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ABSTRACT Mechanised watercress harvesting involves clamping and cutting its stalks, which can result in their incomplete breaking and crushing. The harvest quality is directly affected by the force used to clamp and cut the watercress stalks. Therefore, studying the physical and mechanical properties of the stalks is important to accurately calculate the force that needs to be applied. Herein, the microstructure of watercress stalk sections with and without nodes was observed using scanning electron microscopy. Moreover, the basic physical properties, such as the total length, internode outer diameter, internode inner diameter and water content, of watercress stalks were measured. Additionally, the mechanical properties of watercress stalks at different positions were measured using four modes: tension, compression, shear and bending. Results revealed that watercress stalks with nodes exhibited a more pronounced medullary cavity and a greater number of internal vascular bundles. The lower section of the watercress stalks was considerably more resistant to mechanical stress than the rest of the stalk. Further, in terms of resisting load, the stalks with nodes were stronger than those without nodes. This study provides useful information for efficient watercress harvesting.

Abstract Background Long non-coding RNA (lncRNA) has been implicated in the pathogenesis of pulmonary tuberculosis (PTB). This study aims to investigate the involvement of lncRNA THRIL and HOTAIR gene single nucleotide polymorphisms (SNPs) and their expression levels in PTB susceptibility. Methods A total of 456 PTB patients and 464 healthy controls participated in our study. we genotyped six SNPs of THRIL and HOTAIR genes using an improved multiple ligase detection reaction (iMLDR). Additionally, real-time reverse-transcriptase polymerase chain reaction was employed to detect the expression levels of THRIL and HOTAIR in peripheral blood mononuclear cells (PBMC) from 78 PTB patients and 84 healthy controls. Results No significant differences in allele and genotype frequencies were observed for THRIL rs1055472, rs11058000, and HOTAIR rs12427129, rs1899663, rs4759314, and rs7958904 polymorphisms between PTB patients and healthy controls (all P > 0.05). Moreover, genotype frequencies of all SNPs did not show any association with PTB susceptibility in the dominant–recessive model. However, the frequencies of rs7958904 CC genotype and C allele in the HOTAIR gene were significantly correlated with leukopenia in PTB patients. Furthermore, the expression levels of the HOTAIR gene were significantly elevated in PTB patients compared to controls. Conclusions Our study indicates that THRIL and HOTAIR gene SNPs might not contribute to PTB susceptibility, while the level of HOTAIR was increased in PTB patients.

Protecting crops from pests is a major issue in the current agricultural production system. The agricultural digital twin system, as an emerging product of modern agricultural development, can effectively achieve intelligent control of pest management systems. In response to the current problems of heavy use of pesticides in pest management and over-reliance on managers’ personal experience with pepper plants, this paper proposes a digital twin system that monitors changes in aphid populations, enabling timely and effective pest control interventions. The digital twin system is developed for pest management driven by data and model fusion. First, a digital twin framework is presented to manage insect pests in the whole process of crop growth. Then, a digital twin model is established to predict the number of pests based on the random forest algorithm optimized by the genetic algorithm; a pest control intervention based on a twin data search strategy is designed and the decision optimization of pest management is conducted. Finally, a case study is carried out to verify the feasibility of the system for the growth state of pepper and pepper pests. The experimental results show that the virtual and real interactive feedback of the pepper aphid management system is achieved. It can obtain prediction accuracy of 88.01% with the training set and prediction accuracy of 85.73% with the test set. The application of the prediction model to the decision-making objective function can improve economic efficiency by more than 20%. In addition, the proposed approach is superior to the manual regulatory method in pest management. This system prioritizes detecting population trends over precise species identification, providing a practical tool for integrated pest management (IPM).

