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Large bone defects resulting from fractures and diseases have become a significant medical concern, usually impeding spontaneous healing through the body's self-repair mechanism. Calcium phosphate (CaP) bioceramics are widely utilized for bone regeneration, owing to their exceptional biocompatibility and osteoconductivity. However, their bioactivities in repairing healing-impaired bone defects characterized by conditions such as ischemia and infection remain limited. Recently, an emerging bioceramics zinc-strontium phosphate (ZSP, Zn2Sr(PO4)2) has received increasing attention due to its remarkable antibacterial and angiogenic abilities, while its plausible biomedical utility on tissue regeneration is nonetheless few. In this study, gallic acid-grafted gelatin (GGA) with antioxidant properties was injected into hydrogels to scavenge reactive oxygen species and regulate bone microenvironment while simultaneously incorporating ZSP to form GGA-ZSP hydrogels. The GGA-ZSP hydrogel exhibits low swelling, and in vitro cell experiments have demonstrated its favorable biocompatibility, osteogenic induction potential, and ability to promote vascular regeneration. In an in vivo bone defect model, the GGA-ZSP hydrogel significantly enhanced the bone regeneration rates. This study demonstrated that the GGA-ZSP hydrogel has pretty environmentally friendly therapeutic effects in osteogenic differentiation and massive bone defect repair.
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Regeneración Ósea , Ácido Gálico , Gelatina , Hidrogeles , Osteogénesis , Ácido Gálico/química , Ácido Gálico/farmacología , Regeneración Ósea/efectos de los fármacos , Gelatina/química , Hidrogeles/química , Hidrogeles/farmacología , Animales , Osteogénesis/efectos de los fármacos , Fosfatos/química , Fosfatos/farmacología , Estroncio/química , Estroncio/farmacología , Zinc/química , Zinc/farmacología , Ratones , Humanos , Huesos/efectos de los fármacos , Masculino , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacologíaRESUMEN
Covariate-adaptive randomization methods are widely used in clinical trials to balance baseline covariates. Recent studies have shown the validity of using regression-based estimators for treatment effects without imposing functional form requirements on the true data generation model. These studies have had limitations in certain scenarios; for example, in the case of multiple treatment groups, these studies did not consider additional covariates or assumed that the allocation ratios were the same across strata. To address these limitations, we develop a stratum-common estimator and a stratum-specific estimator under multiple treatments. We derive the asymptotic behaviors of these estimators and propose consistent nonparametric estimators for asymptotic variances. To determine their efficiency, we compare the estimators with the stratified difference-in-means estimator as the benchmark. We find that the stratum-specific estimator guarantees efficiency gains, regardless of whether the allocation ratios across strata are the same or different. Our conclusions were also validated by simulation studies and a real clinical trial example.
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Distribución Aleatoria , Simulación por ComputadorRESUMEN
Spherical/aspherical mirrors are widely used in optical systems and imaging systems, but their reflectivity is affected by the surface roughness. In this study, the effects of plastic side flow and elastic recovery on the diffraction phenomenon and reflectivity are analyzed systematically. The energy ratio of an ultra-precision turning surface is calculated by rigorous coupled-wave method, the influence of aberration on diffraction efficiency is considered in combination with the specific structural parameters of spherical/aspherical surface, and the appropriate measuring beam diameter is selected. Through predicted results and experimental observations, it can be found that with the increase of plastic side flow height, the energy ratio of zero-order diffracted light reduces, the brightness weakens, and the diffraction light spots become more obvious. This is because large plastic side flow height leads to more complex three-dimensional surface topography and great roughness P-V value. The influence of elastic recovery on the reflectivity is different from that of plastic side flow. As the elastic recovery increases, the roughness P-V value lessens. As a result, the energy ratio of zero-order diffracted light enlarges, and the brightness strengthens. This paper provides a theoretical basis for machining of spherical/aspheric mirrors with high reflectivity.
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In this paper the influence of vibration on reflectivity is systematically analyzed. A three-dimensional topography model of a machined surface considering vibration is established first. Based on the three-dimensional morphology model, the reflectivity of a diamond turned surface is calculated by a rigorous coupled wave method. The influences of cutting parameters on the diffraction effect of a diamond turned surface are discussed. The predicted and experimental results reveal that as the vibration intensifies with an increase in cutting depth and feed rate, the peak-valley (PV) roughness of the machined surface increases, which yields an increasing diffraction effect, i.e., resulting in a decrease in reflectivity. When the spindle speed is low, the tool and workpiece have a small sliding velocity, causing a great deal of friction, which amplifies the deformation of the workpiece surface. In this case, the PV value of the machined surface roughness is large, leading to a greater diffraction effect and bad reflectivity. With the increment of spindle rotation speed, the friction is relieved quickly, but the vibration is intensified, which produces increasing reflectivity. When the spindle speed is set to about 1200r/min, the reflectivity reaches the maximum value. When the spindle speed is larger than 1200r/min, the increase of vibration is dominant, resulting in a gradual increase in PV surface roughness and a decrease in reflectivity.
