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Antibiotic resistance genes (ARGs) raise public concern as emerging contaminants. The abundance and variation of 11 ARGs, intI1 and 16S rRNA gene were deciphered using quantitative PCR (qPCR) in two drinking water treatment systems that include river, wetland, drinking water treatment plants (DWTPs) and tap water from the Yangtze River Delta. The influencing factors for ARG abundance in river water were also explored. All investigated genes were detected in river water and there was no significant difference between the two systems, with sulfonamide ARGs occupying the highest abundance. Temperature had a significant effect on the ARG distribution based on permutational multivariate analysis of variance (PERMANOVA). Further Spearman analysis demonstrated that temperature was strongly correlated with the abundance of sul1, sul2, tetA and tetC, and these genes were significantly correlated with environmental factors (including temperature, total organic carbon (TOC) and dissolved oxygen (DO)). Considering the frequency and abundance of ARGs, as well as their correlation with other genes, sul1, sul2, tetA and tetC could be used as indicators of ARGs in river water. No significant reduction was noted for the absolute abundance of ARGs from river water to wetland water. Principle coordinates analysis (PCoA) combined with PERMANOVA revealed that drinking water treatment was responsible for reducing 16S rRNA gene and ARG abundance resulting in 3-log reductions. However, it should be noted that after transportation of distribution pipeline, both 16S rRNA gene and ARGs still detected in tap water, which indicated persistence of ARGs and will require further research., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The conversion of low value-added phytosterols into 9α-hydroxy-4-androstene-3,17-dione (9-OHAD) by mycobacteria is an important step in the steroid pharmaceutical industry. However, the highly dense cell envelope with extremely low permeability largely affects the overall transformation efficiency. Here, we preliminarily located the key gene embC required for the synthesis of lipoarabinomannan from lipomannan in Mycobacterium neoaurum. The genetic manipulation of embC indicated that it might be the only functional enzyme catalyzing the above synthesis process. The deficiency of lipoarabinomannan led to a significantly increased cell permeability, which in turn caused the enhanced uptake capacity of cells. The sterol substrate conversion efficiency of mycobacterial cells was increased by about 52.4 % after 72-h conversion. Ultimately, the absence of embC increased the productivity from 0.0927 g/L/h to 0.1031 g/L/h, as confirmed by a resting cell system. This study verified the feasibility of improving the efficiency of the microbial conversion system through the cell envelope engineering strategy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

NASA's Magnetospheric Multi-Scale (MMS) mission is designed to explore the proton- and electron-gyroscale kinetics of plasma turbulence where the bulk of particle acceleration and heating takes place. Understanding the nature of cross-scale structures ubiquitous as magnetic cavities is important to assess the energy partition, cascade and conversion in the plasma universe. Here, we present theoretical insight into magnetic cavities by deriving a self-consistent, kinetic theory of these coherent structures. By taking advantage of the multipoint measurements from the MMS constellation, we demonstrate that our kinetic model can utilize magnetic cavity observations by one MMS spacecraft to predict measurements from a second/third spacecraft. The methodology of "observe and predict" validates the theory we have derived, and confirms that nested magnetic cavities are self-organized plasma structures supported by trapped proton and electron populations in analogous to the classical theta-pinches in laboratory plasmas.

The surface crack of ballastless track slab can seriously reduce the serviceability and durability of high-speed railway (HSR). Aiming at accurately and efficiently detecting the slab cracks, this research proposes an infrared thermography (IRT)-based method for the surface crack, which is the most serious and common crack type in track slab. A three dimensional finite element (FE) model of IRT detection of concrete slab with surface cracks is established. The relation between the width of detectable cracks and the ambient temperature can be thereby obtained by inputting the measured thermodynamic parameters in the model. Parametric study shows that with ambient temperature higher than 15 °C, cracks with a width of no less than 0.2 mm can be well detected. Scale model test and field test are conducted, IRT method can effectively locate the slab surface cracks with width as small as 0.14 mm when ambient temperature is no less than 20 °C.

Objective: To investigate the related risk factors and predictive nomogram of postoperative hypoxaemia in elderly patients with femoral neck fractures., Methods: This study included patients aged ≥65 years who underwent surgical treatment of acute femoral neck fractures. Univariate and multivariate logistic analyses were performed to determine the incidence of and risk factors for postoperative hypoxaemia. A predictive nomogram was constructed based on the multivariable model. Using the bootstrap method, discrimination was determined by the C-index and calibration plot., Results: The logistic regression analysis showed that the anaesthesia type, surgical procedure, American Society of Anesthesiologists (ASA) classification, preoperative hypoxaemia occurrence, and age were independent predictors of development of postoperative hypoxaemia. The predictive formula for hypoxaemia was established as follows: hypoxaemia=-0.8668×spinal anaesthesia (whether)+0.1162×nerve anaesthesia (whether)+1.9555×plate/screw fixation (whether)+1.4950×hip replacement (whether)+0.4883×ASA classification+1.7153×preoperative oxygenation index+0.1608×age. With the bootstrap method, the prediction curve fit well with the ideal curve, suggesting that the prediction curve constructed in this study has good predictive ability., Conclusions: Anaesthesia type, surgical procedure, ASA classification, preoperative hypoxaemia occurrence, and age were risk factors for postoperative hypoxaemia in elderly patients with femoral neck fractures. The predictive nomogram was designed for preoperative assessment of the risk of postoperative hypoxaemia by calculating the risk score.

