Search

Abstract Background High myopia (HM), characterized by a severe myopic refractive error, stands as a leading cause of visual impairment and blindness globally. HM is a multifactorial ocular disease that presents high genetic heterogeneity. Employing a genetic risk score (GRS) is useful for capturing genetic susceptibility to HM. Methods This study assesses the effectiveness of these strategies via incorporating rare variations into the GRS assessment. This study enrolled two independent cohorts: 12,600 unrelated individuals of Han Chinese ancestry from Myopia Associated Genetics and Intervention Consortium (MAGIC) and 8682 individuals of European ancestry from UK Biobank (UKB). Results Here, we first estimate the heritability of HM resulting in 0.53 (standard error, 0.06) in the MAGIC cohort and 0.21 (standard error, 0.10) in the UKB cohort by using whole-exome sequencing (WES) data. We generate, optimize, and validate an exome-wide genetic risk score (ExGRS) for HM prediction by combining rare risk genotypes with common variant GRS (cvGRS). ExGRS improved the AUC from 0.819 (cvGRS) to 0.856 for 1219 Han Chinese individuals of an independent testing dataset. Individuals with a top 5% ExGRS confer a 15.57-times (95% CI, 5.70–59.48) higher risk for developing HM compared to the remaining 95% of individuals in MAGIC cohort. Conclusions Our study suggests that rare variants are a major source of the missing heritability of HM and that ExGRS provides enhanced accuracy for HM prediction in Han Chinese ancestry, shedding new light on research and clinical practice.

Abstract The layout of methane sensors in the working face cannot meet the needs for monitoring methane concentrations within confined spaces, and it is challenging to determine the precise locations for manual inspections. Therefore, the working face is firstly divided into different areas and grids. Then combined with the characteristics of methane emissions and the measured data on site, the boundary conditions of simulation experiments are set up and the research is carried out on the diffusion law of methane in the confined space of the working face under different conditions. The experimental results show that methane emission intensity from coal walls affects its distribution. As emission intensity rises, methane nearer the coal wall decreases, while methane further away increases. Among coal mining points, point 2 shows the widest methane diffusion range. Rising wind speeds decrease methane diffusion from the coal wall, increasing vertical diffusion distance. Methane from the coal wall shifts to the air inlet, while methane from the mining point diffuses increasingly to the downwind side. The location of the maximum methane concentration generated from falling coal and its transportation process is only related to the location of the coal mining point. The key areas for methane monitoring in confined spaces of the working face should be the overlapping locations of the vertical‐3 and vertical‐4 areas and the horizontal‐1 and horizontal‐3 areas. The key areas for manual inspection should be the overlapping locations of the vertical‐2 and vertical‐3 areas and the horizontal‐1 area.

Objectives: The TGF-β signaling pathway is widely acknowledged for its role in various aspects of cancer progression, including cellular invasion, epithelial-mesenchymal transition, and immunosuppression. Immune checkpoint inhibitors (ICIs) and pharmacological agents that target TGF-β offer significant potential as therapeutic options for cancer. However, the specific role of TGF-β in prognostic assessment and treatment strategies for breast cancer (BC) remains unclear. Methods: The Cancer Genome Atlas (TCGA) database was utilized to develop a predictive model incorporating five TGF-β signaling-related genes (TSRGs). The GSE161529 dataset from the Gene Expression Omnibus was employed to conduct single-cell analyses aimed at further elucidating the characteristics of these TSRGs. Additionally, an unsupervised clustering algorithm was applied to categorize BC patients into two distinct groups based on the five TSRGs, with a focus on immune response and overall survival (OS). Further investigations were conducted to explore variations in pharmacotherapy and the tumor microenvironment across different patient cohorts and clusters. Results: The predictive model for BC identified five TSRGs: FUT8, IFNG, ID3, KLF10, and PARD6A. Single-cell analysis revealed that IFNG is predominantly expressed in CD8+ T cells. Consensus clustering effectively categorized BC patients into two distinct clusters, with cluster B demonstrating a longer OS and a more favorable prognosis. Immunological assessments indicated a higher presence of immune checkpoints and immune cells in cluster B, suggesting a greater likelihood of responsiveness to ICIs. Conclusion: The findings of this study highlight the potential of the TGF-β signaling pathway for prognostic classification and the development of personalized treatment strategies for BC patients, thereby enhancing our understanding of its significance in BC prognosis.

Abstract Experimental investigations of silica under high pressure and temperature offer crucial insights into modeling of Earth and super‐Earths’ interiors. Despite extensive studies on Hugoniots of silica polymorphs like fused‐silica (2.20 g/cm3), quartz (2.65 g/cm3) and stishovite (4.29 g/cm3) up to a terapascal, unexplored region of melting and liquid of silica at high pressures is leaved because of the Hugoniots dependence on ambient density. This emphasizes the urgence to supplement the phase diagram to constrain silica properties under extreme conditions. Here, the Hugoniot and shock temperature of coesite (2.92 g/cm3) were studied by laser shock compression experiments up to 950 GPa. Our findings confirm shock‐induced superheating in coesite, revealing a higher Grüneisen parameter and lower electrical conductivity compared to those of fused‐silica and quartz along an isothermal line (

The human CPAMD8 gene encodes proteins in the A2M/C3 (alpha-2-macroglobulin/complement 3) family, predominantly expressed in the distal tips of the retinal neuroepithelium that form the iris and ciliary body. Mutations in CPAMD8 have been linked to anterior segment dysplasia and congenital glaucoma. Using CRISPR/Cas9 editing, we inserted a 3*EAAAK-EGFP fluorescent tag into the CPAMD8 gene, enabling real-time observation of its expression and providing insights into its biological functions. The resulting gene-edited cell line retained normal stem cell morphology and karyotype, expressed essential pluripotency markers, and exhibited differentiation potential.

