Toxic effects of bisphenol AF on the embryonic development of marine medaka (Oryzias melastigma).

Bisphenol AF (BPAF), an emerging environmental endocrine disruptor, has been detected in surface waters worldwide and has adverse effects on aquatic organisms. The accumulation of BPAF in oceans and its potential toxic effect on marine organisms are important concerns. In this study, the effects of BPAF (10, 100, 1, and 5 mg/L) on marine medaka (Oryzias melastigma) were evaluated, including effects on the survival rate, heart rate, hatchability, morphology, and gene expression in embryos. The survival rate of marine medaka embryos was significantly lower after treatment with 5 mg/L BPAF than in the solvent control group. Exposure to 1 mg/L and 5 mg/L BPAF significantly reduced hatchability. Low-dose BPAF (10 µg/L) significantly accelerated the heart rate of embryos, while high-dose BPAF (5 mg/L) significantly decreased the heart rate. BPAF exposure also resulted in notochord curvature, pericardial edema, yolk sac cysts, cardiovascular bleeding, and caudal curvature in marine medaka. At the molecular level, BPAF exposure affected the transcript levels of genes involved in the thyroid system (dio1, dio3a, trhr2, tg, and thra), cardiovascular system (gata4, atp2a1, and cacna1da), nervous system (elavl3 and gap43), and antioxidant and inflammatory systems (sod, pparß, and il-8) in embryos. These results indicate that BPAF exposure can alter the expression of functional genes, induce abnormal development, and reduce the hatching and survival rates in marine medaka embryos. Overall, BPAF can adversely affect the survival and development of marine medaka embryos, and BPAF may not be an ideal substitute for BPA.

Effects of application of rapeseed cake as organic fertilizer on rice quality at high yield level.

BACKGROUND: Applying organic fertilizer coupled with chemical fertilizer has been widely adopted to improve crop productivity and quality and develop sustainable agriculture. However, little information is available about the effects of organic fertilizer on the grain quality of rice (Oryza sativa L.), especially nutritional quality and starch quality. In the present study, high yielding 'super' rice cultivars were grown in the field with three cultivation practices, including zero nitrogen application (0N), local high yielding practice with chemical fertilizer (T1) and T1 treatment with additional organic fertilizer (T2). RESULTS: Application of organic fertilizer synergistically improved rice production, nitrogen use efficiency, milling and appearance quality, and nutritional quality, including the contents of glutelin, essential amino acids and microelements, and also increased amylopectin and the ratio of the short chain of amylopectin, leading to a reduction in relative crystallinity, and decreased prolamin content. Application of organic fertilizer also increased the viscosity and breakdown values, whereas it decreased the pasting temperature and gelatinization enthalpy, resulting in better cooking and eating quality. CONCLUSION: Overall, application of organific fertilizer could synergistically improve nitrogen use efficiency and grain quality, including the structure and physicochemical properties of starch, contents of high value protein and amino acids, contents of microelements, and cooking and eating quality. © 2021 Society of Chemical Industry.

Novel nanomicelle butenafine formulation for ocular drug delivery against fungal keratitis: In Vitro and In Vivo study.

Fungal keratitis (FK) is a serious infectious corneal disease that leads to blindness. Butenafine (BTF) is an allylamine drug with high antifungal activity, but its poor water solubility and low bioavailability limit its clinical application in ophthalmology. To increase its aqueous solubility and corneal permeability, butenafine was encapsulated in d-ɑ-tocopheryl polyethylene glycol succinate (TPGS) polymeric nanomicelles to improve the bioavailability of the drug for the treatment of FK. Butenafine was successfully fabricated into nanomicelles with a high EE of 96.34 ± 1.65 % and DL of 6.71 ± 0.099 %. The BTF-NM showed an average particle size of 13.12 ± 0.24 nm, a zeta potential of -0.56 ± 0.44 mV and a narrow PDI of 0.12 ± 0.02 with a nearly spherical shape. The characterization results of FTIR, XRD and DSC indicated that BTF was encapsulated in the TPGS nanomicelles. The BTF-NM formulation also showed high storage stability, and the in vitro drug release study showed typical biphasic-release characteristics. In addition, the BTF-NM formulation displayed good cellular tolerance and excellent ocular tolerance in rabbits. Significantly elevated in vitro antifungal activity was also observed in the BTF-NM formulation, and remarkable improvements regarding in vivo corneal permeation were observed compared with the BTF suspension formulation. Finally, the in vivo antifungal activity studies indicated that the BTF-NM formulation had a good therapeutic effect on FK and had similar efficacy to that of commercial natamycin suspension eye drops. These results suggest that the BTF-NM ophthalmic formulation could be a promising ocular drug delivery system for the treatment of FK.

