QSAR aided design of potent c-Met inhibitors using molecular docking, molecular dynamics simulation and binding free energy calculation.

Mesenchymal-epithelial transition factor (c-Met) is a tyrosine kinase receptor. Under certain disease conditions, the cellular transformation process may be over-activated, resulting in carcinogenesis. Therefore, molecularly targeted therapy targeting the receptor tyrosine kinase c-Met is achieved by inhibiting c-Met activity and thus effectively suppressing cancer propagation. In this paper, 41 compounds were selected from the reported literature as a dataset to build stable Topomer CoMFA and HQSAR models. The feasibility of the constructed models was evaluated by internal and external validation techniques. Based on the Topomer CoMFA model basis the fragments with higher contribution values were screened and the combination yielded 19 compounds with higher than template molecules. Through molecular docking, the ligand complexes formed hydrogen and hydrophobic bonds with strong stable structures. The ligand-protein complexes with better scoring results were selected for MD simulations, and Y14 exhibited a stable and favourable binding pocket. In addition, ADMET results showed that the ligand-complexes have potential medicinal effects on c-Met inhibition. This study provides a reference for molecularly targeted therapy targeting receptor tyrosine-kinetic c-Met.

Coupling eco-environmental quality and ecosystem services to delineate priority ecological reserves-A case study in the Yellow River Basin.

Priority ecological reserves (PER) aim to protect areas with significant ecological value and crucial ecological functions, optimizing resource allocation to maximize the benefits of ecological conservation. However, most previous studies have considered only ecosystem services (ESs) in delineating PER, neglecting eco-environmental quality (EEQ). This study used the Remote Sensing-based Ecological Index (RSEI) to represent EEQ and combined it with ESs to delineate PER at the county scale in the Yellow River Basin (YRB). Additionally, it employed Multiscale Geographically Weighted Regression to identify the driving factors influencing the ESs and EEQ of PER. The results showed that: (1) From 2000 to 2020, both RSEI and the Comprehensive ESs (CES) in the YRB exhibited a fluctuating upward trend; (2) Three types of PER were extracted, with ESs reserve mainly distributed in the upstream region, EEQ reserve primarily in the middle and lower reaches, and integrated ecological reserve mainly in the midstream region, all dominated by vegetation land-use types; (3) Within the extracted PER, RSEI was mainly influenced by soil, aspect, population (pop), PM2.5, temperature (tmp), and potential evapotranspiration (pet), while CES was affected by soil, pop, PM2.5, slope, tmp, precipitation, and pet. To enhance the EEQ and ESs of the YRB, it was recommended to incorporate at least 105,379 km2 into the existing protected areas in the YRB. These areas should be subdivided based on their ecological status, with specific management measures for different types of PER. This study provides recommendations for environmental protection and land planning in the YRB, actively responding to current policies on high-quality development and ecological environmental protection in the YRB.

Dynamic monitoring of aboveground biomass in inner Mongolia grasslands over the past 23 Years using GEE and analysis of its driving forces.

