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The chemokine receptor CXCR4 has become an attractive therapeutic target for HIV-1 infection, hematopoietic stem cell mobilization, and cancer metastasis. A wide variety of synthetic antagonists of CXCR4 have been developed and studied for a growing list of clinical applications. To compare the biological effects of different antagonists on CXCR4 functions and their common and/or distinctive molecular interactions with the receptor, we conducted head-to-head comparative cell-based biological and mutational analyses of the interactions with CXCR4 of eleven reported antagonists, including HC4319, DV3, DV1, DV1 dimer, V1, vMIP-II, CVX15, LY2510924, IT1t, AMD3100, and AMD11070 that were representative of different structural classes of D-peptides, L-peptide, natural chemokine, cyclic peptides, and small molecules. The results were rationalized by molecular modeling of CXCR4--antagonist interactions from which the common as well as different receptor binding sites of these antagonists were derived, revealing a number of important residues such as W94, D97, H113, D171, D262, and E288, mostly of negative charge. To further examine this finding, we designed and synthesized new antagonistic analogs by adding positively charged residues Arg to a D-peptide template to enhance the postulated charge--charge interactions. The newly designed analogs displayed significantly increased binding to CXCR4, which supports the notion that negatively charged residues of CXCR4 can engage in interactions with moieties of positive charge of the antagonistic ligands. The results from these mutational, modeling and new analog design studies shed new insight into the molecular mechanisms of different types of antagonists in recognizing CXCR4 and guide the development of new therapeutic agents. [ABSTRACT FROM AUTHOR]

Diabetic vascular complications are one of the main causes of death and disability. Previous studies have reported that genetic variation is associated with diabetic vascular complications. In this study, we aimed to investigate the association between GRB10 polymorphisms and susceptibility to type 2 diabetes mellitus (T2DM) vascular complications. Eight single nucleotide polymorphisms (SNPs) in the GRB10 gene were genotyped by MassARRAY system and 934 patients with type 2 diabetes mellitus (T2DM) were included for investigation. We found that GRB10 rs1800504 CC+CT genotypes were significantly associated with increased risk of coronary heart disease (CHD) compared with TT genotype (OR = 2.24; 95%CI: 1.36–3.70, p = 0.002). Consistently, levels of cholesterol (CHOL) (CC+CT vs. TT, 4.44 ± 1.25 vs. 4.10 ± 1.00 mmol/L; p = 0.009) and low density lipoprotein cholesterin (LDL-CH) (CC+CT vs. TT, 2.81 ± 1.07 vs. 2.53 ± 0.82 mmol/L; p = 0.01) in T2DM patients with TT genotype were significant lower than those of CC+CT genotypes. We further validated in MIHA cell that the total cholesterol (TC) level in GRB10-Mut was significantly reduced compared with GRB10-WT; p = 0.0005. Likewise, the reversed palmitic acid (PA) induced lipid droplet formation in GRB10-Mut was more effective than in GRB10-WT. These results suggest that rs1800504 of GRB10 variant may be associated with the blood lipids and then may also related to the risk of CHD in patients with T2DM.

Epilepsy is one of the most common neurological disorders and severely impacts the life quality of patients. Polyamines are ubiquitous, positively charged aliphatic amines that are present at a relatively high level and help regulate the maintenance of cell membrane excitability and neuronal physiological functions in the central nervous system. Studies have shown abnormalities in the synthesis and catabolism of polyamines in patients with epilepsy and in animal models of epilepsy. The polyamine system seems to involve in the pathophysiological processes of epilepsy via several mechanisms such as the regulation of ion permeability via interaction with ion channels, involvement in antioxidation as hydroperoxide scavengers, and the induction of cell damage via the production of toxic metabolites. In this review, we try to describe the possible associations between polyamines and epilepsy and speculate that the polyamine system is a potential target for the development of novel strategies for epilepsy treatment.