Background: Postoperative analgesia is an essential component of enhanced recovery after surgery following abdominal surgery. Studies comparing the effectiveness of epidural analgesia with that of other analgesic modalities after liver surgery have reported inconsistent results. Consequently, the use of epidural analgesia for open hepatectomy is controversial. Objective: The present single-center retrospective study aimed to compare the efficacy and safety of patient-controlled epidural analgesia (PCEA) and patient-controlled intravenous analgesia (PCIA) in adults undergoing open hepatectomy. Methods: Patients who underwent open hepatectomy between January 2018 to December 2019 at Zhongshan Hospital, Fudan University were retrospectively analyzed. Propensity score matching was used to adjust baseline information between the PCEA and PCIA groups. The primary outcome measure was scores of the numeric rating scales (NRSs) for resting, exercise, and nocturnal pain at postoperative 24 h (postoperative day 1 [POD1]) and 48 h (POD2). The secondary outcome indicators included postoperative nausea and vomiting (PONV), hypotension, pruritus, respiratory depression, functional activity score (FAS), effective analgesic pump compression ratio, analgesic relief rate, discontinuation of the analgesic pump, reasons for discontinuation of the analgesic pump, and patient satisfaction with postoperative analgesia. Results: The NRS scores of the PCEA group on POD1 were significantly lower than those of the PCIA group (P

Abstract Background Weight management has been an important component of the service in obstetric care offered to pregnant women. Current gestational weight gain recommendations were primarily for the general obstetric population, raising concern about the applicability to women with gestational diabetes mellitus (GDM). We aimed to assess the difference in weight progression and adherence to the recommended gestational weight gain targets between women with gestational diabetes mellitus (GDM) and women with normal glucose tolerance (NGT). Methods This was a hospital-based retrospective study of 56,616 pregnant women (9,430 GDM women and 47,186 NGT women) from Guangzhou between 2017 and 2021. The average change in weight progression was estimated based on serial weight measurements throughout pregnancy, using a mixed effects model with a random intercept to account for repeated measures of the same individual. Results Women with GDM gained less weight (12.07 [SD 5.20] kg) than women with NGT (14.04 [SD 5.04] kg) throughout pregnancy. Before OGTT, a small difference was observed in the average change in weight progression between the two groups (GDM, 0.44 kg/week vs. NGT, 0.45 kg/week, p

Currently, photocatalysis of the two-dimensional (2D) conjugated phthalocyanine framework with a single Fe atom (CPF-Fe) has shown efficient photocatalytic activities for the removal of harmful effluents and antibacterial activity. Their photocatalytic mechanisms are dependent on the redox reaction—which is led by the active species generated from the photocatalytic process. Nevertheless, the molecular mechanism of CPF-Fe antimicrobial activity has not been sufficiently explored. In this study, we successfully synthesized CPF-Fe with great broad-spectrum antibacterial properties under visible light and used it as an antibacterial agent. The molecular mechanism of CPF-Fe against Escherichia coli and Salmonella enteritidis was explored through multi-omics analyses (transcriptomics and metabolomics correlation analyses). The results showed that CPF-Fe not only led to the oxidative stress of bacteria by generating large amounts of h+ and ROS but also caused failure in the synthesis of bacterial cell wall components as well as an osmotic pressure imbalance by disrupting glycolysis, oxidative phosphorylation, and TCA cycle pathways. More surprisingly, CPF-Fe could disrupt the metabolism of amino acids and nucleic acids, as well as inhibit their energy metabolism, resulting in the death of bacterial cells. The research further revealed the antibacterial mechanism of CPF-Fe from a molecular perspective, providing a theoretical basis for the application of CPF-Fe photocatalytic antibacterial nanomaterials.

To fulfill the requirement for deformation measurement within the failure area during rock failure, a newly developed digital image algorithm, known as the corner correlation method, was implemented. A corner correlation measurement system was established by utilizing a Split Hopkinson Pressure Bar (SHPB) and a high-speed camera. The study focused on monitoring the deformation and failure characteristics of sandstone samples under dynamic loading. The results show that the corner correlation method has its unique advantages in rock dynamic mechanics experiments, and can obtain the deformation of the failure region during the rock failure process. Specifically, the initiation, extension, and contraction processes of surface cracks on sandstone were examined. Parameters such as crack width, width propagation rate, and extension shrinkage rate were measured. The entire crack development process was analyzed, including crack width, crack initiation point, crack extension and contraction trajectory, elongation and contraction velocity, width expansion rate, and longitudinal crack penetration, which were obtained at any given time on the surface of the rock sample. Additionally, the attenuation law of stress, characterized by an exponential decay of the stress peak value, was obtained through numerical simulation using a similar model.