Aboveground biomass (AGB) in grasslands directly reflects the net primary productivity, making it a sensitive indicator of grassland resource quality and ecological degradation. Accurately estimating AGB over large regions to reveal long-term AGB evolution trends remains a formidable challenge. In this study, we divided Inner Mongolia Autonomous Region (IMAR) grasslands into three study regions based on their spatial distribution of grassland types. We combined remote sensing data with ground-based sample data collected over the past 19 years from 6114 field plots using the Google Earth Engine platform. We constructed random forest (RF) and traditional regression AGB inversion models for each region and selected the best-performing model through accuracy assessment to estimate IMAR grassland AGB for the period 2000-2022. We also examined the trends in AGB changes and identified the driving forces affecting IMAR grasslands through the application of Theil-Sen estimation, Mann-Kendall trend analysis, and the Geodetector model. The main findings are as follows: (1) Compared with the univariate parametric traditional regression model, the AGB monitoring accuracy of the multivariate non-parametric RF model in the three study regions increased by 5.94%, 5.08% and 19.14%, respectively. (2) The average AGB per unit area of IMAR grasslands from 2000 to 2022 was 731.41 kg/hm2, with alpine meadow having the highest average AGB (1271.70 kg/hm2) and temperate grassland desertification having the lowest (469.06 kg/hm2). IMAR grasslands exhibited an overall increasing trend in AGB over the past 23 years (6.01 kg/hm2•yr), with the increasing trend covering 83.52% of the grassland area and the decreasing trend covering 16.48%. (3) Spatially, IMAR grassland AGB showed a gradual decline from northeast to southwest and exhibited an increasing trend with increasing longitude (45.423 kg/hm2 per degree) and latitude (71.9 kg/hm2 per degree). (4) Meteorological factors were the most significant factors affecting IMAR grassland AGB, with precipitation (five-year average q value of 0.61) being the most prominent. In the western part of IMAR, where precipitation is consistently limited throughout the year, the primary drivers of influence were human activities, with particular emphasis on the number of livestock (with a five-year average q value of 0.44). It is evident that reducing human activity disturbance and pressure in fragile grassland areas or implementing near-natural restoration measures will be beneficial for the sustainable development of grassland ecosystems. The results of this research hold substantial reference importance for the protection and restoration of grasslands, the supervision and administration of grassland resources, as well as the development of policies related to grassland management.

Dual-Tower Counterfactual Session-Aware Recommender System.

In the complex dynamics of modern information systems such as e-commerce and streaming services, managing uncertainty and leveraging information theory are crucial in enhancing session-aware recommender systems (SARSs). This paper presents an innovative approach to SARSs that combines static long-term and dynamic short-term preferences within a counterfactual causal framework. Our method addresses the shortcomings of current prediction models that tend to capture spurious correlations, leading to biased recommendations. By incorporating a counterfactual viewpoint, we aim to elucidate the causal influences of static long-term preferences on next-item selections and enhance the overall robustness of predictive models. We introduce a dual-tower architecture with a novel data augmentation process and a self-supervised training strategy, tailored to tackle inherent biases and unreliable correlations. Extensive experiments demonstrate the effectiveness of our approach, outperforming existing benchmarks and paving the way for more accurate and reliable session-based recommendations.

The effects of intrinsic water-use efficiency and climate on wood anatomy.

Climate warming may induce growth decline in warm-temperate areas subjected to seasonal soil moisture deficit, whereas increasing atmospheric CO2 concentration (Ca) is expected to enhance tree growth. An accurate understanding of tree growth and physiological processes responding to climate warming and increasing Ca is critical. Here, we analyzed tree-ring stable carbon isotope and wood anatomical traits of Pinus tabuliformis from Qinling Mountains in China to understand how lumen diameter (LD) determining potential hydraulic conductivity and cell-wall thickness (CWT) determining carbon storage responded to climate and Ca. The effects of climate and Ca on intrinsic water-use efficiency (iWUE) were isolated, and iWUE values due to only-climate (iWUEClim) and only-CO2 effects (iWUECO2) were obtained. During a low-iWUE period, the influences of climate on earlywood (EW) LD and latewood (LW) CWT prevailed. During a high-iWUE period, CO2 fertilization promoted cell enlargement and carbon storage but this was counteracted by a negative influence of climate warming. The limiting direct effects of iWUEClim and indirect effects of climate on EW LD were greater than on LW CWT. P. tabuliformis in temperate forests will face a decline of growth and carbon fixation, but will produce embolism-resistant tracheids with narrow lumen responding to future hotter droughts.

An Improved DDPG and Its Application in Spacecraft Fault Knowledge Graph.

We construct a spacecraft performance-fault relationship graph of the control system, which can help space robots locate and repair spacecraft faults quickly. In order to improve the performance-fault relationship graph, we improve the Deep Deterministic Policy Gradient (DDPG) algorithm, and propose a relationship prediction method that combines representation learning reasoning with deep reinforcement learning reasoning. We take the spacecraft performance-fault relationship graph as the agent learning environment and adopt reinforcement learning to realize the optimal interaction between the agent and the environment. Meanwhile, our model uses a deep neural network to construct a complex value function and strategy function, which makes the agent have excellent perceptual decision-making ability and accurate value judgment ability. We evaluate our model on a performance-fault relationship graph of the control system. The experimental results show that our model has high prediction speed and accuracy, which can completely infer the optimal relationship path between entities to complete the spacecraft performance-fault relationship graph.