Global navigation satellite system (GNSS) plays a crucial role in many fields, such as aerospace and transportation. Integrity is the measure of trust used in GNSS positioning especially in safety-critical applications. Advanced receiver autonomous integrity monitoring (ARAIM), taking full advantage of multi-constellation GNSS, shows huge potential to provide vertical navigation in civil aviation en route navigation and terminal approaches. However, the multi-constellation ARAIM also greatly exposes computational complexity and potential performance hazards in fault modes determination and fault-tolerant positioning. From the perspective of integrity risk control, rather than the pursuit of better positioning accuracy blindly for safety-critical applications, the concept of constellation dynamic selection is proposed and implemented in ARAIM and the performance analysis is discussed in this paper. Only the best two constellations which have the best vertical geometry performance are involved in ARAIM calculation anytime anywhere. The proposed method shows superiority in both integrity availability and computational complexity in both simulations and actual GNSS signal experiments. While the computational complexity is less than 10% of that using four constellations, 100% availability under LPV-200 criteria can be achieved in worldwide coverage experiment. The proposed method also overcomes the shortcomings of ARAIM with two fixed constellations and shows good robustness under depleted scenarios. Furthermore, the statistics results from observation stations proved the applicability and generality of the proposed method under current developing GNSS constellations.

Heterogeneity in glucocorticoid response to experimental stress conditions has shown to differentiate individuals with healthy from maladaptive real-life stress responses in a number of distinct domains. However, it is not known if this heterogeneity influences the risk for developing stress related disorders or if it is a biological consequence of the stress response itself. Determining if glucocorticoid response to stress induction prospectively predicts psychological vulnerability to significant real life stressors can adjudicate this issue. To test this relationship, salivary cortisol as well as catecholamine responses to a laboratory stressor during academy training were examined as predictors of empirically identified distress trajectories through the subsequent 4 years of active duty among urban police officers routinely exposed to potentially traumatic events and routine life stressors (N = 234). During training, officers were exposed to a video vignette of police officers exposed to real-life trauma. Changes in salivary 3-methoxy-4-hydroxyphenylglycol (MHPG) and cortisol in response to this video challenge were examined as predictors of trajectory membership while controlling for age, gender, and baseline neuroendocrine levels. Officers who followed trajectories of resilience and recovery over 4 years mounted significant increases in cortisol in response to the experimental stressor, while those following a trajectory of chronic increasing distress had no significant cortisol change in response to the challenge. MHPG responses were not associated with distress trajectories. Cortisol response prospectively differentiated trajectories of distress response suggesting that a blunted cortisol response to a laboratory stressor is a risk factor for later vulnerability to distress following significant life stressors.

This paper examines the phenomenal growth of social work in China and the complexities and challenges faced by the profession and related stakeholders in the context of neoliberal economic practice within a hierarchical top-down political system. It proposes developmental social work as a viable indigenous social work practice mode. This analysis based on a collection of academic papers and relevant government reports sheds light on the interplay between welfare developmentalism, institutional dynamics, and professional challenges in the broader sociopolitical context, not least the neoliberal co-optation of social development aligned increasingly with economic goals to the detriment of broader social and structural issues. It shows how the political parameters of the Chinese Communist Party and its pursuit of community integration and social development shaped China's approach to social work. It sees the necessity for a system of welfare services to address socio-structural issues and the indigenization and cultural adaption of social work in China as an expressly political process. Regarding the former, the government's strategy of outsourcing public services to accord with its agenda has resulted in a contractual relationship between social organizations, including nongovernment and social work organizations, and the state. This has limited the independence and hindered the development of a strong civil society, and curtailed social workers' autonomy, exacerbating professional challenges relating inter alia to the low number of qualified social work practitioners, limited job opportunities outside major urban centers, high staff turnover, and poor quality services provided by those without formal social work training. To enhance professional recognition in China, the paper suggests a holistic developmental approach that involves the resolution of individual problems through investing in people, helping them to build their capacity, drawing on social capital, and capitalizing on market opportunities to promote self-reliance, thereby contributing to community and social development. [ABSTRACT FROM AUTHOR]