Semi-volatile organic compounds (SVOCs) are ubiquitous and toxic environmental pollutants, and have recently attracted much research attention. However, their occurrence in tapwater and the associated potential health risks have not been thoroughly studied. This work examined 26 household tapwater samples collected in 26 Chinese cities during August and September 2019. Concentrations of 79 SVOCs, including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polychlorobenzenes (CBs), were determined using an emerging method of high throughput organic analysis testing combined with high volume solid phase extraction (Hi-throat/Hi-volume SPE). Total concentrations of PAHs, PCBs, OCPs, and CBs were in the ranges 8.70-103 ng L -1 (average 42.1 ng L -1 ), 61.6-434 pg L -1 (average 274 pg L -1 ), 13.1-266 pg L -1 (average 59.8 pg L -1 ), and 3.5-83.0 pg L -1 (average 13.8 pg L -1 ), respectively. PAHs were the dominant SVOCs, with concentrations 10-100 times those of PCBs, OCPs, and CBs. All the studied SVOCs had concentrations deemed acceptable by Chinese national tapwater standards. These measured SVOCs displayed little spatial variation across China, but were significantly correlated with the size of the economy and population of each city. The human non-carcinogenic and carcinogenic risks associated with the studied SVOCs in Chinese tapwater are negligible., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Oncolytic virus (OV) immunotherapy is characterized by viruses which specifically target cancer cells and cause their cytolysis. They provide a unique and promising new tool for the eradication of cancer as they interact with and affect the tumor microenvironment (TME), vasculature, and immune system. Advancements of genetic engineering have allowed for these viruses to be armed in such a way to have enhanced targeting, strong immunomodulation properties, and an ability to modify the TME. However, there are still major limitations in their use, mostly due to difficulties in delivering the viral particles to the tumors and in ensuring that the immunomodulatory properties are able to stimulate the host immune response to mount a complete response. Using novel delivery systems and using OVs as a complementary therapy in a combinatorial treatment have shown some significant successes. In this review, we discuss the major issues and difficulties in using OVs as anti-tumor agents and some of the strategies put in place so far to overcome these limitations. KEY POINTS: • Oncolytic viruses (OVs) infect cancer cells and cause their cytolysis. • The major limitations in using OVs as anti-tumor therapy were discussed. • The potential strategies to overcome these limitations were summarized.

Objective: To evaluate the effectiveness and safety of allogeneic tendons for functional reconstruction of severe hand injuries., Methods: From August 2007 to July 2014, we performed functional reconstruction with tendon allografts for severe hand injuries affecting two or more tendons. At the final follow-up, we assessed total active motion (TAM); pincer pinch strength; grip strength; Disabilities of the Arm, Shoulder, and Hand (DASH) score; degree of satisfaction; and adhesion. We measured the white blood cell count, C-reactive protein concentration, erythrocyte sedimentation rate, total T-cell count, and CD4 + T/CD8 + T ratio to evaluate the immune response and check for infection., Results: Ten patients received 26 allogeneic tendons to reconstruct hand function. The average follow-up period was 50.0 months (range, 24-82 months). The TAM was 126.4° (12°-253°), pincer pinch strength was 0.83 kg (0-4.5 kg), and grip strength was 13.69 kg (4-41.5 kg). The DASH score was 14.25 (3.3-30.8), and seven and three patients were satisfied and partially satisfied, respectively. One patient developed tendon adhesion. All immune and infectious parameters were within the reference range., Conclusion: Functional reconstruction using allogeneic tendons for severe hand injuries with multiple tendon defects was effective and safe; however, more research is needed.

Background and Aims: Helicobacter pylori (H. pylori) infection can occur in early childhood, without eradication therapies such infection can persist throughout life and cause many different diseases. This study investigated the metabolic characteristics and explored the underlying mechanism of children with H. pylori infection, and identified potential biomarkers for evaluating the efficacy of H. pylori eradication therapies., Methods: We performed 1 H NMR-based metabonomics coupled with multivariate analysis to investigate the metabolic profiling of serum samples between Children with and without H. pylori infection. In the same manner, we compared the alternations of metabolites in H. pylori-infected children before and after H. pylori eradication therapies., Results: 21 metabolites from serum in H. pylori-infected and H. pylori-uninfected children were identified, which were mainly involved in energy, amino acid, lipid and microbial metabolism. We found that the serum levels of trimethylamine N-oxide and alanine were significantly higher in H. pylori-infected children compared to uninfected sera, whereas lactate was significantly lower. We also found that the levels of trimethylamine N-oxide and creatine in H. pylori-infected children was significantly decreased after H. pylori eradication therapies, whereas lactate and low-density lipoprotein/very low-density lipoprotein was significantly increased., Conclusions: This is the first study using 1 H NMR-based metabolomics approach to explore the effects of H. pylori infection in children. Our results demonstrated that the disturbances of metabolism in energy, amino acids, lipids and microbiota could play an important role in the pathogenesis of gastrointestinal and extragastric diseases caused by H. pylori infection. Trimethylamine N-oxide and lactate might serve as potential serum biomarkers for evaluating the efficacy of H. pylori eradication therapies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Oxygen glucose deprivation/re-oxygenation (OGD/R) induces neuronal injury via mechanisms that are believed to mimic the pathways associated with brain ischemia. In SH-SY5Y cells and primary murine neurons, we report that OGD/R induces the accumulation of the microRNA miR-422a, leading to downregulation of miR-422a targets myocyte enhancer factor-2D (MEF2D) and mitogen-activated protein kinase kinase 6 (MAPKK6). Ectopic miR-422a inhibition attenuated OGD/R-induced cell death and apoptosis, whereas overexpression of miR-422a induced significant neuronal cell apoptosis. In addition, OGD/R decreased the expression of the long non-coding RNA D63785 (Lnc-D63785) to regulate miR-422a accumulation. Lnc-D63785 directly associated with miR-422a and overexpression of Lnc-D63785 reversed OGD/R-induced miR-422a accumulation and neuronal cell death. OGD/R downregulated Lnc-D63785 expression through increased methyltransferase-like protein 3 (METTL3)-dependent Lnc-D63785 m6A methylation. Conversely METTL3 shRNA reversed OGD/R-induced Lnc-D63785 m6A methylation to decrease miR-422a accumulation. Together, Lnc-D63785 m6A methylation by OGD/R causes miR-422a accumulation and neuronal cell apoptosis.