Ability of volume measures of hydronephrosis to predict need for surgery and evaluate renal function in children with ureteropelvic junction obstruction.

OBJECTIVE: To explore the efficacy of quantitative renal volume measures on magnetic resonance urography images in predicting need for surgery among children with ureteropelvic junction obstruction and their ability to evaluate renal function. METHODS: A total of 88 cases of hydronephrosis in 50 patients were collected between 1 April 2018 and 31 March 2020, including 30 operated kidney and 58 unoperated kidney cases. Clinical data were collected, and quantitative analysis of magnetic resonance urography was performed. Renal volume, hydronephrosis volume and the volume ratio of hydronephrosis (hydronephrosis volume/renal volume) were measured and calculated. We analyzed the relationships between the above indices in the two groups and compared these with renal function. RESULTS: Compared with the unoperated kidney group, hydronephrosis volume, renal volume and hydronephrosis volume/renal volume of the operated kidney group increased significantly. Hydronephrosis volume (area under the curve 0.972, 95% confidence interval 0.943-1.000; P < 0.001) and hydronephrosis volume/renal volume (area under the curve 0.968, 95% confidence interval 0.939-0.998; P < 0.001) were superior to ultrasonography and renal function examination in predicting the probability of surgery, and their sensitivity values (hydronephrosis volume/renal volume: 96.67%; hydronephrosis volume: 93.33%) were higher than those of the renal function test (50%). There was a significant difference among different renal function groups in the pairwise comparison of hydronephrosis volume and hydronephrosis volume/renal volume (P < 0.05). CONCLUSION: Quantitative volume measures of hydronephrosis by magnetic resonance urography had a greater ability to predict need for surgery than ultrasonography and dynamic renal imaging, and it can be used as method by which to evaluate surgery. Hydronephrosis volume and hydronephrosis volume/renal volume have greater predictive ability, and play an important role in the deterioration of renal function.

Comparison of laparoscope-assisted single-needle laparoscopic percutaneous extraperitoneal closure versus open repair for pediatric inguinal hernia.

BACKGROUND: Laparoscopic-assisted repairs for pediatric inguinal hernia have gained gradual acceptance over the past decade. However, consensus about the optimal management is still lacking. The aim of this study is to compare outcomes of a modified laparoscope-assisted single-needle laparoscopic percutaneous extraperitoneal closure (LPEC) versus open repair of pediatric hernias/hydrocele in a single institution. MATERIALS AND METHODS: We retrospectively reviewed the medical data of children who underwent laparoscope-assisted single-needle LPEC and open repair (OR) for inguinal hernia from 2014 to 2019. Data collection included demographics, laterality of hernia, surgical time and time to follow-up. We also reviewed and analyzed the evidence of recurrence, the incidence of metachronous contralateral inguinal hernia (MCIH), and other complications. RESULTS: In our cohort, 961 patients in the OR group and 1098 patients in the LPEC group were analyzed retrospectively. Mean operative time was significantly shorter in the LPEC group (22.3 ± 3.5 min) than in the OR group (27.8 ± 5.9 min) for bilateral hernia repair (p < 0.001). Postoperative recurrence was 1.3% (13/1035) in the OR group and 0.5% (6/1182) in the LPEC group (p = 0.056). Iatrogenic cryptorchidism occurred statistically more frequently in the OR group than in the LPEC group (0.4% vs. 0%, p = 0.013). In addition, the incidence of MCIH was 3.7% (33/887) in the OR group and 0.3% (3/1014) in the LPEC group (p < 0.01). CONCLUSION: Comparing to open technique, laparoscope-assisted single-needle LPEC provides a simple and effective option for pediatric inguinal hernia/hydrocele repair with excellent outcomes, a low incidence of recurrence, and reduced MCIH.

Dynamic of land use, landscape, and their impact on ecological quality in the northern sand-prevention belt of China.