Introduction: Yinchenzhufu decoction (YCZFD) is a traditional Chinese medicine formula with hepatoprotective effects. In this study, the protective effects of YCZFD against cholestatic liver fibrosis (CLF) and its underlying mechanisms were evaluated. Methods: A 3, 5-diethoxycarbonyl-1, 4-dihydro-collidine (DDC)-induced cholestatic mouse model was used to investigate the amelioration of YCZFD on CLF. Data-independent acquisition-based mass spectrometry was performed to investigate proteomic changes in the livers of mice in three groups: control, model, and model treated with high-dose YCZFD. The effects of YCZFD on the expression of key proteins were confirmed in mice and cell models. Results: YCZFD significantly decreased the levels of serum biochemical, liver injury, and fibrosis indicators of cholestatic mice. The proteomics indicated that 460 differentially expressed proteins (DEPs) were identified among control, model, and model treated with high-dose YCZFD groups. Enrichment analyses of these DEPs revealed that YCZFD influenced multiple pathways, including PI3K-Akt, focal adhesion, ECM--receptor interaction, glutathione metabolism, and steroid biosynthesis pathways. The expression of platelet derived growth factor receptor beta (PDGFRβ), a receptor associated with the PI3K/AKT and focal adhesion pathways, was upregulated in the livers of cholestatic mice but downregulated by YCZFD. The effects of YCZFD on the expression of key proteins in the PDGFRβ/PI3K/AKT pathway were further confirmed in mice and transforming growth factor-β-induced hepatic stellate cells. We uncovered seven plant metabolites (chlorogenic acid, scoparone, isoliquiritigenin, glycyrrhetinic acid, formononetin, atractylenolide I, and benzoylaconitine) of YCZFD that may regulate PDGFRβ expression. Conclusion: YCZFD substantially protects against DDC-induced CLF mainly through regulating the PDGFRβ/PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Summary: Aryl–heteroatom (C–X) bonds ubiquitously exist in organic, medicinal, and material chemistry, but a universal method to construct diverse C–X bonds is lacking. Here we report our discovery of a convenient and efficient approach to construct various C–X bonds using arylammonium salts as the substrate via an SNAr process. This strategy features mild reaction condition, no request of transition metal catalyst, and easy formation of various C–X bonds (C–S, C–Si, C–Sn, C–Ge, C–Se, C–N). The method was successfully applied to a late-stage functionalization of an existing antibiotic drug, to a Clickable reaction of NBD-based ammonium salt as turn-on fluorescent probe to recognize L-cysteine and homocysteine, and to the synthesis of a DNA encoded library (DEL) bearing different C–X bonds. : Organic Chemistry; Organic Synthesis; Chemical Reaction Engineering Subject Areas: Organic Chemistry, Organic Synthesis, Chemical Reaction Engineering

Collaborative filtering (CF) has been generally used in recommender systems when faced some practical problems. Due to the sparsity of the rating matrix, the traditional CF-based approach has a significant decline in recommendation performance. Gradually, a hybrid method, using side information and rating information, has been widely employed and achieves great performance. Together with side information and rating information, the hybrid method can overcome the data sparsity and cold-start problems. However, they seem to fail to take into consideration the fact that the sparsity of single side information. To solve this problem, we take full advantage of the characteristics of deep learning that can learn effective representation and propose a novel deep learning model named additional variational autoencoder that considers both content and tag information of the item. The model learns effective latent representations from additional side information, including content information and tag information in an unsupervised manner. With the help of graphical models, it can extract the implicit relationships between users and items effectively. A large number of experimental results on two actual datasets show that our proposed model is superior to other methods, and the performance improvement is achieved.