To investigate the clinical value of changes in the subtypes of peripheral blood lymphocytes and levels of inflammatory cytokines in patients with COVID-19, the total numbers of lymphocytes and CD4+ lymphocytes and the ratio of CD4+/CD8+ lymphocytes were calculated and observed in different groups of patients with COVID-19. The results show that the lymphocytopenia in patients with COVID-19 was mainly manifested by decreases in the CD4+ T lymphocyte number and the CD4+/CD8+ ratio. The decreased number of CD4+ T lymphocytes and the elevated levels of TNF-α and IL-6 were correlated with the severity of COVID-19 disease., Competing Interests: The authors have declared that no competing interests exist.

Osteosarcoma (OS) is the most common primary bone malignancy in the adolescent population. Recent studies demonstrate that p38 gamma (p38γ) phosphorylates retinoblastoma (Rb) to promote cyclin expression, cell-cycle entry and tumorigenesis. Studying the potential function of p38γ in human OS, we show that p38 γ mRNA and protein expression are significantly elevated in OS tissues and OS cells, whereas its expression is relatively low in normal bone tissue and in human osteoblasts/osteoblastic cells. Knockdown of p38γ in established (U2OS) and primary human OS cells potently inhibited cell growth, proliferation, migration and invasion, while promoting cell apoptosis. Furthermore, CRISPR/Cas9-induced p38γ knockout inhibited human OS cell progression in vitro . Conversely, ectopic overexpression of p38γ in primary human OS cells augmented cell growth, proliferation and migration. Signaling studies show that retinoblastoma (Rb) phosphorylation and cyclin E1/cyclin A expression were decreased following p38γ shRNA knockdown and knockout, but increased after ectopic p38γ overexpression. Collectively, these results show that p38γ overexpression promotes human OS cell progression.

Wounds present serious medical complications and their healing requires strategies that promote angiogenesis, deposition of collagen as well as re-epithelialization of wounds. Currently used conventional wound healing strategies have become less effective due to various issues associated with them. Thus, novel strategies are needed to be developed for early and effective healing of wounds. Metal-organic frameworks (MOFs), formed by linking of metal ions through organic bridging ligands, are highly tunable hybrid materials and have attracted more considerable scientific attention due to their charming and prominent properties, such as abundant pore structures and multiple functionalities. Surface engineering of MOFs with unique ligands can overcome issues associated with conventional wound healing methods, thus resulting in early and effective wound healing. This review has been undertaken to elaborate wound healing, and the use of surface engineered MOFs for effective and rapid wound healing. The process of wound healing will be discussed followed by a detailed review of recent literature for summarizing applications of surface engineered MOFs for wound healing. MOFs wound healing will be discussed in terms of their use as antibacterial agents, therapeutic delivery vehicles, and dressing systems in wound healing., (Copyright © 2020 Fu, Chen, Cai, Tao, Fan and Mou.)

Objective: To investigate the mechanism by which total alkaloids of Sophora alopecuroides (TASA) and matrine (MT) impair biofilm to increase the susceptibility of Staphylococcus epidermidis ( S. epidermidis ) to ciprofloxacin., Methods: The minimum biofilm inhibitory concentration (mBIC) was determined using a 2-fold dilution method. Structure of biofilm of S. epidermidis was examined by Confocal Laser Scanning Microscope (CLSM). The cellular reactive oxygen species (ROS) was determined using a DCFH-DA assay. The key factors related to the regulation of ROS were accessed using respective kits., Results: TASA and MT were more beneficial to impair biofilm of S. epidermidis than ciprofloxacin (CIP) ( P  < 0.05). TASA and MT were not easily developed resistance to biofilm-producing S. epidermidis . The mBIC of CIP decreased by 2-6-fold following the treatment of sub-biofilm inhibitory concentration (sub-BIC) TASA and MT, whereas the mBIC of CIP increased by 2-fold following a treatment of sub-BIC CIP from the first to sixth generations. TASA and MT can improve the production of ROS in biofilm-producing S. epidermidis . The ROS content was decreased 23%-33% following the treatment of sub-mBIC CIP, whereas ROS content increased 7%-24% following treatment with TASA + CIP and MT + CIP combination from the first to sixth generations. Nitric oxide (NO) as a ROS, which was consistent with the previously confirmed relationship between ROS and drug resistance. Related regulatory factors-superoxide dismutase (SOD) and glutathione peroxidase (GSH) could synergistically maintain the redox balance in vivo ., Conclusion: TASA and MT enhanced reactive oxygen species to restore the susceptibility of S. epidermidis to ciprofloxacin., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)

Introduction: With the development of social economy, transportation and various infrastructures have also developed, but it has objectively increased the number of patients with head injury. Although the current craniocerebral medicine technology continues to advance, long-term bed rest and other complications have led to an insignificant decrease in the mortality rate of coma patients. It is not uncommon for patients with disturbance of consciousness caused by head injury in major hospitals., Methods/design: This will be a retrospective, single-blind clinical observational study. We will select 50 cases that meet the subject's selection criteria. According to whether they received acupuncture treatment or not, they will be randomly divided into 2 groups, namely treatment group and control group. The control group will be given conventional Western medicine treatment, and the treatment group will be given acupuncture method of removing-stasis and resuscitating treatment on the basis of the control group., Discussion: Our purpose is to observe the role of acupuncture method of removing-stasis and resuscitating in promoting the recovery of patients with severe head injury. We aim to provide more evidence-based medical evidence for acupuncture treatment of this disease., Trial Registration: ClinicalTrials.gov, ChiCTR2000034732, Registered on 19 July 2020.

