OLB-AC: toward optimizing ligand bioactivities through deep graph learning and activity cliffs.

MOTIVATION: Deep graph learning (DGL) has been widely employed in the realm of ligand-based virtual screening. Within this field, a key hurdle is the existence of activity cliffs (ACs), where minor chemical alterations can lead to significant changes in bioactivity. In response, several DGL models have been developed to enhance ligand bioactivity prediction in the presence of ACs. Yet, there remains a largely unexplored opportunity within ACs for optimizing ligand bioactivity, making it an area ripe for further investigation. RESULTS: We present a novel approach to simultaneously predict and optimize ligand bioactivities through DGL and ACs (OLB-AC). OLB-AC possesses the capability to optimize ligand molecules located near ACs, providing a direct reference for optimizing ligand bioactivities with the matching of original ligands. To accomplish this, a novel attentive graph reconstruction neural network and ligand optimization scheme are proposed. Attentive graph reconstruction neural network reconstructs original ligands and optimizes them through adversarial representations derived from their bioactivity prediction process. Experimental results on nine drug targets reveal that out of the 667 molecules generated through OLB-AC optimization on datasets comprising 974 low-activity, noninhibitor, or highly toxic ligands, 49 are recognized as known highly active, inhibitor, or nontoxic ligands beyond the datasets' scope. The 27 out of 49 matched molecular pairs generated by OLB-AC reveal novel transformations not present in their training sets. The adversarial representations employed for ligand optimization originate from the gradients of bioactivity predictions. Therefore, we also assess OLB-AC's prediction accuracy across 33 different bioactivity datasets. Results show that OLB-AC achieves the best Pearson correlation coefficient (r2) on 27/33 datasets, with an average improvement of 7.2%-22.9% against the state-of-the-art bioactivity prediction methods. AVAILABILITY AND IMPLEMENTATION: The code and dataset developed in this work are available at github.com/Yueming-Yin/OLB-AC.

Design and experiment of impeller seed guide device for rice internal suction hole direct seeding device.

Multi-grain hole-forming sowing and uniform hole spacing are important agronomic requirements for precise hole-direct seeding of rice.This paper designs a kind of impeller type seed guiding device. The main structural parameters of the impeller seed guide device were analyzed by constructing the kinematics model of the rice seed in the impeller seed guide process. The experiment analysis were carried out with the long-grain rice variety Chuangliangyou 4418 as the seeding object. The optimal structural parameter combination of seeding-guiding device was determined as inner impeller radius 56 mm, blade offset angle 11° and seeding angle 36°. On this basis, the seeding performance test of different seed guiding devices of internal suction seed-metering device was carried out by using rice seeds with different external dimensions. The test results show that the impeller has better cavitation and hole spacing uniformity than the seed guide tube. The average hole diameter is not higher than 21.7 mm, the qualified rate of hole diameter is not lower than 96.1%, and the coefficient of variation of hole spacing is not higher than 10.1%. Compared with the seed guide tube, which is increased by 32%, 16% and 34% respectively, and the average hole distance is about 200 mm in theory.

Percutaneous endoscopic lumbar discectomy for single and double segment lumbar disc herniation with sciatic scoliosis in adults: a retrospective study.

OBJECTIVE: Sciatic scoliosis can be seen in patients with lumbar disc herniation. Percutaneous endoscopic lumbar discectomy (PELD) is a common surgical method for the treatment of lumbar disc herniation. The difference between single-segment lumbar disc herniation and double-segment lumbar disc herniation with Sciatic Scoliosis in adults after PELD needs further study. The aim of this study was to compare the imaging features of single-segment and double-segment lumbar disc herniation with Sciatic Scoliosis in adults and to further explore the clinical outcomes of functional improvement and scoliosis imaging parameters of the two groups after PELD. METHODS: Adult patients with lumbar disc herniation with sciatic scoliosis who received PELD from January 2019 to June 2022 were analyzed retrospectively. According to the number of operative segments, the patients were divided into a single-segment group and a double-segment group. Perioperative parameters were observed and compared between the two groups. The Visual Analogue Scale (VAS) score, Oswestry dysfunction index (ODI), Japanese Orthopaedic Association scores (JOA) and imaging parameters of the two groups were recorded and compared before the operation and during the follow-up. RESULTS: A total of 53 patients with single segments and 21 patients with double segments were included in this study. During the follow-up, the VAS score, ODI index and JOA score of the two groups were significantly improved as compared with those before the operation(P < 0. 05). Ninety-two point five percent of single-segment patients and 90.5% of double segment patients returned to normal scoliosis within 12 months after the operation. The operation time, number of intraoperative fluoroscopy times and the amount of intraoperative blood loss in single-segment patients were better than those in double-segment group(P < 0. 05). At the last follow-up, the AVT, CBD and SVA in the double-segment group were 5.2 ± 2.3, 5.1 ± 1.0 and 12.2 ± 3.0 mm, respectively, which were higher than those in the single-segment group (1.9 ± 0.4, 1.1 ± 1.6 and 3.9 ± 2.1 mm) (P < 0. 05). CONCLUSION: PELD is an effective treatment for single-segment and double-segment lumbar disc herniation with Sciatic scoliosis. Double-segment patients can enjoy similar clinical efficacy to single-segment patients, avoiding complications caused by decompression, fusion, and internal fixation. Scoliosis was corrected spontaneously within 12 months after operation, and the sagittal curve was significantly improved in both groups. The improvement of coronal and sagittal balance in double -segment patients may take longer.

