Search

Transmissible gastroenteritis virus (TGEV)-induced enteritis is characterized by watery diarrhea, vomiting, and dehydration, and has high mortality in newborn piglets, resulting in significant economic losses in the pig industry worldwide. Conventional cell lines have been used for many years to investigate inflammation induced by TGEV, but these cell lines may not mimic the actual intestinal environment, making it difficult to obtain accurate results. In this study, apical-out porcine intestinal organoids were employed to study TEGV-induced inflammation. We found that apicalout organoids were susceptible to TGEV infection, and the expression of representative inflammatory cytokines was significantly upregulated upon TGEV infection. In addition, retinoic acid-inducible gene I (RIG-I) and the nuclear factor-kappa B (NF-κB) pathway were responsible for the expression of inflammatory cytokines induced by TGEV infection. We also discovered that the transcription factor hypoxia-inducible factor-1α (HIF-1α) positively regulated TGEV-induced inflammation by activating glycolysis in apical-out organoids, and pig experiments identified the same molecular mechanism as the ex vivo results. Collectively, we unveiled that the inflammatory responses induced by TGEV were modulated via the RIG-I/NF-κB/HIF-1α/glycolysis axis ex vivo and in vivo. This study provides novel insights into TGEV-induced enteritis and verifies intestinal organoids as a reliable model for investigating virus-induced inflammation. IMPORTANCE Intestinal organoids are a newly developed culture system for investigating immune responses to virus infection. This culture model better represents the physiological environment compared with well-established cell lines. In this study, we discovered that inflammatory responses induced by TGEV infection were regulated by the RIG-I/NF-κB/HIF-1α/glycolysis axis in apical-out porcine organoids and in pigs. Our findings contribute to understanding the mechanism of intestinal inflammation upon viral infection and highlight apical-out organoids as a physiological model to mimic virus-induced inflammation. [ABSTRACT FROM AUTHOR]

The transmission of viral diseases is highly unstable and highly contagious. As the carrier of virus transmission, cell is an important factor to explore the mechanism of virus transmission and disease. However, there is still a lack of effective means to continuously monitor the process of viral infection in cells, and there is no rapid, highthroughput method to assess the status of viral infection. On the basis of the virus light diffraction fingerprint of cells, we applied the gray co-occurrence matrix, set the two parameters effectively to distinguish the virus status and infection time of cells, and visualized the virus infection process of cells in high throughput. We provide an effcient and nondestructive testing method for the selection of excellent livestock and poultry breeds at the cellular level. Meanwhile, our work provides detection methods for the recessive transmission of human-to-human, animal-to-animal, and zoonotic diseases and to inhibit and block their further development. [ABSTRACT FROM AUTHOR]

In gene therapy, intravenous injection of viral vectors reigns as the primary administration route. These vectors include adeno-associated viruses, adenoviruses, herpes viruses, rhabdoviruses and others. However, these naturally occurring viruses lack inherent tissue or organ tropism for tailored disease treatment. To address this, we devised an optimized process involving directed viral capsid evolution, organ-specific humanized mouse models and in vitro-in vivo virus screening. Our approach allows for the rapid generation specifically modified adeno-associated virus variants, surpassing the time required for natural evolution, which spans millions of years. Notably, these variants exhibit robust targeting of the liver, favouring chimeric human liver cells over murine hepatocytes. Furthermore, certain variants achieve augmented targeting with reduced off-target organ infection, thereby mitigating dosage requirements and enhancing safety in gene therapy. [ABSTRACT FROM AUTHOR]

AbstractWe consider the estimation problem in high-dimensional semi-supervised learning. Our goal is to investigate when and how the unlabeled data can be exploited to improve the estimation of the regression parameters of linear model in light of the fact that such linear models may be misspecified in data analysis. We first establish the minimax lower bound for parameter estimation in the semi-supervised setting, and show that this lower bound cannot be achieved by supervised estimators using the labeled data only. We propose an optimal semi-supervised estimator that can attain this lower bound and therefore improves the supervised estimators, provided that the conditional mean function can be consistently estimated with a proper rate. We further propose a safe semi-supervised estimator. We view it safe, because this estimator is always at least as good as the supervised estimators. We also extend our idea to the aggregation of multiple semi-supervised estimators caused by different misspecifications of the conditional mean function. Extensive numerical simulations and a real data analysis are conducted to illustrate our theoretical results. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

In this paper, we propose a new framework to construct confidence sets for a |$d$| -dimensional unknown sparse parameter |${\boldsymbol \theta }$| under the normal mean model |${\boldsymbol X}\sim N({\boldsymbol \theta },\sigma ^{2}\bf{I})$|⁠. A key feature of the proposed confidence set is its capability to account for the sparsity of |${\boldsymbol \theta }$|⁠ , thus named as sparse confidence set. This is in sharp contrast with the classical methods, such as the Bonferroni confidence intervals and other resampling-based procedures, where the sparsity of |${\boldsymbol \theta }$| is often ignored. Specifically, we require the desired sparse confidence set to satisfy the following two conditions: (i) uniformly over the parameter space, the coverage probability for |${\boldsymbol \theta }$| is above a pre-specified level; (ii) there exists a random subset |$S$| of |$\{1,...d\}$| such that |$S$| guarantees the pre-specified true negative rate for detecting non-zero |$\theta _{j}$| 's. To exploit the sparsity of |${\boldsymbol \theta }$|⁠ , we allow the confidence interval for |$\theta _{j}$| to degenerate to a single point 0 for any |$j\notin S$|⁠. Under this new framework, we first consider whether there exist sparse confidence sets that satisfy the above two conditions. To address this question, we establish a non-asymptotic minimax lower bound for the non-coverage probability over a suitable class of sparse confidence sets. The lower bound deciphers the role of sparsity and minimum signal-to-noise ratio (SNR) in the construction of sparse confidence sets. Furthermore, under suitable conditions on the SNR, a two-stage procedure is proposed to construct a sparse confidence set. To evaluate the optimality, the proposed sparse confidence set is shown to attain a minimax lower bound of some properly defined risk function up to a constant factor. Finally, we develop an adaptive procedure to the unknown sparsity. Numerical studies are conducted to verify the theoretical results. [ABSTRACT FROM AUTHOR]

This article explores statistical inference for streamed longitudinal data in biomedical research. The authors propose a new framework to reduce the memory and computational burdens of analyzing the entire dataset. They discuss alternative approaches, such as constructing confidence intervals and hypothesis tests using different estimators. The article includes a simulation study comparing the performance of these estimators and suggests improvements for the quadratic inference function estimator. The document also explains the quadratic decorrelated inference function and its application in making inferences on a specific parameter. The authors acknowledge the support of the National Science Foundation and National Institutes of Health. [Extracted from the article]