A Top-Down Design Approach for Generating a Peptide PROTAC Drug Targeting Androgen Receptor for Androgenetic Alopecia Therapy.

While large-scale artificial intelligence (AI) models for protein structure prediction and design are advancing rapidly, the translation of deep learning models for practical macromolecular drug development remains limited. This investigation aims to bridge this gap by combining cutting-edge methodologies to create a novel peptide-based PROTAC drug development paradigm. Using ProteinMPNN and RFdiffusion, we identified binding peptides for androgen receptor (AR) and Von Hippel-Lindau (VHL), followed by computational modeling with Alphafold2-multimer and ZDOCK to predict spatial interrelationships. Experimental validation confirmed the designed peptide's binding ability to AR and VHL. Transdermal microneedle patching technology was seamlessly integrated for the peptide PROTAC drug delivery in androgenic alopecia treatment. In summary, our approach provides a generic method for generating peptide PROTACs and offers a practical application for designing potential therapeutic drugs for androgenetic alopecia. This showcases the potential of interdisciplinary approaches in advancing drug development and personalized medicine.

Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy.

BACKGROUND: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. METHODS: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system. FINDINGS: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. INTERPRETATION: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. FUNDING: The funding details can be found in the Acknowledgements section.

Ocular Pharmacokinetic Properties of Intravitreally Injected Aflibercept in Rabbits After Using Brinzolamide/Timolol Eye Drops.

Purpose: To investigate the ocular pharmacokinetic properties of intravitreally injected aflibercept in rabbits after using brinzolamide 1%/timolol maleate 0.5% fixed-combination eye drops. Methods: The right eye of 5 rabbits was topically administered 30 µL of brinzolamide and timolol maleate eye drops twice a day (q12h). The 2 eyes of each rabbit were injected with 1.0 mg (0.025 cc) of aflibercept on the 2nd day after instilling the eye drops. The intraocular pressure of the rabbits was measured before injection and sampling. The aqueous humor was drawn at 1, 3, 7, 14, 21, and 28 days. Aflibercept concentrations in aqueous humor and vitreous humor (28 days) were measured by enzyme-linked immunosorbent assay. Results: The aflibercept aqueous concentrations in the right eye at days 7, 14, 21, and 28 after injection were all significantly higher than those in the left eye (P > 0.05, n = 5). The peak aqueous concentrations of aflibercept in right eyes (49.5 µg/mL) and left eyes (50.9 µg/mL) were both observed at 1 day after injection. The elimination half-life of aflibercept in the aqueous humor of the right eye (4.70 days) was 1 day longer than that of the left eye (3.65 days). The average percentage of residual aflibercept in the vitreous humor of the right eye (3.35%) was also significantly higher than that of the left eye (0.63%). Conclusions: Brinzolamide 1%/timolol maleate 0.5% fixed-combination eye drops can significantly extend the ocular residence time of intravitreally injected aflibercept.

The effect of charges on the corneal penetration of solid lipid nanoparticles loaded Econazole after topical administration in rabbits.