Revealing a causal relationship between gut microbiota and lung cancer: a Mendelian randomization study.

Background: The gut microbiota has been found to be associated with the risk of lung cancer. However, its causal relationship with various types of lung cancer remains unclear. Methods: We conducted a Mendelian randomization (MR) study using the largest genome-wide association analysis of gut microbiota data to date from the MiBioGen consortium, with pooled statistics for various types of lung cancer from the Transdisciplinary Research in Cancer of the Lung, the International Lung Cancer Consortium, and FinnGen Consortium R7 release data. Inverse variance weighted, weighted model, MR-Egger regression, and weighted median were adapted to assess the causal relationship between gut microbiota and various types of lung cancer. Sensitivity analysis was used to test for the presence of pleiotropy and heterogeneity in instrumental variables. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. Multivariable Mendelian randomization (MVMR) was conducted to assess the direct causal impact of gut microbiota on the risk of various types of lung cancer. Results: Using IVW as the primary analytical method, we identified a total of 40 groups of gut microbiota with potential causal associations with various subtypes of lung cancer, of which 10 were associated with lung cancer, 10 with lung adenocarcinoma, 9 with squamous cell lung cancer, and 11 groups of bacteria associated with small cell lung cancer. After performing FDR correction, we further found that there was still a significant causal relationship between Peptococcaceae and lung adenocarcinoma. Sensitivity analyses demonstrated the robustness of these results, with no heterogeneity or pleiotropy found. Conclusions: Our results confirm a causal relationship between specific gut microbiota and lung cancer, providing new insights into the role of gut microbiota in mediating the development of lung cancer.

Boosting the inherent activity of NiFe layered double hydroxide via erbium incorporation for water oxidation.

Enhancing the inherent activity of transition metal-based compounds involving Ni and Fe for the electrocatalytic oxygen evolution reaction (OER) is of vital importance, especially NiFe layered double hydroxide (LDH). Here, we doped erbium (Er) into NiFe LDH (Er-NiFe LDH) nanostructures using simple liquid-phase synthesis. The OER activity tests at the same mass loading demonstrated that Er-NiFe LDH has a smaller overpotential and lower Tafel slope than undoped NiFe LDH and commercial RuO2 powders, needing only a small overpotential of 243 mV to achieve a constant current at 10 mA cm-2. Additionally, Er-NiFe LDH was grown in situ on hydrophilic carbon paper substrates (Er-NiFe LDH@CP) to fabricate a three-dimensional (3D) electrode with large catalyst loading, which is favorable for analyzing the stability of morphology structure and elementary components after OER measurement. The galvanostatic measurement suggested that the Er-NiFe LDH@CP electrode possess higher electrochemical durability than a modified glassy carbon electrode due to the stronger mechanical binding between Er-NiFe LDH nanostructures and carbon paper substrate. More importantly, physical characterizations (e.g., SEM and XPS) revealed that Er-NiFe LDH has an excellent stability of morphology, and Ni, Fe, and Er still exist on the catalyst 24 h after the operation. This work provides an effective way for improving the inherent catalytic activity and stability of polymetallic OER catalysts in the future.

Using nutrigenomics to guide personalized nutrition supplementation for bolstering immune system.