Abstract The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR–aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.

Abstract Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ −10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3’s role in EM pathogenesis.

CPAMD8, a constituent of the A2M/C3 (α-2-macroglobulin/complement 3) protein family, is strikingly expressed in the human fetal lens and distal neural retina. Mutations in CPAMD8 have been linked to anterior segment dysgenesis and primary congenital glaucoma. We utilized CRISPR/Cas9 technology to establish a homozygous CPAMD8 knockout human embryonic stem cell line for differentiating retinal organoids, with the intent of exploring the role of CPAMD8 in the early development of the human eye. The CPAMD8 knockout cell line exhibits normal morphology, pluripotency, and karyotype, serving as a valuable research tool for investigating the functions of CPAMD8 in ophthalmology.

Abstract DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Increasing research has shown that the abnormal expression of microRNA (miRNA) is associated with many complex diseases. However, biological experiments have many limitations in identifying the potential disease-miRNA associations. Therefore, we developed a computational model of Three-Layer Heterogeneous Network based on the Integration of CircRNA information for MiRNA-Disease Association prediction (TLHNICMDA). In the model, a disease-miRNA-circRNA heterogeneous network is built by known disease-miRNA associations, known miRNA-circRNA interactions, disease similarity, miRNA similarity, and circRNA similarity. Then, the potential disease-miRNA associations are identified by an update algorithm based on the global network. Finally, based on global and local leave-one-out cross validation (LOOCV), the values of AUCs in TLHNICMDA are 0.8795 and 0.7774. Moreover, the mean and standard deviation of AUC in 5-fold cross-validations is 0.8777+/−0.0010. Especially, the two types of case studies illustrated the usefulness of TLHNICMDA in predicting disease-miRNA interactions.

In this paper, the numerical simulation method is used to study the ballistic performances of hourglass lattice sandwich structures with the same mass under the vertical incidence of fragments. Attention is paid to elucidating the influences of rod cross-section dimensions, structure height, structure layer, and rod inclination angle on the deformation mode, ballistic performances, and ability to change the ballistic direction of fragments. The results show that the ballistic performances of hourglass lattice sandwich structures are mainly affected by their structural parameters. In this respect, structural parameters optimization of the hourglass lattice sandwich structures enable one to effectively improve their ballistic limit velocity and, consequently, ballistic performances.

To meet the demand of accurate water level prediction of the reservoir in Liuxihe River Basin, this paper proposes an improved long short-term memory (LSTM) neural network based on the Bayesian optimization algorithm and wavelet decomposition coupling. Based on the improved model, the water levels of Liuxihe Reservoir and Huanglongdai Reservoir are simulated and predicted by the 1 h prediction length, and the prediction accuracy of the improved model is verified separately by the 3, 6 and 12 h prediction lengths. The results show that: first, Bayesian optimization coupling can significantly reduce the average absolute error and root mean square error of the model and improve the overall prediction accuracy, but this algorithm is insufficient in the optimization of model extremum; Wavelet decomposition coupling can significantly reduce the outliers in model prediction and improve the accuracy of extremum, but it plays relatively weaker role in the overall optimization of the model. Second, by the prediction lengths of 1, 3, 6 and 12 h, the improved model based on the LSTM neural network and coupled with Bayesian optimization and wavelet decomposition is superior to Bayesian optimization and wavelet decomposition coupling model in overall prediction accuracy and prediction accuracy of extremum. HIGHLIGHTS Quantifying the impacts of coupling model on reservoir water level.; Proposing an improved prediction model for long short-term memory neural network.; Quantifying the impacts of different input characteristics on the model.;

Objective To explore the effectiveness of different knee arthroscopic medial collateral ligament release techniques in the treatment of patients with medial meniscus posterior horn injury and their prognoses. Methods A total of 54 patients with medial meniscus posterior horn injury who underwent surgical treatment at the Department of Sports Medicine in our hospital from June to August 2021 were enrolled. They were divided into group A (who underwent knee arthroscopic percutaneous outside-in, superficial release) and group B (who underwent knee arthroscopic inside-out, anteromedial release) based on the conditions and wishes of the patients. The two groups of patients were recorded and compared for surgical duration and follow-up outcomes of the following indices at 1, 3, and 12 months after surgery: local symptom duration, visual analogue score of knee pain, Lysholm score of knee joints, International Knee Documentations Committee Rating System-based score, and knee joint range of motion score. Results There was no significant difference in surgical duration between the two groups of patients (P>0.05), but the local symptom duration in group B was significantly shorter than that in group A (t=11.950,P0.05). Conclusion For patients with simple medial meniscus posterior horn injury, it is recommended to use knee arthroscopic anteromedial inside-out, superficial release if the surgeons are confident of the condition.