Purpose • Acupuncture has been used for almost half a century to treat and prevent cardiovascular (CV) problems. However, most of its effects are poorly understood, and there are few studies based on bibliometric analysis of the general trends in acupuncture therapy in cardiovascular disorders (CVD). Thus, we aimed to show the present state and trends in this sector during the last few years. Methods • Articles were obtained from the Web of Science Core Collection (WOSCC) from its inception to May 30, 2021. The acquired information from the articles was analyzed by The Online Bibliometric Analysis Platform website (https://bibliometric.com), Citespace and VOSviewer in respective form in order to assess and forecast the hottest areas and trends in this field. Results • The final analysis included a total of 384 articles and reviews. Over the years, the number of publications has gradually increased. The United States and University of California Irvine were the country and institution that contributed the most to the field. John C Longhurst was the most productive author; Li P the most cited author. Co-occurrence analysis revealed 5 branches (including acupuncture, blood pressure, electroacupuncture, stimulation, cardiovascular responses) and 12 clusters. Recent keyword bursts included “reflex,” “arcuate nucleus,” “electroacupuncture,” “cardiovascular disease” and “hypertension.” Conclusion • Yearly publications continue to increase every decade, indicating a bright future in this scientific field. Acupuncture’s function in CVD is a future study priority. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia (PE), characterized by hypertension and proteinuria, leads to serious maternal and infant complications. Uridine-cytidine kinase 2 (UCK2) belongs to the UCK family, a class of enzymes that catalyzes the conversion of uridine and cytidine to monophosphate form. However, the role of UCK2 in PE has not been reported. Methods: The expression of UCK2 was detected in the placenta of PE patients and N(?)-nitro-L-arginine methyl esterinduced PE mouse model. Through forced up-regulation or down-regulation of UCK2 in vitro, we examined the effects of UCK2 on the proliferation, apoptosis, migration, and invasion of trophoblast cells. Stattic, the inhibitor of STAT3 pathway, was used to investigate whether the STAT3 pathway mediates the biological function of UCK2 in trophoblast cells. Results: The present study found that UCK2 showed low expression in the placenta of PE patients and PE mouse model. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and flow cytometry assays verified that up-regulation of UCK2 promoted the proliferation of trophoblast cells, while the silence of UCK2 suppressed cell proliferation. Besides, flow cytometry and TdT-mediated dUTP Nick-End Labeling assays demonstrated that knockdown of UCK2 resulted in apoptosis of trophoblast cells. The wound healing and transwell assays showed that the migration and invasion activities of the trophoblast cells were facilitated by the overexpression of UCK2 and were blocked by the silence of UCK2. Furthermore, the expression of phosphorylated STAT3 was increased with the upregulation of UCK2 and decreased with the inhibition of UCK2. When the STAT3 pathway was blocked by its inhibitor stattic, the promotion effects of UCK2 on trophoblast cells were suppressed. Conclusion: UCK2 promotes the proliferation, migration, and invasion of trophoblast cells, and these effects may be partly mediated by the activation of the STAT3 pathway. [ABSTRACT FROM AUTHOR]

Human esophageal cancer has a global impact on human health due to its high incidence and mortality. Therefore, there is an urgent need to develop new drugs to treat or prevent the prominent pathological subtype of esophageal cancer, esophageal squamous cell carcinoma (ESCC). Based upon the screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of human ESCC in vitro. Next, we conducted a series of cell-based assays and found that Arbidol treatment inhibited the proliferation and colony formation ability of ESCC cells and promoted G1-phase cell cycle arrest. Phosphoproteomics experiments, in vitro kinase assays and pull-down assays were subsequently performed in order to identify the underlying growth inhibitory mechanism. We verified that Arbidol is a potential ataxia telangiectasia and Rad3-related (ATR) inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of minichromosome maintenance protein 2 at Ser108. Finally, we demonstrated Arbidol had the inhibitory effect of ESCC in vivo by a patient-derived xenograft model. All together, Arbidol inhibits the proliferation of ESCC in vitro and in vivo through the DNA replication pathway and is associated with the cell cycle. [ABSTRACT FROM AUTHOR]

Intestinal stem cells (ISCs) play an important role in tissue repair after injury. A recent report delineates the effect of transmissible gastroenteritis virus (TGEV) infection on the small intestine of recovered pigs. However, the mechanism behind the epithelium regeneration upon TGEV infection remains unclear. To address this, we established a TGEV infection model based on the porcine intestinal organoid monolayer. The results illustrated that the porcine intestinal organoid monolayer was susceptible to TGEV. In addition, the TGEV infection initiated the interferon and inflammatory responses following the loss of absorptive enterocytes and goblet cells. However, TGEV infection did not disturb epithelial integrity but induced the proliferation of ISCs. Furthermore, TGEV infection activated the Wnt/β-catenin pathway by upregulating the accumulation and nuclear translocation of β-catenin, as well as promoting the expression of Wnt target genes, such as C-myc, Cyclin D1, Mmp7, Lgr5, and Sox9, which were associated with the selfrenewal of ISCs. Collectively, these data demonstrated that the TGEV infection activated the Wnt/β-catenin pathway to promote the self-renewal of ISCs and resulted in intestinal epithelium regeneration. [ABSTRACT FROM AUTHOR]

This paper presents an in-depth study on the new mode of intelligent multidistance teaching of English with the help of virtual scenes of the Internet of Things. The virtual simulation technology is integrated into the traditional IoT teaching, and the professional education of IoT application technology is tapped; from the analysis of the current situation of IoT skills teaching and the feasibility of carrying out virtual simulation teaching, the "four-driven" design principle is proposed, and the teaching design is combined with the virtual simulation technology teaching, and the case design of the skill-based virtual simulation technology teaching of experience, demonstration, interaction, and assessment in the virtual environment is given. This paper presents the case design of virtual simulation teaching in a virtual environment with experience, demonstration, interaction, and assessment, and the multidimensional effect evaluation of IoT skills teaching and researches the application of virtual simulation to IoT skills teaching through the above four aspects. In this paper, a framework for distributed collaborative computing is built using an asynchronous message queue MQ, which enables multiple nodes to serve a task through task splitting. The DeepCluster module can effectively cluster the time series by deep representation learning and obtain the typical variation of time series patterns. In the task offloading module of the framework, a task offloading decision algorithm based on a value-constrained multi 0–1 backpacking model is designed to minimize task processing latency with an optimal offloading solution. The system test results show that the proposed distributed computing framework and offloading decision algorithm can significantly reduce the processing latency of large tasks. [ABSTRACT FROM AUTHOR]