Immunity refers to the ability of the human immune system to resist pathogen infection. Immune system has the basic functions of immune defense, immune self stabilization and immune surveillance. Balanced nutrition is the cornerstone of the immune system to play its immune function, and nutritional intervention is also an important means to maintain and improve immunity. Previous studies have confirmed that T cells have individual differences in recognizing viral antigens of virus infected cells, and the body's response to antigens is controlled by a variety of genetic genes, such as human leukocyte antigen (HLA) genes, immune response (Ir) genes, etc. In this paper, through immunity genetic testing, we screen out genetically susceptible people with low immunity and people with the risk of nutrient metabolism disorders; through using lifestyle questionnaire and physical examination results, we analyze people's physical condition, dietary habits, and exercise habits to evaluate people's nutrient deficiency degree. Then, combining multi-dimensional health data, we evaluate users' immune status and nutritional deficiency risk comprehensively, further, we implemented personalized nutrition intervention on the types and doses of nutritional supplements to improve immunity. We also validated the effectiveness of our personalized nutrition solution through a population-based cohort study.

Single-Cell Sequencing Reveals that DBI is the Key Gene and Potential Therapeutic Target in Quiescent Bladder Cancer Stem Cells.

Background: Drug resistance and recurrence often develop during the treatment of muscle-invasive bladder cancer (MIBC). The existence of cancer stem cells (CSCs) in MIBC makes the formulation of effective treatment strategies extremely challenging. We aimed to use single-cell RNA sequencing approaches to identify CSCs and evaluate their molecular characteristics and to discover possible therapeutic measures. Methods: GEO data sets GSE130001 and GSE146137 were used to construct an expression matrix. After cells were identified by type, malignant epithelial cells inferred by InferCNV were extracted for stemness evaluation. The subset of cells with the highest stemness was subjected to weighted gene coexpression network analysis (WGCNA) and pseudotime analysis to identify key genes. In addition, we predicted drug sensitivity relationships for key genes in CTD and predicted the correlation between drugs and survival through siGDC. Results: We found that there were some CSCs in MIBC samples. The CSC population was heterogeneous during tumor development and was divided into quiescent and proliferating CSCs. We identified DBI as the key gene in quiescent CSCs. Analysis of a TCGA data set showed that higher DBI expression indicated higher histological grade. In addition, we predicted that acetaminophen can reduce DBI expression, thereby reducing the stemness of CSCs. Thus, we identified a potential new use of acetaminophen. Conclusion: We systematically explored CSCs in tumors and determined that DBI may be a key gene and potential therapeutic target in quiescent CSCs. In addition, we confirmed that acetaminophen may be a candidate drug targeting CSCs, improving our understanding of CSC-targeting therapeutic strategies.

Preliminary screening of fluorine-stained osteoblastic apoptosis-related microRNA.

Endemic fluorosis is a chronic systemic disease that seriously endangers human health. In high fluoride areas, people consume excessive fluoride for a long time through drinking water or food, which leads to chronic cumulative fluorosis in the body. Fluorosis can cause changes in the expression of some miRNA in cells, and the miRNA can participate in fluoride-induced osteoblast activation through various signal pathways. To observe the differential expression of apoptosis-related microRNA (miRNA) in mouse osteoblasts under the action of excessive fluoride. Primary cultured mouse osteoblasts, identified by osteocalcin (OC) and alkaline phosphatase (ALP) staining, were treated with 20 mg/L sodium fluoride and 40 mg/L sodium fluoride for 12/24 hr, respectively, to establish the fluoride staining model for comparing and analyzing the sequence of miRNA among groups by bioinformatics methods; four miRNA chains were verified by fluorescence quantitative PCR. After treatment with 20 mg/L sodium fluoride for 12 hr and 24 hr, 128 miRNA expressions were up-regulated while 36 miRNA expressions were down-regulated. In Group 40 mg/L, 130 miRNA expressions were up-regulated while 29 miRNA expressions were down-regulated after 12 hr and 24 hr; 72 miRNA were up-regulated and 2 miRNA were down-regulated at the two time points. 10 up-regulated miRNA and 2 down-regulated miRNA with higher scores in Bioinformatics software were analyzed the target genes. Fluorescence quantitative PCR verified that the expressions of four miRNA were up-regulated. Target gene analysis of the 10 selected mouse osteoblastic apoptosis-related miRNA reveals their involvement of the functions of inhibiting or promoting apoptosis, which has certain theoretical significance for early identification of skeletal fluorosis. The involved signaling pathways include the Wnt signaling pathway, ubiquitin-regulated proteolysis, Toll signaling pathway, TNF signaling pathway, pluripotent stem cell signaling pathway, MAPK signaling pathway, phosphatidylinositide metabolism, FoxO signaling pathway, ErbB signaling pathway, autophagy, and so forth.

