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The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.

Abstract Background Papillary thyroid cancer (PTC) is an indolent disease with a favorable prognosis but characterized by a high recurrence rate. We aimed to improve precise stratification of recurrence risk in PTC patients with early stage using multi-gene signatures. Patients and methods The present study was performed using data from The Cancer Genome Atlas (TCGA) and multi-center datasets. Unsupervised consensus clustering was used to obtain the optimal molecular subtypes and least absolute shrinkage and selection operator (LASSO) analysis was performed to identify potential genes for the construction of recurrence signature. Kaplan-Meier survival analysis and the log-rank test was used to detect survival differences. Harrells concordance index (C-index) was used to assess the performance of the DNA damage repair (DDR) recurrence signature. Results Through screening 8 candidate gene sets, the entire cohort was successfully stratified into two recurrence-related molecular subtypes based on DDR genes: DDR-high subtype and DDR-low subtype. The recurrence rate of DDR-high subtype was significantly lower than DDR-low subtype [HR = 0.288 (95%CI, 0.084–0.986), P = 0.047]. Further, a two-gene DDR recurrence signature was constructed, including PER1 and EME2. The high-risk group showed a significantly worse recurrence-free survival (RFS) than the low-risk group [HR = 10.647 (95%CI, 1.363–83.197), P = 0.024]. The multi-center data demonstrated that proportion of patients with low expression of PER1 and EME2 was higher in the recurrence group than those in the non-recurrence group. Conclusions These findings could help accurately and reliably identify PTC patients with high risk of recurrence so that they could receive more radical and aggressive treatment strategies and more rigorous surveillance practices.

Background: Diabetic retinopathy (DR), one of the most common microvascular complications of diabetes mellitus (DM), is a major contributor of vision impairment and blindness worldwide. Studies have shown that air pollution exposure is adversely associated with DM. However, evidence is scarce regarding how air pollution exposure affects DR. This study aimed to investigate the association between ambient air pollution exposure and DR risk. Methods: The study population was based on the Fujian Eye Study (FJES), an ophthalmologic, epidemiologic survey investigating the eye health condition of residents in Fujian Province from 2018 to 2019. Daily average concentrations of ambient air pollutants (PM2.5, PM10, SO2, NO2, and O3) were acquired from a high-resolution air quality dataset in China from 2013 to 2018. We used a logistic regression model to examine the associations between DR risk and long-term air pollution at various exposure windows. Results: A total of 2405 out of the 8211 participants were diagnosed with diabetes, among whom 183 had DR. Ambient air pollution, especially particulate matter (i.e., PM2.5 and PM10) and NO2 were positively associated with DR prevalence among all the study subjects. Ambient SO2 and O3 concentrations were not associated with DR prevalence. PM2.5 and NO2 seemed to be borderline significantly associated with increased prevalence of DR in subjects with DM, especially under the model adjusted for sex, age, BMI, SBP, and DBP. Conclusions: These findings showed that long-term exposure to ambient particulate matter and NO2 was associated with a high DR risk in Fujian province, where ambient air pollution is relatively low.

BackgroundMajor depressive disorder (MDD) pathogenesis may involve metalloids in a significant way. The aim of our study was to identify potential links between MDD and metalloid elements [boron (B), germanium (Ge), arsenic (As), antimony (Sb)].MethodsA total of 72 MDD cases and 75 healthy controls (HCs) were recruited from Zhumadian Second People’s Hospital in Henan Province, China. The levels of four metallic elements (B, Ge, As, and Sb) in the serum and urine were measured using inductively coupled plasma mass spectrometry (ICP-MS).ResultsIn comparison to the HCs, the B, As, and Sb levels were considerably lower in the MDD group (p < 0.05) in the serum; the MDD group had significantly higher (p < 0.05) and significantly lower (p < 0.001) B and Sb levels in the urine. After adjusting for potential confounders, serum B (OR = 0.120; 95% CI, 0.048, 0.300; p < 0.001) and Sb (OR = 0.133; 95% CI, 0.055, 0.322; p < 0.001) showed a negative correlation with MDD. Urine B had a negative correlation (OR = 0.393; 95% CI, 0.193, 0.801; p = 0.01) with MDD, while urine Sb had a positive correlation (OR = 3.335; 95% CI, 1.654, 6.726; p = 0.001) with MDD. ConclusionOur current research offers insightful hints for future investigation into the function of metalloids in connection to MDD processes.

Mode converter (MC) is an indispensable element in the mode multiplexing and demultiplexing system. Most previously reported mode converters have been of the transmission type, while reflective mode converters are significantly lacking. In this paper, we propose an ultra-compact reflective mode converter (RMC) structure, which comprises a slanted waveguide surface coated with a metallic film and a subwavelength metamaterial refractive index modulation region. The results demonstrate that this RMC can achieve high-performance mode conversion within an extremely short conversion length. In the two-dimensional (2D) case, the conversion length for TE0–TE1 is only 810 nm, and the conversion efficiency reaches to 94.1% at the center wavelength of 1.55 μm. In a three-dimensional (3D) case, the TE0–TE1 mode converter is only 1.14 μm, with a conversion efficiency of 92.5%. Additionally, for TE0–TE2 mode conversion, the conversion size slightly increases to 1.4 μm, while the efficiency reaches 94.2%. The proposed RMC demonstrates excellent performance and holds great potential for application in various integrated photonic devices.

The global agriculture industry is encountering challenges due to labor shortages and the demand for increased efficiency. Currently, fruit yield estimation in guava orchards primarily depends on manual counting. Machine vision is an essential technology for enabling automatic yield estimation in guava production. To address the detection of guava in complex natural environments, this paper proposes an improved lightweight and efficient detection model, V-YOLO (VanillaNet-YOLO). By utilizing the more lightweight and efficient VanillaNet as the backbone network and modifying the head part of the model, we enhance detection accuracy, reduce the number of model parameters, and improve detection speed. Experimental results demonstrate that V-YOLO and YOLOv10n achieve the same mean average precision (mAP) of 95.0%, but V-YOLO uses only 43.2% of the parameters required by YOLOv10n, performs calculations at 41.4% of the computational cost, and exhibits a detection speed that is 2.67 times that of YOLOv10n. These findings indicate that V-YOLO can be employed for rapid detection and counting of guava, providing an effective method for visually estimating fruit yield in guava orchards.

BackgroundThe gut microbiota has been significantly associated with differentiated thyroid cancer (DTC). However, the causal relationship between the gut microbiota and DTC remains unexplored.MethodsGenome-wide association study (GWAS) summary databases were utilized to select exposures and outcomes. The Mendelian randomization (MR) method was employed to investigate the causal relationship between the gut microbiota and DTC. A sensitivity analysis was performed to assess the reliability of the findings.ResultsFour bacterial traits were associated with the risk of DTC: Class Mollicutes [odds ratio (OR) = 10.953, 95% confidence interval (95% CI): 2.333–51.428, p = 0.002], Phylum Tenericutes (OR = 10.953, 95% CI: 2.333–51.428, p = 0.002), Genus Eggerthella (OR = 3.219, 95% CI: 1.033–10.024, p = 0.044), and Order Rhodospirillales (OR = 2.829, 95% CI: 1.096–7.299, p = 0.032). The large 95% CI range for the Class Mollicutes and the Phylum Tenericutes may be attributed to the small sample size. Additionally, four other bacterial traits were negatively associated with DTC: Genus Eubacterium fissicatena group (OR = 0.381, 95% CI: 0.148–0.979, p = 0.045), Genus Lachnospiraceae UCG008 (OR = 0.317, 95% CI: 0.125–0.801, p = 0.015), Genus Christensenellaceae R-7 group (OR = 0.134, 95% CI: 0.020–0.886, p = 0.037), and Genus Escherichia Shigella (OR = 0.170, 95% CI: 0.037–0.769, p = 0.021).ConclusionThese findings contribute to our understanding of the pathological mechanisms underlying DTC and provide novel insights for the clinical treatment of DTC.