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Coat color is an important phenotypic characteristic of the domestic rabbit (Oryctolagus cuniculus) and has specific economic importance in the Rex rabbit industry. Coat color varies considerably among different populations of rabbits, and several causal genes for this variation have been thoroughly studied. Nevertheless, the candidate genes affecting coat color variation in Chinese Rex rabbits remained to be investigated. In this study, we collected blood samples from 250 Chinese Rex rabbits with six different coat colors. We performed genome sequencing using a restriction site-associated DNA sequencing approach. A total of 91,546 single nucleotide polymorphisms (SNPs), evenly distributed among 21 autosomes, were identified. Genome-wide association studies (GWAS) were performed using a mixed linear model, in which the individual polygenic effect was fitted as a random effect. We detected a total of 24 significant SNPs that were located within a genomic region on chromosome 4 (OCU4). After re-fitting the most significant SNP (OCU4:13,434,448, p = 1.31e-12) as a covariate, another near-significant SNP (OCU4:11,344,946, p = 7.03e-07) was still present. Hence, we conclude that the 2.1-Mb genomic region located between these two significant SNPs is significantly associated with coat color in Chinese Rex rabbits. The well-studied coat-color-associated agouti signaling protein (ASIP) gene is located within this region. Furthermore, low genetic differentiation was also observed among the six coat color varieties. In conclusion, our results confirmed that ASIP is a putative causal gene affecting coat color variation in Chinese Rex rabbits.
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Spinal cord injury (SCI) is a serious disease characterized by hemorrhage, edema, local ischemia and hypoxia, inflammatory reaction, and degeneration of the injured spinal cord, which lacks effective clinical treatments. We design a PEG-SH-GNPs-SAPNS@miR-29a delivery system to repair impaired spinal cord by building a regenerative microenvironment for the recruitment of endogenous neural stem cells. The miR-29a, as an axonal regeneration-related miRNA that overexpression of miR-29a significantly inhibits the expression of PTEN and promotes axonal regeneration of the injured spinal cord. The gold nanoparticles and self-assembling peptide hydrogel composite scaffold (PEG-SH-GNPs-SAPNS@miR-29a delivery system) applied to deliver miR-29a, which recruit endogenous neural stem cells simultaneously. Sustained release of miR-29a and recruitment of endogenous neural stem cells give rise to favorable axonal regeneration and recovery of motor function after spinal cord injury. These findings suggest that the PEG-SH-GNPs-SAPNS@miR-29a delivery system may be an alternative strategy for the treatment of SCI.
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Nanopartículas del Metal , MicroARNs , Traumatismos de la Médula Espinal , Humanos , Oro , Traumatismos de la Médula Espinal/tratamiento farmacológico , Regeneración Nerviosa , Médula Espinal/metabolismo , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
With the rapid development of photoelectric communication and other fields, the demand for high-precision aspheric mirrors has been increasing. Predicting dynamic cutting forces is vital in selecting machining parameters and also affects the surface quality of the machined surface. This study comprehensively considers the effects of different cutting parameters and workpiece shape parameters on dynamic cutting force. The actual width of cut, depth of cut, and shear angle are modelled while considering the effects of vibration. A dynamic cutting-force model considering the aforementioned factors is then established. Using experimental results, the model accurately predicts the average value of dynamic cutting force under different parameters and the range of fluctuation of dynamic cutting force, with a controlled relative error of about 15%. The influence of workpiece shape and workpiece radial size on dynamic cutting force is also considered. The experimental results show that the greater the surface slope, the more dramatic the dynamic cutting force fluctuations. This lays the foundation for subsequent writing on vibration suppression interpolation algorithms. The influence of the radius of the tool tip on dynamic cutting forces leads to the conclusion that to achieve the goal of reducing the fluctuation of cutting forces, diamond tools with different parameters should be selected for different feed rates. Finally, a new interpolation-point planning algorithm is used to optimize the position of interpolation points in the machining process. This proves the reliability and practicability of the optimization algorithm. The results of this study are of great significance to the processing of high-reflectivity spherical/aspheric surfaces.