In multicentre research, individual-level data are often protected against sharing across sites. To overcome the barrier of data sharing, many distributed algorithms, which only require sharing aggregated information, have been developed. The existing distributed algorithms usually assume the data are homogeneously distributed across sites. This assumption ignores the important fact that the data collected at different sites may come from various subpopulations and environments, which can lead to heterogeneity in the distribution of the data. Ignoring the heterogeneity may lead to erroneous statistical inference. We propose distributed algorithms which account for the heterogeneous distributions by allowing site-specific nuisance parameters. The proposed methods extend the surrogate likelihood approach (Wang et al. 2017 ; Jordan et al. 2018) to the heterogeneous setting by applying a novel density ratio tilting method to the efficient score function. The proposed algorithms maintain the same communication cost as existing communication-efficient algorithms. We establish a nonasymptotic risk bound for the proposed distributed estimator and its limiting distribution in the two-index asymptotic setting, which allows both sample size per site and the number of sites to go to infinity. In addition, we show that the asymptotic variance of the estimator attains the Cramér–Rao lower bound when the number of sites is smaller in rate than the sample size at each site. Finally, we use simulation studies and a real data application to demonstrate the validity and feasibility of the proposed methods. [ABSTRACT FROM AUTHOR]

[Display omitted] • Multi-copy integration of key genes increased the squalene synthesis in cytosol. • Screening the peroxisome signal peptide with high targeting efficiency. • Introducing squalene synthesis pathway into the peroxisomes. • Strengthening the supply of acetyl-CoA in peroxisomes and cytosol. • The highest squalene titer (51.2 g/L) reported to date in the 5L bioreactor. Squalene, a high-value acyclic triterpenoid compound, is broadly used in the food and medical industries. Although the large acetyl-CoA pool and hydrophobic space of Yarrowia lipolytica are suitable for the accumulation of squalene, the current production level in Y. lipolytica is still not sufficient for industrial production. In this study, two rounds of multicopy integration of genes encoding key enzymes were performed to enhance squalene anabolic flux in the cytoplasm. Furthermore, the mevalonate pathway was imported into peroxisomes through the compartmentalization strategy, and the production of squalene was significantly increased. By augmenting the acetyl-CoA supply in peroxisomes and the cytoplasm, the squalene was boosted to 2549.1 mg/L. Finally, the squalene production reached 51.2 g/L by fed-batch fermentation in a 5-L bioreactor. This is the highest squalene production reported to date for microbial production, and this study lays the foundation for the synthesis of steroids and squalene derivatives. [ABSTRACT FROM AUTHOR]

Objective: To investigate the etiology, clinical manifestations, diagnosis, treatment and prognosis of neonatal cerebral infarction (NCI) to further improve the understanding of the disease. Methods: Clinical data and follow-up results of 33 cases of NCI in neonatal intensive care unit of a firstclass hospital from September 2009 to September 2019 were retrospectively analyzed. Results: All 33 patients were diagnosed with NCI by MRI. Among them, 31 cases (93.94%) were fullterm infants, 25 cases (75.76%) were mother's first birth, and 18 (54.55%) cases were males. Pregnancy complications were reported in 18 cases (54.55%), and 19 cases (57.58%) had perinatal hypoxia history. Seizures were the most common first symptom and clinical manifestation in the course of disease (81.8%). There were 27 cases (81.82%) of patent foramen ovale (PFO) among NCI cohort. Ischemic cerebral infarction occurred in 32 cases (96.97%). The middle cerebral artery and its branches were more frequently involved, mainly on the left side. The acute stage of NCI was managed by symptomatic support treatment, and the recovery stage involved mainly rehabilitation treatment. Among the 33 cases, five cases were lost to follow-up, two patients died, 26 patients survived without complications, one case had cerebral palsy, one case had language retardation, and six cases had dyskinesia. Poor prognosis was associated with the involvement of deep gray matter nuclei or multiple lobes, and intrapartum complications. Vaginal mode of delivery and longer hospital stay were associated with better prognosis. Conclusions: Complications leading to placental circulation disorder during pregnancy and perinatal hypoxia are common high-risk factors of NCI. The seizure is the most common clinical manifestation. There is a possible correlation between PFO and NCI. Involvement of deep gray matter or multiple lobes and intrapartum complications may indicate poor prognosis, while vaginal delivery and prolonged hospitalizations are associated with better prognosis of NCI. [ABSTRACT FROM AUTHOR]

Inhibition of vascular endothelial growth factor (VEGF) has been widely applied in anti-neovascularization therapies. As a novel anti-VEGF agent, KH902 (conbercept) is designed to restrain pathological angiogenesis. However, the effects of KH902 on retinal hypoxia have not been well studied. In a mouse model of oxygen-induced retinopathy (OIR), we assessed retinal hypoxia at postnatal days 14 (P14) and P17, as well as retinal neovascularization (RNV) at P17. In addition, we evaluated the protein level of VEGF and galectin-1 (Gal-1). Changes of the neuroretinal structure were also examined. Our results indicated that KH902 could remit retinal hypoxia in OIR at P14 and P17, which was an exciting novel finding for KH902 function. Additionally, we confirmed that KH902 markedly reduces RNV. Our results indicated that administration of KH902 downregulated VEGF expression, as well as Gal-1. Damage of neuroretinal structure after KH902 injection was not observed, which was also an encouraging result. Our study suggests that KH902 plays a role in alleviating retinal hypoxia and that it could be used for the treatment of other neovascular ocular diseases. [ABSTRACT FROM AUTHOR]

The article discusses the development of a new mouse model, NSG-Pro, with physiological levels of human prolactin (hPRL). This model supports the establishment of therapy-naïve, estrogen-dependent patient-derived xenograft (PDX) tumors that progress to metastatic disease, providing valuable insights into the resistance mechanisms and vulnerabilities in human luminal breast cancers.