Objective Evidence from observational studies has reported possible associations between the gut microbiome (GM) and glaucoma. However, the causal effect of GM on glaucoma risk remains to be determined.Methods and analysis We conducted two-sample bidirectional Mendelian randomisation (MR) analyses to explore the causal association between GM and glaucoma. Genome-wide association study summary statistics of 196 GM taxa (n=18 340) and glaucoma (18 902 cases and 358 375 controls) were obtained from MiBioGen and FinnGen Consortium. Inverse variance weighted, MR-Egger, weighted median, weighted mode, Mendelian Randomisation Pleiotropy Residual Sum and Outlier, MR-Egger intercept and Cochran’s Q statistical analyses were used to supplement MR results and sensitivity analysis. An independent cohort from the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MRC-IEU) Consortium (1715 cases and 359 479 controls) was used to validate causal effects.Results Results of the MR analysis suggested that the family Oxalobacteraceae (OR 0.900, 95% CI 0.843 to 0.961, p=0.002) and the genus Eggerthella (OR 0.881, 95% CI 0.811 to 0.957, p=0.003) had a negative effect on glaucoma, whereas the genus Bilophila (OR 1.202, 95% CI 1.074 to 1.346, p=0.001), LachnospiraceaeUCG010 (OR 1.256, 95% CI 1.109 to 1.423, p=0.0003) and Ruminiclostridium 9 (OR 1.258, 95% CI 1.083 to 1.461, p=0.003) had a positive effect on glaucoma. Among these, the positive causal effect of LachnospiraceaeUCG010 (OR 1.002, 95% CI 1.000 to 1.004, p=0.033) on glaucoma was replicated in an independent cohort.Conclusion This MR analysis from large population studies demonstrated the causal effect of GM on glaucoma risk and supported the role of GM in influencing glaucoma susceptibility.

Summary: Whole-exome sequencing (WES) is a major approach to uncovering gene-disease associations and pinpointing effector genes. Here, we present a protocol for estimating genetic associations of rare and common variants in large-scale case-control WES studies using MAGICpipeline, an open-access analysis pipeline. We describe steps for assessing gene-based rare-variant association analyses by incorporating multiple variant pathogenic annotations and statistical techniques. We then detail procedures for identifying disease-related modules and hub genes using weighted correlation network analysis, a systems biology approach.For complete details on the use and execution of this protocol, please refer to Su et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

PurposeTo investigate the contrast sensitivity function (CSF) changes in simple high myopia (SHM) and evaluate the correlations between these changes with the early changes in the retinal microstructure.MethodsThis prospective study comprised 81 subjects, 20 with emmetropia (EM), 26 with low myopia and moderate myopia (LM/MM), and 35 with SHM. The area under the log CSF curve (AULCSF) and the cut-off spatial frequency (Cut-off SF) were employed as measures of CSF. Adaptive optics (AO) was employed to quantify the cone density, spacing, and regularity. The thickness and blood flow of the retinal sublayers were determined from vertical and horizontal optical coherence tomography angiography (OCTA) A-scans. Swept-source optical coherence tomography (SS-OCT) was employed to analyze the choroidal thickness (CT) and choroidal vascularity using a custom algorithm. Differences in the retinal and choroidal parameters, cone distribution, AULCSF, and Cut-off SF were compared among the three groups. Multivariate linear mixed models were used to elucidate the associations between photoreceptor morphological alterations, retinal and choroidal parameters, and AULCSF.ResultsThe AULCSF and Cut-off SF were significantly lower in the SHM group compared to the EM and LM groups (p

Abstract The audible noise (AN) of HVDC transmission lines, as an external manifestation of the corona discharge, intensifies with the increase of altitude. In high‐altitude area, the AN has been a key factor in determining the type of conductors for transmission lines. In order to study the characteristics of corona current and AN of HVDC transmission lines at high‐altitude, we erected a HVDC test line at an altitude of 4300 m, and carried out AN and corona current tests under different voltages. Through the test, the basic data of AN and corona current of HVDC test line at high‐altitude were obtained. Based on the corona current curve, the corona inception electric field strength of the conductor was proposed. The relationship between the equivalent A‐weight sound level and the high‐frequency noise component was clarified. The relational expression of the AN and corona current for the HVDC test line were suggested. The research results show that, there is a relatively fixed difference of about 7–8.3 dB between the equivalent A‐weight sound level and the 8 kHz sound pressure level at altitude 4300 m, and a clear logarithmic relationship between the equivalent A‐weight sound level and the average value of the corona current.