Summary: Constitutive explorations indicate a correlation between circular RNAs (circRNAs) and cardiovascular diseases. However, the involvement of circRNAs in endothelial recuperation and in-stent restenosis (ISR) remains underexplored. CircTMEM165 has first been reported to be highly expressed in hypoxic human umbilical vein endothelial cells (HUVECs). Here, we identified that circTMEM165 was downregulated in ISR patients, inversely correlating with ISR severity. Functionally, circTMEM165 was found to be abundant in endothelial cells, inhibiting inflammation, and adhesion. Particularly, we first observed that circTMEM165 could alleviate HUVECs apoptosis and mitochondrial fission induced by lipopolysaccharide (LPS). Mechanistically, circTMEM165, as a miR-192-3p sponge, enhancing SCP2 expression, which serves as a critical regulator of HUVECs biological functions. Moreover, in vivo, circTMEM165 attenuated intimal hyperplasia and facilitated repair following classic rat carotid artery balloon injury model. These findings investigated the circTMEM165-miR-192-3p-SCP2 axis as a critical determinant of endothelial health and a potential biomarker and therapeutic target for vascular disorders.

Post-translational modifications (PTM) are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids. PTMs play essential roles in biological function and regulation and have been linked with several diseases. Modifications of protein acylation (Kac), a type of PTM, are known to induce epigenetic regulatory processes that promote various diseases. Thus, an increasing number of studies focusing on acylation modifications are being undertaken. Butyrylation (Kbu) is a new acylation process found in animals and plants. Kbu has been recently linked to the onset and progression of several diseases, such as cancer, cardiovascular diseases, diabetes, and vascular dementia. Moreover, the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels, suggesting that butyrylation may play a therapeutic role in these diseases. In addition, butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth, development, and metabolism of rice. The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated. This study reviews the potential role of histone Kbu, as well as the mechanisms underlying this process. It also summarizes various enzymes and analytical methods associated with Kbu, with the goal of providing new insights into the role of Kbu in gene regulation and diseases.

This paper focuses on achieving leader-follower mean square consensus in semi-Markov jump multi-agent systems. To effectively reduce communication costs and control updates, we propose an event-triggered protocol based on stochastic sampling. The stochastic sampling interval randomly switches between finite given values, while the event-triggered function depends on the stochastic sampled data from neighboring agents. Using the event-triggered strategy, we present sufficient conditions to ensure mean square consensus. Finally, we provide a numerical example demonstrating the effectiveness of the theoretical results.

Background: Ginsenoside Rg2 (Rg2) has a variety of pharmacological activities and provides benefits during inflammation, cancer, and other diseases. However, there are no reports about the relationship between Rg2 and atherosclerosis. Methods: We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to detect the cell viability of Rg2 in vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs). The expression of inflammatory factors in HUVECs and the expression of phenotypic transformation-related marker in VSMCs were detected at mRNA levels. Western blot method was used to detect the expression of inflammation pathways and the expression of phenotypic transformation at the protein levels. The rat carotid balloon injury model was performed to explore the effect of Rg2 on inflammation and phenotypic transformation in vivo. Results: Rg2 decreased the expression of inflammatory factors induced by lipopolysaccharide in HUVECs–without affecting cell viability. These events depend on the blocking regulation of NF-κB and p-ERK signaling pathway. In VSMCs, Rg2 can inhibit the proliferation, migration, and phenotypic transformation of VSMCs induced by platelet derived growth factor-BB (PDGF-BB)–which may contribute to its anti-atherosclerotic role. In rats with carotid balloon injury, Rg2 can reduce intimal proliferation after injury, regulate the inflammatory pathway to reduce inflammatory response, and also suppress the phenotypic transformation of VSMCs. Conclusion: These results suggest that Rg2 can exert its anti-atherosclerotic effect at the cellular level and animal level, which provides a more sufficient basis for ginseng as a functional dietary regulator.

Incorporating crop residues into the soil is an effective method for improving soil carbon sequestration, fertility, and crop productivity. Such potential benefits, however, may be offset if residue addition leads to a substantial increase in soil greenhouse gas (GHG) emissions. This study aimed to quantify the effect of different crop residues with varying C/N ratios and different nitrogen (N) fertilizers on GHG emissions, yield, and yield-scaled emissions (GHGI) in winter wheat. The field experiment was conducted during the 2018–2019 winter wheat season, comprising of four residue treatments (no residue, maize residue, soybean residue, and maize-soybean mixed residue) and four fertilizer treatments (control, urea, manure, and manure + urea). The experiment followed a randomized split-plot design, with N treatments as the main plot factor and crop residue treatments as the sub-plot factor. Except for the control, all N treatments received 150 kg N ha−1 season−1. The results showed that soils from all treatments acted as a net source of N2O and CO2 fluxes but as a net sink of CH4 fluxes. Soybean residue significantly increased soil N2O emissions, while mixed residue had the lowest N2O emissions among the three residues. However, all residue amendments significantly increased soil CO2 emissions. Furthermore, soybean and mixed residues significantly increased grain yield by 24% and 21%, respectively, compared to no residue amendment. Both soybean and mixed residues reduced GHGI by 25% compared to maize residue. Additionally, the urea and manure + urea treatments exhibited higher N2O emissions among the N treatments, but they contributed to significantly higher grain yields and resulted in lower GHGI. Moreover, crop residue incorporation significantly altered soil N dynamics. In soybean residue-amended soil, both NH4+ and NO3− concentrations were significantly higher (p < 0.05). Conversely, soil NO3− content was notably lower in the maize-soybean mixed residue amendment. Overall, our findings contribute to a comprehensive understanding of how different residue additions from different cropping systems influence soil N dynamics and GHG emissions, offering valuable insights into effective agroecosystems management for long-term food security and soil sustainability while mitigating GHG emissions.