This work is motivated by learning the individualized minimal clinically important difference, a vital concept to assess clinical importance in various biomedical studies. We formulate the scientific question into a high-dimensional statistical problem where the parameter of interest lies in an individualized linear threshold. The goal is to develop a hypothesis testing procedure for the significance of a single element in this parameter as well as of a linear combination of this parameter. The difficulty dues to the high-dimensional nuisance in developing such a testing procedure, and also stems from the fact that this high-dimensional threshold model is nonregular and the limiting distribution of the corresponding estimator is nonstandard. To deal with these challenges, we construct a test statistic via a new bias-corrected smoothed decorrelated score approach, and establish its asymptotic distributions under both null and local alternative hypotheses. We propose a double-smoothing approach to select the optimal bandwidth in our test statistic and provide theoretical guarantees for the selected bandwidth. We conduct simulation studies to demonstrate how our proposed procedure can be applied in empirical studies. We apply the proposed method to a clinical trial where the scientific goal is to assess the clinical importance of a surgery procedure. for this article are available online. [ABSTRACT FROM AUTHOR]

Phytopathogenic Fusarium graminearum poses significant threats to crop health and soil quality. Although our laboratory-cultivated Pseudomonas sp. P13 exhibited potential biocontrol capacities, its effectiveness against F. graminearum and underlying antifungal mechanisms are still unclear. In light of this, our study investigated a significant inhibitory effect of P13 on F. graminearum T1, both in vitro and in a soil environment. Conducting genomic, metabolomic, and transcriptomic analyses of P13, we sought to identify evidence supporting its antagonistic effects on T1. The results revealed the potential of P13, a novel Pseudomonas species, to produce active antifungal components, including phenazine-1-carboxylate (PCA), hydrogen cyanide (HCN), and siderophores [pyoverdine (Pvd) and histicorrugatin (Hcs)], as well as the dynamic adaptive changes in the metabolic pathways of P13 related to these active ingredients. During the logarithmic growth stage, T1-exposed P13 strategically upregulated PCA and HCN biosynthesis, along with transient inhibition of the tricarboxylic acid (TCA) cycle. However, with growth stabilization, upregulation of PCA and HCN synthesis ceased, whereas the TCA cycle was enhanced, increasing siderophores secretion (Pvd and Hcs), suggesting that this mechanism might have caused continuous inhibition of T1. These findings improved our comprehension of the biocontrol mechanisms of P13 and provided the foundation for potential application of Pseudomonas strains in the biocontrol of phytopathogenic F. graminearum. [ABSTRACT FROM AUTHOR]

Hierarchical Bayes, or E‐Bayes, is frequently used to estimate the failure probability when solving a zero‐failure reliability evaluation model; however, the accuracy of the reliability estimation using these methods is not very good in practice. Due to this, a novel double‐modified hierarchical Bayes (DMH‐Bayes) is proposed for Weibull characteristic data in this study to enhance failure probability estimation and improve reliability point estimation accuracy. Meanwhile, in order to guarantee the preservation of the assessment findings' consistency and confidence level, the parametric Bootstrap method (P‐Bootstrap) and the L‐moment estimation method based on point estimation are introduced to obtain reliability confidence interval estimates. Based on Monte–Carlo simulation testing and analysis of a gyroscope bearing, the new model is confirmed to have better applicability and robustness while improving the accuracy of reliability assessment. [ABSTRACT FROM AUTHOR]

Coronary artery calcium is a strong and independent marker of atherosclerosis and cardiovascular disease. Typically, the accurate segmentation of computed tomography images of the chest is an important prerequisite and basis for coronary artery calcium identification and analysis. However, this is very challenging in practice because the boundaries of coronary artery calcium, the small lesions with large shape variation, are very blurry, resulting in poor performance in existing studies. To tackle this challenge, we present a novel Attention‐based Multi‐Scale Network called AMSN, which can process information through both the main and boundary branches in parallel. Key to our AMSN is a new non‐local multi‐scale context encoder module, which is mainly composed of the multi‐scale attention mechanism and local global long short‐term memory module. By aggregating the multi‐scale context information, i.e. high‐resolution low‐level and low‐resolution high‐level features, the model's feature representative capability and deployment ability are improved effectively. Besides, we introduce a new boundary preserving loss, which can consider the boundary information of all coronary artery calcium together and establish links for the segmentation of different coronary artery calcium simultaneously. Extensive experiments demonstrate our AMSN enables reliable accurate coronary artery calcium segmentation for assisted cardiovascular disease diagnosis clinically. [ABSTRACT FROM AUTHOR]

• Dynamic modulus and VDOS are introduced into the study of grain-beam system. • The equivalent theoretical model of grain-beam system is established. • The negative effective parameters are proposed to explain the appearance of new peaks. • The relation between jamming transition and jump phenomenon is established qualitatively. We experimentally investigated the system of a simply supported beam immersed in a granular medium, which displays jump and new peaks in its amplitude-frequency curve under harmonic excitation. The relationship between the macroscopic nonlinear response and microscopic state of the granular medium was studied using the discrete element method. Using the dynamic modulus and vibrational density of states as indicators, we show that the granular medium changes from a solid-like to liquid-like state when the frequency increases to approach the jumping point. Considering the similarity between this system and acoustic metamaterial beams, an equivalent theoretical model was established for the former. Numerical results of the theoretical model were consistent with the experimental ones. It was revealed that the new peak and jump phenomena were caused by negative equivalent mass, negative equivalent stiffness of the granular medium and abrupt change in the additional stiffness cause by the jamming transition. This theoretical model is useful for studying the nonlinear dynamic characteristics of this coupled grain-beam system. [Display omitted] [ABSTRACT FROM AUTHOR]

The article focuses on visualizing the DNA repair process by a photolyase at atomic resolution. Topics discussed include the dimerization of thymine bases, the use of time-resolved serial femtosecond crystallography (TR-SFX) to visualize the catalytic process, and the uncovering of the atomic mechanism of DNA repair in real-time, revealing ordered breaking of covalent C-C bonds and conformational changes in the photolyase and its flavin adenine dinucleotide (FAD) coenzyme.

A stable and efficient path planning algorithm can improve the accuracy and efficiency of sediment sampling process. To determine a path that can guide the sampler to the preset landing point within the shortest traveling time, an improved mutation operator genetic algorithm (IMOGA) is proposed herein. First, an attitude-adjusting mechanism is introduced. Then, a three-dimensional ocean current model is developed. A hydrodynamic model of the sediment sampler is developed via CFD simulations, and an adaptive cost function for the path-planning mathematical model is proposed to improve the convergence problem. Finally, the problem is solved using a basic genetic algorithm and IMOGA separately. The comparison of the simulation results reveals that the IMOGA can achieve a better global optimal solution in less computing time than the basic genetic algorithm. The improved path planning algorithm can be used for sediment samplers and landers that deploy instruments at a designated point as well as for profiles that need to adjust their position. • Accurate and efficient sediment sampling through three-dimensional path planning based on genetic algorithm. • The adaptive cost function solves the convergence problem. • The algorithm based on a mutation probability distribution function saves computing time and sampler falling time. • The influence of algorithm control parameters is evaluated and the achievable region is analyzed. [ABSTRACT FROM AUTHOR]