Abstract Background Despite receiving orthokeratology (ortho-k), the efficacy of retarding ocular elongation during myopia varies among myopic children. The current study aimed to investigate the early changes of choroidal vasculature at one month after ortho-k treatment and its association with one-year ocular elongation, as well as the role of such choroidal responses in predicting the one-year control efficacy of ortho-k treatment. Methods A prospective cohort study was conducted in myopic children treated with ortho-k. Myopic children aged between 8 and 12 years who were willing to wear ortho-k lenses were recruited consecutively from the Eye Hospital of Wenzhou Medical University. Subfoveal choroidal thickness (SFCT), submacular total choroidal luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), choriocapillaris flow deficit (CcFD) were evaluated by optical coherence tomography (OCT) and OCT angiography over a one-year period. Results Fifty eyes from 50 participants (24 males) who finished one-year follow-ups as scheduled were included, with a mean age of 10.31 ± 1.45 years. The one-year ocular elongation was 0.19 ± 0.17 mm. The LA (0.03 ± 0.07 mm2), SA (0.02 ± 0.05 mm2) increased proportionally after one-month of ortho-k wear (both P

【Objective】The study aims to verify the application effect of bacterial agent PA9 degrading omethoate which residual in the soil. Soil physical and chemical properties, tomato growth and soil microbial diversity affect by bacterial agent PA9 were researched at the same time.【Method】Bacterial agent PA9 was made from bacteria strain ZZY-C13-1-9, when omethoate artificial add into the soil about 100 mg/kg, the bacterial agent PA9 were applied 0.1%. The period of remediation lasted for 50 days. Soil samples were taken every 10 days. The content of omethoate in soil were measured by HPLC. A selective culture medium is used to isolate strain ZZY-C13-1-9. The microbial diversity were measured by illumina miSeq high-throughput sequencing. Soil physical and chemical indexes were determined by national standard method. Tomato growth index were monitored.【Result】Initial content of omethoate in soil was 100 mg/kg at 0 days. After 40 days, the omethoate content in soil decrease to 5.3 mg/kg at remediation experimental group, which was significantly different with control group (48.79 mg/kg). Microbial strain ZZY-C13-1-9 could colonize in the soil and the proportion of soil microorganisms in omethoate soil increased after 10 - 20 days of remediation. The residual omethoate content in the soil was significantly reduced, which indicated that the functional strain could play a role in degrading omethoate in contaminated soil. The results of high-throughput sequencing showed that the proportion of Pseudomonas sp. in soil microbial flora decreased with the decrease of omethoate content, indicating that the bacterial agent PA9 would not permanently change the distribution of soil microbial diversity, and the restored soil could effectively restore the diversity of bacterial flora. The contents of total nitrogen, microbial nitrogen, available phosphorus and MWD in soil aggregates increased significantly compared with the control, and the use of microbial agent PA9 had no negative effect on the growth of tomato.【Conclusion】The bacterial agent PA9 can colonize and accelerate the degradation of omethoate in omethoate-contaminated soil in a short period of time, improve the microbial diversity of contaminated soil and have no adverse effects on the physical and chemical properties of the soil and the planting of tomatoes.

In situ electric heating is an important method used to increase production capacity during the extraction of natural gas hydrates. This work numerically evaluated the sensitivity of different heating parameters on gas production behavior with a vertical well depressurization in the Shenhu Sea area hydrate reservoir, the production pressure difference of 4 MPa, and continuous depressurization for 1080 days. The results showed that the in situ electric heating method can effectively enhance production capability by promoting hydrate dissociation and eliminating secondary hydrates. Compared with scenarios without heating, implementing whole wellbore heating (100 W/m) increases cumulative gas production (Vg) by 118.56%. When intermittent heating is applied to the local wellbore (15 m) located in the three-phase layer (with an interval of 30 days) and stops heating in advance at 480 days, there is no significant difference in Vg compared to the whole wellbore heating case, and the cumulative heat input is only 4.76%. We recommend considering intermittent heating of the local wellbore and stopping heating in advance during vertical well depressurization as this approach significantly reduces heating energy consumption while simultaneously improving production capacity.

Owing to the poor cold tolerance of Stenotaphrum Trin and the urgent need for shade-tolerant grass species in temperate regions of East China, this study evaluated the cold tolerance of 55 Stenotaphrum accessions, aiming to provide shade-tolerant materials for temperate regions. A fine cold-tolerant turfgrass should have both the advantages of delayed fall dormancy and early spring green-up. However, previous research on the cold resistance of turfgrass has mainly focused on the performance of the spring green-up, with less attention paid to the fall dormancy, which has affected the ornamental and application value of turfgrass. This study first dynamically investigated the leaf colour of each accession during the fall dormancy and the coverage during the spring green-up and evaluated the cold resistance of the accession through membership functions and cluster analysis. Significant differences in the cold resistance were found with the assignment of breeding lines to four categories. The weak correlation (R2 = 0.1682) between leaf colour during the fall dormancy and coverage during the spring green-up indicates that using the performance of a single period to represent the cold resistance of accessions is not appropriate. To test whether using the laboratory-based LT50 and stolon regrowth rating analysis can replace the above-improved method, we conducted a related analysis and found that the fit between these two methods is very poor. This phenomenon is attributed to the poor correlation between the laboratory-based parameters and the pot-investigated data. Therefore, this study presents a cold resistance evaluation method for Stenotaphrum that integrates performance in both the fall dormancy and spring green-up periods. This improved evaluation method cannot be simplified by the growth performance of a single period or replaced by using laboratory-based LT50 and stolon regrowth tests. With the help of this improved method, several excellent cold tolerance accessions (ST003, S13, and S12) were identified for temperate regions of East China.