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Due to their high electromechanical coupling and energy density properties, ultrathin piezoelectric films have recently been intensively studied as key materials for the construction of miniaturized energy transducers, and in this paper we summarize the research progress. At the nanoscale, even a few atomic layers, ultrathin piezoelectric films have prominent shape anisotropic polarization, that is, in-plane polarization and out-of-plane polarization. In this review, we first introduce the in-plane and out-of-plane polarization mechanism, and then summarize the main ultrathin piezoelectric films studied at present. Secondly, we take perovskite, transition metal dichalcogenides, and Janus layers as examples to elaborate the existing scientific and engineering problems in the research of polarization, and their possible solutions. Finally, the application prospect of ultrathin piezoelectric films in miniaturized energy converters is summarized.
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BACKGROUND: Nipple-sparing mastectomy (NSM) offers superior cosmetic outcomes and has been gaining wide acceptance. It has always been difficult to objectively quantify the risk of nipple-areola complex involvement (NACi). The goal was to develop a prediction model for clinical application. METHODS: Patients who had a total mastectomy (TM) between January 2016 and January 2020 at a single institute formed the development cohort (n = 578) and those who had NSM + immediate breast reconstruction (IBR) between January 2020 and January 2021 formed the validation cohort (n = 112). The prediction model was developed using univariate and multivariate logistic regression studies. Based on NACi risk variables identified in the development cohort, a nomogram was created and evaluated in the validation cohort. Meanwhile, stratified analysis was performed based on the model's risk levels and was combined with intraoperative frozen pathology (IFP) to optimize the model. RESULTS: Tumor central location, clinical tumor size (CTS) > 4.0 cm, tumor-nipple distance (TND) ≤ 1.0 cm, clinical nodal status positive (cN +), and KI-67 ≥ 20% were revealed to be good predictive indicators for NACi. A nomogram based on these major clinicopathologic variables was employed to quantify preoperative NACi risk. The accuracy was verified internally and externally. The diagnostic accuracy of IFP was 92.9%, sensitivity was 64.3%, and specificity was 96.9% in the validation group. Stratified analysis was then performed based on model risk. The diagnostic accuracy rates of IFP and NACiPM in low-risk, intermediate-risk, and high-risk respectively were 96.0%, 93.3%, 83.9%, 61.3%, 66.7%, and 83.3%. CONCLUSION: We created a visual nomogram to predict NACi risk in breast cancer patients. The NACiPM can be used to distinguish the low, intermediate, and high risk of NAC before surgery. Combined with IFP, we can develop a decision-making system for the implementation of NSM.
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Neoplasias de la Mama , Mamoplastia , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/cirugía , Pezones/cirugía , Nomogramas , MastectomíaRESUMEN
Rerandomization discards assignments with covariates unbalanced in the treatment and control groups to improve estimation and inference efficiency. However, the acceptance-rejection sampling method used in rerandomization is computationally inefficient. As a result, it is time-consuming for rerandomization to draw numerous independent assignments, which are necessary for performing Fisher randomization tests and constructing randomization-based confidence intervals. To address this problem, we propose a pair-switching rerandomization (PSRR) method to draw balanced assignments efficiently. We obtain the unbiasedness and variance reduction of the difference-in-means estimator and show that the Fisher randomization tests are valid under PSRR. Moreover, we propose an exact approach to invert Fisher randomization tests to confidence intervals, which is faster than the existing methods. In addition, our method is applicable to both nonsequentially and sequentially randomized experiments. We conduct comprehensive simulation studies to compare the finite-sample performance of the proposed method with that of classical rerandomization. Simulation results indicate that PSRR leads to comparable power of Fisher randomization tests and is 3-23 times faster than classical rerandomization. Finally, we apply the PSRR method to analyze two clinical trial datasets, both of which demonstrate the advantages of our method.
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Proyectos de Investigación , Simulación por Computador , Tamaño de la MuestraRESUMEN
Clear cell odontogenic carcinoma is a rare malignancy, which is vary in behavior from indolent tumor to cases with frequent recurrence and rare metastasis. In this manuscript, we report a case of clear cell odontogenic carcinoma of right lower mandible with cervical lymph node metastasis in a 50-year-old female. The tumor recurred and metastasized to vertebra and pleura after adjuvant radiation and chemotherapy, and the patient died of the disease 29 months after diagnosis. Pathologically, the tumor was composed of epithelial nests dominated by clear cells with ameloblastoma-like pattern and biphasic pattern. The tumor cells showed strong positive for AE1/AE3, KRT19, KRT5/6, P63, focal positive for KRT7, and weak positive for MUC1. Molecularly, EWSR1::ATF1 gene fusion was identified. To our knowledge, this report describes the first case of metastasis of clear cell odontogenic carcinoma involving regional lymph nodes and distant pleural and vertebral areas, demonstrating an aggressive clinical course of clear cell odontogenic carcinoma.