Nitrogen (N) fertilizer and crop residue amendments are important agricultural practices that could increase soil health, fertility, and crop yield. Such practices may also change soil denitrification processes where contradictory observations have been reported on soil N2O emissions with fewer studies on N2 emissions due to its large atmospheric background concentrations limiting its soil-borne measurement. This study aims to investigate N2O production and reduction of N2 emissions under a conducive denitrifying environment (like anaerobic microsites, 80% WFPS, available N and C) after rice straw amendment and KNO3 application to three different soil types (fluvo-aquic, black, and paddy soils). In this regard, three treatments for three different soil types were set consisting of (a) a non-amended treatment (control), (b) a KNO3 treatment (KNO3, 20 mM KNO3), and (c) a straw plus KNO3 treatment (2.5 g rice straw kg−1 dry soil and 20 mM KNO3), which were incubated under 80% WFPS. Moreover, direct N2O and N2 fluxes were measured over 17 days in the current incubation experiment with a robotized incubation system using a helium atmosphere. Results showed that rice straw amendment combined with N fertilizer increased both N2O and N2 fluxes compared with control or KNO3 treatments in all three soil types. Overall, compared with the black and paddy soils, the N2O and N2 fluxes were higher in the fluvo-aquic soil, with a maximum of 234.2 ± 6.3 and 590.1 ± 27.3 g N ha−1 from F_SK treatment, respectively, during the incubation period. The general trends in three soil types of both N2O and N2 emissions were control < KNO3 < rice straw plus KNO3 treatments. Straw amendment in combination with KNO3 can stimulate a high denitrification rate (less N2O and higher N2), whereas their effect on stoichiometric ratios of N2O/(N2O + N2) highly depends on soil nitrate concentration, oxygen level, soil moisture content, and labile C. The current study underscores that the rice straw amendment in combination with N fertilizer can trigger denitrification with less increment on soil N2O but higher N2 emissions under conditions favoring denitrification.

Soil and water conservation measures (SWCMs) are vital in reducing runoff and ultimately affect water security and regional development. However, previous studies have mainly focused on the impact of a single SWCM, neglecting to distinguish between the effects of different SWCMs on runoff reduction. A Soil and Water Assessment Tool (SWAT) model was established in the Jing River catchment to identify the responses to runoff changes resulting from climate change and human activities. The model was used to quantitatively analyse the impact of different SWCMs on runoff reduction. The results indicated that human activities contributed significantly more to runoff reduction than climate change. The reduction benefits of different unit area changes for each SWCM on discharge, surface runoff and water yield at the outlet were ranked as follows: changing cultivated land to forest land > changing cultivated land to grassland > building terraces on a 5–15° slope > building terraces on a 5–25° slope > building terraces on a 15–25° slope. Regional authorities should comprehensively consider the effects of various SWCMs on water reduction, and optimise the layout of vegetation and terracing measures, to support the efficient utilization of water resources in the Jing River catchment.

IntroductionTo document the successional processes of shrub-herb communities after large-scale human disturbance, and understand how changing environmental conditions affect species replacement in semi-humid hilly areas.MethodsUtilizing the established permanent plots in the hilly area of Taihang Mountain, we evaluated temporal patterns of vegetation and soil following grass-to-shrub succession.Results and DiscussionAlong secondary succession, Vitex negundo var. heterophylla gradually dominated in dry sunny slope and shared the dominance with Leptodermis oblonga in shaded slope. Herbaceous dominant species in shrub-herb communities switched from Themeda japonica, Bothriochloa ischaemum, Artemisia sacrorum, and Cleistogenes chinensis in 1986 census to B. ischaemum and A. sacrorum in 2008 census, but herb was no longer dominant in 2020 census. As succession progresses, species dominance increased while richness decreased generally, and herb cover and aboveground biomass decreased, whereas shrub height, cover, and aboveground biomass increased significantly. Soil organic matter (SOM), total nitrogen (TN), total phosphorus (TP), and total potassium (TK) in topsoil increased significantly while pH declined by 1.04 units over the past three decades. Plant communities transitioned from perennial herbs to shrub-herb and then shrub communities, and V. negundo var. heterophylla dominated in the succession of shrub-herb communities. Climate and soil properties, combined with plant attributes, together drive post-disturbance secondary succession. From a management perspective, the tight coupling between vegetation and soil under local climatic conditions should be considered to improve the fragile ecosystem in the hilly area of Taihang Mountain.

Purpose: This study aimed to determine the efficacy of the dexamethasone (DEX) intravitreal implant for the regression of macular edema and the improvement of best-corrected visual acuity (BCVA) after the removal of idiopathic epiretinal membrane (ERM).Methods: This prospective randomized controlled trial recruited 81 patients with idiopathic ERM. These patients all underwent 25-gauge pars plana vitrectomy combined with ERM and internal limiting membrane peeling surgery. Among them, 41 eyes in the DEX group received additional DEX implants and 40 in the non-DEX group did not. Outcomes including central retinal thickness (CRT), BCVA, and intraocular pressure were measured 1 and 3 months after surgery.Results: The DEX group had thinner CRTs compared to the non-DEX group at 1 month postoperatively (p

Abstract Introduction It remains controversial whether polypoidal choroidal vasculopathy (PCV) represents a subtype of neovascular age-related macular degeneration (nAMD) or is a distinct disease entity. This study aimed to compare and analyze systemic and serum risk factors for nAMD and PCV in an aging Chinese population. Methods A retrospective study was performed on 108 patients with nAMD, 131 patients with PCV, and 219 control subjects. Serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1 (APOA1), apolipoprotein B (APOB), complement 3 (C3), and complement 4 (C4) together with data on systemic risk factors, including hyperlipidemia, hypertension, diabetes mellitus (DM), coronary artery disease (CAD), and asthma, were collected. Chi-square tests, independent-samples t tests, and binary logistic regression analyses were performed to evaluate the associations of risk factors with nAMD and PCV. Results Patients with PCV and those with nAMD were likely to have hyperlipidemia (P 0.05), DM was associated with PCV development (OR = 0.535, P = 0.044). Regarding serum risk factors, HDL, LDL, TG, APOB, and C3 were significantly associated with nAMD (OR 0.05). Conclusion Our findings indicate that hyperlipidemia is significantly associated with both nAMD and PCV. Serum lipid and complement levels have an effect on the pathogenesis of nAMD and PCV, and consideration of the differences between systemic and serum risk factors should be taken into account in clinical management.

Abstract There was growing evidence that inflammatory responses played significant roles in malignancies. However, the impact of pro-inflammatory-to-anti-inflammatory factor ratio in tumor tissues has not been investigated in gastric cancer (GC) yet. We collected patient data from The Cancer Genome Atlas (TCGA) database. A total of 270 stomach adenocarcinoma (STAD) patients without distant metastasis were included in the study. After screening 12 candidate pro-inflammatory-to-anti-inflammatory pairs, only the IL-6/IL-10 mRNA expression ratio in tumor tissues had a significant effect on overall survival (OS) of STAD patients (P = 0.014). X-tile analysis showed that the greatest survival differences were obtained when the cutoff value of IL-6/IL-10 mRNA expression ratio was set at 1.3 and 5.5. With the low-ratio group (IL-6/IL-10 mRNA expression ratio: 5.5) was significantly shorter (P

Microbial residue nitrogen can indicate soil quality and is crucial for soil nitrogen retention and supply. However, it is still unclear how the dynamic changes in soil microbial residue nitrogen affect crop nitrogen uptake in agricultural practice. Based on a long-term wheat-maize rotation experiment with different nitrogen application rates (150 kg N ha−1, 200 kg N ha−1, and 300 kg N ha−1), 15N-labeled nitrogen fertilizer was applied during the wheat season to track the dynamics of soil microbial residue nitrogen and its mediated fertilizer nitrogen. The results showed that nitrogen addition was beneficial to the accumulation of microbial residue nitrogen (mainly fungal microbial residue nitrogen). Its contribution rate to soil total nitrogen is 54.87–56.55%, and the fertilizer nitrogen allocated to it accounts for 27.10–47.50% of the remaining fertilizer nitrogen in the soil. Ultimately, 6.77–10.24% of the nitrogen fertilizer applied remained in the soil as microbial residue nitrogen. In addition, microbial residue nitrogen is mainly mineralized during the jointing and filling stages of wheat. In a word, the accumulation and mineralization of soil microbial residue nitrogen during the application of 200 kg N ha−1 better guaranteed the uptake of nitrogen by wheat, which provided a reliable basis for guiding farmland fertility improvement and nitrogen fertilizer reduction in the North China Plain.

Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, which thereby affects retinal angiogenesis. But the genetic factors contributing to FEVR’s development or pathogenesis remain elusive. In a Chinese family with FEVR with 19 members, by using whole-exome sequencing, we identified a candidate disease-causing DNA variant in sorting nexin 31 (SNX31) (c.963delG; p. Trp321Cys), which results in a frameshift mutation. We studied the biochemical mechanism of this mutation and determined that it is deficient in β1-integrin binding and stability. The SNX31 c.963delG point mutation mouse model (SNX31m/m) was constructed with CRISPR/Cas9 technology. At 2–4 months of age, SNX31m/m mice showed fundus phenotypes similar to FEVR-like changes, including vascular leakage and retinal atrophy. Moreover, we found that VEGF and apoptotic pathways were involved in these ocular phenotypes. Hence, our study extended the FEVR mutation spectrum to include SNX31. These findings expanded our understanding of the molecular pathogenesis of FEVR and may facilitate the development of methods for the diagnosis and prevention of FEVR.

Abstract Background Hypospadias is a congenital anomaly of the male urogenital system. Genetics factors play an important role in its pathogenesis. To search for potential causal genes/variants for hypospadias, we performed exome sequencing in a pedigree with three patients across two generations and a cohort of 49 sporadic patients with hypospadias. Results A novel BRAF variant (NM_004333.6: c.362C > A) was found to co-segregate with the hypospadias phenotype in the disease pedigree. In cells overexpressing the BRAF mutant, the phosphorylation level of p38 MAPK was significantly increased as compared with the cells overexpressing the wild-type BRAF or RASopathy-related BRAF mutant. This variant further led to a reduced transcription level of the SRY gene, which is essential for the normal development of the male reproductive system. In the cohort of sporadic patients, we identified two additional variants in p38 MAPK signaling-related genes (TRIM67 and DAB2IP) potentially associated with hypospadias. Conclusion Our study expands the phenotypic spectrum of variants affecting p38 MAPK signaling toward the involvement of hypospadias.

Abstract Purpose To describe the objective and design of the Fujian Eye Study and to introduce the general characteristics and vision condition of this study. Methods The Fujian Eye Study (FJES) is a population-based cross-sectional survey on the public eye health status of residents over 50 years old in the entire Fujian Province of Southern China, which contains both urban and rural areas and coastal and inland regions. 10,044 participants were enrolled using a two-stage cluster sampling design and underwent a questionnaire and a series of standard examinations both physical and ocular. The main subgroups of data collection included age, sex, region, refractive error, education background, income, eating habits, smartphone usage in the dark, complaints of eye discomfort, history of chronic diseases, consumption of tobacco, alcohol, or tea. Results 8211 (81.8%) participants were finally included and were divided into urban populations (4678 subjects) and rural populations (3533 subjects) and coastal residents (6434 subjects) and inland residents (1777 subjects); 4836 participants were female. The mean age was 64.39 (SD 8.87) years (median 64 years; range 50–98 years). 227 (3.33%) had vision impairment (VI), 195 (2.87%) had low vision and 14 (0.21%) were blind. The mean presenting near visual acuity (PNVA) was 0.28 (0.17), the mean presenting distance visual acuity (PDVA) was 0.61 (0.30), and the mean best corrected visual acuity (BCVA) was 0.82 (0.28). Conclusions The FJES collected detailed questionnaire information and overall ocular and physical examinations, which provide the opportunity to identify risk factors and images of VI and eye diseases and to evaluate their associations with chronic diseases and basic personal information.

Acoustic manipulation is a set of versatile platforms with excellent manipulation capabilities. In recent years, researchers have increasingly achieved specific manipulations beyond the translation and capture of particles. Here, we focus on the acoustic field momentum mechanism that generates an acoustic radiation force (ARF). A phononic crystal (PC) waveguide is established to amplify the forward momentum of the acoustic beam through the mode conversion of the acoustic field. Based on the conservation of momentum, the object gains reverse momentum. Thus, acoustic pulling can be achieved through the mode conversion of the acoustic field. Furthermore, we analyze the ARFs of two identical objects. It turns out that they can be manipulated separately by opposing forces. Our study provides a new way to achieve stable long-range acoustic pulling, and will explore, beneficially, the interaction between acoustic waves and matter.

The BIM (building information model), as an innovative architectural technology, has received sufficient attention in the AEC (architecture, engineering, and construction) industry, providing many possibilities for improving building management. Therefore, exploring the factors influencing of how BIM technology is applied has strong practical significance for promoting the application of BIM technology. Based on previous research, this article identified 16 factors that affect the application of BIM and established a relationship function between the influencing factors based on the current actual situation. A system dynamics (SD) model was constructed to analyze the mechanism of these factors and explore the key influencing factors of BIM application. The research results indicate that BIM technology maturity, the difficulty level of BIM software operation, and the degree of collaboration among various departments within an enterprise are key influencing factors. This article conducts an empirical analysis of a large project in China. Based on the research results, targeted improvement measures are proposed to improve the current level of BIM technology application and promote further development of BIM technology. However, due to the rapid development of BIM technology, the effects and weights of the influencing factors in different eras may not be consistent. The reference effect of this study’s results on era period of ten years or even longer is weakened, and scholars will need to continuously update this article in the future.

Abstract Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.