Stepwise depressurization is an important depressurization strategy in the development of natural gas hydrates. This work numerically analyzes the effects of different depressurization gradients and constant pressure durations on gas and water production during stepwise depressurization extraction with a vertical well in the Shenhu Sea area hydrate reservoir of the South China Sea. The results indicate that stepwise depressurization can reduce water production and raise the gas-to-water ratio in the early stages of production while ensuring cumulative gas output. When the vertical well is deployed at the model’s center with a completion length of 70 m and a constant pressure duration of 10 days, a depressurization gradient of 0.5 MPa, stepwise depressurization by 6 MPa, and continuous production for one year is achieved. Compared with direct depressurization, its cumulative gas production is 2.966 × 106 ST m3, which only decreases by 2.94%. However, it maintains a higher gas-to-water ratio in the early stages of production. Considering factors such as engineering operability, cumulative gas output, and gas-to-water ratio, it is recommended to use a small pressure gradient and a medium constant pressure stabilization time for stepwise depressurization Stepwise depressurization can maintain a high gas-to-water ratio while ensuring gas production and reducing water production can alleviate sand production problems and improve economic efficiency. The understanding gained from this work has reference value for the development of similar hydrate reservoirs worldwide.

Improving the production capacity of natural gas hydrates (NGHs) is crucial for their commercial development. Based on the data of the first on-site testing production of NGHs in the Shenhu Sea area, numerical methods were used to analyze the production behavior of radial lateral well (RLW) and horizontal snake well (HSW) with different completion lengths when they deployed at different layers of the Class-1 type hydrate reservoir (with a fixed pressure difference of 6 MPa and continuous production for 360 days). The results indicate that compared with the single vertical well production, RLW and HSW can effectively increase production capacity by enlarging drainage area and the productivity is directly proportional to the total completion length. The RLW and HSW deployed at the three-phase layer (TPL) have optimal mining performance within a 360-day production period. Different to the previous research findings, during a short-term production period of 360 days, regardless of the deployment layer, the overall production capacity of HSW is better than RLW’s. The total gas production of HSW-2 circles well type is about four times that of a single vertical well, reaching 1.554 × 107 ST m3. Moreover, the HSW-1 lateral well type stands out with an average Qg of 3.63 × 104 ST m3/d and a specific production index J of 16.93; it has the highest J-index among all well types, which means the best mining efficiency. It is recommended to choose the HSW-1 circle well type, if the coiled tubing drilling technique is used for on-site testing production of NGHs in the future. The research results provide insights into the potential applications of RLW and HSW in this sea area.

Glaucoma is a complex multifactorial disease. Oxidative stress has been implicated in its pathogenesis. However, establishing a causal relationship between oxidative stress and glaucoma is challenging due to confounding and reverse causality. In this study, we performed bidirectional two-sample Mendelian randomization (MR) analyses based on genetic instrumental variables as proxies for 11 biomarkers of oxidative stress injury to investigate the causal relationship between oxidative stress and glaucoma. Eight significant associations were identified. Increased circulating levels of catalase (OR = 0.915, 95 % CI: 0.848–0.987, P = 0.022), retinol (OR = 0.481, 95 % CI: 0.248–0.932, P = 0.044) and superoxide dismutase (OR = 0.779, 95 % CI: 0. 616-0.986, P = 0.038) are associated with a decreased risk of glaucoma, whereas an increased myeloperoxidase level (OR = 2.145, 95 % CI: 1.119–4.111, P = 0.029) is associated with an increased risk of glaucoma. Glaucoma was causally associated with lower levels of total bilirubin (OR = 0.961, 95 % CI: 0.927–0.997, P = 0.039), glutathione peroxidase (OR = 0. 934, 95 % CI: 0.890–0.981, P = 0.006), paraoxonase (OR = 0.883, 95 % CI: 0.810–0.963, P = 0.005) and albumin (OR = 0.988, 95 % CI: 0.978–0.998, P = 0.014). The bidirectional MR analysis revealed a causal relationship between oxidative stress and glaucoma. These findings provide a greater understanding of the underlying mechanisms of glaucomatous neurodegeneration and imply a potential therapeutic approach for glaucoma through targeting oxidative stress pathways.

Summary: LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/β hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.

IntroductionBreast cancer (BC) is the most common malignant tumor in the female population. Despite staging and treatment consensus guidelines, significant heterogeneity exists in BC patients' prognosis and treatment efficacy. Alterations in one-carbon (1C) metabolism are critical for tumor growth, but the value of the role of 1C metabolism in BC has not been fully investigated.MethodsTo investigate the prognostic value of 1C metabolism-related genes in BC, 72 1C metabolism-related genes from GSE20685 dataset were used to construct a risk-score model via univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression algorithm, which was validated on three external datasets. Based on the risk score, all BC patients were categorized into high-risk and low-risk groups. The predictive ability of the model in the four datasets was verified by plotting Kaplan-Meier curve and receiver operating characteristic (ROC) curve. The candidate genes were then analyzed in relation to gene mutations, gene enrichment pathways, immune infiltration, immunotherapy, and drug sensitivity.ResultsWe identified a 7-gene 1C metabolism-related signature for prognosis and structured a prognostic model. ROC analysis demonstrated that the model accurately predicted the 2-, 3-, and 5-year overall survival rate of BC patients in the four cohorts. Kaplan-Meier analysis revealed that survival time of high-risk patients was markedly shorter than that of low-risk patients (p < 0.05). Meanwhile, high-risk patients had a higher tumor mutational burden (TMB), enrichment of tumor-associated pathways such as the IL-17 signaling pathway, lower levels of T follicular helper (Tfh) and B cells naive infiltration, and poorer response to immunotherapy. Furthermore, a strong correlation was found between MAT2B and CHKB and immune checkpoints.DiscussionThese findings offer new insights into the effect of 1C metabolism in the onset, progression, and therapy of BC and can be used to assess BC patients' prognosis, study immune infiltration, and develop potentially more effective clinical treatment options.