Fungal keratitis is an infectious disease caused by pathogenic fungi with a high blindness rate. Econazole (ECZ) is an imidazole antifungal drug with insoluble ability. Econazole-loaded solid lipid nanoparticles (E-SLNs) were prepared by microemulsion method, then modified with positive and negative charge. The mean diameter of cationic E-SLNs, nearly neutral E-SLNs and anionic E-SLNs were 18.73±0.14, 19.05±0.28, 18.54±0.10 nm respectively. The Zeta potential of these different charged SLNs formulations were 19.13±0.89, -2.20±0.10, -27.40±0.67 mV respectively. The Polydispersity Index (PDI) of these three kinds of nanoparticles were all about 0.2. The Transmission Electron Microscopy (TEM) and Differential Scanning Calorimetry (DSC) analysis showed that the nanoparticles were a homogeneous system. Compared with Econazole suspension (E-Susp), SLNs exhibited sustained release capability, stronger corneal penetration and enhanced inhibition of pathogenic fungi without irritation. The antifungal ability was further improved after cationic charge modification compared with E-SLNs. Studies on pharmacokinetics showed that the order of the AUC and t1/2 of different preparations was cationic E-SLNs > nearly neutral E-SLNs > anionic E-SLNs > E-Susp in cornea and aqueous humor. It was shown that SLNs could increase corneal penetrability and ocular bioavailability while these capabilities were further enhanced with positive charge modification compared with negative charge ones.

Divergent responses of plant functional traits and biomass allocation to slope aspects in four perennial herbs of the alpine meadow ecosystem.

Slope aspect can cause environmental heterogeneity over relatively short distances, which in turn affects plant distribution, community structure, and ecosystem function. However, the response and adaptation strategies of plants to slope aspects via regulating their physiological and morphological properties still remain poorly understood, especially in alpine ecosystems. Here, we selected four common species, including Bistorta macrophylla, Bistorta vivipara, Cremanthodium discoideum, and Deschampsia littoralis, to test how biomass allocation and functional traits of height, individual leaf area, individual leaf mass, and specific leaf area (SLA) respond to variation in slope aspect in the Minshan Mountain, eastern Tibetan Plateau. We found that the slope aspect affected SLA and stem, flower mass fraction with higher values at southwest slope aspect, which is potentially related to light environment. The low-temperature environment caused by the slope aspect facilitates the accumulation of root biomass especially at the northeast slope aspect. Cremanthodium discoideum and D. littoralis invested more in belowground biomass in southeast and southwest slope aspects, although a large number of significant isometric allocations were found in B. macrophylla and B. vivipara. Finally, we found that both biotic and abiotic factors are responsible for the variation in total biomass with contrasting effects across different species. These results suggest that slope aspect, as an important topographic variable, strongly influences plant survival, growth, and propagation. Therefore, habitat heterogeneity stemming from topographic factors (slope aspect) can prevent biotic homogenization and thus contribute to the improvement of diverse ecosystem functioning.

A prognostic mathematical model based on tumor microenvironment-related genes expression for breast cancer patients.

Background: Tumor microenvironment (TME) status is closely related to breast cancer (BC) prognosis and systemic therapeutic effects. However, to date studies have not considered the interactions of immune and stromal cells at the gene expression level in BC as a whole. Herein, we constructed a predictive model, for adjuvant decision-making, by mining TME molecular expression information related to BC patient prognosis and drug treatment sensitivity. Methods: Clinical information and gene expression profiles were extracted from The Cancer Genome Atlas (TCGA), with patients divided into high- and low-score groups according to immune/stromal scores. TME-related prognostic genes were identified using Kaplan-Meier analysis, functional enrichment analysis, and protein-protein interaction (PPI) networks, and validated in the Gene Expression Omnibus (GEO) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to construct and verify a prognostic model based on TME-related genes. In addition, the patients' response to chemotherapy and immunotherapy was assessed by survival outcome and immunohistochemistry (IPS). Immunohistochemistry (IHC) staining laid a solid foundation for exploring the value of novel therapeutic target genes. Results: By dividing patients into low- and high-risk groups, a significant distinction in overall survival was found (p < 0.05). The risk model was independent of multiple clinicopathological parameters and accurately predicted prognosis in BC patients (p < 0.05). The nomogram-integrated risk score had high prediction accuracy and applicability, when compared with simple clinicopathological features. As predicted by the risk model, regardless of the chemotherapy regimen, the survival advantage of the low-risk group was evident in those patients receiving chemotherapy (p < 0.05). However, in patients receiving anthracycline (A) therapy, outcomes were not significantly different when compared with those receiving no-A therapy (p = 0.24), suggesting these patients may omit from A-containing adjuvant chemotherapy. Our risk model also effectively predicted tumor mutation burden (TMB) and immunotherapy efficacy in BC patients (p < 0.05). Conclusion: The prognostic score model based on TME-related genes effectively predicted prognosis and chemotherapy effects in BC patients. The model provides a theoretical basis for novel driver-gene discover in BC and guides the decision-making for the adjuvant treatment of early breast cancer (eBC).