Death-associated protein kinase 1 (DAPK1) is upregulated in the brains of human Alzheimer's disease (AD) patients compared with normal subjects, and aberrant DAPK1 regulation is implicated in the development of AD. However, little is known about whether and how DAPK1 function is regulated in AD. Here, we identified melatonin as a critical regulator of DAPK1 levels and function. Melatonin significantly decreases DAPK1 expression in a post-transcriptional manner in neuronal cell lines and mouse primary cortical neurons. Moreover, melatonin directly binds to DAPK1 and promotes its ubiquitination, resulting in increased DAPK1 protein degradation through a proteasome-dependent pathway. Furthermore, in tau-overexpressing mouse brain slices, melatonin treatment and the inhibition of DAPK1 kinase activity synergistically decrease tau phosphorylation at multiple sites related to AD. In addition, melatonin and DAPK1 inhibitor dramatically accelerate neurite outgrowth and increase the assembly of microtubules. Mechanistically, melatonin-mediated DAPK1 degradation increases the activity of Pin1, a prolyl isomerase known to play a protective role against tau hyperphosphorylation and tau-related pathologies. Finally, elevated DAPK1 expression shows a strong correlation with the decrease in melatonin levels in human AD brains. Combined, these results suggest that DAPK1 regulation by melatonin is a novel mechanism that controls tau phosphorylation and function and offers new therapeutic options for treating human AD., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.

Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss. It is responsible for 2-5% of congenital deafness. WS is classified into four types depending on the clinical phenotypes. Currently, pathogenic mutation of PAX3 , MITF , EDNRB , EDN3 , SNAI2 , or SOX10 can cause corresponding types of WS. Among them, SOX10 mutation is responsible for approximately 15% of type II WS or 50% of type IV WS. We report the case of a proband in a Chinese family who was diagnosed with WS type II. Whole exome sequencing (WES) of the proband detected a novel heterozygous spontaneous mutation: SOX10 c.246delC. According to analysis based on nucleic acid and amino acid sequences, this mutation may produce a truncated protein, with loss of the HMG structure domain. Therefore, this truncated protein may fail to activate the expression of the MITF gene, which regulates melanocytic development and plays a key role in WS. Our finding expands the database of SOX10 mutations associated with WS and provides more information regarding the molecular mechanism of WS., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Sen Chen et al.)

Objective: To analyze and compare the hidden blood loss of minimally invasive percutaneous plate osteosynthesis(MIPPO) combined with locking plate fixation and intramedullary nail fixation in the treatment of tibial shaft fracture., Methods: One hundred and ninety-one cases of tibial shaft fracture treated from January 2017 to January 2019 were analyzed retrospectively. The patients were all treated with closed reduction and divided into two groups:group A (110 cases) and group B (81 cases). In group A, 78 males and 32 females were treated with MIPPO combined with locking plate. The age ranged from 19 to 74 (45.32±11.79) years old. According to AO classification, 42cases were type 42-A, 45 were type 42-B and 23 were type 42-C fractures. Group B was treated with intramedullary nail, including 65 males and 16 females, aged 19 to 84 (45.44± 14.32) years old. According to AO classification, there were 39 cases of type 42-A, 29 cases of type 42-B and 13 cases of type 42-C. The operation time, intraoperative blood loss and hidden blood loss were observed and compared between the two groups., Results: On the first day, the hidden blood loss was (155.27±47.89) ml in group A and (160.43±131.42) ml in group B, the difference was statistically significant ( P <0.001);on the third day, the hidden blood loss was (102.70±94.79) ml in group A and (338.23±85.24) ml in group B, the difference was statistically significant ( P <0.001). There was no significant difference between the two groups in gender, age, height, weight, fracture type and preoperative Hct ( P >0.05)., Conclusion: In the treatment of tibial shaft fracture with intramedullary nail, there is obvious hidden blood loss, which is much higher than expected.

PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of Pin1, or introduction of a BRCA1-mutant refractory to Pin1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition. SIGNIFICANCE: PARP inhibitors have been limited to treat homologous recombination-deficient tumors. All-trans retinoic acid, by inhibiting Pin1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination-proficient tumors. See related commentary by Cai, p. 2977 ., (©2020 American Association for Cancer Research.)

Tumor associated macrophages (TAMs) are the most frequent immune cells within tumor microenvironment (TME). There is growing evidence that TAMs are involved in tumor progression via multiple mechanisms. TAMs create an immunosuppressive TME by producing growth factors, chemokines, and cytokines which modulate recruitment of immune cells and inhibit anti-tumor responses. They also serve as angiogenesis promoting cells by production of pro-angiogenic factors and matrix metalloproteinases (MMPs) and vascular constructing which guarantee supplying oxygen and nutrients to solid tumor cells. Furthermore, TAMs play important functions in tumor metastasis through contributing to invasion, extravasation, survival, intravasation, and colonization of tumor cells. In this review, we summarized macrophage classification, TAMs polarization, and mechanisms underlying TAM-promoting angiogenesis and metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Osteoblast cells are responsible for synthesizing new bone tissue, and determining how to control osteoblastic differentiation is vital to the treatment of osteoporosis. In the present study, we show that pentraxin 3 (PTX3) signaling is involved in the regulation of osteoblastic differentiation in MC3T3-E1 cells. Our data reveal that PTX3 is abundantly expressed in MC3T3-E1 cells and that its expression is inducible by the introduction of osteogenic induction medium (OIM). Overexpression of PTX3 was observed to significantly increase the expression of four osteoblast signature genes, including Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteocalcin (OCN) and osterix (OSX), suggesting that the overexpression of PTX3 promotes osteoblastic differentiation. The relative level of gene expression between OIM and OIM plus overexpressed PTX3 was evaluated using the Affymetrix Gene Chip® mouse gene microarray. PTX3-related differentially expressed genes (DEGs) were screened. Gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathway enrichment analyses were performed, and the PI3K/Akt signaling pathway was primarily involved in the osteogenic differentiation of PTX3. Protein-protein interactions (PPIs) were also constructed, and the molecular complex detection (MCODE) plugin calculated modules of PPI networks. Moreover, we show that the effect of PTX3 is mediated by its induction of the PI3K/Akt signaling pathway. Mechanistically, we show that the action of PTX3 requires the activation of PI3K and Akt, and deactivation of PI3K by its inhibitor LY294002 weakens the PTX3-mediated induction of osteoblast signature genes, ALP and matrix mineralization. The present study revealed a new role played by PTX3 and suggest a potential mechanism governing the osteoblastic differentiation of MC3T3-E1 cells., (© 2020 The Author(s).)