Effect of ultrasound on the structural characteristics of fresh skim milk.

The structural changes of skim milk caused by sonication were evaluated by particle size, zeta-potential, turbidity, scanning electron microscopy, Fourier transform infrared spectroscopy, and intrinsic and 8-anilino-1-naphthalenesulfonic acid sodium salt fluorescence properties. The results showed that the particle size and zeta-potential of skim milk remained constant with 1 min ultrasonication, and increased significantly when the duration of sonication was extended to 3 min. With 3-10 min ultrasonic treatment, the diameter and net charge of particles in skim milk changed scarcely. According to the topography, the integrity of casein micelles was not damaged by 30 min sonication, but the turbidity decreased sharply with sonication above 5 min. The secondary structure of protein in skim milk changed after 1 min sonication, shown by a significant increase of α-helix content and decrease in the irregularity of ß-sheet. The intrinsic fluorescence intensity of skim milk with 1 min sonication increased dramatically with a shift in the maximum emission wavelength. The fluorescence properties revealed that the spatial structure of protein in skim milk changed by sonication.

Influence of succinylation on physicochemical property of yak casein micelles.

Succinylation is a chemical-modification method that affects the physicochemical characteristics and functional properties of proteins. This study assessed the influence of succinylation on the physicochemical properties of yak casein micelles. The results revealed that surface hydrophobicity indices decreased with succinylation. Additionally, denaturation temperature and denaturation enthalpy decreased with increasing succinylation level, except at 82%. The buffering properties of yak casein micelles were affected by succinylation. It was found that chemical modification contributed to a slight shift of the buffering peak towards a lower pH value and a markedly increase of the maximum buffering values of yak casein micelles at pH 4.5-6.0 and pH < 3. Succinylation increased yak casein micellar hydration and whiteness values. The findings obtained from this study will provide the basic information on the physicochemical properties of native and succinylated yak casein micelles.

Influence of succinylation on the conformation of yak casein micelles.

Succinylation modifies the physicochemical characteristics and improves the functional properties of proteins. This study assessed the effects of succinylation on the conformation of yak casein micelles with seven degree of modification. The results revealed that succinylation contributed to the dissociation of casein micelles. With the increase of succinylated degree, soluble nitrogen and minerals content increased, while casein micelle size and polydispersity index of micelles decreased. Succinylation affected the spatial conformation of yak casein micelles: turn decreased, ß-sheet and α-helix increased, and irregular structure were non-significantly affected. The intrinsic and ANS fluorescence intensity decreased and the maximum emission wavelength shifted red with increasing succinylation. Based on the results, the structure of yak casein micelles was characteristic of the sub-micelle model.

Effect of low-level laser irradiation on oxygen free radicals and ventricular remodeling in the infarcted rat heart.

OBJECTIVE: The purpose of this study was to assess the effects of low-level laser irradiation (LLLI) on the expression of oxygen free radicals (OFR) and ventricular remodeling (VR) in the model of rat myocardial infarction (RMMI). BACKGROUND DATA: LLLI reduces the infarct size and formation of scar tissue in the rat heart after myocardial infarction (MI). However, the exact mechanism has not been demonstrated so far. METHODS: RMMI was induced by ligating the left anterior descending coronary artery (LAD). After 3 weeks, LLLI (635 nm, 6 mW laser, 7.64 mW/cm(2), 125 sec, 0.96 J/cm(2)) was applied to the surface of heart directly. Four to six rats were euthanized at 1 h, 24 h, 48 h, 72 h, and 1 week after LLLI, and the infarcted myocardia were excised for the measurement of the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA). At the end of 4 weeks after MI, the hearts were harvested for histological analysis. RESULTS: Myocardial SOD activity with LLLI was lower compared with control (p<0.05), and myocardial MDA content with LLLI was higher compared with control (p<0.05), at all the time points. In all rats, the activity of SOD was down to the minimum and the content of MDA was up to the peak at 48 h after laser irradiation. The infarct size was reduced (35±10% vs. 18±9%, p<0.05), the left ventricular wall thickness was increased (0.31±0.03 vs. 0.84±0.02 mm, p<0.05) and the percentage of collagen fibers in the infarcted area was attenuated (64.34±2.20% vs. 30.97±2.60%) by LLLI. CONCLUSIONS: LLLI could cause OFR accumulation, reduce infarct size, increase ventricular wall thickness, and attenuate the formation of collagen fibers, suggesting the beneficial effects of LLLI on improvement of VR after MI.