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Ameloblastoma , Carcinoma , Tumores Odontogénicos , Femenino , Humanos , Persona de Mediana Edad , Pleura/patología , Tumores Odontogénicos/patología , Ameloblastoma/patología , Columna Vertebral/patologíaRESUMEN
Traditional Chinese medicine (TCM) formulas can be adjusted on the basis of TCM basic theory to achieve the best curative effect, especially for diseases with complex pathogenesis, such as post-weaning diarrhea (PWD). Shugan Jianwei Sijunzi decoction (SJ-SJZD) can be recognized as modified Sijunzi Decoction (SJZD) supplemented with Astragalus mongholicus Bunge, Bupleurum chinense DC, Citrus × aurantium L., and Crataegus pinnatifida Bunge (fruit) in a fixed dosage ratio. The inactive ingredients were subsequently added to make granule, which was Shugan Jianwei Sijunzi granule (SJ-SJZG). Previous studies have confirmed the antagonism of SJ-SJZG to PWD. However, the mechanism of SJ-SJZG protective effects on small intestine in weaned Rex rabbits remained unclear. Animals were randomly divided into negative control (NC), low dose (LD), medium dose (MD), high dose (HD), and positive control (PC). SJ-SJZG significantly increased the intestinal length and the jejunum villi length. The SIgA level was statistically increased in duodenum and jejunum with the ELISA. Immunohistochemical detection showed that SIgA protein expression was also increased significantly in jejunum. Meanwhile, the relative expression of Zo1 in duodenum and jejunum of SJ-SJZG group increased significantly. SJ-SJZG significantly increased the relative expression of occludin in duodenum and jejunum as well. Moreover, real-time PCR results showed a significant increase in GLUT2 and SGLT1 relative expression in ileum. SJ-SJZG could also obviously enhance the expression of GLUT2 in jejunum and the expression of SGLT1 in duodenum. In conclusion, SJ-SJZG had been proven to be effective in promoting the development of small intestine and improving the immunity of small intestine. Moreover, SJ-SJZG could ensure the integrity of mucosal barrier and increase the ability of intestine to absorb glucose in small intestine.
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Linear regression is arguably the most fundamental statistical model; however, the validity of its use in randomized clinical trials, despite being common practice, has never been crystal clear, particularly when stratified or covariate-adaptive randomization is used. In this article, we investigate several of the most intuitive and commonly used regression models for estimating and inferring the treatment effect in randomized clinical trials. By allowing the regression model to be arbitrarily misspecified, we demonstrate that all these regression-based estimators robustly estimate the treatment effect, albeit with possibly different efficiency. We also propose consistent non-parametric variance estimators and compare their performances to those of the model-based variance estimators that are readily available in standard statistical software. Based on the results and taking into account both theoretical efficiency and practical feasibility, we make recommendations for the effective use of regression under various scenarios. For equal allocation, it suffices to use the regression adjustment for the stratum covariates and additional baseline covariates, if available, with the usual ordinary-least-squares variance estimator. For unequal allocation, regression with treatment-by-covariate interactions should be used, together with our proposed variance estimators. These recommendations apply to simple and stratified randomization, and minimization, among others. We hope this work helps to clarify and promote the usage of regression in randomized clinical trials.
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Modelos Estadísticos , Humanos , Distribución Aleatoria , Modelos Lineales , Simulación por ComputadorRESUMEN
This paper presents the vibration response analysis and optimal structural design of a microgripper driven by linear ultrasonic motors (LUMs) dedicated to improving end-point positioning accuracy. Based on structural vibration theory, a parametric vibration response model of the microgripper finger was established, and the relative sensitivities of the structural and material parameters that affect the vibration amplitude of the fingertip were calculated within the structural and material constraints. Then, according to the sensitivity calculation results, a multidimensional constrained nonlinear optimization model was constructed to suppress the vibration of the end-effector. The improved internal penalty function method combined with Newton iteration was adopted to obtain the optimal structural parameters. Finally, the vibration experimental results show that the vibration amplitude of the initial microgripper fingertip is 16.31 µm, and the value measured after optimization was 2.49 µm, exhibiting a reduction of 84.7%. Therefore, the proposed optimal design method can effectively restrain the vibration of the microgripper end-effector and improve manipulation stability.
