Microenvironment Signals and Mechanisms in the Regulation of Osteosarcoma

Osteosarcoma (OS) is the most common malignant primary bone tumor in children and adolescents and features rapid development, strong metastatic ability, and poor prognosis. It has been well established that diverse genetic aberrations and metabolic alterations confer the tumorigenesis and development of OS. The intricate metabolism and vascularization that contributes to the nutrient and structural support for tumor progression should be thoroughly clarified to help us gain novel insights into OS and its clinical diagnoses and treatments. With regard to the complex bone extracellular matrix (ECM) and local cell populations, we intend to illustrate the interrelationship between various microenvironmental signals and the different stages of OS evolution. Solid evidence has noted two crucial factors of the OS microenvironment in the acquisition of stem cell phenotypes - transforming growth factor-β1 (TGF-β1) signaling and hypoxia. Different cell subtypes in the local environment might also serve as unique contributors that interact with each other and communicate with distant cells, thus participating in local invasion and metastasis. Proper models have been established and improved to reveal the evolutionary footsteps of how normal cells transform into a neoplastic state and progress toward malignancy

Characterization and density functional theory study of the antioxidant activity of quercetin and its sugar-containing analogues

Inhibition of free radicals using quercetin, hyperin and rutin is examined to determine their antioxidant effects and the structure-activity relationships of flavonoids. Two species of the free radicals are used, including hydroxyl radical (.OH) and superoxide anion radical (O-2(-)). Density functional theory calculations under the level of B3LYP/6-311G (d) have been utilized to explore the structure, molecular properties and antioxidant abilities of the three flavonoids. Bond dissociation enthalpy (BDE) and frontier molecular orbital energy gap are investigated. They are compared with the experiment results assayed by the spectrophotometric. All of the flavonoids show a high activity on inhibiting OH and O-2(-) radicals. Scavenging activity determined by half maximal inhibitory concentration (IC50) values of the three flavonoids decreases in the order: quercetin > hyperin > rutin. The calculations show that quercetin owns the lowest BDE values, which agree well with the experimental results of antioxidant activity determined by IC50 values

K-LITE: Learning Transferable Visual Models with External Knowledge

Recent state-of-the-art computer vision systems are trained from natural language supervision, ranging from simple object category names to descriptive captions. This free form of supervision ensures high generality and usability of the learned visual models, based on extensive heuristics on data collection to cover as many visual concepts as possible. Alternatively, learning with external knowledge about images is a promising way which leverages a much more structured source of supervision. In this paper, we propose K-LITE (Knowledge-augmented Language-Image Training and Evaluation), a simple strategy to leverage external knowledge to build transferable visual systems: In training, it enriches entities in natural language with WordNet and Wiktionary knowledge, leading to an efficient and scalable approach to learning image representations that can understand both visual concepts and their knowledge; In evaluation, the natural language is also augmented with external knowledge and then used to reference learned visual concepts (or describe new ones) to enable zero-shot and few-shot transfer of the pre-trained models. We study the performance of K-LITE on two important computer vision problems, image classification and object detection, benchmarking on 20 and 13 different existing datasets, respectively. The proposed knowledge-augmented models show significant improvement in transfer learning performance over existing methods.Comment: Preprint. The first three authors contribute equall

Energy evolution mechanism during rockburst development in structures of surrounding rocks of deep rockburst-prone roadways in coal mines

Influenced by the deep high-stress environment, geological structures, and mining disturbance in coal mines, the frequency of rockburst disasters in roadways is increasing. This research analyzed energy evolution characteristics during rockburst development in the elastic bearing zone and energy conversion in the plastic failure zone. The critical energy criteria for structural instability of roadway surrounding rocks were deduced. Numerical software was also applied to simulate the energy evolution during rockburst development in surrounding rocks of rockburst-prone roadways under conditions of different mining depths and coal pillar widths. The occurrence mechanism of rockburst deep in coal mines was analyzed from the perspective of energy in structures of deep roadway surrounding rock in coal mines. The research results show that the critical energy criteria are closely related to the elastic strain energy stored in deep roadway surrounding rocks and the energy absorbed by support systems. The impact energy in roadways is directly proportional to the square of the stress concentration factor k. Moreover, as the mining depth increases, the location of the peak point of maximum energy density gradually shifts to coal ahead of the working face. The larger the mining depth is, the more significantly the energy density is influenced by advanced abutment pressure of the working face and the wider the affected area is. With the increment of the coal pillar width, the distance from the peak point of energy density to the roadway boundary enlarges abruptly at first and then slowly, and the critical coal pillar width for gentle change in the distance is 30 m. Changes in the peak elastic energy density in coal pillars with the coal pillar width can be divided into four stages: the slow increase stage, abrupt increase stage, abrupt decrease stage, and slow decrease stage. The elastic energy density is distributed asymmetrically in deep roadway surrounding rocks in coal mines. Under the action of structures of roadway surrounding rocks, energy evolution in these structures differs greatly during rockburst development under conditions of different coal pillar widths. This research provides an important theoretical basis for the support of rockburst-prone roadways during deep coal mining

ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death

Amyotrophic Lateral Sclerosis (ALS) is a group of neurodegenerative disorders that featured with the death of motor neurons, which leads to loss of voluntary control on muscles. The etiologies vary among different subtypes of ALS, and no effective management or medication could be provided to the patients, with the underlying mechanisms incompletely understood yet. Mutations in human Optn (Optineurin), particularly E478G, have been found in many ALS patients. In this work, we report that NF-κB activity was increased in Optn knockout (Optn−/−) MEF (mouse embryonic fibroblast) cells expressing OPTN of different ALS-associated mutants especially E478G. Inflammation was significantly activated in mice infected with lenti-virus that allowed overexpression of OPTNE478G mutation in the motor cortex, with marked increase in the secretion of pro-inflammatory cytokines as well as neuronal cell death. Our work with both cell and animal models strongly suggested that anti-inflammation treatment could represent a powerful strategy to intervene into disease progression in ALS patients who possess the distinctive mutations in OPTN gene

The advances of adjuvants in mRNA vaccines

Abstract The remarkable success of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has propelled the rapid development of this vaccination technology in recent years. Over the last three decades, numerous studies have shown the considerable potential of mRNA vaccines that elicit protective immune responses against pathogens or cancers in preclinical studies or clinical trials. These effective mRNA vaccines usually contain specific adjuvants to obtain the desired immune effect. Vaccine adjuvants traditionally are immunopotentiators that bind to pattern recognition receptors (PRRs) of innate immune cells to increase the magnitude or achieve qualitative alteration of immune responses, finally enhancing the efficacy of vaccines. Generally, adjuvants are necessary parts of competent vaccines. According to the existing literature, adjuvants in mRNA vaccines can be broadly classified into three categories: 1) RNA with self-adjuvant characteristics, 2) components of the delivery system, and 3) exogenous immunostimulants. This review summarizes the three types of adjuvants used in mRNA vaccines and provides a comprehensive understanding of molecular mechanisms by which adjuvants exert their functions in mRNA vaccines

Estimation of the Optimal Ratio of Standardized Ileal Digestible Threonine to Lysine for Finishing Barrows Fed Low Crude Protein Diets

Two experiments were conducted to determine the standardized ileal digestible (SID) lysine (Lys) requirement and the ideal SID threonine (Thr) to Lys ratio for finishing barrows. In Exp. 1, 120 barrows with an average body weight of 72.8±3.6 kg were allotted to one of six dietary treatments in a randomized complete block design conducted for 35 d. Each diet was fed to five pens of pigs containing four barrows. A normal crude protein (CP) diet providing 15.3% CP and 0.71% SID Lys and five low CP diets providing 12% CP with SID Lys concentrations of 0.51, 0.61, 0.71, 0.81 and 0.91% were formulated. Increasing the SID Lys content of the diet resulted in an increase in weight gain (linear effect p = 0.04 and quadratic effect p = 0.08) and an improvement in feed conversion ratio (FCR) (linear effect p = 0.02 and quadratic effect p = 0.02). For weight gain and FCR, the estimated SID Lys requirement of finishing barrows were 0.71 and 0.71% (linear broken-line analysis), 0.79 and 0.78% (quadratic analysis), respectively. Exp. 2 was a 26 d dose-response study using SID Thr to Lys ratios of 0.56, 0.61, 0.67, 0.72 and 0.77. A total of 138 barrows weighing 72.5±4.4 kg were randomly allotted to receive one of the five diets. All diets were formulated to contain 0.61% SID Lys (10.5% CP), which is slightly lower than the pig’s requirement. Weight gain was quadratically (p = 0.03) affected by SID Thr to Lys ratio while FCR was linearly improved (p = 0.02). The SID Thr to Lys ratios for maximal weight gain and minimal FCR and serum urea nitrogen (SUN) were 0.67, 0.71 and 0.64 using a linear broken-line model and 0.68, 0.78 and 0.70 using a quadratic model, respectively. Based on the estimates obtained from the broken-line and quadratic analysis, we concluded that the dietary SID Lys requirement for both maximum weight gain and minimum FCR was 0.75%, and an optimum SID Thr to Lys ratio was 0.68 to maximize weight gain, 0.75 to optimize FCR and 0.67 to minimize SUN for finishing barrows

Leucine Supplementation in a Chronically Protein-Restricted Diet Enhances Muscle Weight and Postprandial Protein Synthesis of Skeletal Muscle by Promoting the mTOR Pathway in Adult Rats

Low protein intake causes a decrease in protein deposition in most animal tissues. The purpose of this study was to investigate whether leucine supplementation would increase the synthesis rate of protein and muscle weight in adult rats, which chronically consume only 58.8% of their protein requirements. Thirty-six male Sprague-Dawley rats were assigned to one of three dietary treatments including a 20% casein diet (CON), a 10% casein + 0.44% alanine diet (R), and a 10% casein + 0.87% leucine diet (RL). After a 10 d dietary treatment, plasma amino acid levels were measured after feeding, the gastrocnemius muscles and soleus muscles were harvested and weighed, and the fractional synthesis rate (FSR) and mammalian target of rapamycin (mTOR) signaling proteins in skeletal muscle were measured. Regarding the plasma amino acid level, the RL group had the highest concentration of leucine (P < 0.05) and the lowest concentration of isoleucine (P < 0.05) among the three groups, and the CON group had a lower concentration of valine (P < 0.05) than the R and RL groups. Compared with the R and RL groups, the CON group diet significantly increased (P < 0.05) feed intake, protein synthesis rate, and the phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and decreased the weight of abdominal adipose. Compared with the R group, the RL group significantly increased in gastrocnemius muscle weight, protein synthesis rate, and phosphorylation of both ribosomal protein S6 kinase 1 (S6K1) and 4E-BP1. In conclusion, when protein is chronically restricted in adult rat diets, leucine supplementation moderately improves body weight gain and increases muscle protein synthesis through mTOR activation