In this paper, a visible-light-promoted cross-coupling of 4-alkyl-1,4-dihydropyridines with thio-/selenium sulfonates under transition-metal-free conditions is described. This strategy features easily available substrates, mild reaction conditions, high yields, and high chemoselectivity. A novel synthetic route for the construction of a sulfide or selenide C sp3 -S or C sp3 -Se bond under transition-metal-free conditions without an additive oxidant or base is developed. This method is well extended to the synthesis of a class of thiolated or selenylated glycosides that has not been explored before. Sulfoxides were also successfully chemoselectively observed via a facile variation of the atmosphere under photocatalyzed conditions.

Triple-negative breast cancer (TNBC) has a greater risk of recurrence and metastasis along with a worse prognosis compared with other subtypes of breast cancer. Studies have revealed that mitogenic estrogen signaling is involved in the malignant proliferation of TNBC cells through a novel variant of the estrogen receptor, estrogen receptor α-36 (ER-α36). The results of the present study demonstrated that knockdown of ER-α36 expression in TNBC cells using short hairpin RNA inhibited rapid estrogen signaling bypass activation of the PI3K/AKT signaling pathway. Moreover, the ER-α36 modulator icaritin inhibited the proliferation of TNBC cells both in vitro and in vivo . Here, it was revealed that the combination of icaritin and cetuximab, a therapeutic epidermal growth factor receptor (EGFR) neutralizing antibody, induced apoptosis and inhibited cell proliferation synergistically in TNBC cells. The results of the present study improved the understanding of the underlying mechanisms of TNBC progression and supported the therapeutic potential of combined treatment targeting the ER-α36 and EGFR., (Copyright: © Yin et al.)

The capability of high-throughput sequencing (HTS) for detection of known and unknown viruses timely makes it a powerful tool for public health emergency response. Third-generation sequencing (TGS) offers advantages in speed and length of detection over second-generation sequencing (SGS). Here, we presented the end-to-end workflows for both Oxford Nanopore MinION and Pacbio Sequel on a viral disease emergency event, along with Ion Torrent PGM as a reference. A specific pipeline for comparative analysis on viral genomes recovered by each platform was assembled, given the high errors of base-calling for TGS platforms. All the three platforms successfully identified and recovered at least 85% Norovirus GII genomes. Oxford Nanopore MinION spent the least sample-to-answer turnaround time with relatively low but enough accuracy for taxonomy classification. Pacbio Sequel recovered the most accurate viral genome, while spending the longest time. Overall, Nanopore metagenomics can rapidly characterize viruses, and Pacbio Sequel can accurately recover viruses. This study provides a framework for designing the appropriate experiments that are likely to lead to accurate and rapid virus emergency response.

Oncolytic virotherapy is a promising antitumor strategy which utilizes the lytic nature of viral replication to kill cancer cells. Oncolytic viruses (OVs) can induce cancer cell death and trigger immune responses to metastatic cancer in vivo. Reverse genetic systems have aided the insertion of anticancer genes into various OVs to augment their oncolytic capacity. Furthermore, OVs target and destroy the population of tumor-initiating cancer stem cells. These cancer stem cells are associated with metastasis and development of resistance to conventional anticancer approaches. Targeting cancer stem cells is essential since killing only differentiated tumor cells may lead to enrichment of cancer stem cells and thus indicate a poor prognosis. In this review, we summarize the oncolytic activity of various classes of OVs towards different types of cancer stem cells and also discuss the synergistic activity achieved by the combination of OVs with traditional therapies on chemo- and radiotherapy-resistant cancer stem cells.

Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds) in the ECG waveforms. The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia. Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations. Here, using next-generation sequencing (NGS), we identified a compound heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A (known) in KCNQ1 gene as the possible pathogenic cause of JLNS, which suggested a high risk of cardiac events in a deaf child. The hearing of this patient improved significantly with the help of cochlear implantation (CI). But life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery. Our findings extend the KCNQ1 gene mutation spectrum and contribute to the management of deaf children diagnosed with JLNS for otolaryngologists (especially cochlear implant teams)., Competing Interests: The authors declare that they have no competing interests regarding the publication of this paper., (Copyright © 2020 Yue Qiu et al.)