Cerebral infarction (CI) has become one of the leading causes of death and acquired disability worldwide. Astragaloside IV (AST IV), one of the basic components of Astragalus membranaceus, has a protective effect on CI. However, the underlying mechanism has not been conclusively elucidated. Therefore, this study aims to explore the underlying mechanism of AST IV improving brain injury after CI. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral infarction injury in SD rats and HUVECs cells. Neurologic score, Evans blue, TTC and HE staining were used to observe brain injury in rats. Cell viability and migration were measured in vitro. Angiogenesis was detected by immunofluorescence and tube formation assay, and cell cycle was detected by flow cytometry. Western blot was used to find the expression of related proteins. Molecular docking, virtual mutation, site-directed mutagenesis, MST, and lentivirus silencing were used for target validation. The results showed that AST IV alleviated neurological impairment and promoted angiogenesis after CI. Moreover, AST IV greatly increased the transcription levels of SIRT6 and SIRT7, but had no effect on SIRT1-SIRT5, and promoted cell viability, migration, angiogenesis and S phase ratio in OGD/R-induced HUVECs. Furthermore, AST IV up-regulated the protein expressions of CDK4, cyclin D1, VEGFA and VEGF2R. Interestingly, AST IV not only bound to SIRT7, but also increased the expression of SIRT7. Silencing SIRT7 by lentivirus neutralizes the positive effects of AST IV. Taken together, the present study revealed that AST IV may improve brain tissue damage after CI by targeting SIRT7/VEGFA signaling pathway to promote angiogenesis.

At present, ginkgo leave are still picked manually. A brush roller ginkgo leaf picker has been designed to improve harvesting efficiency and reduce losses caused by manual failure to pick leaves in time under large-scale planting areas. The ginkgo leaf picker is mainly composed of crawler chassis, gantry frame, brush roller picking parts, and collecting box. The kinematics of the brush roller is analyzed for the picking omission situation. An experimental platform for picking ginkgo biloba leaves was established. Three parameters, namely roller speed, moving speed, and roller inclination, were selected for optimization. Then the maximum net harvest rate and the minimum damage rate were achieved. The orthogonal test showed that when the roller speed was 130 rev/min, the moving speed was 0.25 m/s, and the roller inclination was 32°, the picking effect was the best, the net harvest rate was 93.32%, the damage rate was 1.42%, and the damage degree of the trunks was slight. The experiment proved that the brush-roller ginkgo leaf picker has a good picking effect, which can provide a reference for the optimization design of ginkgo leaf harvesting machinery under the dwarf dense planting mode.

IntroductionAccurate and timely detection of plant stress is essential for yield protection, allowing better-targeted intervention strategies. Recent advances in remote sensing and deep learning have shown great potential for rapid non-invasive detection of plant stress in a fully automated and reproducible manner. However, the existing models always face several challenges: 1) computational inefficiency and the misclassifications between the different stresses with similar symptoms; and 2) the poor interpretability of the host-stress interaction.MethodsIn this work, we propose a novel fast Fourier Convolutional Neural Network (FFDNN) for accurate and explainable detection of two plant stresses with similar symptoms (i.e. Wheat Yellow Rust And Nitrogen Deficiency). Specifically, unlike the existing CNN models, the main components of the proposed model include: 1) a fast Fourier convolutional block, a newly fast Fourier transformation kernel as the basic perception unit, to substitute the traditional convolutional kernel to capture both local and global responses to plant stress in various time-scale and improve computing efficiency with reduced learning parameters in Fourier domain; 2) Capsule Feature Encoder to encapsulate the extracted features into a series of vector features to represent part-to-whole relationship with the hierarchical structure of the host-stress interactions of the specific stress. In addition, in order to alleviate over-fitting, a photochemical vegetation indices-based filter is placed as pre-processing operator to remove the non-photochemical noises from the input Sentinel-2 time series.Results and discussionThe proposed model has been evaluated with ground truth data under both controlled and natural conditions. The results demonstrate that the high-level vector features interpret the influence of the host-stress interaction/response and the proposed model achieves competitive advantages in the detection and discrimination of yellow rust and nitrogen deficiency on Sentinel-2 time series in terms of classification accuracy, robustness, and generalization.