Effects of Salt Stress on Grain Yield and Quality Parameters in Rice Cultivars with Differing Salt Tolerance.

Rice yield and grain quality are highly sensitive to salinity stress. Salt-tolerant/susceptible rice cultivars respond to salinity differently. To explore the variation in grain yield and quality to moderate/severe salinity stress, five rice cultivars differing in degrees of salt tolerance, including three salt-tolerant rice cultivars (Lianjian 5, Lianjian 6, and Lianjian 7) and two salt-susceptible rice cultivars (Wuyunjing 30 and Lianjing 7) were examined. Grain yield was significantly decreased under salinity stress, while the extent of yield loss was lesser in salt-tolerant rice cultivars due to the relatively higher grain filling ratio and grain weight. The milling quality continued to increase with increasing levels. There were genotypic differences in the responses of appearance quality to mild salinity. The appearance quality was first increased and then decreased with increasing levels of salinity stress in salt-tolerant rice but continued to decrease in salt-susceptible rice. Under severe salinity stress, the protein accumulation was increased and the starch content was decreased; the content of short branched-chain of amylopectin was decreased; the crystallinity and stability of the starch were increased, and the gelatinization temperature was increased. These changes resulted in the deterioration of cooking and eating quality of rice under severe salinity-stressed environments. However, salt-tolerant and salt-susceptible rice cultivars responded differently to moderate salinity stress in cooking and eating quality and in the physicochemical properties of the starch. For salt-tolerant rice cultivars, the chain length of amylopectin was decreased, the degrees of order of the starch structure were decreased, and pasting properties and thermal properties were increased significantly, whereas for salt-susceptible rice cultivars, cooking and eating quality was deteriorated under moderate salinity stress. In conclusion, the selection of salt-tolerant rice cultivars can effectively maintain the rice production at a relatively high level while simultaneously enhancing grain quality in moderate salinity-stressed environments. Our results demonstrate specific salinity responses among the rice genotypes and the planting of salt-tolerant rice under moderate soil salinity is a solution to ensure rice production in China.

A Versatile Hemolin With Pattern Recognitional Contributions to the Humoral Immune Responses of the Chinese Oak Silkworm Antheraea pernyi.

Hemolin is a distinctive immunoglobulin superfamily member involved in invertebrate immune events. Although it is believed that hemolin regulates hemocyte phagocytosis and microbial agglutination in insects, little is known about its contribution to the humoral immune system. In the present study, we focused on hemolin in Antheraea pernyi (Ap-hemolin) by studying its pattern recognition property and humoral immune functions. Tissue distribution analysis demonstrated the mRNA level of Ap-hemolin was extremely immune-inducible in different tissues. The results of western blotting and biolayer interferometry showed recombinant Ap-hemolin bound to various microbes and pathogen-associated molecular patterns. In further immune functional studies, it was detected that knockdown of hemolin regulated the expression level of antimicrobial peptide genes and decreased prophenoloxidase activation in the A. pernyi hemolymph stimulated by microbial invaders. Together, these data suggest that hemolin is a multifunctional pattern recognition receptor that plays critical roles in the humoral immune responses of A. pernyi.

Development of a Luliconazole Nanoemulsion as a Prospective Ophthalmic Delivery System for the Treatment of Fungal Keratitis: In Vitro and In Vivo Evaluation.