Abstract Background Identifying breast cancer patients with DNA repair pathway-related germline pathogenic variants (GPVs) is important for effectively employing systemic treatment strategies and risk-reducing interventions. However, current criteria and risk prediction models for prioritizing genetic testing among breast cancer patients do not meet the demands of clinical practice due to insufficient accuracy. Methods The study population comprised 3041 breast cancer patients enrolled from seven hospitals between October 2017 and 11 August 2019, who underwent germline genetic testing of 50 cancer predisposition genes (CPGs). Associations among GPVs in different CPGs and endophenotypes were evaluated using a case-control analysis. A phenotype-based GPV risk prediction model named DNA-repair Associated Breast Cancer (DrABC) was developed based on hierarchical neural network architecture and validated in an independent multicenter cohort. The predictive performance of DrABC was compared with currently used models including BRCAPRO, BOADICEA, Myriad, PENN II, and the NCCN criteria. Results In total, 332 (11.3%) patients harbored GPVs in CPGs, including 134 (4.6%) in BRCA2, 131 (4.5%) in BRCA1, 33 (1.1%) in PALB2, and 37 (1.3%) in other CPGs. GPVs in CPGs were associated with distinct endophenotypes including the age at diagnosis, cancer history, family cancer history, and pathological characteristics. We developed a DrABC model to predict the risk of GPV carrier status in BRCA1/2 and other important CPGs. In predicting GPVs in BRCA1/2, the performance of DrABC (AUC = 0.79 [95% CI, 0.74–0.85], sensitivity = 82.1%, specificity = 63.1% in the independent validation cohort) was better than that of previous models (AUC range = 0.57–0.70). In predicting GPVs in any CPG, DrABC (AUC = 0.74 [95% CI, 0.69–0.79], sensitivity = 83.8%, specificity = 51.3% in the independent validation cohort) was also superior to previous models in their current versions (AUC range = 0.55–0.65). After training these previous models with the Chinese-specific dataset, DrABC still outperformed all other methods except for BOADICEA, which was the only previous model with the inclusion of pathological features. The DrABC model also showed higher sensitivity and specificity than the NCCN criteria in the multi-center validation cohort (83.8% and 51.3% vs. 78.8% and 31.2%, respectively, in predicting GPVs in any CPG). The DrABC model implementation is available online at http://gifts.bio-data.cn/ . Conclusions By considering the distinct endophenotypes associated with different CPGs in breast cancer patients, a phenotype-driven prediction model based on hierarchical neural network architecture was created for identification of hereditary breast cancer. The model achieved superior performance in identifying GPV carriers among Chinese breast cancer patients.

IntroductionThe aim of this study was to assess the effects of preoperative intravitreal aflibercept (IVA) injection on the incidence of postoperative vitreous hemorrhage (VH) after vitrectomy for proliferative diabetic retinopathy (PDR).MethodsThis study involved a prospective, randomized clinical trial. One hundred twenty-eight eyes of 128 patients of PDR who underwent pars plana vitrectomy (PPV) were enrolled. Sixty-four eyes were assigned randomly to either the IVA group (IVA injection 1 to 5 days before PPV) or the control group (no IVA injection). The primary outcome was the incidence of VH at 1 month after PPV. Secondary outcome measures were best-corrected visual acuity (BCVA) changes from baseline to at 1 week, 1 month, 2 months, and 3 months after surgery.ResultsThe VH incidences in the IVA group and the control group were 14.8 and 39.3% at week 1, 8.6 and 31.7% at month 1, 11.7 and 30.5% at month 2, and 8.6 and 30.5% at month 3, respectively. Intergroup differences showed a significantly decreased VH rate in the IVA group compared with that in the control group at week 1, month 1, and month 3 (p = 0.021, 0.006, and 0.047, respectively). Compared to the baseline, neither the mean BCVA nor the BCVA change in the Logarithm of the Minimum Angle of Resolution (logMAR) scale did differ significantly between the two groups at each visit point. There are a greater number of eyes with BCVA improvement of more than 2 logMAR in the IVA group than in the control group at week 1 (8 vs. 2, p = 0.048).ConclusionsThis study found that the adjunctive use of preoperative IVA reduces early and late postoperative VH in vitrectomy for PDR.

Abstract Purpose To study whether retinal pigment epithelium (RPE) disruption and choroidal hyper-transmission on spectral-domain optical coherence tomography (SD-OCT) are signs of inflammatory neovascularization (CNV) in punctate inner choroidopathy (PIC). Methods This is a prospective cohort study. Seventeen patients (18 eyes) were diagnosed as PIC without CNV at baseline. Changes of morphological characteristics including choroidal hyper-transmission, hypo-transmission, RPE disruption, and ellipsoid zone (EZ) damage on SD-OCT were observed and recorded at baseline, 4, 8 and 12 weeks, respectively. The occurrence of CNV was detected by OCTA at each visit. Fisher’s exact test was used to compare the relationship with each morphological sign and evaluate the predictable capability of secondary CNV in PIC (PIC+CNV) based on the structure changes on OCT. Results Among the 18 eyes, a total of 5 eyes (27.8%) developed PIC+CNV subsequently within 4 weeks follow-up. At 4, 8 and 12 weeks of follow-up, RPE disruption and choroidal hyper-transmission were found in all 5 PIC+CNV eyes. The incidence of RPE disruption was significant higher in PIC+CNV eyes compared with PIC eyes (P=0.001). PIC eyes with hyper-transmission had a higher risk for developing CNV compared with those without hyper-transmission (P=1.17×10-3). 2 out of 5 PIC+CNV eyes had a choroidal hypo-transmission component adjacent to hyper-transmission zone at 4 weeks of follow-up, and hypo-transmission could be observed in all 5 PIC+CNV eyes at 8 weeks of follow-up. The incidence of choroidal hypo-transmission was significant higher in PIC+CNV eyes than PIC eyes after 8 weeks. EZ damage began to recover at 4 weeks of follow-up and had no significant difference in the PIC eyes and PIC+CNV eyes (P=0.150, 0.196, 0.353). Conclusion The presence of choroidal hyper-transmission and RPE disruption on SD-OCT is associated with the PIC+CNV. SD-OCT imaging facilitates the differentiation and track of the progression of inflammatory lesions and secondary CNV in PIC.

Purpose: The purpose of this study was to explore the potential underlying mechanism of anti-vascular effects of peroxisome proliferator–activated receptor α (PPARα) agonist fenofibrate against corneal neovascularization (CNV) through the changes of lipid metabolism during CNV.Methods: A suture-induced CNV model was established and the clinical indications were evaluated from day 1 to day 7. Treatments of vehicle and fenofibrate were performed for 5 days after suture and the CNV areas were compared among the groups. The eyeballs were collected for histological analysis, malondialdehyde (MDA) measurement, terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeling (TUNEL) staining, western blot, quantitative real-time PCR (qRT-PCR) assays and immunohistochemical (IHC) staining to elucidate pathological changes and the underlying mechanism.Results: Lipi-Green staining and MDA measurement showed that lipid deposition and peroxidation were increased in the CNV cornea while the expression of long-chain acyl-coenzyme A synthetase 1 (ACSL1), carnitine palmitoyltransterase 1A(CPT1A) and medium-chain acyl-coenzyme A dehydrogenase (ACADM), which are key enzymes of fatty acid β-oxidation (FAO) and targeted genes of peroxisome proliferator-activated receptor alpha (PPARα) pathway, were decreased in CNV cornea. Fenofibrate suppressed lipid accumulation and peroxidation damage in the CNV cornea. Fenofibrate upregulated the expression levels of PPARα, ACSL1, CPT1A, and ACADM compared with vehicle group. IHC staining indicated that fenofibrate also decreased the expression of VEGFa, VEGFc, TNFα, IL1β and CD68.Conclusion: Disorder of lipid metabolism may be involved in the formation of suture-induced CNV and fenofibrate played anti-neovascularization and anti-inflammatory roles on cornea by regulating the key enzymes of lipid metabolism and ameliorating lipid peroxidation damage of cornea through PPARα signaling pathway.

