Genetic polymorphisms in DNA repair genes and their association with risk of cervical cancer: A systematic review and meta-analysis.

BACKGROUND: There have been a large number of epidemiologic studies regarding the association between genetic polymorphisms in DNA repair genes and onset of cervical cancer. However, results are inconsistent. METHODS: Articles published before June 2021 and regarding genetic polymorphisms in DNA repair genes and cervical cancer were searched in following databases: PubMed, Web of Science, Google Scholar, and CNKI. With at least three articles for each polymorphism, we made meta-analysis to compute multivariate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: The present study showed significant associations between XRCC1 Arg399Gln polymorphisms and risk of cervical cancer in Asian, whereas no significant association between them were showed in Caucasian (Asian: GA vs. GG: OR = 1.27, 95%CI 1.06-1.52; AA vs. GG: OR = 1.91, 95%CI 1.29-2.83; GA + AA vs. GG: OR = 1.36, 95%CI 1.12-1.65; AA vs. GG + GA: OR = 1.66, 95%CI 1.17-2.37; Caucasian: GA vs. GG: OR = 1.08, 95%CI 0.83-1.41; AA vs. GG: OR = 2.18, 95%CI 0.75-6.31; GA + AA vs. GG: OR = 1.23, 95%CI 0.85-1.78; AA vs. GG + GA: OR = 1.70, 95%CI 0.69-4.18). In addition, there were significant associations between ERCC2 rs13181 polymorphisms and risk of cervical cancer in Asian (AC vs AA: OR = 0.53, 95%CI 0.37-0.75, I2 = 0.0%, p value of Q test = 0.847; AC + CC vs AA: OR = 0.50, 95%CI 0.36-0.70, I2 = 0.0%, p value of Q test = 0.856). CONCLUSIONS: The meta-analysis showed that there were significant associations between XRCC1 Arg399Gln and ERCC2 rs13181 polymorphisms and risk of cervical cancer.

Developmental neurotoxicity and immunotoxicity induced by graphene oxide in zebrafish embryos.

Graphene oxide (GO) has emerged as the worldwide promising candidate for biomedical application, such as for drug delivery, bio-sensing and anti-cancer therapy. This study was focused on the zebrafish and RAW264.7 cell line as in vivo and in vitro models to assess the potential developmental neurotoxicity and immunotoxicity of GO. No obvious acute developmental toxicity was observed upon treatments with 0.01, 0.1, and 1 µg/mL GO for five consecutive days. However, decreased hatching rate, increased malformation rate, heart beat rate and hypoactivity of locomotor behavior were detected when exposed to 10 µg/mL GO. Also, RT-PCR analysis revealed that expressions of genes related to the nervous system were up-regulated. The potential risk of GO for developmental neurotoxicity may be ascribed to the high level of oxidative stress induced by high concentration of GO. Most importantly, the mRNA levels of immune response associated genes, such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNFα), interferon-γ (IFN-γ) were significantly increased under environmental concentration exposure. The activation of pro-inflammatory immune response was also observed in macrophage cell line. Taken together, our results demonstrated that immunotoxicity is a sensitive indicator for assessment of bio-compatibility of GO.

Synthesis, antitumor evaluation and molecular docking studies of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives.

A series of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives have been synthesized and evaluated for their antitumor activities. These compounds exhibited potent antiproliferative activities against MCF-7, Bewo and HL-60 cells and c-Met kinase inhibitory activities. Three compounds were highly effective against MCF-7, Bewo and HL-60 cells with IC50 values in 1.09-2.24µM. Molecular docking was further performed to study the inhibitor-c-Met kinase interactions, and the results show that compound 4j was potently bound to the c-Met kinase with three hydrogen bonds. The further research on acute toxicity and in vivo antitumor activity of compound 4j to ICR (Institute of Cancer Research) mice were carried out, and found 4j with a certain toxicity but good efficacy in vivo. Based on the preliminary results, it is deduced that compound 4j with potent c-Met kinase inhibitory activity may be a potential anticancer agent.

