenal corticosteroid hormones. Chromatographic separation was achieved on a C18 column before electrospray ionization triple-quadrupole mass spectrometry in multiple reaction monitoring mode with a run time of 7 min. The samples were extracted by liquid-liquid extraction and required no derivatization. Analytical performance was evaluated, including linearity, analytical sensitivity, accuracy, precision, and specificity. Plasma specimens from 32 congenital adrenal hyperplasia (CAH) patients and 30 healthy volunteers were analyzed to further reveal the diagnostic value of multiple steroid hormones in the synthetic and metabolic pathways of adrenal corticosteroid in CAH diagnosis. All hormones were effectively extracted and separated using our method. The method was essentially free from potential interference of isomers or structural analogues. The imprecisions were 0.998) were also obtained for most hormones in the required concentration range, except for 21-deoxycortisol (r2 = 0.9967) and androstenediol (r2 = 0.9952). The recoveries for the steroid hormones ranged from 91.7 to 109.8%. We developed the UHPLC-MS/MS method for the simultaneous measurement of steroid hormones. The results showed that measurement of steroid hormones simultaneously could improve the diagnostic efficiency of CAH.

Moult is a normal physiological phenomenon in poultry. Induced molting (IM) is the most widely used and economical molting technique. By inducing moult, the laying hens can grow new feathers during the next laying cycle and improve laying performance. However, the lack of energy supply has a huge impact on both the liver and intestines and acts on the intestines and liver through the “gut-liver axis”. More importantly, lipid metabolism in the liver is closely related to the laying performance of laying hens. Therefore, in this study, cecal metabolites and liver transcriptome data during IM of laying hens at the late stage of laying (stop feeding method) were analyzed together to reveal the regulatory mechanism of “gut-liver axis” affecting the laying performance of laying hens from the perspective of lipid metabolism. Transcriptome analysis revealed that 4,796 genes were obtained, among which 2,784 genes had significant differences (p < 0.05). Forty-nine genes were associated with lipid metabolism, and five core genes (AGPAT2, SGPL1, SPTLC1, PISD, and CYP51A1) were identified by WGCNA. Most of these differential genes are enriched in steroid biosynthesis, cholesterol metabolism, drug metabolism—cytochrome P450, synthesis and degradation of ketone bodies, PPAR signaling pathway, and bile secretion. A total of 96 differential metabolites were obtained by correlating them with metabolome data. Induced moult affects laying performance by regulating genes related to lipid metabolism, and the cecal metabolites associated with these genes are likely to regulate the expression of these genes through the “enterohepatic circulation”. This experiment enriched the theoretical basis of induced moult and provided the basis for prolonging the feeding cycle of laying hens.

Inspired by the neuroscience research results that the human brain can produce dynamic responses to different emotions, a new electroencephalogram (EEG)-based human emotion classification model was proposed, named R2G-ST-BiLSTM, which uses a hierarchical neural network model to learn more discriminative spatiotemporal EEG features from local to global brain regions. First, the bidirectional long- and short-term memory (BiLSTM) network is used to obtain the internal spatial relationship of EEG signals on different channels within and between regions of the brain. Considering the different effects of various cerebral regions on emotions, the regional attention mechanism is introduced in the R2G-ST-BiLSTM model to determine the weight of different brain regions, which could enhance or weaken the contribution of each brain area to emotion recognition. Then a hierarchical BiLSTM network is again used to learn the spatiotemporal EEG features from regional to global brain areas, which are then input into an emotion classifier. Especially, we introduce a domain discriminator to work together with the classifier to reduce the domain offset between the training and testing data. Finally, we make experiments on the EEG data of the DEAP and SEED datasets to test and compare the performance of the models. It is proven that our method achieves higher accuracy than those of the state-of-the-art methods. Our method provides a good way to develop affective brain–computer interface applications.