PurposeClinical guidelines presently recommend total thyroidectomy for the treatment of medullary thyroid cancer (MTC). This study was aimed to investigate whether lobectomy could be the initial treatment for stage I MTC patients.MethodsThe retrospective study was based on data from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The risk factors of survival were estimated by the univariate and multivariate Cox proportional-hazards model. The effect of age on death risk was estimated using restricted cubic splines. Survival curves were constructed according to the Kaplan–Meier method.ResultsA total of 988 stage I MTC patients was included in the study. Among them, 506 (51.2%) MTC patients received lobectomy and 482 (48.8%) received total thyroidectomy. The only independent prognostic factor for overall survival (OS) and disease-specific survival (DSS) was age, according to univariate and multivariate Cox regression analysis. The hazard ratio (HR) increased relatively slowly with age growing under the age of approximately 60 years. However, the death risk of MTC patients began to rise sharply with increasing age above 60 years. For patients under the age of 60, a significant survival difference for OS and DSS was observed between the lobectomy group and total thyroidectomy group (p < 0.05). However, for patients aged above 60, no significant survival difference was observed for OS or DSS (p > 0.05).ConclusionTotal thyroidectomy was an appropriate treatment for stage I MTC patients under the age of 60, which was consistent with the recommendation of the clinical guidelines. However, for those over the age of 60, lobectomy may be explored as a better surgical option. The findings may provide the evidence base for improving the clinical management of stage I MTC patients. Further prospective multicenter clinical studies are needed including information regarding RET status as well as calcitonin and CEA levels.

The COVID-19 pandemic has dramatically reshaped consumers' grocery shopping behavior. Meanwhile, change in consumer shopping behavior might further exert a considerable and far-reaching impact on the food retail industry. Although the existing literature provides investigation on the impact of the pandemic on the retail industry, very few studies discuss the impact of changes in consumer shopping behavior on the stock market performance of the retail industry. This paper investigates selected food retailers listed in China's stock market. To overcome the problems of the Chow test, the Quandt-Andrews test was used to identify the dates of breakpoints of structural change in the stock price performance of those selected companies. The results suggest that there has indeed been an industry-wide structural change in the stock market performance during the pandemic. The study found that the dates of breakpoints for the selected companies were concentrated in the first half of 2020, when China was hit by the Covid-19 pandemic the most. Our survey shows that under strict epidemic prevention and control measures, consumers have gradually adapted to the new normal of epidemic prevention to a certain extent, established safety awareness, and changed their consumption behavior. Our study on stock price data implies that Chinese consumers experienced a shift from physical store offline purchases to online purchasing model.

The United Nations predicts that by 2050, the world’s total population will increase to 9.15 billion, but the per capita cropland will drop to 0.151°hm2. The acceleration of urbanization often comes at the expense of the encroachment of cropland, the unplanned expansion of urban area has adversely affected cultivation. Therefore, the automatic extraction of buildings, which are the main carriers of urban population activities, in remote sensing images has become a more meaningful cropland observation task. To solve the shortcomings of traditional building extraction methods such as insufficient utilization of image information, relying on manual characterization, etc. A U-Net based deep learning building extraction model is proposed and named AttsegGAN. This study proposes an adversarial loss based on the Generative Adversarial Network in terms of training strategy, and the additionally trained learnable discriminator is used as a distance measurer for the two probability distributions of ground truth Pdata and prediction Pg. In addition, for the sharpness of the building edge, the Sobel edge loss based on the Sobel operator is weighted and jointly participated in the training. In WHU building dataset, this study applies the components and strategies step by step, and verifies their effectiveness. Furthermore, the addition of the attention module is also subjected to ablation experiments and the final framework is determined. Compared with the original, AttsegGAN improved by 0.0062, 0.0027, and 0.0055 on Acc, F1, and IoU respectively after adopting all improvements. In the comparative experiment. AttsegGAN is compared with state-of-the-arts including U-Net, DeeplabV3+, PSPNet, and DANet on both WHU and Massachusetts building dataset. In WHU dataset, AttsegGAN achieved 0.9875, 0.9435, and 0.8907 on Acc, F1, and IoU, surpassed U-Net by 0.0260, 0.1183, and 0.1883, respectively, demonstrated the effectiveness of the proposed components in a similar hourglass structure. In Massachusetts dataset, AttsegGAN also surpassed state-of-the-arts, achieved 0.9395, 0.8328, and 0.7130 on Acc, F1, and IoU, respectively, it improved IoU by 0.0412 over the second-ranked PSPNet, and it was 0.0025 and 0.0101 higher than the second place in Acc and F1.

Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.

AimsTo describe the long-term effect of scleral buckling (SB) surgery for stage 4A retinopathy of prematurity (ROP).MethodsA retrospective chart review was conducted for patients with a diagnosis of stage 4A ROP who underwent SB between October 2010 and October 2021. Basic data were collected from patient charts, including gender, birth weight, gestational age at birth, disease stage, presence of plus disease, preoperative treatment [laser photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) agent therapy, or a combination of both] and complications (vitreous hemorrhages), postmenstrual age at surgery, intraoperative combined treatment, and total length of follow-up. Retinal attachment status after surgery, postoperative complications (glaucoma, cataract), date and type of subsequent retinal surgeries (if performed), and refractive status 1 year after surgery were evaluated. The follow-up time after the first procedure was over 1 year.ResultsSix-two eyes from forty-eight patients met the inclusion criteria for this study. The initial reattachment rate was 93.5% (58/62 eyes), and the final reattachment rate was 100% after two procedures at the end of follow-up. The incidence of cataracts was 3.2% (2/62), with no eye subsequently needing lensectomy surgery. None of the patients developed glaucoma during the follow-up time. The average spherical equivalent refraction value for patients was −3.00 ± 2.51 D (−7.60 D to +2.75 D) 1 year after surgery.ConclusionSB, especially segmental buckling, which induces less myopia and does not require buckle removal, has the potential to provide a significant positive impact in the treatment of stage 4A ROP.

Purpose: We report a case of a 19-year-old male who presented with bilateral Vogt-Koyanagi-Harada (VKH)-like panuveitis following an injection of an inactivated Covid-19 vaccine. Observations: A 19-year-old male was referred to our clinic with a 2-week history of blurred vision on both eyes and headaches, 12 hours following the administration of the first dose of an inactivated Covid-19 virus vaccine (Sinovac). He denied any past ocular or medical history. Clinical examination and multimodal imaging tests identified serous retinal detachment and choroidal thickening posteriorly and deep yellow foci in the far peripheral retina. Aqueous humor analysis ruled out viral and bacterial infection including Covid-19, but demonstrated an elevated interleukin-6 level. A workup ruled out systemic infection or autoimmune disease. Although the patient received a single positive T-SPOT result, no other clinical evidence supported active tuberculosis infection. Non-infectious panuveitis was diagnosed and treated with periocular steroids that quickly resolved the serous retinal detachment. Conclusions and Importance: This is the first report of VKH-like uveitis following an inactivated Covid-19 vaccine, with aqueous humor analysis ruling out viral or bacterial infection and demonstrating an elevated interleukin-6 level. Though rare, VKH-like uveitis may be associated with administration of an inactivated Covid-19 vaccine.