Structural insight into tetrameric hTRPV1 from homology modeling, molecular docking, molecular dynamics simulation, virtual screening, and bioassay validations.

The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency.

Compressive Fracture Behavior of Zirconia/Resin Composites Prepared by Fused Deposition Modeling Combined with Vacuum Infiltration.

Although bioceramic materials exhibit good biocompatibilities and bone conductivities, their high brittleness and low toughness properties limit their applications. Zirconia (ZrO2)/resin composites with idealized structures and properties were prepared by fused deposition modeling (FDM) combined with a vacuum infiltration process. The porous structure was prepared using the FDM three-dimensional printing technology, with granular zirconia as the raw material, and the relationship between the pore shape, pore size, and deformation was discussed. The results showed that square pores were more suitable than honeycomb pores for printing small pore sizes, and the resolution was high. Scanning electron microscopy observations showed that the superposition of multiple printing paths promoted the emergence of hole defects. The effects of the resin and the pore shape on the compressive strengths of the composites were studied. It was found that the compressive strengths of the honeycomb pore ZrO2/resin composites and porous ceramics were superior to those of the square pore samples. The introduction of the resin had a significant effect on the compressive strengths of the composites. The compressive strength increased in the direction perpendicular to the pores, while it decreased in the direction parallel to the pores.

Case report: Bilateral parotid abscess in a 54-day-old infant.

Acute parotid abscess (PA) is rare in children and is prone to occur in neonates or preterm infants with high-risk factors. Sporadic cases of unilateral PA have been reported in older children. Here, we report a case of a 54-day-old child who developed bilateral PA due to Staphylococcus aureus infection. The infant showed bilateral cervical lymphadenopathy initially following a 13-valent pneumococcal conjugate vaccine (PCV13). However, bilateral PA developed 6 h after he was diagnosed with lymphadenitis on Day 9 of illness. Rapid PA progression from cervical lymphadenitis is rare. He recovered quickly under treatment with appropriate antibiotics based on susceptibility testing and surgical incision and drainage.

Combined exposure to titanium dioxide and tetracycline induces neurotoxicity in zebrafish.

In aquatic environment, engineered materials may inevitably interact with the coexisted organic pollutants, which affect their bioavailability and toxicity. In this contribution, the combined impacts of tetracycline (TC) and titanium dioxide nanoparticles (TiO2 NPs) on the neurodevelopment of zebrafish larvae were investigated, and the underlying mechanisms were further elucidated. Firstly, it was confirmed that the co-existence of TC would increase the size and decrease the zeta potential of TiO2 NPs. Following, developmental indicators and motor behaviors were investigated. Our results indicated that co-exposure to TC and TiO2 NPs exhibited enhanced embryonic malformation rates and abnormal nervous system development in zebrafish embryos. Meanwhile, the locomotor behavior was increased upon treatment of TC and TiO2 NP. Further, pathway enrichment analyses of transcriptomic sequencing provided detailed information that either lipid metabolism or PPAR signaling pathway were significantly affected in the co-exposure group. Also, TC + TiO2 NP exposure significantly changed the mRNA expression of neural development-related genes and up-regulated the expression levels of neurotransmitters like 5-hydroxytryptamine, dopamine, acetylcholinesterase, and γ-aminobutyric acid. Taken together, our results demonstrated that the co-exposure of TC and TiO2 NPs had the potential to cause neurotoxicity in zebrafish embryos.

Distributed convex optimization of bipartite containment control for high-order nonlinear uncertain multi-agent systems with state constraints.