Recently, product images have been gaining the attention of recommender system researchers in the field of visual recommendation. This is because the visual appearance of products has a significant impact on consumers' decisions. Extensive studies have been done to integrate the features extracted by convolutional neural networks directly into recommendations. This improves the performance of recommender systems. Style features, an important type of features, are rarely considered. Style features play a vital role in the visual recommendation as a user's decision depends largely on whether the product fits his/her style. However, the representation of the conventional image features fails in capturing the styles of a product. To bridge this gap, we propose introducing style feature modeling, which is highly relevant with user preference, into the visual recommendation model. Furthermore, we propose incorporating the style features into collaborative learning to create awareness pertaining to the preferences of users. The experiments conducted on two public implicit feedback datasets demonstrate the effectiveness of our approach for the visual recommendation.

Cotton is an important economic crop. Cotton Verticillium wilt caused by Verticillium dahliae seriously damages production. Phytosterols play roles in plant-pathogen interaction. To explore the function and related mechanism of phytosterols in the interaction between Verticillium dahliae and cotton plants, and the resistance to Verticillium wilt, in this study, we analyzed the changes of sterol composition and content in cotton roots infected by Verticillium dahliae, and identified the sterol C22-desaturase gene GhCYP710A1 from upland cotton. Through overexpressing and silencing the gene in cotton plant, and ectopically expressing the gene in Arabidopsis, we characterized the changes of sterol composition and the resistance to Verticillium wilt in transgenic plants. The infection of Verticillium dahliae resulted in the content of total sterol and each sterol category decreasing in cotton root. The ratio of stigmasterol to sitosterol (St/Si) increased, indicating that the conversion of sitosterol to stigmasterol was activated. Consistently, the expression level of GhCYP710A1 was upregulated after infection. The GhCYP710A1 has the conservative domain that is essential for sterol C22-desaturase in plant and is highly expressed in root and stem, and its subcellular location is in the endoplasmic reticulum. The ectopic expression of GhCYP710A1 gene promoted the synthesis of stigmasterol in Arabidopsis. The St/Si value is dose-dependent with the expression level of GhCYP710A1 gene. Meanwhile, the resistance to Verticillium wilt of transgenic Arabidopsis increased and the permeability of cell membrane decreased, and the content of ROS decreased after V991 (a strain of Verticillium dahliae) infection. Consistently, the resistance to Verticillium wilt significantly increased in the transgenic cotton plants overexpressing GhCYP710A1. The membrane permeability and the colonization of V991 strain in transgenic roots were decreased. On the contrary, silencing GhCYP710A1 resulted in the resistance to Verticillium wilt being decreased. The membrane permeability and the colonization of V991 were increased in cotton roots. The expression change of GhCYP710A1 and the content alteration of stigmasterol lead to changes in JA signal transduction, hypersensitivity and ROS metabolism in cotton, which might be a cause for regulating the Verticillium wilt resistance of cotton plant. These results indicated that GhCYP710A1 might be a target gene in cotton resistance breeding.

In the study of sequence stratigraphy in continental rift basins, the use of seismic data to track different levels of sequence stratigraphic boundaries laterally is the key to the division of sequence stratigraphic units at all levels and the establishment of an isochronous sequence stratigraphic framework. Traditional seismic interpretation and the establishment of a 3D sequence stratigraphic structure model are a difficult research work. This paper introduces the concept of cost function minimization and performs global stratigraphic scanning on 3D seismic data to interpret horizons and faults in a large grid. Constrained by the results, human-computer interactive intelligent interpretation, by adding iterative interpretation of geological knowledge, established a global stratigraphic model with a relative geological age. The application in the Lower Cretaceous Shahezi Formation of Xujiaweizi fault depression shows that this technology has improved the accuracy and efficiency of sequence stratigraphic interpretation, and the application of this technology has achieved the interpretation of each event horizon under the current seismic data resolution conditions. In this way, a continuous sequence stratigraphic model is established. From this stratigraphic model, any high-frequency sequence-interpreted seismic horizon can be extracted, which provides a basis for the combination of lateral resolution and longitudinal resolution of subsequent reservoir prediction.