BackgroundBreast cancer is the key global menace to women’s health, which ranks first by mortality rate. The rate reduction and early diagnostics of breast cancer are the mainstream of medical research. Immunohistochemical examination is the most important link in the process of breast cancer treatment, and its results directly affect physicians’ decision-making on follow-up medical treatment.PurposeThis study aims to develop a computer-aided diagnosis (CAD) method based on deep learning to classify breast ultrasound (BUS) images according to immunohistochemical results.MethodsA new depth learning framework guided by BUS image data analysis was proposed for the classification of breast cancer nodes in BUS images. The proposed CAD classification network mainly comprised three innovation points. First, a multilevel feature distillation network (MFD-Net) based on CNN, which could extract feature layers of different scales, was designed. Then, the image features extracted at different depths were fused to achieve multilevel feature distillation using depth separable convolution and reverse depth separable convolution to increase convolution depths. Finally, a new attention module containing two independent submodules, the channel attention module (CAM) and the spatial attention module (SAM), was introduced to improve the model classification ability in channel and space.ResultsA total of 500 axial BUS images were retrieved from 294 patients who underwent BUS examination, and these images were detected and cropped, resulting in breast cancer node BUS image datasets, which were classified according to immunohistochemical findings, and the datasets were randomly subdivided into a training set (70%) and a test set (30%) in the classification process, with the results of the four immune indices output simultaneously from training and testing, in the model comparison experiment. Taking ER immune indicators as an example, the proposed model achieved a precision of 0.8933, a recall of 0.7563, an F1 score of 0.8191, and an accuracy of 0.8386, significantly outperforming the other models. The results of the designed ablation experiment also showed that the proposed multistage characteristic distillation structure and attention module were key in improving the accuracy rate.ConclusionThe extensive experiments verify the high efficiency of the proposed method. It is considered the first classification of breast cancer by immunohistochemical results in breast cancer image processing, and it provides an effective aid for postoperative breast cancer treatment, greatly reduces the difficulty of diagnosis for doctors, and improves work efficiency.

Reasonable nitrogen fertilizer application is an important strategy to maintain optimal growth of grasslands, thereby enabling them to better fulfil their ecological functions while reducing environmental pollution caused by high nitrogen fertilizer production and application. Optimizing the ammonium (NH4+):nitrate (NO3-) ratio is a common approach for growth promotion in crops and vegetables, but research on this topic in grass plants has not received sufficient attention. Centipedegrass, which is widely used in landscaping and ecological protection, was used as the experimental material. Different NH4+:NO3- ratios (0: 100, 25:75, 50:50, 75:25, 100:0) were used as the experimental treatments under hydroponic conditions. By monitoring the physiological and morphological changes under each treatment, the appropriate NH4+:NO3- ratio for growth and its underlying mechanism were determined. As the proportion of ammonium increased, the growth showed a “bell-shaped” response, with the maximum biomass and total carbon and nitrogen accumulation achieved with the NH4+:NO3- ratio of 50:50 treatment. Compared with the situation where nitrate was supplied alone, increasing the ammonium proportion increased the whole plant biomass by 93.2%, 139.7%, 59.0%, and 30.5%, the whole plant nitrogen accumulation by 44.9%, 94.6%, 32.8%, and 54.8%, and the whole plant carbon accumulation by 90.4%, 139.9%, 58.7%, and 26.6% in order. As a gateway for nitrogen input, the roots treated with an NH4+:NO3- ratio of 50:50 exhibited the highest ammonium and nitrate uptake rate, which may be related to the maximum total root length, root surface area, average root diameter, root volume, and largest root xylem vessel. As a gateway for carbon input, leaves treated with an NH4+:NO3- ratio of 50:50 exhibited the highest stomatal aperture, stomatal conductance, photosynthetic rate, transpiration rate, and photosynthetic products. The NH4+:NO3- ratio of 50:50 treatment had the largest stem xylem vessel area. This structure and force caused by transpiration may synergistically facilitate root-to-shoot nutrient translocation. Notably, the change in stomatal opening occurred in the early stage (4 hours) of the NH4+:NO3- ratio treatments, indicating that stomates are structures that are involved in the response to changes in the root NH4+:NO3- ratio. In summary, we recommend 50:50 as the appropriate NH4+:NO3- ratio for the growth of centipedegrass, which not only improves the nitrogen use efficiency but also enhances the carbon sequestration capacity.