Luliconazole (LCZ), a novel imidazole drug, has broad-spectrum and potential antifungal effects, which makes it a possible cure for fungal keratitis; nevertheless, its medical use in ocular infections is hindered by its poor solubility. The purpose of this study was to design and optimize LCZ nanoemulsion (LCZ-NE) formulations using the central composite design-response surface methodology, and to investigate its potential in improving bioavailability following ocular topical administration. The LCZ-NE formulation was composed of Capryol 90, ethoxylated hydrogenated castor oil, Transcutol® P and water. The shape of LCZ-NE was spherical and uniform, with a droplet size of 18.43 ± 0.05 nm and a low polydispersity index (0.070 ± 0.008). The results of an in vitro release of LCZ study demonstrated that the LCZ-NE released more drug than an LCZ suspension (LCZ-Susp). Increases in the inhibition zone indicated that the in vitro antifungal activity of the LCZ-NE was significantly improved. An ocular irritation evaluation in rabbits showed that the LCZ-NE had a good tolerance in rabbit eyes. Ocular pharmacokinetics analysis revealed improved bioavailability in whole eye tissues that were treated with LCZ-NE, compared with those treated with LCZ-Susp. In conclusion, the optimized LCZ-NE formulation exhibited excellent physicochemical properties, good tolerance, enhanced antifungal activity and bioavailability in eyes. This formulation would be safe, and shows promise in effectively treating ocular fungal infections.

A sensitive and rapid bioanalytical method for the quantitative determination of luliconazole in rabbit eye tissues using UPLC-MS/MS assay.

Luliconazole (LCZ) is a novel antifungal imidazole with broad-spectrum and high susceptibility of Aspergillus and Fusarium are the dominant species of fungal keratitis, may potentially be a new medical treatment option for ocular fungal infection. To evaluate LCZ distribution in ocular tissues after topical application for the development of ophthalmic delivery system, it is important to have a bioanalytical method for measuring the drug concentrations in different ocular tissues and aqueous humor (AH). A selective and sensitive ultrahigh performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method was developed for the quantification of LCZ in rabbit ocular tissues, including conjunctiva, cornea, AH, iris, lens, vitreous humor (VH), retinal choroid and sclera, using lanoconazole as internal standard (IS). Chromatographic separation was achieved on a Xterra MS, C18 column (2.1 × 50 mm, 3.5 µm) using mobile phase with formic acid solution (0.2%, v/v): acetonitrile (50:50, v/v) at a flow rate of 0.2 ml/min, and the run time was 2.5 min. Detection was performed using the transitions 354.1 → 150.3 m/z for LCZ and 320.1 → 150.3 m/z for IS by positive ion electrospray ionization in multiple reaction monitoring (MRM) mode. Method validation was conducted in accordance with U.S. Food and Drug Administration's regulatory guidelines for bioanalytical method validation. The calibration curves were linear over the concentration range from 2.80 ng/ml to 2038 ng/ml for conjunctiva, cornea and sclera, 2.09 ng/ml to 1019 ng/ml for AH, 2.09 ng/ml to 509.5 ng/ml for iris, 2.09 ng/ml to 203.8 ng/ml for retinal choroid and VH, 2.04 ng/ml to 101.9 ng/ml for lens, with all the squared correlation coefficients (r2) more than 0.99. The accuracy of the method was within the acceptable limit of 89.34%∼112.78% at the lower limit of quantification and other concentrations, Inter-day and intra-day precision values, expressed in terms of RSD (%), in all tissues were within 15% at all concentrations. The mean recoveries of LCZ in rabbit ocular tissues was 84.85%∼100.52%. No interference was found due to matrix components. Luliconazole was stable during the stability studies, including autosampler stability, benchtop stability, freeze/thaw stability and long-term stability. The method was successfully applied to the ocular pharmacokinetic and tissues distribution studies of LCZ in rabbit after topical administration of LCZ ophthalmic drug delivery system.

Improving the solubility of vorinostat using cyclodextrin inclusion complexes: The physicochemical characteristics, corneal permeability and ocular pharmacokinetics of the drug after topical application.

Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved drug for cutaneous T cell lymphoma, has antiangiogenic and anti-inflammatory activity and thus has therapeutic potential for inflammatory corneal neovascularization (CNV). However, its practical administration is limited due to its poor aqueous solubility and permeability. This study aimed to enhance the corneal permeability of SAHA by promoting its inclusion into a complex with hydroxypropyl-ß-CD (HPßCD) for topical application. In phase-solubility studies, the solubility of SAHA with HPßCD and sulfobutyl ether-ß-CD (SEßCD) was assessed at different temperatures, and complexation efficiencies (K) were calculated. The inclusion complexes (ICs) were prepared and characterized by differential scanning calorimetry (DSC), infrared spectrometry (IR), scanning electron microscopy (SEM), and X-ray diffraction (XRD) after freeze-drying. The phase-solubility study showed that the complexation efficiencies of SAHA were higher in HPßCD solutions (297.35 M-1, 115.28 M-1 and 122.75 M-1) than in SEßCD solutions (169.75 M-1, 91.33 M-1 and 96.49 M-1) at 4 °C, 25 °C and 37 °C. HPßCD was selected for SAHA-IC preparation, and characterization revealed IC formation. SAHA existed in an amorphous state in the ICs. The ex vivo corneal permeability of SAHA was also evaluated and found to be greater when formulated as an HPßCD solution than as a suspension. Irritation assays in rabbit eyes showed that the SAHA-IC solution was not irritating after topical application. The ocular pharmacokinetics of SAHA in New Zealand White rabbits were assessed following topical administration (0.2%), and a 0.2% SAHA suspension was used as the control. Compared to its formulation as a suspension, the formulation of SAHA as an HPßCD solution increased its corneal bioavailability by more than 3-fold and its conjunctival bioavailability by more than 2-fold. Thus, IC formation was effective at improving the ocular bioavailability of SAHA. This study provides an important alternative approach for developing liquid pharmaceutical formulations of SAHA for topical ocular applications.

Prediction of axillary lymph node pathological complete response to neoadjuvant therapy using nomogram and machine learning methods.

Purpose: To determine the feasibility of predicting the rate of an axillary lymph node pathological complete response (apCR) using nomogram and machine learning methods. Methods: A total of 247 patients with early breast cancer (eBC), who underwent neoadjuvant therapy (NAT) were included retrospectively. We compared pre- and post-NAT ultrasound information and calculated the maximum diameter change of the primary lesion (MDCPL): [(pre-NAT maximum diameter of primary lesion - post-NAT maximum diameter of preoperative primary lesion)/pre-NAT maximum diameter of primary lesion] and described the lymph node score (LNS) (1): unclear border (2), irregular morphology (3), absence of hilum (4), visible vascularity (5), cortical thickness, and (6) aspect ratio <2. Each description counted as 1 point. Logistic regression analyses were used to assess apCR independent predictors to create nomogram. The area under the curve (AUC) of the receiver operating characteristic curve as well as calibration curves were employed to assess the nomogram's performance. In machine learning, data were trained and validated by random forest (RF) following Pycharm software and five-fold cross-validation analysis. Results: The mean age of enrolled patients was 50.4 ± 10.2 years. MDCPL (odds ratio [OR], 1.013; 95% confidence interval [CI], 1.002-1.024; p=0.018), LNS changes (pre-NAT LNS - post-NAT LNS; OR, 2.790; 95% CI, 1.190-6.544; p=0.018), N stage (OR, 0.496; 95% CI, 0.269-0.915; p=0.025), and HER2 status (OR, 2.244; 95% CI, 1.147-4.392; p=0.018) were independent predictors of apCR. The AUCs of the nomogram were 0.74 (95% CI, 0.68-0.81) and 0.76 (95% CI, 0.63-0.90) for training and validation sets, respectively. In RF model, the maximum diameter of the primary lesion, axillary lymph node, and LNS in each cycle, estrogen receptor status, progesterone receptor status, HER2, Ki67, and T and N stages were included in the training set. The final validation set had an AUC value of 0.85 (95% CI, 0.74-0.87). Conclusion: Both nomogram and machine learning methods can predict apCR well. Nomogram is simple and practical, and shows high operability. Machine learning makes better use of a patient's clinicopathological information. These prediction models can assist surgeons in deciding on a reasonable strategy for axillary surgery.