This article investigates a penalty-based distributed optimization algorithm of bipartite containment control for high-order nonlinear uncertain multi-agent systems with state constraints. The proposed method addresses the distributed optimization problem by designing a penalty function in the form of a quadratic function, which is the sum of the global objective function and the consensus constraint. Moreover, the observer is presented to address the unmeasurable state of each agent. Radial basis function neural networks (RBFNN) are employed to approximate the unknown nonlinear functions. Then, by integrating RBFNN and dynamic surface control (DSC) techniques, an adaptive backstepping controller based on the barrier Lyapunov function (BLF) is proposed. Finally, the effectiveness of the suggested control strategy is verified under the condition that the state constraints are not broken. Simulation results indicate that the output trajectories of all agents remain within the upper and lower boundaries, converging asymptotically to the global optimal signal.

An Analysis of the Clinical Medication Rules of Traditional Chinese Medicine for Polycystic Ovary Syndrome Based on Data Mining.

Objective: The aim of the present study is to investigate the rules and characteristics of the clinical administration of traditional Chinese medicine (TCM) in the treatment of polycystic ovary syndrome (PCOS) using data mining methods. Method: Medical cases of well-known contemporary TCM doctors treating PCOS were collected from the China National Knowledge Infrastructure, Chinese Biomedical Literature Service System, Wanfang, Chinese Scientific Journals Database, and PubMed; the data were then characterized, and a standardized database of medical cases was built. This database was used to (1) count the frequency of syndrome types and the herbs used in medical cases by data mining methods and (2) analyze drug association rules and systematic clustering methods. Results: A total of 330 papers were included, involving 382 patients and a total of 1,427 consultations. The most common syndrome type was kidney deficiency; sputum stasis was the core pathological product and causative factor. A total of 364 herbs were used. Among them, 22 herbs were used >300 times, including Danggui (Angelicae Sinensis Radix), Tusizi (Semen Cuscutae), Fuling (Poria), Xiangfu (Nutgrass Galingale Rhizome), and Baizhu (Atractylodis Macrocephalae Rhizoma). Additionally, 22 binomial associations were obtained from the analysis of association rules; five clustering formulae were obtained via the analysis of high-frequency drug clusters; and 27 core combinations were obtained by k-means clustering of formula. Conclusion: In the treatment of PCOS, TCM is primarily employed as a combination approach involving tonifying the kidneys, strengthening the spleen, eliminating damp and dissolving phlegm, activating blood circulation, and resolving blood stasis. The core prescription is primarily a compound intervention based on the Cangfu Daotan pill, Liuwei Dihuang pill, and Taohong Siwu decoction.

Protein engineering strategies to stimulate the functions of bacterial pseudokinases.

Enzymes orchestrate an array of concerted functions that often culminate in the chemical conversion of substrates into products. In the bacterial kingdom, histidine kinases autophosphorylate, then transfer that phosphate to a second protein called a response regulator. Bacterial genomes can encode large numbers of histidine kinases that provide surveillance of environmental and cytosolic stresses through signal stimulation of histidine kinase activity. Pseudokinases lack these hallmark catalytic functions but often retain binding interactions and allostery. Characterization of bacterial pseudokinases then takes a fundamentally different approach than their enzymatic counterparts. Here we discuss models for how bacterial pseudokinases can utilize protein-protein interactions and allostery to serve as crucial signaling pathway regulators. Then we describe a protein engineering strategy to interrogate these models, emphasizing how signals flow within bacterial pseudokinases. This description includes design considerations, cloning strategies, and the purification of leucine zippers fused to pseudokinases. We then describe two assays to interrogate this approach. First is a C. crescentus swarm plate assay to track motility phenotypes related to a bacterial pseudokinase. Second is an in vitro coupled-enzyme assay that can be applied to test if and how a pseudokinase regulates an active kinase. Together these approaches provide a blueprint for dissecting the mechanisms of cryptic bacterial pseudokinases.

The influence of titanium dioxide nanoparticles on their cellular response to macrophage cells.