Under "measurement constraints," responses are expensive to measure and initially unavailable on most of records in the dataset, but the covariates are available for the entire dataset. Our goal is to sample a relatively small portion of the dataset where the expensive responses will be measured and the resultant sampling estimator is statistically efficient. Measurement constraints require the sampling probabilities can only depend on a very small set of the responses. A sampling procedure that uses responses at most only on a small pilot sample will be called "response-free." We propose a response-free sampling procedure optimal sampling under measurement constraints (OSUMC) for generalized linear models. Using the A-optimality criterion, that is, the trace of the asymptotic variance, the resultant estimator is statistically efficient within a class of sampling estimators. We establish the unconditional asymptotic distribution of a general class of response-free sampling estimators. This result is novel compared with the existing conditional results obtained by conditioning on both covariates and responses. Under our unconditional framework, the subsamples are no longer independent and new martingale techniques are developed for our asymptotic theory. We further derive the A-optimal response-free sampling distribution. Since this distribution depends on population level quantities, we propose the OSUMC algorithm to approximate the theoretical optimal sampling. Finally, we conduct an intensive empirical study to demonstrate the advantages of OSUMC algorithm over existing methods in both statistical and computational perspectives. We find that OSUMC's performance is comparable to that of sampling algorithms that use complete responses. This shows that, provided an efficient algorithm such as OSUMC is used, there is little or no loss in accuracy due to the unavailability of responses because of measurement constraints. for this article are available online. [ABSTRACT FROM AUTHOR]

Composite likelihood functions are often used for inference in applications where the data have a complex structure. While inference based on the composite likelihood can be more robust than inference based on the full likelihood, the inference is not valid if the associated conditional or marginal models are misspecified. In this paper, we propose a general class of specification tests for composite likelihood inference. The test statistics are motivated by the fact that the second Bartlett identity holds for each component of the composite likelihood function when these components are correctly specified. We construct the test statistics based on the discrepancy between the so-called composite information matrix and the sensitivity matrix. As an illustration, we study three important cases of the proposed tests and establish their limiting distributions under both null and local alternative hypotheses. Finally, we evaluate the finite-sample performance of the proposed tests in several examples. [ABSTRACT FROM AUTHOR]

The intestinal organoid culture system is a pathbreaking working model for investigating pathogen-host interactions in the intestines. However, due to the limitations of the first generation of intestinal organoids, basal-out structure and growth in Matrigel, most pathogens can rarely attach to the apical membrane directly and hardly initiate infection. In this study, we first developed a next-generation porcine intestinal organoid culture system, characterized by an apical membrane on the surface, called apical-out. To investigate the infectivity and antiviral immune responses of this apical-out porcine intestinal organoid, a swine enteric virus, transmissible gastroenteritis virus (TGEV), was employed to inoculate the culture system. Both RT-qPCR and IFA analysis demonstrated that TGEV replicated in the apical-out porcine intestinal organoid culture system. Additionally, our results illustrated that TGEV infection significantly upregulated the expression levels of IFN-a, IFN-1, ISG15, ISG58, TNF-a, and IL-6 in this culture system. Hence, we successfully developed a porcine intestinal apical-out organoid culture system, which will facilitate the investigation of pathogen-host interactions in pig intestines. [ABSTRACT FROM AUTHOR]

Associations of metastasis-associated protein 1 (MTA1) expression with computed tomography (CT) features, pathology and prognosis of elderly patients with non-small cell lung cancer (NSCLC), and its clinical significance were explored. A total of 98 elderly patients with NSCLC were selected and underwent CT examination. The expression of MTA1 in carcinoma tissues and para-carcinoma normal tissues was detected via immunohistochemistry, and its associations with CT features, pathology and prognosis were analyzed. The results manifested that the expression of MTA1 in carcinoma tissues was significantly higher than that in para-carcinoma normal tissues, and it was associated with the degree of differentiation, stage and lymph node metastasis (P<0.05). Besides, the high expression of MTA1 was also related to the spicule sign, pleural indentation and lymph node metastasis (P<0.05) as well as the CT perfusion parameter capillary permeability (PMB) (P<0.05), but not to blood volume (BV), blood flow (BF) or time to peak (TTP). Moreover, the patients with high expression of MTA1 had significantly shorter survival time and a remarkably lower 5-year survival rate than those with low expression of MTA1 (P<0.05). In conclusion, MTA1 plays a certain role in the occurrence and development of NSCLC in elderly patients and has an association with their prognosis, which can provide references for the treatment and prognosis of NSCLC, with important clinical significance. [ABSTRACT FROM AUTHOR]

We propose a robust method to estimate the average treatment effects in observational studies when the number of potential confounders is possibly much greater than the sample size. Our method consists of three steps. We first use a class of penalized |$M$| -estimators for the propensity score and outcome models. We then calibrate the initial estimate of the propensity score by balancing a carefully selected subset of covariates that are predictive of the outcome. Finally, the estimated propensity score is used to construct the inverse probability weighting estimator. We prove that the proposed estimator, which we call the high-dimensional covariate balancing propensity score, has the sample boundedness property, is root- |$n$| consistent, asymptotically normal, and semiparametrically efficient when the propensity score model is correctly specified and the outcome model is linear in covariates. More importantly, we show that our estimator remains root- |$n$| consistent and asymptotically normal so long as either the propensity score model or the outcome model is correctly specified. We provide valid confidence intervals in both cases and further extend these results to the case where the outcome model is a generalized linear model. In simulation studies, we find that the proposed methodology often estimates the average treatment effect more accurately than existing methods. We also present an empirical application, in which we estimate the average causal effect of college attendance on adulthood political participation. An open-source software package is available for implementing the proposed methodology. [ABSTRACT FROM AUTHOR]

In biomedical studies, testing for homogeneity between two groups, where one group is modeled by mixture models, is often of great interest. This paper considers the semiparametric exponential family mixture model proposed by Hong et al. (2017) and studies the score test for homogeneity under this model. The score test is nonregular in the sense that nuisance parameters disappear under the null hypothesis. To address this difficulty, we propose a modification of the score test, so that the resulting test enjoys the Wilks phenomenon. In finite samples, we show that with fixed nuisance parameters the score test is locally most powerful. In large samples, we establish the asymptotic power functions under two types of local alternative hypotheses. Our simulation studies illustrate that the proposed score test is powerful and computationally fast. We apply the proposed score test to an UK ovarian cancer DNA methylation data for identification of differentially methylated CpG sites. [ABSTRACT FROM AUTHOR]