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Human islet amyloid polypeptides (hIAPP) aggregate into amyloid deposits in the pancreatic islets of Langerhans, contributing to the loss of ß-cells of patients with type 2 diabetes. Despite extensive studies of membrane disruption associated with hIAPP aggregates, the molecular details regarding the complex interplay between hIAPP aggregates and raft-containing membranes are still very limited. Using all-atom molecular dynamics simulations, we investigate the impact of hIAPP aggregate insertion on lipid segregation. We have found that the domain separation of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) is enhanced upon hIAPP membrane permeabilization in the absence of cholesterol, while within our simulation timescale, we cannot provide definitive evidence regarding the impact of hIAPP insertion on domain segregation in the ternary mixture (DOPC/DPPC/cholesterol). When the lipid domains are perturbed, their restoration occurs rapidly and spontaneously in the presence of hIAPP aggregates. hIAPP insertion affects membrane thickness in its immediate surroundings. On average, hIAPP causes the fluidity of lipids to increase and even cholesterol shows enhanced diffusivity. The acyl chain packing of the lipids near hIAPP is disrupted as compared to that further away from it. Cholesterol not only modulates membrane mobility and ordering but also hIAPP aggregates' structure and relative orientation to the membrane. Our investigations on the interaction between hIAPP aggregates and raft-containing membranes could lead to a better understanding of the mechanisms of amyloid cytotoxicity.
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Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Microdominios de Membrana/metabolismo , Biopolímeros/metabolismo , Colesterol/metabolismo , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/química , Fluidez de la Membrana , Lípidos de la Membrana/metabolismo , Microscopía de Fuerza Atómica , Simulación de Dinámica Molecular , Conformación Proteica en Lámina betaRESUMEN
INTRODUCTION AND IMPORTANCE: In surgery, misdiagnosis is not uncommon, usually a result of erroneous image interpretations and pathology diagnosis especially involving a tumor or cancer. Misdiagnosis may cause increased morbidity, mortality and surgical risks. CASE PRESENTATION: A 49-year-old man presented for the second time with a right upper abdominal mass of 7 months. Previous CT scan of abdomen and exploratory surgery made the diagnosis of liver cancer. Two other tertiary hospitals drew the similar conclusions. At a cancer hospital the needle biopsy was suspicious for gastrointestinal stromal tumor, Imatinib was recommended but not started due to high cost. During this re-admission, the diagnosis of liver cancer or GIST was challenged. A high risk surgery was done with successive removal of a giant tumor. A final diagnosis of paraganlioma was made and the patient is now tumor free for 6 years. CLINICAL DISCUSSION: There are 4 lessons from this case. First, a paraganlioma may be misdiagnosed. Second, the misdiagnosis may be misled by CT scan and pathology. Third, a misdiagnosis can cause increased morbidity, mortality and surgical risks. Forth, massive intraoperative hemorrhage is a high risk of surgery. CONCLUSION: Careful clinical evaluation combined with pathology diagnosis may reduce the misdiagnosis of some tumor/cancer. Surgical resection may be the only way to reach a diagnosis in patient with paraganlioma. Massive intraoperative hemorrhage is a high risk of surgery in such patients.
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STUDY DESIGN: Animal experimental study. OBJECTIVE: The aim of this study was to investigate the optimal time of hydrogel injection for regenerating intervertebral disc degeneration (IDD) based on T1ρ magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: Currently, different approaches are being pursued to regenerate the IDD. However, the optimal timing for the regenerative intervention is unclear. METHODS: The slowly, progressive IDD models were established in 18 rhesus monkeys. On the basis of the MR T1ρ values of the discs, the rhesus monkeys were divided into severe (T1ρ values: <81 ms), moderate (T1ρ values: 81â¼95 ms), and mild (T1ρ values: 96â¼110 ms) degeneration groups. Biocompatible hydrogel was injected into the central part of the nucleus pulposus of the discs under fluoroscopic guidance. Treatment effects were investigated using radiography, T1ρ MRI, and histology until 12 months postoperatively. RESULTS: After injection, the T1ρ values of all the discs increased significantly at 1 month postoperatively, and then remained at approximately 110 ms in the mild and moderate groups during the whole observation period, with no significant difference compared to the values at 1 month (Pâ>â0.05). However, in the severe group, the T1ρ values decreased significantly after 1 month and leveled at approximately 70 ms after 6 months, with significant difference compared to the values at 1 month (Pâ<â0.05). In the mild and moderate groups, there were no significant differences between preoperative histological scores and those at 12 months (Pâ>â0.05). However, the histological score in the severe group at 12 months was significantly higher than the preoperative scores (Pâ<â0.05). CONCLUSION: This study suggested that the moderate degenerative stage of IDD (T1ρ values from 95 to 80 ms) could be the optimal time for hydrogel injection aimed at the regenerative intervention, based on T1ρ-MR imaging technique and quantitative analysis. LEVEL OF EVIDENCE: N/A.