Background: To investigate the differences of spontaneous functional connectivity (FC) of the primary visual cortex (V1) between patients with retinal vein occlusion (RVO) and healthy controls (HCs) using resting-state functional magnetic resonance imaging (rs-fMRI) data., Methods: Twenty-one patients with RVO in total (11 males, 10 females) and 21 HCs similarly analogue in age and sex background were enrolled and inspected with rs-fMRI. The difference in FC of V1 between two groups were compared using two-sample t-test. We used the receiver operating characteristic (ROC) curve to distinguish average FC values of RVO subjects from HCs. The interrelationships between FC signals of specific cerebrum regions and clinical features in RVOs were assessed with the Pearson's correlation analysis., Results: Compared with HCs, FC in left V1 and right middle frontal gyrus increased significantly in RVO group, while FC in left V1 and right cuneus decreased significantly. Meanwhile, patients with RVO presented increased FC between the right V1 and right middle frontal gyrus, right superior frontal gyrus, but declining FC between right V1 and right cuneus. The mean FC value between the right cuneus and the right V1 as well as the left V1 were negative correlated with the foveal thickness of RVO patients. ROC curve analysis of each brain regions showed the accuracy of AUC was excellent., Conclusions: RVO involves aberrant FC in V1 in different brain areas including visual-related and cognitive-related region, which might assist to unveil the underlying neural mechanisms of impaired visual function in RVO., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims.2020.03.24). The authors have no conflicts of interest to declare., (2020 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Condylomata acuminata (CA) are a common sexually transmitted disease. The recurrence rate of condyloma acuminatum using traditional treatments is higher than that of applying photodynamic therapy, and a variety of adverse reactions after treatment. At the same time, different parts of condyloma acuminatum after treatment recurrence rate is also different, especially for intra anal-rectal warts. Objective: To evaluate whether using photodynamic therapy (PDT) can effectively reduce recurrence of condylomata acuminata for intra anal-rectal warts. Methods: After the confirmation of the diagnosis of intra anal-rectal warts, the patients were treated with PDT with 5-aminolevulinic acid hydrochloride (ALA). PDT was performed with irradiation of 18-36 J/cm 2 at an irradiance of 20-40 mW/cm 2 with light-emitting diode (LED) light energy, wavelength 635 nm. We used a special PDT light equipment for intra anal-rectal area warts. PDT was repeated once every week for 4 weeks. Results: After PDT, the complete clearance rate was 76.1% (35 of 46 patients). At the end of the 12 weeks followed, recurrence occurred in five cases. We recorded pain in all 46 patients and the average visual analog scale (VAS) pain score was 6.96 ± 1.41 points. Conclusion: The treatment with PDT is effective in reducing the high rate of recurrence for intra anal-rectal warts. Pain is still a great challenge for the therapy.

Within the past decade, immune-checkpoint inhibitors (ICPIs), including anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand 1 (PD-L1), and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, are undoubtfully the most remarkable advances in cancer therapy. The immune responses are modulated by these ICPIs via blocking the inhibitory PD-1/PD-L1 path and result in immune activation in the suppressive microenvironment of the tumor. While ICPIs result in benefits for numerous patients with malignancy and lead to disease control and survival, toxicity and safety problems have emerged as well. Although immune mediated adverse effects due to ICPIs could involve any organ system, skin, endocrine glands, and gastrointestinal tract, are one of the most commonly affected. Fortunately, in most of the cases, these immune‑mediated adverse effects (imAEs) are manageable, while in some cases these toxicities are fulminant and fatal and lead to the withdrawal of treatment. Numerous attempts have been started and are continuing to reduce the incidence rate of imAEs. Further studies are required for a better understanding of these imAEs, decrease the occurrence, and lighten the severity. In this work, we overview the imAEs and also, highlight the most important aspects of the imAEs management., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

The structure of a decagonal quasicrystal in the Zn 58 Mg 40 Y 2 (at.%) alloy was studied using electron diffraction and atomic resolution Z -contrast imaging techniques. This stable Frank-Kasper Zn-Mg-Y decagonal quasicrystal has an atomic structure which can be modeled with a rhombic/hexagonal tiling decorated with icosahedral units at each vertex. No perfect decagonal clusters were observed in the Zn-Mg-Y decagonal quasicrystal, which differs from the Zn-Mg-Dy decagonal crystal with the same space group P 10/ mmm . Y atoms occupy the center of 'dented decagon' motifs consisting of three fat rhombic and two flattened hexagonal tiles. About 75% of fat rhombic tiles are arranged in groups of five forming star motifs, while the others connect with each other in a 'zigzag' configuration. This decagonal quasicrystal has a composition of Zn 68.3 Mg 29.1 Y 2.6 (at.%) with a valence electron concentration ( e / a ) of about 2.03, which is in accord with the Hume-Rothery criterion for the formation of the Zn-based quasicrystal phase ( e / a = 2.0-2.15)., (© Wang et al. 2020.)

The role of forkhead box O3 (FOXO3) as a tumor suppressor gene and its association with the human lifespan is well documented. However, several studies have indicated that high expression of FOXO3 is also significantly associated with tumorigenesis. The aim of the present study was to determine the clinical significance of FOXO3 in the development and prognosis of hepatocellular carcinoma (HCC). mRNA expression data of FOXO3 from The Cancer Genome Atlas database was analyzed through the UALCAN online tool to compare the expression of FOXO3 between HCC and normal liver tissues. Subsequently, the expression of FOXO3 at the protein level was investigated via immunohistochemical staining of 314 HCC and 150 non-cancerous liver tissue samples. The association between protein expression and clinicopathological parameters was analyzed using the χ 2 test, and the effect of FOXO3 expression on survival was assessed via Kaplan-Meier analysis. The expression of FOXO3 mRNA was significantly higher in HCC in comparison with healthy tissues. High FOXO3 protein expression was revealed in 43/150 non-cancerous liver tissues, and in 238/314 HCC samples. A significant association was demonstrated between FOXO3 expression and metastasis, Tumor-Node-Metastasis stage, Edmondson grade, α-fetoprotein level and overall survival. In conclusion, the high expression of FOXO3 predicts a poor prognosis in patients with HCC, indicating this protein as a potential therapeutic target in HCC., (Copyright: © Song et al.)