In inter-datacenter elastic optical networks, multi-controller deployment is adopted to improve the stability and scalability of the control plane. As the network scale increases, the traditional multi-controller deployment scheme ignores the dynamic characteristics of traffic, resulting in unbalanced load among multiple controllers. In response to this problem, the existing switch migration mechanism is proposed to achieve balanced distribution of control loads. However, most of the existing research work does not consider the additional cost of switch migration, and the load balancing performance of the controller is not significantly improved after switch migration. In this paper, we propose a cost-aware switch migration (CASM) strategy for controller load balancing. The proposed CASM strategy first measures the controller load through multiple performance indicators that affect the controller load, and then judges whether the controller is overloaded or underloaded based on the controller’s response time to the request message, thereby improving the load balancing performance of the controller. Additionally, when selecting the switch to be migrated, the CASM selects the optimal switch for migration based on minimizing the migration cost, thereby reducing the cost of switch migration. The performance evaluation shows that CASM significantly improves load balancing performance of controllers and reduces the migration cost compared to existing solutions.

With the rapid development of technology based on the Internet of Things (IoT), numerous IoT devices are being used on a daily basis. The rise in cloud computing plays a crucial role in solving the resource constraints of IoT devices and in promoting resource sharing, whereby users can access IoT services provided in various environments. However, this complex and open wireless network environment poses security and privacy challenges. Therefore, designing a secure authentication protocol is crucial to protecting user privacy in IoT services. In this paper, a lightweight authentication protocol was designed for IoT-enabled cloud computing environments. A real or random model, and the automatic verification tool ProVerif were used to conduct a formal security analysis. Its security was further proved through an informal analysis. Finally, through security and performance comparisons, our protocol was confirmed to be relatively secure and to display a good performance.

Increasing evidence indicates the pivotal role of long noncoding RNAs in a variety of cancers, but there is limited focus on the link between long noncoding RNAs and gestational choriocarcinoma. This study aimed to examine the role of long noncoding RNA OGFRP1 in JEG-3 and JAR cells. Small interfering RNA was used to downregulate long noncoding RNA OGFRP1 level. Cell proliferation was measured by cell counting kit-8 and clone formation assays. Cell cycle and apoptosis were analyzed by flow cytometry. Cell invasion was examined by transwell assay. Protein expression was determined by Western blot. A double-effect inhibitor (BEZ235) that inhibits AKT and mTOR phosphorylation was used as a positive control. Knockdown of long noncoding RNA OGFRP1 significantly inhibited the proliferation of JEG-3 and JAR cells. Knockdown of long noncoding RNA OGFRP1 induced cell cycle arrest in G1 phase and apoptosis. On the other hand, knockdown of long noncoding RNA OGFRP1 inhibited the invasion of JEG-3 and JAR cells. Finally, knockdown of long noncoding RNA OGFRP1 resulted in the inactivation of AKT/mTOR signaling pathway. In addition, knockdown of long noncoding RNA OGFRP1 caused changes in the expression of intracellular cell cycle–related proteins and apoptosis-related proteins, including downregulation of CDK4, CDK6, Cyclin D1, Nusap1, and Bcl2 protein expression and upregulation of Bax protein expression. In conclusion, we found that downregulation of long noncoding RNA OGFRP1 inhibited cell proliferation, cell cycle progression, and invasion of JEG-3 and JAR cells and induced apoptosis through AKT/mTOR pathway. This study extends the understanding of the function of long noncoding RNA OGFRP1 in tumorigenesis, and these findings may be important for developing a potential therapeutic target for gestational choriocarcinoma therapy.