Changes in land use and landscapes have a direct impact on the regional eco-environment. It is of great importance to understand the change pattern of land use, landscapes, and their mechanism on the ecological quality, especially ecologically fragile areas. The northern sand-prevention belt (NSPB) is an important ecologically fragile area in China, which has a large influence on the ecological security of the entire country. Based on the land use data of the NSPB in 2000, 2010, and 2018, we studied the spatio-temporal characteristics of land-use change and change in landscape patterns. The ecological quality represented by the remote sensing-based desertification index (RSDI) was calculated using satellite images. The effects of land use and landscape patterns on RSDI were analyzed by geographic detector and geographically weighted regression. Important results include the following: (1) Land-use change in the study area was high during 2000-2010 but slower in 2010-2018. Grassland was the largest land-use type in the NSPB, and varied greatly in terms of total change and spatial location. The major change was the conversion between dense and moderate grass, with 64,860 km2 of dense grass turning into moderate grass, and 48,505 km2 changing the other way. (2) Among the four landscape metrics, patch density, area-weighted mean fractal dimension, and edge density increased, whereas the aggregation index decreased, which indicated that the landscape was developing towards heterogeneity, fragmentation, complexity, and aggregation. Spatially, the landscape metrics presented a strip distribution in the east of the NSPB. (3) The effects of various land-use types on ecological quality, from high to low, were unused land, woodland, dense grass, cropland, moderate grass, built-up land, sparse grass, and waterbody. The areas where the ecological quality was greatly affected by the landscape patterns were concentrated in the agro-pastoral ecotone and the forest-steppe ecotone. The results of this study reveal the trends of land use and landscape patterns in the NSPB over 18 years and can help to understand their mechanism on ecological quality, which is of significance for the management of this area.

Leydig-like cells derived from reprogrammed human foreskin fibroblasts by CRISPR/dCas9 increase the level of serum testosterone in castrated male rats.

In the past few years, Leydig cell (LC) transplantation has been regarded as an effective strategy for providing physiological patterns of testosterone in vivo. Recently, we have successfully converted human foreskin fibroblasts (HFFs) into functional Leydig-like cells (iLCs) in vitro by using the CRISPR/dCas9 system, which shows promising potential for seed cells. However, it is not known whether the reprogrammed iLCs can survive or restore serum testosterone levels in vivo. Therefore, in this study, we evaluate whether reprogrammed iLCs can restore the serum testosterone levels of castrated rats when they are transplanted into the fibrous capsule. We first developed the castrated Sprague Dawley rat model through bilateral orchiectomy and subsequently injected extracellular matrix gel containing transplanted cells into the fibrous capsule of castrated rats. Finally, we evaluated dynamic serum levels of testosterone and luteinizing hormone (LH) in castrated rats, the survival of implanted iLCs, and the expression levels of Leydig steroidogenic enzymes by immunofluorescence staining and Western blotting. Our results demonstrated that implanted iLCs could partially restore the serum testosterone level of castrated rats, weakly mimic the role of adult Leydig cells in the hypothalamic-pituitary-gonadal axis for a short period, and survive and secrete testosterone, through 6 weeks after transplantation. Therefore, this study may be valuable for treating male hypogonadism in the future.

Oct-4 Enhanced the Therapeutic Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Acute Kidney Injury.