Objective: To investigate the correlation of the Netrin-1 expression level with the clinical characteristics in children with acute lymphoblastic leukemia (ALL) and to explore its possible regulatory mechanism., Methods: ELISA was used to detect the expression level of Netrin-1 in peripheral blood serum from 48 child ALL patients (newly diagnosed, recurrent), and its relevance with clinical indicators was statistically analyzed. The blood serum samples from 27 children with non malignant hematological diseases were choosen as controls. Leukemia cell lines of Jurkat,Molt-4,SUP-B15 and Raji were cultivated in vitro, after treated with different concentrations of recombinant human Netrin-1 protein， the invasive ability of the cells was detected by Transwell method； the effect of Netrin-1 to the proli feration of cells was detected by CCK-8 method； The expression and phosphorylation level of key molecules, such as FAK,Erk1/2,PI3K and Akt signaling pathway were detected by Western blot., Results: The expression of Netrin-1 in child patients was significantly higher than that of the control group (P<0.05). With the increasing of Netrin-1 level, the level of Plt (r=0.483, P<0.05) increased, while the level of WBC (r=-0.290, P<0.05) decreased, and there were no significant correlation with age, Hb level and the proportion of immature cells in bone marrow. When the concentration of Netrin-1 was 25-50 ng/ml, the level of Netrin-1 positively correlated with WBC (r=0.886, P<0.05) ; the level of Netrin-1 significantly decreased when the patient's WBC was ＞50×10 9 /L and Plt ＞20×10 9 /L(P=0.042，P=0.001); The expression level of Netrin-1 was significantly different in the risk group(P=0.017), and level of Netrin-1 in high-risk group was significantly higher than that in low risk group and middle risk group, but there was no significant difference of Netrin-1 expression in sex, hepatosplenomegaly, MRD, recurrence and chromosome abnormality. Netrin-1 could promote the invasiveness of the four kinds of cells (P<0.05). With the increase of Netrin-1 concentration, the number of cells increased at first and then decreased, and the number of cells in the invading chamber was the highest when the concentration of Netrin-1 was 100 ng/ml; the survival rate of the four kinds of cells significantly increased when the concentration of Netrin-1 was 25 ng/ml(P<0.05), and SUP-B15 cells showed the highest cell survival rate at a concentration of 100 ng/ml; The survival rate of the four kinds of cells showed a tendency : survival of cells increased at low concentration of Netrin-1 and survival of cells decreased at high concentration of Netrin-1. The results of Western blot showed that Netrin-1 activated the phosphorylation level of key molecules such as FAK,Erk1/2,PI3K,Akt signaling pathway (P<0.05)., Conclusion: There is abnormal expression of Netrin-1 in serum of children with ALL. Netrin-1 may affect the occurrence and development of ALL by increasing the proliferation and invasiveness of leukemia cells, and may become a risk factor of ALL or a potential target in biotherapy.

Background: Citron kinase (CIT) is a protein related to cytokinesis and is an important abscission regulator. However, the relationship between CIT and hepatocellular carcinoma (HCC) is unclear. The aim of this study was to investigate the expression CIT in HCC tissues, and explore the connection between this expression and clinicopathological characteristics of HCC., Methods: Immunohistochemistry staining on 235 HCC tissues and 96 non-tumorous liver tissues controls was performed to examine the CIT protein expression. We then analyzed the correlation between protein expression and clinicopathological parameters via χ 2 tests, and we performed overall survival analyses via the Kaplan-Meier survival approach. Based on the online Oncomine Expression Array and UALCAN databases, we more broadly compared CIT mRNA expression between normal and HCC tissues. Finally, we compared CIT mRNA expression in these databases to protein expression in our study and explored potential sources for any observe differences., Results: Compared to normal tissues, CIT expression was significantly lower in HCC tissues. Low CIT expression was found to be related to gender, tumor size, Edmondson Grade, Microvascular invasion, serum AFP levels and poor overall survival. Based on the online databases, CIT mRNA expression was found to be high in HCC tissues and decreased in normal tissues. We hypothesize that this unexpected result is due to a negative feedback loop whereby low protein CIT levels mediate increased CIT mRNA levels., Conclusions: Lower CIT protein levels are associated with a poorer prognosis in HCC patients, and lower CIT protein levels may mediate a negative feedback loop leading to increased CIT mRNA levels., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2020.03.58). All authors reports grants from Zhejiang Province Bureau of Health, during the conduct of the study., (2020 Translational Cancer Research. All rights reserved.)

Background: Previous studies have just found skeletal muscle mass decline is associated with arterial stiffness, but it is unclear whether muscle strength and physical performance as important compositions of sarcopenia are associated with arterial stiffness. The aim of this study was to investigate the relationship between sarcopenia, the components of sarcopenia and arterial stiffness among elderly in the community., Methods: This study enrolled 450 elderly people who received general medical examinations in Tianjin First Center Hospital. Each of the subjects was greater than 65 years old, including 266 male and 184 female subjects. Based on the diagnostic criteria for sarcopenia in older people developed by the Asian Working Group for Sarcopenia (AWGS), 89 subjects were separated into the sarcopenia group. The living habits, disease status, general status and laboratory examinations of all subjects were collected. The body composition (including appendicular skeletal muscle mass and visceral fat area (VFA) of each participant) was measured by bioimpedance analysis. HS, usual gait speed (GS), and brachial ankle pulse wave velocity (baPWV) were measured., Results: Sarcopenia subjects had higher baPWV, nutrition risk and lower appendicular skeletal muscle index (ASMI), Handgrip strength (HS), GS, body mass index (BMI), triacylglycerol (TG), serum albumin (ALB) and creatinine (Cr) than did non-sarcopenia subjects; Sarcopenia subjects also had higher visceral fat area (VFA) than did non-sarcopenia subjects (p < 0.05). ASMI and HS were negatively associated with baPWV (t = - 5.807, p = 0.000 and t = - 3.085, p = 0.002), but the relationship between baPWV and GS was not statistically significant (t = - 0.862, p = 0.389) by multivariable linear regression. After adjusting for confounders, a multivariate logistic regression analysis revealed that sarcopenia was related with age, BMI, sports and baPWV in community dwelling elderly., Conclusions: ASMI and HS were negatively associated with baPWV in community dwelling elderly in China; and baPWV was a risk factor of sarcopenia.