During the movement or operation of coal mining equipment such as a roadheader, the vibration of the vehicle body can easily cause blurring of the onboard camera video. This leads to a decrease in the precision and reliability of machine vision detection based on the onboard video. In order to solve the above problem, an onboard video stabilization algorithm for roadheader based on CLAHE and Kalman filter is proposed. This algorithm consists of three parts: motion estimation, trajectory smoothing, and motion compensation. In the motion estimation stage, the contrast limited adaptive histogram equalization (CLAHE) algorithm is used to enhance the image of the underground roadway. The Shi-Tomasi algorithm is used to obtain the feature points of each image frame. The obtained feature points are tracked and matched by optical flow, and then the motion trajectory of the camera is calculated. In the trajectory smoothing stage, Kalman filtering is used to predict the current time value based on the optimal value of the previous frame of the video. It avoids the problem of pre-storing sampling data of mean filtering and improves the real-time performance of image stabilization. In the motion compensation stage, the jitter video is compensated frame by frame based on the relationship between the original motion path and the smooth path, generating a stable video sequence. The experimental results show the following points: ① After CLAHE enhancement processing, the success rate of feature point matching is increased by 58% compared to the non-enhancement processing and 43% compared to the HE enhancement processing. It indicates that the CLAHE algorithm can effectively improve the matching number of image feature points. ② Through pixel offset analysis, differential image analysis, and peak signal-to-noise ratio (PSNR) analysis, it is verified that the onboard video stabilization algorithm for roadheader based on CLAHE and Kalman filter has a good image stabilization effect. ③ Compared with the traditional HE+mean filtering algorithm, the algorithm based on CLAHE and Kalman filter reduces the overall time consumption of processing 100 frames of video images by 0.379 seconds, effectively improving the real-time performance of the video stabilization while removing jitter.

RNA structure plays a crucial role in gene regulation, in RNA stability and the essential biological processes. RNA secondary structure (RSS) motifs are the basic building blocks for investigating the biological mechanisms of structure. Here, we present a strategy for structural motif-based dynamic alignment, namely, RNA secondary-structural motif-comparing (RNAsmc), to identify structural motifs and quantitatively evaluate their underlying molecular functions. RNAsmc also has strong robustness to sequence length, folding protocol and RNA structural profile by chemical probing. Notably, it is also applicable to quantify structural variation in special RNA editing events (SNVs or SNPs, fragment insertion or deletion, etc.). The findings indicate that RNAsmc can uncover the heterogeneity of RNA secondary structure and score for similarities among components, which provides an impetus to cluster RNA families and evaluate allosteric effects. We find that RNAsmc exhibits remarkable detection efficiency for experimentally-derived RiboSNitches. Finally, the pipeline was assembled into an R software package to serve as an automated toolkit to explore, align, and cluster RSS. It is freely available for download at https://CRAN.R-project.org/package=RNAsmc.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Summary: Tibetans are the ideal population to study genetic adaptation in extreme environments. Here, we performed systematic phenotyping of 11,880 highlanders, covering 133 quantitative traits of 13 organ systems. We provided a comprehensive phenotypic atlas by comparing altitude adaptation and altitude acclimatization. We found the differences between adaptation and acclimatization are quantitative rather than qualitative, with a whole-system “blunted effect” seen in the adapted Tibetans. We characterized twelve different functional changes between adaptation and acclimatization. More importantly, we established a landscape of adaptive phenotypes of indigenous Tibetans, including 45 newly identified Tibetan adaptation-nominated traits, involving specific changes of Tibetans in internal organ state, metabolism, eye morphology, and skin pigmentation. In addition, we observed a sex-biased pattern between altitude acclimatization and adaptation. The generated atlas of phenotypic landscape provides new insights into understanding of human adaptation to high-altitude environments, and it serves as a valuable blueprint for future medical and physiological studies.

Enhancing the production capacity of natural gas hydrates (NGHs) is critical for its commercial development. Complex structure wells may efficiently increase drainage areas while enhancing exploitation efficiency. Based on the field data of China’s first offshore NGH test production, the numerical method was used to analyze the production performance of different complex structure well types by continuous depressurization production for 360 days under the preconditions of fixed effective completion length of 300 m and a pressure difference of 6 MPa. Results indicated that the complex structure well types deployed at the three-phase layer demonstrated superior production performance within 240 days of production; the DLW2 and HW2 well types stood out, with an average gas production rate Qg reaching 43,333 m3/d and a specific production index J of 24.1. After 360 days of production, benefiting from multi-layer combined production, the Cluster vertical well deployed at the multi-layer had the best production performance, with an average Qg of 34,444 m3/d and a J-index of 19.1. The research results provided insights into the complex structure well-type selection strategy for NGH depressurization in this sea area.