Assessment to the Antifungal Effects in vitro and the Ocular Pharmacokinetics of Solid-Lipid Nanoparticle in Rabbits.

INTRODUCTION: Fungal keratitis (FK) remains a severe sight-threatening disease, and case management is difficult due to ocular intrinsic barriers and drug shortages. Econazole (ECZ), a broad-spectrum antifungal agent, is limited in ocular applications due to the poor water solubility and strong irritant property. METHODS: We successfully prepared solid-lipid nanoparticle-based ECZ eye drops (E-SLNs) by microemulsion method, and the physicochemical properties of E-SLNs were investigated. Corneal permeability, antifungal ability against Fusarium spp., irritation and bioavailability compared to ECZ Suspension (E-Susp) were evaluated in vitro and in vivo. RESULTS: E-SLNs were a uniform and stable system which had an average particle size of 19 nm and a spherical morphology. E-SLNs also exhibited controlled release, enhanced antifungal activity without irritation. The pharmacokinetic analysis in vivo confirmed that E-SLNs showed an improved ocular bioavailability and the drug concentration in the cornea were above minimum inhibitory concentration (MIC) for 3 h after single administration. CONCLUSION: The E-SLNs colloid system is a promising therapeutic approach for fungal keratitis and could serve as a candidate strategy for other ocular diseases.

Foundation species across a latitudinal gradient in China.

Foundation species structure forest communities and ecosystems but are difficult to identify without long-term observations or experiments. We used statistical criteria--outliers from size-frequency distributions and scale-dependent negative effects on alpha diversity and positive effects on beta diversity--to identify candidate foundation woody plant species in 12 large forest-dynamics plots spanning 26 degrees of latitude in China. We used these data (1) to identify candidate foundation species in Chinese forests, (2) to test the hypothesis--based on observations of a midlatitude peak in functional trait diversity and high local species richness but few numerically dominant species in tropical forests--that foundation woody plant species are more frequent in temperate than tropical or boreal forests, and (3) to compare these results with data from the Americas to suggest candidate foundation genera in northern hemisphere forests. Using the most stringent criteria, only two species of Acer, the canopy tree Acer ukurunduense and the shrubby treelet Acer barbinerve, were identified in temperate plots as candidate foundation species. Using more relaxed criteria, we identified four times more candidate foundation species in temperate plots (including species of Acer, Pinus, Juglans, Padus, Tilia, Fraxinus, Prunus, Taxus, Ulmus, and Corlyus) than in (sub)tropical plots (the treelets or shrubs Aporosa yunnanensis, Ficus hispida, Brassaiopsis glomerulata, and Orophea laui). Species diversity of co-occurring woody species was negatively associated with basal area of candidate foundation species more frequently at 5- and 10-m spatial grains (scale) than at a 20-m grain. Conversely, Bray-Curtis dissimilarity was positively associated with basal area of candidate foundation species more frequently at 5-m than at 10- or 20-m grains. Both stringent and relaxed criteria supported the hypothesis that foundation species are more common in mid-latitude temperate forests. Comparisons of candidate foundation species in Chinese and North American forests suggest that Acer be investigated further as a foundation tree genus.

Deep Learning for Ultrasound Localization Microscopy.