The 2019 Refinement to the 2006 IPCC Guidelines for National Greenhouse Gas Inventories added the method of assimilating atmospheric CO2 concentrations to invert carbon sources and sinks; however, many global carbon inversion models are not publicly available. In addition, our regional assimilation inversion system, CCMVS-R (China Carbon Monitoring, Verification and Supporting for Regional), needs a global carbon inversion model with higher assimilation efficiency to provide boundary conditions. Here, an inversion model based on the global atmospheric chemistry model GEOS-Chem and a more accurate and easier-to-implement ensemble square root Kalman filter (EnSRF) algorithm is constructed and used to infer global and China's carbon fluxes in 2019. Atmospheric CO2 concentrations from ObsPack sites and five additional CO2 observational sites from China's Greenhouse Gas Observation Network (CGHGNET) were used for data assimilation to improve the estimate. The inverted annual global terrestrial and oceanic carbon uptake is 2.12 and 2.53 Pg C per year, respectively, accounting for 21.1% and 25.1% of global fossil fuel CO2 emissions. The remaining 5.41 Pg C per year in the atmosphere is consistent with the global atmospheric CO2 growth rates of 5.44 Pg C per year reported by the National Oceanic and Atmospheric Administration (NOAA), showing that the inversion model can provide a reasonable estimate of global-scale natural carbon sinks. The inverted terrestrial carbon sink of China is 0.37 Pg C per year, accounting for approximately 13% of China's fossil CO2 emissions.

AIM: To evaluate trends in glaucoma procedures at the Peking University Eye Center in 2016–2020. METHODS: A retrospective search of all glaucoma procedures performed at our institution were performed. Data were analyzed by calculating the absolute numbers and relative weightage of each procedure per year. RESULTS: The average age of glaucoma patients undergoing surgical procedures was 62.33±17.87y, and 55% were women. From 2016 to 2019, the number of surgical procedures performed in glaucoma patients showed an overall upward trend from 749 to 1460, although it decreased slightly in 2020 (n=1393), probably due to the COVID-19 pandemic. The number of trabeculectomies did not change significantly in 2016 (n=161) to 2018 (n=164) but decreased in 2019 (n=139) to 2020 (n=121), indicating a reduction in its relative weightage among glaucoma procedures (from 21.50% to 8.69%). The number of glaucoma drainage device implantations and minimally invasive glaucoma surgeries both increased (50 and 58 respectively in 2019), except in 2020. The number of transscleral cyclophotocoagulation procedures was relatively stable, increasing until 2017 (n=218) and then decreasing. Cataract surgeries with or without glaucoma procedures accounted for a large number of the total surgeries, increasing from 247 (32.97%) in 2016 to 967 (69.42%), among which cataract extraction combined with goniosynechialysis was the most frequent. CONCLUSION: The overall increase in the number of operating room-based surgical procedures is significant. Trabeculectomy is one of the most commonly performed procedures, despite the relative decline in its weightage. Other procedures, including use of glaucoma drainage devices and mini shunts and minimally invasive glaucoma surgeries, are gaining greater acceptance. Notably, lens-related surgery plays an important role in glaucoma management.

Pepper leaf disease identification based on convolutional neural networks (CNNs) is one of the interesting research areas. However, most existing CNN-based pepper leaf disease detection models are suboptimal in terms of accuracy and computing performance. In particular, it is challenging to apply CNNs on embedded portable devices due to a large amount of computation and memory consumption for leaf disease recognition in large fields. Therefore, this paper introduces an enhanced lightweight model based on GoogLeNet architecture. The initial step involves compressing the Inception structure to reduce model parameters, leading to a remarkable enhancement in recognition speed. Furthermore, the network incorporates the spatial pyramid pooling structure to seamlessly integrate local and global features. Subsequently, the proposed improved model has been trained on the real dataset of 9183 images, containing 6 types of pepper diseases. The cross-validation results show that the model accuracy is 97.87%, which is 6% higher than that of GoogLeNet based on Inception-V1 and Inception-V3. The memory requirement of the model is only 10.3 MB, which is reduced by 52.31%-86.69%, comparing to GoogLeNet. We have also compared the model with the existing CNN-based models including AlexNet, ResNet-50 and MobileNet-V2. The result shows that the average inference time of the proposed model decreases by 61.49%, 41.78% and 23.81%, respectively. The results show that the proposed enhanced model can significantly improve performance in terms of accuracy and computing efficiency, which has potential to improve productivity in the pepper farming industry.