Graphical Abstract

Abstract Background To assess age- and sex-related changes in the superficial retinal capillary plexus (SCP) and deep retinal capillary plexus (DCP) in healthy Chinese adults. Methods In this cross-sectional study, all data were derived from the community-based Jidong Eye Cohort Study. Participants underwent optical coherence tomography angiography (OCTA) and other ocular and systemic examinations. The vessel densities of the whole measured area, parafovea, and four quadrants in the SCP and DCP were measured. Results We recruited 1036 eyes of 1036 healthy participants; the mean age was 40.4 ± 9.8 years, and 449 (43.3%) participants were males. The SCP and DCP vessel densities in all regions, except for temporal and nasal regions in the SCP, non-linearly decreased with age. The DCP vessel densities began to decrease at approximately 35 years of age, while the SCP vessel densities began to decrease at approximately 40 years of age. The DCP vessel densities decreased more rapidly than the SCP vessel densities at 35–50 years of age. The DCP vessel densities remained stable or slightly decreased after the age of 50 years in females, while those decreased linearly in most regions in males. Conclusions The retinal vessel density decreased earlier and more rapidly in the DCP than in the SCP, and the effect of aging on the DCP vessel density was sex-dependent. Our findings suggest that age and sex should be considered when interpreting clinical quantitative OCTA data.

PurposeWe have demonstrated that the depth of unbalanced interocular suppression can be quantified by balancing the interocular luminance differences required when both eyes are viewing simultaneously. In this study, we aimed to investigate the applicability of this method in children with intermittent exotropia (IXT), offering a quantitative assessment of interocular suppression in individuals with binocular imbalance. Additionally, we evaluated its association with the clinical characteristics of IXT.MethodsInterocular suppression in IXT was quantitatively measured using a polarizer and neutral-density (ND) filters. The density of the ND filter was adjusted incrementally from 0.3ND to 3ND, with a step size of 0.3ND (a total of 10 levels). Our prospective study involved 46 patients with IXT (mean age: 10.12 ± 4.89 years; mean ± SD) and 24 normal observers (mean age: 7.88 ± 1.83 years).ResultsThe suppression test exhibited good test–retest reliability, supported by statistical analysis. We observed more pronounced interocular suppression in individuals with IXT compared to controls. Notably, the magnitude of suppression during distant and near viewing significantly differed in IXT (1.55 ± 0.93 vs. 0.57 ± 0.64; Z = 4.764, p

IntroductionWith the increasingly serious problem of antiviral drug resistance, drug repurposing offers a time-efficient and cost-effective way to find potential therapeutic agents for disease. Computational models have the ability to quickly predict potential reusable drug candidates to treat diseases.MethodsIn this study, two matrix decomposition-based methods, i.e., Matrix Decomposition with Heterogeneous Graph Inference (MDHGI) and Bounded Nuclear Norm Regularization (BNNR), were integrated to predict anti-viral drugs. Moreover, global leave-one-out cross-validation (LOOCV), local LOOCV, and 5-fold cross-validation were implemented to evaluate the performance of the proposed model based on datasets of DrugVirus that consist of 933 known associations between 175 drugs and 95 viruses.ResultsThe results showed that the area under the receiver operating characteristics curve (AUC) of global LOOCV and local LOOCV are 0.9035 and 0.8786, respectively. The average AUC and the standard deviation of the 5-fold cross-validation for DrugVirus datasets are 0.8856 ± 0.0032. We further implemented cross-validation based on MDAD and aBiofilm, respectively, to evaluate the performance of the model. In particle, MDAD (aBiofilm) dataset contains 2,470 (2,884) known associations between 1,373 (1,470) drugs and 173 (140) microbes. In addition, two types of case studies were carried out further to verify the effectiveness of the model based on the DrugVirus and MDAD datasets. The results of the case studies supported the effectiveness of MHBVDA in identifying potential virus-drug associations as well as predicting potential drugs for new microbes.

Background A growing number of experiments have shown that microRNAs (miRNAs) can be used as target of small molecules (SMs) to regulate gene expression for treating diseases. Therefore, identifying SM-related miRNAs is helpful for the treatment of diseases in the domain of medical investigation. Methods This article presents a new computational model, called NIRBMSMMA (neighborhood-based inference (NI) and restricted Boltzmann machine (RBM)), which we developed to identify potential small molecule-miRNA associations (NIRBMSMMA). First, grounded on known SM-miRNAs associations, SM similarity and miRNA similarity, NI was used to predict score of an unknown SM-miRNA pair by reckoning the sum of known associations between neighbors of the SM (miRNA) and the miRNA (SM). Second, utilizing a two-layered generative stochastic artificial neural network, RBM was used to predict SM-miRNA association by learning potential probability distribution from known SM-miRNA associations. At last, an ensemble learning model was conducted to combine NI and RBM for identifying potential SM-miRNA associations. Results Furthermore, we conducted global leave one out cross validation (LOOCV), miRNA-fixed LOOCV, SM-fixed LOOCV and five-fold cross validation to assess performance of NIRBMSMMA based on three datasets. Results showed that NIRBMSMMA obtained areas under the curve (AUC) of 0.9912, 0.9875, 0.8376 and 0.9898 ± 0.0009 under global LOOCV, miRNA-fixed LOOCV, SM-fixed LOOCV and five-fold cross validation based on dataset 1, respectively. For dataset 2, the AUCs are 0.8645, 0.8720, 0.7066 and 0.8547 ± 0.0046 in turn. For dataset 3, the AUCs are 0.9884, 0.9802, 0.8239 and 0.9870 ± 0.0015 in turn. Also, we conducted case studies to further assess the predictive performance of NIRBMSMMA. These results illustrated the proposed model is a useful tool in predicting potential SM-miRNA associations.