By localizing microbubbles (MBs) in the vasculature, ultrasound localization microscopy (ULM) has recently been proposed, which greatly improves the spatial resolution of ultrasound (US) imaging and will be helpful for clinical diagnosis. Nevertheless, several challenges remain in fast ULM imaging. The main problems are that current localization methods used to implement fast ULM imaging, e.g., a previously reported localization method based on sparse recovery (CS-ULM), suffer from long data-processing time and exhaustive parameter tuning (optimization). To address these problems, in this paper, we propose a ULM method based on deep learning, which is achieved by using a modified sub-pixel convolutional neural network (CNN), termed as mSPCN-ULM. Simulations and in vivo experiments are performed to evaluate the performance of mSPCN-ULM. Simulation results show that even if under high-density condition (6.4 MBs/mm2), a high localization precision ( [Formula: see text] in the lateral direction and [Formula: see text] in the axial direction) and a high localization reliability (Jaccard index of 0.66) can be obtained by mSPCN-ULM, compared to CS-ULM. The in vivo experimental results indicate that with plane wave scan at a transmit center frequency of 15.625 MHz, microvessels with diameters of [Formula: see text] can be detected and adjacent microvessels with a distance of [Formula: see text] can be separated. Furthermore, when using GPU acceleration, the data-processing time of mSPCN-ULM can be shortened to ~6 sec/frame in the simulations and ~23 sec/frame in the in vivo experiments, which is 3-4 orders of magnitude faster than CS-ULM. Finally, once the network is trained, mSPCN-ULM does not need parameter tuning to implement ULM. As a result, mSPCN-ULM opens the door to implement ULM with fast data-processing speed, high imaging accuracy, short data-acquisition time, and high flexibility (robustness to parameters) characteristics.

Effects of nitrogen fertilizer on structure and physicochemical properties of 'super' rice starch.

Nitrogen fertilizer is an essential nutrient for rice (Oryza sativa L.), especially, for newly bred 'super' rice cultivars with great yield potential. The effects of nitrogen fertilizer (0, 100, 200, 300, 400 kg N ha-1) on the physicochemical properties of two high yielding 'super' rice Yongyou 2640 and Lianjing 7 were investigated in this study. The application of nitrogen fertilizer affects the structure of rice starch, thus changing its functional properties, which ultimately leads to a change in the quality of both rice cultivars. There were dose effects of nitrogen fertilizer on grain quality. Grain quality was improved under moderate nitrogen inputs (100 & 200 kg N ha-1), but deteriorated at excessive nitrogen levels (300 & 400 kg N ha-1). With moderate N application, starch granule size increased and the surface of starch granule became smoother; there were higher proportion of short branch-chain of amylopectin and lower proportion of long branch-chain of amylopectin with low relative crystallinity, lower degree of order of structure and higher content of amorphous structure at the outer region of the starch granules; peak viscosity, hot viscosity, breakdown value were increased while setback and pasting temperature were decreased; gelatinization temperature, gelatinization enthalpy, retrogradation enthalpy, retrogradation percentage, hardness were decreased while viscosity were increased. At excessive nitrogen inputs, the grain quality was deteriorated and the opposite results of structure and physicochemical properties of rice starch were observed. These results indicate that nitrogen fertilizer significantly affected the structure and physicochemical properties of rice starch, and appropriate fertilization would improve rice grain quality.

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This study aimed at understanding the differences in traits of functional twigs and leaves of a typical alpine shrub species, Rhododendron przewalskii, at Kaka Mountain in the headwater region of Minjiang River. Leaf and twig traits were compared for shrubs at different growth stages (flower bud stage and flowering stage) and altitude (3600 m and 3800 m). The effects of spatial heterogeneity on their correlations and trade-offs were evaluated at leaf and twig levels, respectively. Our results showed that twig length was significantly longer at low altitude than high altitude for the shubs at the same growth stage. The number and mass of flowers at flowering stage were significantly higher at high altitude than those at low altitude. At the same altitude, twig mass, number of leaves, total leaf mass, total leaf area and total petiole mass were all significantly greater at the flower bud stage than those at the flowering stage, while the individual leaf mass and individual petiole mass at flower bud stage were significantly smaller than those at flowering stage. Compared with the flower bud stage, the proportion of leaf mass decreased by 13% at the flowering stage, while biomass proportion of twig significantly increased. At the flower bud stage, twig mass had a higher contribution to total twig mass. In contrast, the contribution of total leaf mass to total twig mass was higher at flowering stage. More biomass of leaf was allocated to individual leaf mass at flower bud stage. More biomass of leaf was allocated to individual petiole mass and individual leaf mass at flowering stage at low altitude and high altitude, respectively. At low altitude, allometric growth patterns presented between twig mass and total leaf area, total leaf mass. Similarly, individual petiole mass and individual leaf area had allometric growth. Our results indicated that the functional traits of twigs and leaves varied across both altitude and plant growth stage.