Quantifying cell-type proportions and their corresponding gene expression profiles in tissue samples would enhance understanding of the contributions of individual cell types to the physiological states of the tissue. Current approaches that address tissue heterogeneity have drawbacks. Experimental techniques, such as fluorescence-activated cell sorting, and single cell RNA sequencing are expensive. Computational approaches that use expression data from heterogeneous samples are promising, but most of the current methods estimate either cell-type proportions or cell-type-specific expression profiles by requiring the other as input. Although such partial deconvolution methods have been successfully applied to tumor samples, the additional input required may be unavailable. We introduce a novel complete deconvolution method, CDSeq, that uses only RNA-Seq data from bulk tissue samples to simultaneously estimate both cell-type proportions and cell-type-specific expression profiles. Using several synthetic and real experimental datasets with known cell-type composition and cell-type-specific expression profiles, we compared CDSeq's complete deconvolution performance with seven other established deconvolution methods. Complete deconvolution using CDSeq represents a substantial technical advance over partial deconvolution approaches and will be useful for studying cell mixtures in tissue samples. CDSeq is available at GitHub repository (MATLAB and Octave code): https://github.com/kkang7/CDSeq.

The previously proposed short comparable encryption (SCE) scheme can infer the plaintext relationship by comparing the ciphertexts relationship as well as ensuring data security in Internet of things.Unfortunately,it will incur high storage and computational burden during the process of comparing ciphertexts and generating tokens.To this end,an efficient short comparable encryption scheme called SCESW was proposed,which was utilizing the sliding window method with the same size window.Formal security analysis shows that the scheme can guarantee weak indistinguishability in standard model as well as data security and integrity.The experimental results demonstrate that the storage of the SCESW scheme is 1 t (t＞1) times shorter than that of the SCE scheme and the efficiency of the SCESW scheme is superior to that of the SCE scheme.

The equation used to model the unidirectional flow of methane gas in coal seams is usually formulated as a nonlinear partial differential equation, which needs to be solved numerically with a computer program. Nevertheless, for people without access to the computer program, the conventional numerical method may be inconvenient. Thus, the objective here is to seek some method simpler than the conventional one for solving the flow problem. A commonly used model of the unidirectional methane gas flow is considered, where the methane adsorption is described by the Langmuir isotherm and the free gas is treated as real gas. By introducing the similarity solution, a simple method for solving the flow model is proposed, which can be done on a hand calculator. It is shown by two examples that the gas pressure profile obtained by the proposed method agrees well with the direct numerical solution of the flow model. Keywords: Coalbed methane, Migration, Unidirectional flow, Similarity solution, Simplified solving, Numerical method

With outsourcing huge amount of images to cloud, it can reduce the local storage and computational overhead of resource-limited users, but the security concerns still impede the adoption of outsourced image processing services. Fortunately, image processing in the encrypted domain can handle this problem very well and has already attracted considerable attention due to its ability to protect valuable image information from being leaked to untrusted parties. However, the existing schemes incur high computational complexity, and none of them can be used as both global feature and local feature. To this end, we present a method to implement Hahn moments in the encrypted domain by using Somewhat Homomorphic Encryption (SHE) in this paper, named Privacy-Preserving Hahn Moments (PPHM). First, a mathematical framework is proposed to implement the PPHM and image reconstruction in the encrypted domain. Then, the detailed theoretical analysis about data expansion and quantization errors shows that plaintext Hahn moments and plaintext image reconstruction can be implemented by utilizing PPHM over encrypted image. Moreover, security analysis shows that the PPHM can guarantee the image content security. Theoretical analysis and experimental results demonstrate that the PPHM scheme can greatly reduce the computational complexity compared with the discrete cosine transform and the discrete wavelet transform in the encrypted domain. In addition, experimental results show that the PPHM has a better performance in both image reconstruction and image recognition. Furthermore, the suitable value of a scaling factor, which can provide guidance to users, is specified for image reconstruction and image recognition, respectively.