BACKGROUND/AIMS: Acute kidney injury (AKI) is a common clinical condition that can lead to chronic kidney failure. Although mesenchymal stem cell-derived extracellular vesicles (MSC EVs) are regarded as a potent AKI treatment, the mechanisms underlying their beneficial effects remain unclear. Oct-4 may play an important role in tissue injury repair. We thus hypothesized that oct-4 overexpression might enhance the therapeutic effects of MSC EVs in AKI treatment. METHODS: Renal tubular epithelial cells were cultured in a low oxygen environment, then cocultured with MSC EVs or control medium for 48 h. BrdU and transferase-mediated dUTP nick-end labeling (TUNEL) staining were used to assess cell proliferation and apoptosis. Mice subjected to ischemia reperfusion were randomly divided into 4 groups, then injected with either phosphate-buffered saline (vehicle), EVs, EVs overexpressing oct-4 (EVs+Oct-4), and EVs not expressing Oct-4 (EVs-Oct-4). Blood creatinine (CREA) and urine nitrone levels were assessed 48 h and 2 weeks after injection. After ischemia reperfusion, renal tissues from each group were stained with TUNEL and proliferating cell nuclear antigen (PCNA) to determine the degree of apoptosis and proliferation. Masson trichrome staining was used to evaluate renal fibrosis progression. Snail gene expression was assessed using polymerase chain reaction (PCR). RESULTS: At 48 h after hypoxic treatment, TUNEL and BrdU staining indicated that the EVs+Oct-4 group had the least apoptosis and the most proliferation, respectively. Treatment with EVs overexpressing Oct-4 significantly decreased serum Crea and blood urea nitrogen levels and rescued kidney fibrosis, as indicated by the low proportion of Masson staining, high number of PCNA-positive cells, and low number of TUNEL-positive cells. PCR analysis indicated that Snail was most upregulated in the vehicle group and least upregulated in the EVs+Oct-4 group. CONCLUSIONS: MSC EVs had a pronounced therapeutic effect on ischemic reperfusion injury-related AKI, and Oct-4 overexpression enhanced these therapeutic effects. Our results may inspire a new direction for AKI treatment with MSC EVs.

CRISPR/dCas9-mediated activation of multiple endogenous target genes directly converts human foreskin fibroblasts into Leydig-like cells.

Recently, Leydig cell (LC) transplantation has been revealed as a promising strategy for treating male hypogonadism; however, the key problem restricting the application of LC transplantation is a severe lack of seed cells. It seems that targeted activation of endogenous genes may provide a potential alternative. Therefore, the aim of this study was to determine whether targeted activation of Nr5a1, Gata4 and Dmrt1 (NGD) via the CRISPR/dCas9 synergistic activation mediator system could convert human foreskin fibroblasts (HFFs) into functional Leydig-like cells. We first constructed the stable Hsd3b-dCas9-MPH-HFF cell line using the Hsd3b-EGFP, dCas9-VP64 and MS2-P65-HSF1 lentiviral vectors and then infected it with single guide RNAs. Next, we evaluated the reprogrammed cells for their reprogramming efficiency, testosterone production characteristics and expression levels of Leydig steroidogenic markers by quantitative real-time polymerase chain reaction or Western blotting. Our results showed that the reprogramming efficiency was close to 10% and that the reprogrammed Leydig-like cells secreted testosterone rapidly and, more importantly, responded effectively to stimulation with human chorionic gonadotropin and expressed Leydig steroidogenic markers. Our findings demonstrate that simultaneous targeted activation of the endogenous NGD genes directly reprograms HFFs into functional Leydig-like cells, providing an innovative technology that may have promising potential for the treatment of male androgen deficiency diseases.

Conversion of human fibroblasts into functional Leydig-like cells by small molecules and a single factor.

Reprogramming fibroblasts into Leydig cells (LCs) offers a promising source for cell-based therapy for male hypogonadism. Recently, it has been achieved by forced expression of multiple transcription factors (TFs). However, for ultimate safe and convenient application, small molecules would be a revolutionary and desirable method to reduce or eliminate the genetic manipulations. Here, we report a defined small-molecule cocktail that enables the highly efficient conversion of human fibroblasts into functional LCs with only one transcription factor. These induced cells resembled human LCs with respect to morphology, marker gene expression and secretary function of testosterone. This study lays a foundation for future pharmacological reprogramming and provides a unique venue for investigating mechanisms underlying reprogramming.

Aromatically functionalized pseudo-crown ethers with unusual solvent response and enhanced binding properties.

Conformational flexibility in the host's structure is often considered detrimental to its binding. Flexible pseudo-crown ethers with aromatic donor/acceptor groups at the chain ends, however, displayed enhanced binding affinity and selectivity, particularly when the direct binding interactions were compromised by unfavorable solvents.

Binding-promoted chemical reaction in the nanospace of a binding site: effects of environmental constriction.

Chemical reactions in a confined nanospace can be very different from those in solution. Imine formation between molecular amines and an aldehyde inside a molecularly imprinted receptor was promoted strongly by the binding. Although how well the amine fit in the binding pocket and its electronic nature both influenced the reaction, the freedom of movement for the amine was the most important factor determining the binding-normalized reactivity.