Abstract This study aimed to determine whether regular recruitment maneuvers (RMs) are essential for obese patients (OPs) undergoing elective laparoscopic bariatric surgery (LBS) during intraoperative ventilation with individualized positive end‐expiratory pressure (PEEP). Patients were randomly assigned to two arms: the RM + PEEP−EIT arm consisted of individualized PEEP titrated by electrical impedance tomography (EIT) with two regular RMs and the PEEP−EIT arm consisted of individualized PEEP titrated by EIT without additional RMs. For these two arms together, EIT‐guided PEEP varied among individuals. The partial pressure of oxygen in arterial blood to fractional inspired oxygen (PaO2/FiO2) ratio in the RM + PEEP−EIT arm was higher than that in the PEEP−EIT arm at 1 h after pneumoperitoneum (p = 0.024) and at the end of surgery (p = 0.035). There was no great difference in the PaO2/FiO2 ratio between these two arms when measured 5 min prior to postanesthesia care unit (PACU) departure and on postoperative day 1. Compared with the PEEP−EIT arm, patients in the RM + PEEP−EIT arm had significantly higher intraoperative dynamic respiratory system compliance (p

AIM: To investigate the visual fatigue of patients with accommodative asthenopia and the difference in scores before and after treatment by using the asthenopia survey scale(ASS), and to evaluate its reliability, validity and responsiveness in this population.METHODS: A total of 112 patients with accommodative asthenopia were admitted to the department of ophthalmology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine and recruited online were investigated using the ASS questionnaire, and 48 subjects were randomly selected and retested 1wk later. A variety of reliability, validity and responsiveness indicators were used to evaluate the scale.RESULTS: The overall Cronbach's α coefficients of the scale entries was 0.91; The split-half reliability coefficients was 0.86; Repeated measurement correlation coefficient of the scale total score was 0.74, there was no significant difference before and after(P>0.05); The results of confirmatory factor analysis showed that the absolute fit index of the three-factor structural model was χ2/df

Due to changes in light intensity, varying degrees of aphid aggregation, and small scales in the climate chamber environment, accurately identifying and counting aphids remains a challenge. In this paper, an improved YOLOv5 aphid detection model based on CNN is proposed to address aphid recognition and counting. First, to reduce the overfitting problem of insufficient data, the proposed YOLOv5 model uses an image enhancement method combining Mosaic and GridMask to expand the aphid dataset. Second, a convolutional block attention mechanism (CBAM) is proposed in the backbone layer to improve the recognition accuracy of aphid small targets. Subsequently, the feature fusion method of bi-directional feature pyramid network (BiFPN) is employed to enhance the YOLOv5 neck, further improving the recognition accuracy and speed of aphids; in addition, a Transformer structure is introduced in front of the detection head to investigate the impact of aphid aggregation and light intensity on recognition accuracy. Experiments have shown that, through the fusion of the proposed methods, the model recognition accuracy and recall rate can reach 99.1%, the value mAP@0.5 can reach 99.3%, and the inference time can reach 9.4 ms, which is significantly better than other YOLO series networks. Moreover, it has strong robustness in actual recognition tasks and can provide a reference for pest prevention and control in climate chambers.

Abstract Poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA‐deficient tumors. However, over 40% of BRCA‐deficient patients fail to respond to PARPi. Here, we report that thioparib, a next‐generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi‐sensitive and ‐resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1‐dependent DNA damage and replication stress, causing S‐phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR‐mediated DNA repair while increasing RAD51 foci formation. Notably, the on‐target inhibition of PARP7 by thioparib‐activated STING/TBK1‐dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome‐scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next‐generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier‐generation PARPi.