As the penetration of renewable energy sources (RES) continues to increase, more and more microgrids (MG) are interconnected with distribution system operators (DSO). To reduce system operational costs between MGs and DSOs, it is necessary to develop certain optimization strategies. This article proposes an optimized collaborative framework for modeling multi-entity distribution networks. In this model, DSOs are placed at the upper level to formulate policies, while MGs are at the lower level to respond in real-time to these policies. Furthermore, the multi-agent relationships in the model are described using Stackelberg game mechanisms, enhancing economic efficiency through dynamic gaming. Additionally, a data-driven multi-agent twin-delayed deep deterministic policy gradient (MATD3) algorithm is investigated to simulate the gaming process and improve the overall model's non-linear optimization capabilities. Considering that the simulation process can lead to violations of the energy storage system capacity constraints, a physics-based model is designed within the framework to ensure the safety of energy storage systems (ESS). Finally, compared to the MADDPG and penalty function methods, the proposed approach reduces the operational costs by 19.05%. [ABSTRACT FROM AUTHOR]

In this paper, a permeability parameter calculation model with six influence coefficients is constructed by taking volume strain and equivalent strain under Coulomb-Mohr criterion as independent variables. The optimal estimates of permeability parameter influence coefficients are applied to the prediction of permeability parameters under a complex loading path, and the prediction results verify the applicability of the model. [ABSTRACT FROM AUTHOR]

The efficient removal of thorium from the environment is critical due to the risks it poses to organisms. Metal–organic frameworks are favored by scholars because of their potential to effectively adsorb a variety of heavy metal ions in wastewater treatment. In this work, the interaction of UiO-66-NH2 surface with graphene, enhances adsorption capacity of MOFs. Optimal adsorption conditions have been identified, and a detailed adsorption mechanism has also been comprehensively discussed. The theoretical maximum adsorption capacity exhibited by UiO-66-GO is 119.57 mg g−1. Moreover, it shows a fast adsorption rate and reached equilibrium within 20 min. The development of materials with good adsorption performance and fast adsorption for Th(IV) plays an important role in the development of Th(IV) adsorption in the future. [ABSTRACT FROM AUTHOR]

Automated pancreas segmentation in abdominal computed tomography (CT) scans is of high clinical relevance (i.e. pancreas cancer diagnosis and prognosis), but extremely difficult because the pancreas is a soft, small, and flexible abdominal organ with high anatomical variability, which causes the previous segmentation methods to result in low precision. In this study, the authors present a new deep recurrent adversarial network (DRAN) to tackle this challenge. DRAN contains three steps: (i) preserving global resolution of CT scans and modifying the receptive field of kernel adaptively through a dilated convolution autoencoder module; (ii) modelling contextual spatial correlation between neighbouring CT scan patches benefits from a specially designed local long short‐term memory module; and (iii) improving the performance and generalisation by leveraging an adversarial module, which can constrain the spatial smoothness consistency between continuous CT scans based on the long‐range spatial interaction. The system is evaluated on a dataset of 80 manually segmented CT volumes, using four‐fold cross‐validation. Its performance surpasses other state‐of‐the‐art methods, with the Dice similarity coefficient of 89.87±3.17% and pixel‐wise accuracy of 95.85±3.04%. Also, they perform a qualitative evaluation by an expert further revealing the effectiveness and potential of their DRAN as a clinical segmentation tool. [ABSTRACT FROM AUTHOR]

The case-time-control design is a tool to control for measured, time-varying covariates that increase montonically in time within each subject while also controlling for all unmeasured covariates that are constant within each subject across time. Until recently, the design was restricted to data with only two timepoints and a single binary covariate, or data with a binary exposure. Sjölander (2017) made an important extension that allows for an arbitrary number of timepoints and covariates and a nonbinary exposure. However, his estimation method requires fairly strong model assumptions, and it may create bias if these assumptions are violated. We propose a novel estimation method for the case-time-control design, which to a large extent relaxes the model assumptions in Sjölander. We show in simulations that this estimation method performs well under a range of scenarios and gives consistent estimates when Sjölander's estimation does not. [ABSTRACT FROM AUTHOR]

In this note, we prove that a non-compact Riemannian manifold M with non-negative Bakry-Émery Ricci curvature and compact minimal boundary ∂M is the isometric product ∂M ×[0,∞), provided that the potential function is bounded from above and has non-negative derivatives at ∂M along inner normal directions. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate the relationship between macroeconomic variables (interest rate, money supply, exchange rate, inflation rate) and overall market return in Hong Kong and Shanghai. The relationship is test by using APT, VECM and Granger-Causility test. Pre-tests of unit root and cointegration are the way to process monthly data in this paper. Results: There do exist an relationship between the selected macroeconomic variables and stock market return in Hong Kong and Shanghai in the long and short period. This paper implies that the investors who are interested in Chinese stock market should be prepared to invest for the long-term. But in Hong Kong stock market, the investors not only focus on the long-term but also focus on the short-term. [ABSTRACT FROM AUTHOR]

Highlights • A unified LB model is developed for immiscible two-phase flow in vuggy carbonates. • The effect of vugs on two-phase flow in artificial porous media is investigated. • Two-phase flow is simulated on 2D CT imaged vuggy carbonate cores at two length scales. • The effects of rock matrix heterogeneity, vug connectivity, rock wetting preference on two-phase distribution and exit mass flow rate are studied. Abstract In addition to intrinsic matrix pores, ranging in size from submicrons to microns, vuggy carbonates often contain significantly larger vug spaces. Immiscible multiphase fluids flowing through this type of microporous systems exhibit complicated flow mechanisms that are involved in the interactions between multiphase fluids and different types of pore spaces. Modeling multiphase fluid flows requires using the appropriate governing equations for different porosity systems. More specifically, while multiphase Darcy's equations might hold for a matrix system, they are not applicable for a vug system. To improve understanding this difficult multiphase flow problem in vuggy carbonates, we developed a unified grayscale lattice Boltzmann (LB) model for multiphase flows. The proposed model combines the generalized LB model in porous media with the pseudo-potential multiphase approach by adding the fluid-fluid interaction force, the fluid-solid interaction force, and the linear and nonlinear drag forces induced by the porous matrix. The model is still within the framework of the generalized LB model, and it switches freely from the Darcy's regime to the free-flow regime via rock property (i.e., porosity). It can also extend to a wide range of porosity systems because we incorporated both the linear and nonlinear drag effects. A continuous flow interface between the porous matrix and the vug region is captured by simulation without incorporating complex interface boundary conditions between the two porosity systems. The current model is validated and calibrated with theory, and then it is applied to a number of test cases. The test cases include the simulations of two-phase displacement in non-vuggy porous media, isolated vuggy porous media, and connected vuggy (fractured) porous media. Moreover, the effect of vug spaces on the interface-front speed and the breakthrough time is investigated. In addition, we simulated water displacing oil in two real vuggy carbonate cores imaged using low-resolution and high-resolution X-ray computed microtomography, and we investigated the effects of matrix heterogeneity, vug connectivity, and matrix wetting preference. [ABSTRACT FROM AUTHOR]