As the most widely application of nanomaterials in biology and medicine, their interaction with biological system and the afterwards cellular responses would be addressed. Here, the agglomerate states of two kinds of TiO2 NPs in culture medium were characterized and the cluster specific cellular responses in RAW264.7 cells were investigated. Owing to the smaller aggregates and more positively charged surface, 21 nm TiO2 NPs exhibited higher cytotoxicity, which correlated with their ability to cause damage to mitochondria. While for 35 nm TiO2 NPs, higher level of cell autophagy and stronger pro-inflammatory immune response were observed, which are responsible for their lower cytotoxicity. These results suggest that physiochemical properties of TiO2 NPs in culture medium are important factor affecting their cellular response to RAW264.7 cells.

The R1 conjugative plasmid increases Escherichia coli biofilm formation through an envelope stress response.

Differential gene expression in biofilm cells suggests that adding the derepressed conjugative plasmid R1drd19 increases biofilm formation by affecting genes related to envelope stress (rseA and cpxAR), biofilm formation (bssR and cstA), energy production (glpDFK), acid resistance (gadABCEX and hdeABD), and cell motility (csgBEFG, yehCD, yadC, and yfcV); genes encoding outer membrane proteins (ompACF), phage shock proteins (pspABCDE), and cold shock proteins (cspACDEG); and phage-related genes. To investigate the link between the identified genes and biofilm formation upon the addition of R1drd19, 40 isogenic mutants were classified according to their different biofilm formation phenotypes. Cells with class I mutations (those in rseA, bssR, cpxA, and ompA) exhibited no difference from the wild-type strain in biofilm formation and no increase in biofilm formation upon the addition of R1drd19. Cells with class II mutations (those in gatC, yagI, ompC, cspA, pspD, pspB, ymgB, gadC, pspC, ymgA, slp, cpxP, cpxR, cstA, rseC, ompF, and yqjD) displayed increased biofilm formation compared to the wild-type strain but decreased biofilm formation upon the addition of R1drd19. Class III mutants showed increased biofilm formation compared to the wild-type strain and increased biofilm formation upon the addition of R1drd19. Cells with class IV mutations displayed increased biofilm formation compared to the wild-type strain but little difference upon the addition of R1drd19, and class V mutants exhibited no difference from the wild-type strain but increased biofilm formation upon the addition of R1drd19. Therefore, proteins encoded by the genes corresponding to the class I mutant phenotype are involved in R1drd19-promoted biofilm formation, primarily through their impact on cell motility. We hypothesize that the pili formed upon the addition of the conjugative plasmid disrupt the membrane (induce ompA) and activate the two-component system CpxAR as well as the other envelope stress response system, RseA-sigma(E), both of which, along with BssR, play a key role in bacterial biofilm formation.

Monolayer CS as a metal-free photocatalyst with high carrier mobility and tunable band structure: a first-principles study.

Producing hydrogen fuel using suitable photocatalysts from water splitting is a feasible method to harvest solar energy. A desired photocatalyst is expected to have suitable band gap, moderate band edge position, and high carrier mobility. By employing first-principles calculations, we explore a α-CS monolayer as a metal-free efficient photocatalyst. The α-CS monolayer shows good energetic, dynamic, and thermal stabilities and is insoluble in water, suggesting its experimental practicability. Monolayer and bilayer α-CS present not only appropriate band gaps for visible and ultraviolet light absorption but also moderate band alignments with water redox potentials in pH neutral water. Remarkably, the α-CS monolayer exhibits high (up to 8453.19 cm2 V-1s-1 for hole) and anisotropic carrier mobility, which is favorable to the migration and separation of photogenerated carriers. In addition, monolayer α-CS experiences an interesting semiconductor-metal transition by applying uniaxial strain and external electric field. Moreover, α-CS under certain strain and electric field is still dynamically stable with the absence of imaginary frequencies. Furthermore, we demonstrate that the graphite (0 0 1) surface is a potential substrate for the α-CS growth with the intrinsic properties of α-CS maintaining. Therefore, our results could pave the way for the application of α-CS as a promising photocatalyst.