ObjectiveThe m6A methylation was involved in the pathogenesis of pulmonary tuberculosis (PTB), and our study aimed to reveal the potential association of m6A demethylase (ALKBH5, FTO) genes variation, expression levels and PTB.MethodsEight SNPs (ALKBH5 gene rs8400, rs9913266, rs12936694, rs4925144 and FTO gene rs6499640, rs8047395, rs1121980, rs9939609) were selected for genotyping by SNPscan technique in 449 PTB patients and 463 healthy controls.ResultsThe mRNA expression levels of ALKBH5, FTO were detected by qRT-PCR. There were no significant differences in genotype, allele distributions of all SNPs between PTB patients and healthy controls. Haplotype analysis demonstrated that the frequency of FTO gene GAAA haplotype was significantly reduced in PTB patients when compared to controls. ALKBH5 rs8400 AA genotype, A allele frequencies were associated with the decreased risk of sputum smear-positive, while AA genotype frequency was related to the increased risk of hypoproteinemia in PTB patients. In addition, rs9913266 variant was linked to the occurrence of drug-induced liver injury, sputum smear-positive, and rs4925144 variant was associated with leukopenia among PTB patients. In FTO gene, rs8047395 GG genotype and G allele frequencies were significantly higher in the PTB patients with drug resistance than that in the PTB patients without drug resistance. The ALKBH5, FTO expression levels were significantly decreased in PTB patients in comparison to controls. Moreover, ALKBH5 level was increased in PTB patients with drug resistance, and FTO level was decreased in PTB patients with sputum smear-positive.ConclusionFTO gene polymorphisms might be associated with PTB susceptibility, and ALKBH5, FTO levels were decreased in PTB patients, suggesting that these m6A demethylase played important roles in PTB.

ObjectiveThe aim of the current study was to investigate the contributing role of gene variation and transcription levels among the m6A methyltransferases METTL3, METTL14, and WTAP in pulmonary tuberculosis (PTB).MethodsA case-control study including 461 PTB patients and 467 normal controls was designed for genotyping. Three SNPs in METTL3 (rs1061027, rs1139130, rs1061026), three SNPs in METTL14 (rs62328061, rs4834698, rs1064034), and two SNPs in WTAP (rs1853259, rs11752345) were genotyped via the SNPscan™ technique. METTL3, METTL14, and WTAP transcription levels were determined in 78 PTB patients and 86 controls via quantitative real-time reverse-transcription PCR.ResultsFrequencies of the METTL14 rs62328061 GG genotype, WTAP rs11752345 CT genotype, and T allele were significantly increased in PTB patients compared to controls. An increased risk of rs62328061 was detected in a recessive model, and a decreased risk of rs11752345 was detected in a dominant model in the PTB group. METTL3 gene variation was not associated with PTB risk. The METTL3 rs1139130 GG genotype was significantly increased with drug resistance, and the G allele was significantly decreased with drug-induced liver injury in PTB patients. A reduced frequency of the METTL14 rs62328061 G allele was associated with leukopenia, a reduced frequency of the WTAP rs11752345 T allele was associated with sputum smear positivity, and a higher frequency of the METTL14 rs4834698 TC genotype was evident in PTB patients with hypoproteinemia. Compared to controls, METTL3, METTL14, and WTAP transcription levels in PTB patients were significantly decreased, and the level of WTAP was increased in PTB patients with drug resistance. METTL3 level was negatively associated with erythrocyte sedimentation rate and aspartate aminotransferase, and METTL14 level was negatively correlated with alanine aminotransferase and aspartate aminotransferase.ConclusionMETTL14 rs62328061 and WTAP rs11752345 variants were associated with the genetic background of PTB, and METTL3, METTL14, and WTAP levels were abnormally decreased, suggesting that these m6A methyltransferases may play important roles in PTB.

Th17 cells play a key role in immunity against Mycobacterium tuberculosis (MTB), and this study aimed to explore the association of Th17 pathway gene polymorphisms with pulmonary tuberculosis (PTB) susceptibility in a Chinese population. A total of 10 single nucleotide polymorphisms in Th17 pathway genes (IL-17A gene rs2275913, rs3748067, rs8193036, rs3819024, IL-17F gene rs7741835, rs763780, IL-21 gene rs907715, rs2055979, IL-23R gene rs11805303, and rs7518660) were genotyped in 456 PTB patients and 466 controls using SNPscan technique. The IL-23R rs11805303 CC genotype, C allele frequencies were significantly lower in PTB patients than in controls, and the rs11805303 variant was significantly associated with the reduced risk of PTB in a recessive model. There were no significant associations between IL-17A, IL-17F, and IL-21 gene variations and PTB risk. In IL-17A gene, rs2275913, rs3748067, and rs3819024 variants were associated with drug resistance in PTB patients. In IL-17F gene, rs7741835 variant affected drug resistance, and rs763780 variant was associated with hypoproteinemia in PTB patients. In addition, the lower frequencies of the TT genotype, T allele of rs2055979 were found in PTB patients with drug-induced liver injury. Haplotype analysis showed that IL-23R CG haplotype frequency was significantly lower in PTB patients than in controls, while the TG haplotype frequency was higher. In conclusion, IL-23R rs11805303 polymorphism may contribute to the genetic underpinnings of PTB in the Chinese population, and the IL-17A, IL-17F, and IL-21 genetic variations are associated with several clinical manifestations of PTB patients.

Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC50 value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC50 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUClast). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties.

The aim of this study was to assess the association of vitamin B12 level and single nucleotide polymorphisms (SNPs) in vitamin B12 metabolic genes with pulmonary tuberculosis (PTB) in Chinese Han population. The plasma vitamin B12 expression level was detected using ELISA. Ten SNPs in six key genes (TCN1, TCN2, CUBN, MMACHC, FUT6, and MUT) of vitamin B12 metabolic pathway were included for genotyping by the SNPscan technique among 454 PTB patients and 467 controls. Our results found that vitamin B12 level was significantly reduced in PTB patients when compared with controls. There was no significant association between TCN1 rs526934, TCN2 rs1801198, CUBN rs7906242, rs10904861, rs1801222, MMACHC rs10789465, FUT6 rs3760776, rs3760775, MUT rs9473555, rs9381784 variants, and PTB susceptibility. TCN2 rs1801198 CC genotype, C allele was significantly associated with hypoproteinemia in PTB patients. In CUBN, rs7906242 GG genotype, G allele, rs10904861 TT genotype, and T allele were significantly related to the decreased frequency of sputum smear-positive, and rs10904861 variant affected the occurrence of drug resistance in PTB patients. In addition, the increased frequency of CUBN rs1801222 AA genotype was significantly associated with leukopenia. The decreased frequency of MUT rs9473555 CC genotype was found in the PTB patients with hypoproteinemia. However, vitamin B12 expression was not associated with the genotype distribution of above SNPs. In conclusion, vitamin B12 level was significantly decreased in PTB patients and genetic variants in vitamin B12 metabolic genes were not contributed to PTB susceptibility. Several SNPs in TCN2, CUBN, and MUT gene might associate with multiple clinical manifestations in PTB.

N6-Methyladenosine (m6A) is associated with many biological processes and the development of multiple diseases. The aim of this study was to analyze the association of m6A readers' genes variation, as well as their expression levels, with pulmonary tuberculosis (PTB). A total of 11 single-nucleotide polymorphisms (SNPs) in m6A readers' genes (i.e., YTHDF1 rs6122103, rs6011668, YTHDF2 rs602345, rs3738067, YTHDF3 rs7464, rs12549833, YTHDC1 rs3813832, rs17592288, rs2293596, and YTHDC2 rs6594732, and rs2416282) were genotyped by SNPscan™ technique in 457 patients with PTB and 466 normal controls. The m6A readers' genes expression levels in peripheral blood mononuclear cells (PBMCs) from 78 patients with PTB and 86 normal controls were detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). There was no significant association between all SNPs in YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 genes and PTB susceptibility. The increased frequencies of YTHDF2 rs3738067 GG genotype and YTHDC1 rs3813832 CC genotype, C allele, were, respectively, found in PTB patients with hypoproteinemia and fever. YTHDC2 rs6594732 variant was significantly associated with drug-induced liver damage and sputum smear-positive, and the rs2416282 variant was significantly associated with fever in patients with PTB. Compared with controls, the YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 mRNA levels were significantly decreased in PTB. Moreover, YTHDF1 level was negatively associated with erythrocyte sedimentation rate (ESR), and YTHDF3 and YTHDC1 levels were negatively related to alanine aminotransferase (ALT) in patients with PTB. Our results demonstrated that YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 genes SNPs did not contribute to PTB susceptibility, while their decreased levels in patients with PTB suggested that these m6A readers might play significant roles in PTB.