Congenital scoliosis (CS) is a congenital disease caused by malformations of vertebrae. Recent studies demonstrated that DNA modification could contribute to the pathogenesis of disease. This study aims to identify epigenetic perturbations that may contribute to the pathogenesis of CS. Four CS patients with hemivertebra were enrolled and underwent spine correction operations. DNA was extracted from the hemivertebrae and spinal process collected from the specimen during the hemivertebra resection. Genome-wide DNA methylation profiling was examined at base-pair resolution using whole-genome bisulfite sequencing (WGBS). We identified 343 genes with hyper-differentially methylated regions (DMRs) and 222 genes with hypo-DMRs, respectively. These genes were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, calcium signaling pathway, and axon guidance in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and were enriched in positive regulation of cell morphogenesis involved in differentiation, regulation of cell morphogenesis involved in differentiation, and regulation of neuron projection development in Biological Process of Gene Ontology (GO-BP) terms. Hyper-DMR-related genes, including IGHG1, IGHM, IGHG3, RNF213, and GSE1, and hypo DMR-related genes, including SORCS2, COL5A1, GRID1, RGS3, and ROBO2, may contribute to the pathogenesis of hemivertebra. The aberrant DNA methylation may be associated with the formation of hemivertebra and congenital scoliosis.

Tetrahedrane-derived compounds consist of n crossed quadrilaterals and possess complex three-dimensional structures with high symmetry and dense spatial arrangements. As a result, these compounds hold great potential for applications in materials science, catalytic chemistry, and other related fields. The Kirchhoff index of a graph G is defined as the sum of resistive distances between any two vertices in G. This article focuses on studying a type of tetrafunctional compound with a linear crossed square chain shape. The Kirchhoff index and degree Kirchhoff index of this compound are calculated, and a detailed analysis and discussion is conducted. The calculation formula for the Kirchhoff index is obtained based on the relationship between the Kirchhoff index and Laplace eigenvalue, and the number of spanning trees is derived for linear crossed quadrangular chains. The obtained formula is validated using Ohm’s law and Cayley’s theorem. Asymptotically, the ratio of Kirchhoff index to Wiener index approaches one-fourth. Additionally, the expression for the degree Kirchhoff index of the linear crossed quadrangular chain is obtained through the relationship between the degree Kirchhoff index and the regular Laplace eigenvalue and matrix decomposition theorem.

The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53. p53 reactivation by inhibiting MDM2–p53 interaction represents a promising therapeutic option in cancer treatment. Here, to develop more effective MDM2 inhibitors with lower off-target toxicities, we synthesized a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, with potent MDM2-p53 inhibition activity. Western blotting and qRT-PCR were performed to detect the impact of XR-4 on MDM2 and p53 protein levels and p53 downstream target gene levels in different cancers. Cancer cell proliferation inhibition and clonogenic activity were also investigated via the CCK8 assay and colony formation assay. A subcutaneous 22Rv1-derived xenografts mice model was used to investigate the in vivo anti-tumour activity of XR-4. The results reveal that XR-4 can induce wild-type p53 accumulation in cancer cells, upregulate the levels of the p53 target genes p21 and PUMA levels, and then inhibit cancer cell proliferation and induce cell apoptosis. XR-4 can also act as a homo-PROTAC that induces MDM2 protein degradation. Meanwhile, the in vivo study results show that XR-4 possesses potent antitumour efficacy and a favourable safety property. In summary, XR-4 is an interesting spiroindolinone pyrrolidinecarboxamide-derivative dimer with effective p53 activation activity and a cancer inhibition ability.

Objective: The objective is to investigate the effect of five-animal frolics on anxiety and depression of hospitalized inpatients. Materials and Methods: Totally 50 inpatients from departments of Internal Medicine, Surgery and General Medicine with hospital admission date between January 2019 and July 2020 were included. All patients exercise five-animal frolics under the professional guidance of the nurse in charge. The Hospital Anxiety and Depression Scale (HADS) was used to assess the conditions of anxiety and depression of patients before and after taking five-animal frolics exercise. Results: The overall score of anxiety patients was significantly lower after five-animal frolics exercise than before [6.0 (5.0, 8.0) vs. 10.0 (8.0, 12.0), Z=-5.466, P

PurposeTo compare the efficacies and treatment outcomes of intravitreal anti-VEGF agents and laser therapy in retinopathy of prematurity (ROP).MethodsA retrospective, non-randomized, comparative study of patients diagnosed with type 1 ROP or aggressive posterior ROP (A-ROP) treated with intravitreal anti-VEGF agents or laser therapy as primary treatment at the People's Hospital of Peking University.ResultsA total of 1,627 eyes of 862 patients were included. In Group 1, 399 eyes of 204 patients were diagnosed with A-ROP or zone I type 1 ROP. The initial regression of the anti-VEGF subgroup was better than that of the laser subgroup, and the reactivation rate and rate of progression to retinal detachment were lower than those of the laser subgroup. In Group 2, 1,228 eyes of 658 patients were diagnosed with zone II type 1 ROP. The reactivation rate of the laser subgroup was lower than that of the anti-VEGF subgroup. No significant differences were found in the initial regression and the probability of developing retinal detachment. Among the anti-VEGF agents, the reactivation rate in eyes treated with conbercept was much lower than that in eyes treated with ranibizumab. The spherical power and spherical equivalents of eyes treated with laser were significantly higher than those of eyes treated with anti-VEGF agents 1 year after initial treatment.ConclusionsIn contrast to laser therapy, anti-VEGF agents as primary treatments have potential advantages for eyes with zone I type 1 ROP and A-ROP. For eyes with zone II type 1 ROP, laser photocoagulation and anti-VEGF agents therapy showed similar efficacy; however, the rate of reactivation with laser therapy was significantly lower than that with anti-VEGF agents. Among the anti-VEGF agents, the reactivation rate was much lower in eyes treated with conbercept than in eyes treated with ranibizumab. Compared to anti-VEGF agents, laser treated eyes had greater trend to myopia.

Leopard coral grouper (Plectropomus leopardus) is an indispensable kind of fish in the coral reef ecosystems and marine aquaculture, and the body color of leopard coral grouper is exhibited in black, brown or red. In order to explore the molecular mechanism affecting the body color of the leopard coral grouper, the illumina sequencing technology was used here, the transcriptome of the skin and brain tissues of the red and black leopard coral grouper were sequenced and the differentially expressed genes between the different body colors of the two tissues were further analyzed in this study. Our results showed that the expressional level of multiple genes in the pathways related to pigment synthesis exhibited significant differences. In addition, encoding gene of microphthalmia-associated transcription factor (MITF) were identified related to the pigment synthesis, phylogenetic analysis and three-dimensional structure predictions on the MITF protein were performed as well. In conclusion, a relatively complete transcriptome data set of different body colors and different tissues in leopard coral grouper were established in this study. The analysis of genes related to the melanin synthesis pathway here will provide a further understanding of the internal mechanism of body color transition in vertebrate.

Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients’ blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of FBN2 and ANKRD11 in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management.