Intramolecularly enhanced molecular tweezers with unusually strong binding for aromatic guests in unfavorable solvents.

Molecular tweezers using aromatic interactions for binding normally work best in polar instead of nonpolar solvents due to the strong solvophobic effect in the binding. Inspired by biological receptors that utilize "delocalized binding interactions" remote from the binding interface to strengthen guest-binding, we constructed molecular tweezers that have a reversed solvent effect. As the direct aromatic binding interactions were weakened by nonpolar solvent, guest-triggered intrahost interactions between two strategically placed carboxylic acids became stronger and contributed to the binding.

Enantioselective synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives via an organocatalytic asymmetric Michael/cyclization cascade reaction.

An efficient enantioselective synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives by a cascade reaction between pyrazolones and isatylidene malononitriles is described. With only 1 mol% of (DHQD)2PYR, chiral spirooxindole derivatives have been produced in excellent yields (96-99%) with good-to-excellent enantioselectivities (up to 91% ee).

[Differentiation of human umblical cord mesenchymal stem cells into Leydig cells in the rat testis interstitium: An experimental study].

OBJECTIVE: To explore the feasibility of inducing human umbilical cord mesenchymal stem cells (HUMSCs) to differentiate into Leydig cells in the interstitial tissue of the rat testis. METHODS: HUMSCs were obtained by tissue blocks culture attachment and their purity and multi-lineage differentiation ability were verified by flow cytometry and chondrogenic/adipogenic/osteogenic differentiation. Then the HUMSCs were marked by CM-Dil and transplanted into the interstitial tissue of the rat testis. At 4 and 8 weeks after transplantation, the survival and differentiation status of the HUMSCs were observed by immunofluorescence staining and flow cytometry. The suspension of the rat Leydig cells was obtained at 8 weeks for determining the expression of the Leydig cell marker 3ß-HSD in the HUMSCs, the cells labeled with CM-Dil were sorted and cultured, and the medium collected after 3 days of culture for measurement of the testosterone level. RESULTS: The expression of the Leydig cell marker CYPllal was not observed in the HUMSCs at 4 weeks but found at 8 weeks after transplantation and the differentiation rate of 3ß-HSD was about 14.5% at 8 weeks. CM-Dil labeled cells survived after sorting and testosterone was detected in the medium. CONCLUSIONS: HUMSCs are likely to differentiate into Leydig cells in the interstitium of the rat testis.

[Human umbilical cord mesenchymal stem cells may differentiate into Leydig cells through conditioned medium induction].

OBJECTIVE: To explore the feasibility of inducing human umbilical cord mesenchymal stem cells (HuMSCs) to differentiate into Leydig cells through conditioned medium derived from Leydig cells. METHODS: HuMSCs and Leydig cells were obtained by tissue blocks culture attachment and enzymatic digestion respectively. HuMSCs were induced by conditioned medium of Leydig cells as an experiment group while those before induction were cultured as a control group. The expressions of LHR, 3ß-HSD and StAR in the induced HuMSCs were determined by RT-PCR after 3, 7 and 10 days of culture; those of CYP11A1, CYP17A1 and 3ß-HSD measured by immunofluorescence staining after 2 weeks; and that of 3ß-HSD detected by Western blot after 4 weeks. RESULTS: The experimental group showed positively expressed LHR, 3ß-HSD and StAR at 3, 7 and 10 days, CYP11A1, CYP17A1 and 3ß-HSD at 2 weeks, and 3ß-HSD at 4 weeks, while the control group revealed negative expressions at all the time points. CONCLUSION: Induced with conditioned culture medium derived from Leydig cells, HuMSCs are likely to differentiate into steroidogenic cells and eventually into Leydig cells.

[Generation and regulation of Leydig cells].

Leydig cells, located in the loose interstitial tissue of seminiferous tubules, are the major site for androgen synthesis and secretion, and play an important role in the reproductively and fertility of males. The dysfunction of Leydig cells may lead to various male diseases, such as primary hypogonadism, cryptorchidism, and hypospadias. This review outlines the recent findings concerning the generation, development and regulation of Leydig cells.