The environmental stimuli experienced by a female can influence phenotypes and gene expression in the subsequent generations. We used a specifically designed domesticated-bird model to examine the transgenerational transmission of maternal stimulus exposure, a phenomenon that has been observed but has not been understood in noninbred animals. We subjected parental generation [filial (F)0] hens to viral- or bacterial-like stimulation after artificial insemination. Subsequent filial generations F1 and F2 transmitted growth or fertility variations without further stimulation in contrast to the controls. The whole-genome bisulfite sequence and next-generation mRNA sequencing of peripheral blood lymphocytes (PBLs) from the F1 generation revealed DNA methylome and transcriptome differences in the F1 polyriboinosinic:polyribocytidylic [poly(I:C)] acid or LPS offspring, compared with the F1 controls. In the F1 offspring, DNA methylation changes induced by maternal immune stimulation may have contributed to transcriptional variation. Pathways analysis indicated that the metabolic processes of xenobiotics and drug metabolism pathways, as well as reproduction-related pathways, were involved in the transgenerational transmission of maternal stimulatory experience. Furthermore, LPS-induced transcriptional transmission may have contributed to subfertility, as indicated by the results of comparative analysis between the transcriptomes of spleen tissues across the F0 and F1 generations, as well as the correlative analysis between the transcriptome and reproductive phenotypes. Our findings provide a framework for determining the mechanisms by which maternal stimulatory factors can be inherited transgenerationally with respect to growth, fertility, DNA methylation, and transcriptional levels in outbred animals. [ABSTRACT FROM AUTHOR]

The article demonstrates a strategy for large-scale fabrication of bioinspired polymeric woods with similar polyphenol matrix materials, and outstanding comprehensive performance by a self-assembly and thermocuring process of traditional resins. It mentions that woods provide bioinspiration for engineering materials due to their superior mechanical performance; and its use for mass production of a series of high-performance biomimetic engineering materials.

Abstract: Efficient ways are presented to accomplish photonic controlled‐phase‐flip gate and entangler with the assistance of imperfect double‐sided quantum‐dot‐microcavity systems, but without ancillary qubits. Compact quantum circuits for implementing entanglement swapping between photon pairs and electron pairs are then designed. Unity fidelities of the schemes can be achieved, and physical imperfections in the construction processes are detected by single‐photon detectors. Also, the efficiencies of the schemes can be further improved by repeating the operation processes when the undesired performances are detected. The evaluations show that the schemes are possible with current experiment parameters. [ABSTRACT FROM AUTHOR]

Abstract: In survival analysis, covariate measurements often contain missing observations; ignoring this feature can lead to invalid inference. We propose a class of weighted estimating equations for right‐censored data with missing covariates under semiparametric transformation models. Time‐specific and subject‐specific weights are accommodated in the formulation of the weighted estimating equations. We establish unified results for estimating missingness probabilities that cover both parametric and non‐parametric modelling schemes. To improve estimation efficiency, the weighted estimating equations are augmented by a new set of unbiased estimating equations. The resultant estimator has the so‐called ‘double robustness’ property and is optimal within a class of consistent estimators. [ABSTRACT FROM AUTHOR]

A gram-negative, motile, and rod-shaped bacterium, strain JF02, was isolated from the liver of diseased GIFT (genetically improved farmed tilapia) in Hainan, China. The strain JF02 was lethal to GIFT, and most GIFT infected with JF02 exhibited the same clinical signs, such as black body, pale or focally necrosis of the gills, scale shedding, fin rot, liver hyperemia, and hydroabdomen. The 16S rRNA gene sequences of strain JF02 showed 99.1% similarity with that of Shewanella xiamenensis strain S4T. In addition, the gyrB gene sequences of strain JP02 showed 99.0% similarity with that of S. xiamenensis strain S4T. Combining the results of morphological, physiological and biochemical characteristics, the isolated strain JF02 was confirmed to be S. xiamenensis. The chemotherapeutic antibiotics tests showed that the strain JF02 was sensitive to most antibiotics except for several common antibiotics that were frequently used in human medicines and treatment of bacterial diseases of fish, indicating that the strain JF02 has obtained many antibiotic resistance genes due to the long-term abuse of antibiotics in aquaculture. In this paper, it was the first time to report that the S. xiamenensis may be a potential pathogen for GIFT. It is time to promote awareness of the potential harm of this strain to the health of human and aquatic animals. [ABSTRACT FROM AUTHOR]

Motivated by analyses of DNAmethylation data, we propose a semiparametricmixture model, namely, the generalized exponential tilt mixturemodel, to account for heterogeneity between differentially methylated and nondifferentially methylated subjects in the cancer group, and capture the differences in higher order moments (e.g.,mean and variance) between subjects in cancer and normal groups. A pairwise pseudolikelihood is constructed to eliminate the unknown nuisance function. To circumvent boundary and nonidentifiability problems as in parametric mixture models, we modify the pseudolikelihood by adding a penalty function. In addition, the test with simple asymptotic distribution has computational advantages compared with permutation-based test for high-dimensional genetic or epigenetic data. We propose a pseudolikelihood-based expectation-maximization test, and show the proposed test follows a simple chisquared limiting distribution. Simulation studies showthat the proposed test controls Type I errorswell and has better power compared to several current tests. In particular, the proposed test outperforms the commonly used tests under all simulation settings considered, especially when there are variance differences between two groups. The proposed test is applied to a real dataset to identify differentially methylated sites between ovarian cancer subjects and normal subjects. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

The new three-dimensional structure that the graphene connected with SWCNTs (G-CNTs, Graphene Single-Walled Carbon Nanotubes) can solve graphene and CNTs′ problems. A comprehensive study of the mechanical and electrical performance of the junctions was performed by first-principles theory. There were eight types of junctions that were constituted by armchair and zigzag graphene and (3,3), (4,0), (4,4), and (6,0) CNTs. First, the junction strength was investigated. Generally, the binding energy of armchair G-CNTs was stronger than that of zigzag G-CNTs, and it was the biggest in the armchair G-CNTs (6,0). Likewise, the electrical performance of armchair G-CNTs was better than that of zigzag G-CNTs. Charge density distribution of G-CNTs (6,0) was the most homogeneous. Next, the impact factors of the electronic properties of armchair G-CNTs were investigated. We suggest that the band gap is increased with the length of CNTs, and its value should be dependent on the combined effect of both the graphene's width and the CNTs' length. Last, the relationship between voltage and current (U/I) were studied. The U/I curve of armchair G-CNTs (6,0) possessed a good linearity and symmetry. These discoveries will contribute to the design and production of G-CNT-based devices. [ABSTRACT FROM AUTHOR]