Grain yield in cereal crops is a complex trait controlled by multiple genes and influenced by developmental processes and environment. Here we report the effects of alleles Rht8 and Ppd-D1a on plant height, time to heading, and grain yield and its component traits. Association analysis and quantitative trait locus mapping using phenotypic data from 15 environments led to the following conclusions. First, both Rht8 and Ppd-D1a reduce plant height. However, Ppd-D1a but not Rht8 causes earlier heading. Second, both Rht8 and Ppd-D1a promote grain yield and affect component traits. Their combined effects are substantially larger than those conferred by either allele alone. Third, promotion of grain yield by Rht8 and Ppd-D1a is through increasing fertile spikelet number. We speculate that Rht8 and Ppd-D1a act independently and additively in control of plant height, grain yield and yield component. Combination of the two alleles is desirable for adjusting plant height and enhancing grain yield and abiotic stress tolerance. Keywords: Association analysis, QTL mapping, Grain number, Grain yield, Triticum aestivum

Salvia splendens is a perennial, ornamental herbaceous flower that is widely cultivated as a bedding plant in gardens. The development of novel S. splendens cultivars and investigating the relevant molecular mechanisms are of great significance. In this study, RNA-sequencing and real-time PCR methods were used to analyze the possible molecular mechanism of S. splendens mutant, SX919M. From the wild-type S. splendens 919CK, we firstly selected a natural mutant, SX919M, which displayed multiple branches, clustered spheroids, and radial symmetrical inflorescence with higher numbers of calyces, ovules, stamens, and perianth tubes. Further, the RNA-seq was used to identify the differentially expressed genes (DEGs) in the mutant which included a total of 3568 upregulated and 3290 downregulated unigenes. We further observed that the indole alkaloid biosynthesis pathway showed the highest DEG enrichment, which was supported by a significant increase in the IAA content in mutant SX919M. In addition, we validated three DEGs, namely, CL2200.Contig2_All encoding methyl IAA esterase, CL12462.Contig1_All and CL12462.Contig2_All, which encoded strictosidine synthase, upregulated in mutant SX919M. We selected a novel S. splendens germplasm SX919M with a high ornamental value and determined that the upregulation of IAA biogenesis may be associated with its development.

Human papillomaviruses are important pathogens responsible for approximately 5% of cancer as well as other important human diseases, but many aspects of the papillomavirus life cycle are poorly understood. To undergo genome replication, HPV DNA must traffic from the cell surface to the nucleus. Recent findings have revolutionized our understanding of HPV entry, showing that it requires numerous cellular proteins and proceeds via a series of intracellular membrane-bound vesicles that comprise the retrograde transport pathway. This paper reviews the evidence supporting this unique entry mechanism with a focus on the crucial step by which the incoming virus particle is transferred from the endosome into the retrograde pathway. This new understanding provides novel insights into basic cellular biology and suggests novel rational approaches to inhibit HPV infection.

The multikinase inhibitor sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Although the clinical application of sorafenib has shown good tolerability in the studied populations, it also causes multiple human dose-limiting toxicities. Thus, there is a strong need to reduce the overall dose of sorafenib. We have reported that the epidermal growth factor receptor variant III (EGFRvIII) expression can decrease the sensitivity of HCC cells to chemotherapeutic drugs. Therefore, we sought to explore whether EGFRvIII can affect the sensitivity of HCC cells to sorafenib. In this study, we observed that EGFRvIII expression significantly decreased the sensitivity of HCC cells to sorafenib. To enhance the antitumor effect and reduce the overall dose of sorafenib, we evaluated the combined effects of CH12, a monoclonal antibody against EGFRvIII, and sorafenib on the growth of HCC cells expressing EGFRvIII in vitro and in vivo. The results showed that, when CH12 was combined with sorafenib, the tumor growth suppression effect was significantly increased, and the concentration of sorafenib required for growth inhibition was substantially reduced. Mechanistically, the combination could more noticeably downregulate the phosphorylation of constitutively active extracellular signal-regulated kinase (ERK), Akt (Thr308), and signal transducer and activator of transcription 3 (STAT3) than sorafenib alone. Collectively, these findings demonstrate that CH12 interacts additively with sorafenib to strongly inhibit the tumor growth of HCC xenografts expressing EGFRvIII by enhancing the sorafenib-mediated inhibition of the MEK/ERK, phosphoinositide 3-kinase/AKT, and STAT3 pathways.