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Hidrogeles/administración & dosificación , Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Animales , Esquema de Medicación , Femenino , Inyecciones , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/efectos de los fármacos , Macaca mulatta , Masculino , Factores de Tiempo , Resultado del TratamientoRESUMEN
Numerous studies have shown that probiotic Bacillus could promote growth and enhance anti-disease ability in animal. In present study, the mixture of three Bacillus strains, which were isolated from rex rabbits and showed high cellulose, protease, and amylase activities, was added into the diet for investigating its effects on young and weaning rex rabbits. For experiment 1, 40 young rex rabbits (9 weeks old) were randomly divided into four groups and fed with diets containing 0 (NC), 1.0 × 105 cfu/g (LC), 1.0 × 106 cfu/g (MC), and 1.0 × 107 cfu/g (HC) Bacillus strains for 4 weeks. For experiment 2, 80 weaning rex rabbits (5 weeks old) were randomly divided into four groups and fed with diet containing 0 (control), 1.0 × 105 cfu/g (T-1), 1.0 × 106 cfu/g (T-2), and 1.0 × 107 cfu/g (T-3) Bacillus strains for 8 weeks. The results showed that Bacillus strains at a dose of 1.0 × 106 cfu/g significantly enhanced growth performance, increased immune organ indexes, improved serum biochemical parameters, and heightened antioxidant capacity. It also markedly improved the intestinal microbiota by increasing Lactobacillus spp., Bacillus spp. counts, and decreased Escherichia coli count. In addition, the Bacillus mixture raised the concentrations of acetic acid, propionic acid, and butyric acid as well as protease, amylase, and cellulase activities of young and weaning rex rabbits. Moreover, for weaning rex rabbits, the inclusion of Bacillus strains also upregulated the abundance of cellulolytic bacteria and improved intestinal morphology. Therefore, our results indicated that Bacillus strains could facilitate the growth of young and weaning rex rabbits by improving digestive function and anti-disease ability. KEY POINTS: ⢠Bacillus with high extracellular enzyme activity were isolated from rex rabbits. ⢠Bacillus could improve growth performance of young and weaning rex rabbits. ⢠The digestive function of young and weaning rex rabbits could be improved by Bacillus.
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Alimentación Animal/microbiología , Bacillus/fisiología , Digestión , Susceptibilidad a Enfermedades , Crecimiento y Desarrollo , Probióticos/administración & dosificación , Factores de Edad , Animales , Femenino , Intestinos/enzimología , Intestinos/microbiología , Intestinos/fisiología , Masculino , Conejos , DesteteRESUMEN
Intrinsically disordered proteins or intrinsically disordered regions (IDPs) have gained much attention in recent years due to their vital roles in biology and prevalence in various human diseases. Although IDPs are perceived as attractive therapeutic targets, rational drug design targeting IDPs remains challenging because of their conformational heterogeneity. Here, we propose a hierarchical computational strategy for IDP drug virtual screening (IDPDVS) and applied it in the discovery of p53 transactivation domain I (TAD1) binding compounds. IDPDVS starts from conformation sampling of the IDP target, then it combines stepwise conformational clustering with druggability evaluation to identify potential ligand binding pockets, followed by multiple docking screening runs and selection of compounds that can bind multi-conformations. p53 is an important tumor suppressor and restoration of its function provides an opportunity to inhibit cancer cell growth. TAD1 locates at the N-terminus of p53 and plays key roles in regulating p53 function. No compounds that directly bind to TAD1 have been reported due to its highly disordered structure. We successfully used IDPDVS to identify two compounds that bind p53 TAD1 and restore wild-type p53 function in cancer cells. Our study demonstrates that IDPDVS is an efficient strategy for IDP drug discovery and p53 TAD1 can be directly targeted by small molecules.