Abstract Background We previously reported a novel clinically distinguishable subtype of congenital scoliosis (CS), namely, TBX6-associated congenital scoliosis (TACS). We further developed the TBX6-associated CS risk score (TACScore), a multivariate phenotype-based model to predict TACS according to the patient’s clinical manifestations. In this study, we aimed to evaluate whether using the TACScore as a screening method prior to performing whole-exome sequencing (WES) is more cost-effective than using WES as the first-line genetic test for CS. Methods We retrospectively collected the molecular data of 416 CS patients in the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study. A decision tree was constructed to estimate the cost and the diagnostic time required for the two alternative strategies (TACScore versus WES). Bootstrapping simulations and sensitivity analyses were performed to examine the distributions and robustness of the estimates. The economic evaluation considered both the health care payer and the personal budget perspectives. Results From the health care payer perspective, the strategy of using the TACScore as the primary screening method resulted in an average cost of $1074.2 (95%CI: $1044.8 to $1103.5) and an average diagnostic duration of 38.7d (95%CI: 37.8d to 39.6d) to obtain a molecular diagnosis for each patient. In contrast, the corresponding values were $1169.6 (95%CI: $1166.9 to $1172.2) and 41.4d (95%CI: 41.1d to 41.7d) taking WES as the first-line test (P

Neovascular age-related macular degeneration (AMD) is characterized by the formation of choroidal neovascularization, which is responsible for more than 80% of cases of severe vision loss. Ubiquitin protein ligase E3D (UBE3D) gene missense has been proven to be associated with neovascular AMD in the East Asian population based on our previous study. In vivo, we explored the role of ube3d in eye development and the mechanisms underlying the development of neovascular AMD in a zebrafish model. In vitro, we investigated the function and mechanism of ube3d in oxidative damage in human retinal pigment epithelium (hRPE) cells. The ube3d gene was knocked down in zebrafish in our experiments, and rescue of ube3d morphants was also performed. We observed the zebrafish model at the molecular level and functional and morphological changes in vivo. Lentivirus-based gene transfer technology was used to overexpress/knockdown ube3d expression in hRPE cells in vitro. hRPE oxidative damage was induced by tert-butyl hydroperoxide (t-TBH). Cell proliferation and migration were assessed. Quantitative real-time PCR and western blot were used to measure the expression levels of UBE3D and CyclinB1. Abnormal eye development was found in zebrafish in this study, including small eyes, delayed retinal development, delayed retrograde melanosome transport, and reduced dark-induced hyper-locomotor activity under light-off conditions. In addition, increased angiogenesis was observed in ube3d morphants. A negative correlation between UBE3D and CyclinB1 was observed. Low UBE3D expression can promote oxidative damage and inflammatory reactions. UBE3D and autophagy have a synergetic effect on anti-oxidative damage. These findings indicate that ube3d may play an important role in the pathogenesis of AMD by affecting retinal development, oxidative damage, and autophagy.

Abstract Background Multiple epiphyseal dysplasia (MED) is a skeletal disorder characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. At least 66% of the reported autosomal dominant MED (AD-MED) cases are caused by COMP mutations. Methods We recruited a four-generation Chinese family with early-onset hip osteoarthritis, flatfoot, brachydactyly, and mild short stature. An assessment of the family history, detailed physical examinations, and radiographic evaluations were performed on the proband and other family members, followed by the performance of whole-exome sequencing (WES). The pathogenicity of the candidate mutation was also analyzed. Results An AD-MED family with 10 affected members and 17 unaffected members was recruited. The main radiographic findings were symmetrical changes in the dysplastic acetabulum and femoral heads, irregular contours of the epiphyses, a shortened femoral neck, and flatfoot. Lower bone density was also observed in the ankle joints, wrist joints, and knees, as well as irregular vertebral end plates. In the proband, we identified the missense mutation c.1153G > T (p. Asp385Tyr), located in exon 11 of the COMP gene. This mutation was assessed as 'pathogenic' because of its low allele frequency and its high likelihood of co-segregation with disease in the reported family. Sanger sequencing validated the novel heterozygous mutation c.1153G > T (p. Asp385Tyr) in exon 11 of COMP in all affected individuals in the family. Conclusions Our results underlined a key role of the Asp385 amino acid in the protein function of COMP and confirmed the pathogenicity of the COMP (c.1153G > T; p. Asp385Tyr) mutation in AD-MED disease. We have therefore expanded the known mutational spectrum of COMP and revealed new phenotypic information for AD-MED.

Abstract Background Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity. Methods We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis. Results We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls. Conclusions Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

High nitrogen (N) input to soil can cause higher nitrous oxide (N2O) emissions, that is, a higher N2O/(N2O+N2) ratio, through an inhibition of N2O reductase activity and/or a decrease in soil pH. We assumed that there were two mechanisms for the effects of N input on N2O emissions, immediate and long-term effect. The immediate effect (field applied fertilizer N) can be eliminated by decreasing the N input, but not the long-term effect (soil accumulated N caused by long–term fertilization). Therefore, it is important to separate these effects to mitigate N2O emissions. To this end, soil samples along a 0‒5.2 m profile were collected from a long-term N fertilization experiment field with two N application rates, that is, 600 kg N ha-1 year-1 (N600) and no fertilizer N input (N0). External N addition was conducted for each subsample in the laboratory incubation study to produce two additional treatments, which were denoted as N600+N and N0+N treatments. The results showed that the combined immediate and long-term effects led to an increase in the N2O/(N2O+N2) ratio by 6.8%. Approximately 32.6% and 67.4% of increase could be explained by the immediate and long-term effects of N input, respectively. Meanwhile, the long-term effects were significantly positively correlated to soil organic carbon (SOC). These results indicate that excessive N fertilizer input to the soil can lead to increased N2O emissions if the soil has a high SOC content. The long-term effect of N input on the N2O/(N2O+N2) ratio should be considered when predicting soil N2O emissions under global environmental change scenarios.

CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.

Ivory shell (Babylonia areolata) is a commercially important aquaculture species mainly found on the southeast coast of China. However, it has been greatly affected by vibriosis in recent years. In this study, FP17 (a potential pathogen) was isolated from a dying ivory shell with “acute death syndrome” and confirmed as a pathogen via infectious experiment. Furthermore, phylogenetic analysis based on the average nucleotide identity (ANI) sequencing of the 16S rRNA gene and housekeeping genes (ftsz, gapA, gyrB, mreB, pyrH, rpoA, and topA) indicated that FP17 was identical to Vibrio tubiashii. Transmission electron microscopy showed that FP17 is curved and has a short rod shape, with a single flagellum. Besides, the calculated LD50 after the intramuscular injection of FP17 was 2.11 × 106 CFU/g at 14 d. The genome of the FP17 strain consists of two chromosomes and one plasmid with 5,261,336 bp and 45.08% GC content, including 4824 open reading frames (ORFs) and 150 non-coding RNAs (ncRNA). Genome mining revealed that 120 candidate gene clusters, including vibrioferrin and flagellum-related proteins, are responsible for virulence. Comparative genomic analysis showed that vibrioferrin genes, such as pvs and type Ⅵ secretion system protein genes (vas), are specific in V. tubiashii FP17 but not in the ATCC19109 strain. Furthermore, 92 antimicrobial resistance (AMR) genes, such as tufA, tet(35), crp, etc., were mapped within the genome as the potential candidate for virulence, consistent with antibiotic susceptibility assay. This is the first study to describe the complete genome sequence of V. tubiashii infecting ivory shell. The genetic characteristics, virulence factors, and antimicrobial resistance of the V. tubiashii strain FP17 were also explored.