Cystine is an important biomolecule in living systems. Although collision-induced dissociation (CID)-based tandem mass spectrometry (MS/MS) is commonly applied for identification and quantification of cystine in both biomedical and nutritional studies, gas-phase fragmentation reactions of cystine in CID has remained unclear. This may lead to improper assay design, which may in turn result in inaccurate test results. In the present study, gas-phase fragmentation reactions of protonated cystine in CID were characterized using high-resolution MS/MS and pseudo MS3. Fragmentations started from cleavages of disulfide bond (S⁻S) and carbon⁻sulfur bond (C⁻S). When cleaving at the S⁻S, protonated cysteine was generated as one of the predominant fragmentation products. Minor fragmentations started from the loss of H2O + CO and the loss of NH3. Our results reveal that the m/z 74 fragment ion, which is commonly used as a product ion of the transition (precursor/product ion pair) in selected reaction monitoring (SRM) assay for quantifying cystine, comprises two isobaric fragments originating from different parts of cystine. This indicates the need for careful selection of a stable isotope-labeled cystine molecule as an internal standard for SRM assays. Here, we provide a clear picture of the fragmentation reactions of protonated cystine in CID. It can serve as a useful guidance for designing MS/MS-based assays for cystine testing.

We recently constructed a novel non-replicating dominant-negative HSV-2 recombinant viral vaccine (CJ2-gD2) capable of expressing various HSV-2 antigens that are dominant targets of HSV-2-specific CD8 T-cell response. Importantly, CJ2-gD2 expresses gD2, the HSV-2 major antigen glycoprotein D, as efficiently as wild-type HSV-2 infection and can lead to a nearly 500-fold reduction in wild-type HSV-2 viral replication in cells co-infected with CJ2-gD2 and wild-type HSV-2. In this report, we show that CJ2-gD2 elicits a strong antibody response to various HSV-2 antigens and is highly effective in the prevention of primary and recurrent HSV-2 genital infection and disease in the immunized guinea pigs. The direct comparison study between CJ2-gD2 and a gD2 subunit vaccine (gD2-alum/MPL) with a formulation akin to a vaccine tested in phase III clinical trials shows that CJ2-gD2 is 8 times more effective than the gD2-alum/MPL subunit vaccine in eliciting an anti-HSV-2 specific neutralizing antibody response and offers significantly superior protection against primary and recurrent HSV-2 genital infections. Importantly, no challenge wild-type HSV-2 viral DNA was detectable in dorsal root ganglia DNA isolated from CJ2-gD2-immunized guinea pigs on day 60 post-challenge. CJ2-gD2 should be an excellent HSV-2 vaccine candidate for protection against HSV-2 genital infection and disease in humans.

In the traditional picking and sorting process of fragrant pears, the quality control process is not perfect, and the identification and extraction methods are not mature enough. By combining the Internet of Things (IoT) and image detection technologies, the image data of pear planting area in the orchard was obtained, and the image of pear was preprocessed, denoised, and feature extracted by the visual background extraction algorithm. In order to verify the actual effect of the optimized identification and extraction method for fragrant pears using IoT and image detection technologies, a comparative experiment was conducted. The results show that compared with the traditional pear recognition and extraction method, the optimized pear recognition and extraction method has a better predictive effectiveness in the process of pear image processing, and the recall and accuracy rates are improved by approximately 8% and 12.7%, respectively. This verifies the reliability and efficiency of the identification extraction method for fragrant pear based on IoT and image detection technologies. In this paper, the traditional pear identification and extraction methods are improved by IoT technology and UAV (unmanned aerial vehicle), which improves the picking efficiency and sorting quality of pear picking robots. [ABSTRACT FROM AUTHOR]