Fluorine, a hazard that is associated with coal, has resulted in serious environmental issues during the production and utilization of coal. In this paper, we provide a detailed review of fluorine in Chinese coal, including the distribution, concentration, modes of occurrence, genetic factors, and environmental effects. The average concentration of fluorine in Chinese coal is 130.0 mg/kg, which is slightly higher than coal worldwide (88.0 mg/kg). The enrichment of fluorine in Chinese coal varies across different coal deposit regions, and it is especially high in Inner Mongolia (Junger coalfield, Daqingshan coalfield) and southwest China (coal mining regions in Yunnan, Guizhou province). The fluorine distribution is uneven, with a relatively high content in southwest coal (including Yunnan, Guizhou, Chongqing, and Sichuan provinces), very high content in the coal of North China (Inner Mongolia) and South China (Guangxi), and is occasionally found in the northwest (Qinghai). Fluorine occurs in various forms in coal, such as independent minerals (fluorine exists as fluorapatite or fluorite in coal from Muli of Qinghai, Taoshuping of Yunnan, Guiding of Guizhou, and Daqingshan of Inner Mongolia), adsorption on minerals (fluorine in coal from Nantong, Songzao of Chongqing, Guxu of Sichuan, and Shengli, Daqingshan, and Junger from Inner Mongolia), substitution in minerals (Wuda coal, Inner Mongolia), and a water-soluble form (Haerwusu coal, Inner Mongolia). The enrichment of fluorine is mainly attributed to the weathering of source rock and hydrothermal fluids; in addition to that, volcanic ash, marine water influence, and groundwater affect the fluorine enrichment in some cases. Some environmental and human health problems are related to fluorine in coal, such as damage to the surrounding environment and husbandry (poisoning of livestock) during the coal combustion process, and many people have suffered from fluorosis due to the burning of coal (endemic fluorosis in southwest China). [ABSTRACT FROM AUTHOR]

Bubble properties, such as local gas holdup, bubble frequency, bubble velocity, bubble size, and interfacial area concentration, are of great significance for the design and scale-up of bubble columns. In the present study, bubble properties in a 0.15 m in diameter bubble column were measured by a dual-tip conductivity probe. A new method was proposed to establish the relationship between chord length distribution (CLD) and bubble size distribution (BSD) without the assumption of fixed bubble aspect ratio. The bubble velocity and BSD measured by the probe were validated by a high speed camera in a square column. The results indicate that considering the decreasing of bubble aspect ratio with bubble diameter is required to obtain accurate BSD from measured CLD. Furthermore, the measured bubble properties at different axial positions show that the flow development is much more rapid in the churn-turbulent regime than that in the homogeneous regime. It is also found that the bubble breakage is dominant over the bubble coalescence in the homogeneous regime due to the large bubbles generated at the perforated distributor. The measured results provide a benchmark data for validation of CFD simulation. [ABSTRACT FROM AUTHOR]

We report on a fiber-optic delay-based quasidistributed temperature sensor with high precision. The device works by detecting the delay induced by the temperature instead of the spectrum. To analyze the working principle of this sensor, the thermal dependence of the fiber-optic delay was theoretically investigated and the delay-temperature coefficient was measured to be 42.2 ps ∕ km°C. In this sensor, quasidistributed measurement of temperature could be easily realized by dense wavelength-division multiplexing and wavelength addressing. We built and tested a prototype quasidistributed temperature sensor with eight testing points equally distributed along a 32.61-km-long fiber. The experimental results demonstrate an average error of <0.1°C. These results prove that this quasidistributed temperature sensor is feasible and that it is a viable option for simple and economic temperature measurements. [ABSTRACT FROM AUTHOR]

Unlike other breast cancer subtypes, targeted therapies for triple negative breast cancer (TNBC) have yet to progress past clinical trial stage to approval. Accumulating evidences demonstrated that expression of estrogen-related receptor alpha (ERRα) indicated worse prognosis and correlated with poor outcome in breast cancers including TNBC. Therefore, ERRα modulators/regulators may be potential in the therapeutic treatment of breast cancers. In the current study, we presented a novel compound LingH2-10 that bound to ERRα, as identified using a time-resolved fluorescence resonance energy transfer assay (TR-FRET) with the IC 50 value of 0.64 ± 0.12 μM. Further, functional activity was determined by transient transfection luciferase reporter assay in order to validate the utility of the binding affinity in a cellular context. LingH2-10 showed selective inhibition on ERRα transcriptional activity with the IC 50 value of 0.58 ± 0.09 μM in cell-based luciferase reporter assay. Moreover, representative in vitro results showed that LingH2-10 suppressed the proliferation of various human cancer cells, and inhibited the migration of triple negative breast cancer cell MDA-MB-231. In addition, our results demonstrated that well known ERRα target genes such as PDK4, Osteopontin and pS2, were all significantly down modulated by LingH2-10. In vivo experiments showed that LingH2-10 (30 mg/kg, every other day) observably suppressed the growth of MDA-MB-231 xenograft tumors by 42.02% compared to untreated xenograft tumors. Taken together, all these data suggested that LingH2-10, as a selective inverse agonist of ERRα, was a lead compound of anti-cancer agents for treating TNBC patients. [ABSTRACT FROM AUTHOR]

Cyclin D1 has become a potential target for anti-tumor therapy. Recently, a novel human anti-cyclin D1 single-chain variable fragment (AD5) was identified, which demonstrated specific binding activity to cyclin D1 and exhibited anti-tumor effects. However, the detailed characteristics of AD5 remain unclear. In the present study, the structure and activity of AD5 in the presence of copper II (Cu2+) or iron III (Fe3+) metal ions was investigated by fluorescence spectroscopy, synchronous fluorescence and enzyme-linked immunosorbent assay. Cu2+ and Fe3+ were able to bind to AD5 and quench the fluorescence intensity of AD5 primarily by static quenching, which slightly altered the conformation of AD5 at temperatures of 293, 298 and 303 K; however, these temperatures demonstrated different effects on the activity of AD5. These results may be of value for the clinical application of anti-cyclin D1 single chain antibodies in the future. [ABSTRACT FROM AUTHOR]