Hypoxia and ischemia are the main underlying pathogenesis of stroke and other neurological disorders. Cerebral hypoxia and/or ischemia (e.g., stroke) can lead to neuronal injury/death and eventually cause serious neurological disorders or even death in the patients. Despite knowing these serious consequences, there are limited neuroprotective strategies against hypoxic and ischemic insults in clinical settings. Recent studies indicate that microRNAs (miRNAs) are of great importance in regulating cerebral responses to hypoxic/ischemic stress in addition to the neuroprotective effect of the δ-opioid receptor (DOR). Moreover, new discovery shows that DOR can regulate miRNA expression and inhibit inflammatory responses to hypoxia/ischemia. We, therefore, summarize available data in current literature regarding the role of DOR and miRNAs in regulating the neuroinflammatory responses in this article. In particular, we focus on microglia activation, cytokine production, and the relevant signaling pathways triggered by cerebral hypoxia/ischemia. The intent of this review article is to provide a novel clue for developing new strategies against neuroinflammatory injury resulting from cerebral hypoxia/ischemia., (Copyright © 2020 Chen, He, Wang and Xia.)

An ideal animal model of azoospermia would be a powerful tool for the evaluation of spermatogonial stem cell (SSC) transplantation. Busulfan has been commonly used to develop such a model, but 30%-87% of mice die when administered an intraperitoneal injection of 40 mg kg -1 . In the present study, hematoxylin and eosin staining, Western blot, immunofluorescence, and quantitative real-time polymerase chain reaction were used to test the effects of busulfan exposure in a mouse model that received two intraperitoneal injections of busulfan at a 3-h interval at different doses (20, 30, and 40 mg kg -1 ) on day 36 or a dose of 40 mg kg -1 at different time points (0, 9, 18, 27, 36, and 63 days). The survival rate of the mice was 100%. When the mice were treated with 40 mg kg -1 busulfan, dramatic SSC depletion occurred 18 days later and all of the germ cells were cleared by day 36. In addition, the gene expressions of glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2), chemokine (C-X-C Motif) ligand 12 (CXCL12), and colony-stimulating factor 1 (CSF1) were moderately increased by day 36. A 63-day, long-term observation showed the rare restoration of endogenous germ cells in the testes, suggesting that the potential period for SSC transplantation was between day 36 and day 63. Our results demonstrate that the administration of two intraperitoneal injections of busulfan (40 mg kg -1 in total) at a 3-h interval to mice provided a nonlethal and efficient method for recipient preparation in SSC transplantation and could improve treatments for infertility and the understanding of chemotherapy-induced gonadotoxicity., Competing Interests: None

In December, 2019, several cases of novel coronavirus pneumonia (NCP) were reported in Wuhan, Hubei. Since then, more and more NCP cases, confirmed or suspected, have been found in China and other parts of the world, and the virus is now showing a tendency towards a wider spread. During the NCP epidemic, all medical workers are confronted with special challenges in the diagnosis and treatment of various diseases and required of even more accurate therapeutic protocols as well as stricter observation of the principles for the prevention and control of NCP. Therefore, the Andrology Branch of Chinese Medical Association convened relevant experts to summarize the special points for andrologic clinicians to attend to in the diagnosis and treatment of male diseases during the NCP epidemic.

Gastric cancer is the third leading cause of cancer-related death worldwide. Diffuse type gastric cancer has the worst prognosis due to notorious resistance to chemotherapy and enrichment of cancer stem-like cells (CSC) associated with the epithelial-to-mesenchymal transition (EMT). The unique proline isomerase PIN1 is a common regulator of oncogenic signaling networks and is important for gastric cancer development. However, little is known about its roles in CSCs and drug resistance in gastric cancer. In this article, we demonstrate that PIN1 overexpression is closely correlated with advanced tumor stages, poor chemo-response and shorter recurrence-free survival in diffuse type gastric cancer in human patients. Furthermore, shRNA-mediated genetic or all- trans retinoic acid-mediated pharmaceutical inhibition of PIN1 in multiple human gastric cancer cells potently suppresses the EMT, cell migration and invasion, and lung metastasis. Moreover, PIN1 genetic or pharmaceutical inhibition potently eliminates gastric CSCs and suppresses their self-renewal and tumorigenicity in vitro and in vivo Consistent with these phenotypes, are that PIN1 biochemically targets multiple signaling molecules and biomarkers in EMT and CSCs and that genetic and pharmaceutical PIN1 inhibition functionally and drastically enhances the sensitivity of gastric cancer to multiple chemotherapy drugs in vitro and in vivo These results demonstrate that PIN1 inhibition sensitizes chemotherapy in gastric cancer cells by targeting CSCs, and suggest that PIN1 inhibitors may be used to overcome drug resistance in gastric cancer., (©2019 American Association for Cancer Research.)

MYCN -amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN -amplified NB., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Owing to its importance in the assessment of reinforced concrete structures, it is essential to determine the chloride diffusivity of fly ash concrete. This paper presents an investigation into the diffusion characteristics of chloride ions in fly ash concrete. Through experiment, the relationship between chloride diffusivity and curing age up to 1800 days is measured and the effects of curing age, water/binder ratio, aggregate volume fraction, and fly ash content (i.e., percentage of total cementitious material by mass) on chloride diffusivity are evaluated. It is found that the chloride diffusivity decreases with the increase of curing age, aggregate volume fraction, and fly ash content, but increases with the increase of water/binder ratio. In analytical modeling, an equivalent aggregate model is constructed and the equivalent interfacial transition zone (ITZ) thickness is derived analytically. With the equivalent aggregate model, three-phase fly ash concrete reduces to a two-phase composite material. By extending the Maxwell method, the chloride diffusivity of fly ash concrete is formulated. Finally, the validity of the analytical method is verified by experimental results.

Background: Porcine infectious pleuropneumonia caused by Actinobacillus pleuropneumoniae (App) is one of the most serious infectious diseases in pigs and has brought huge economic losses to the world pig industry. The aim of this trial was to evaluate the effect of enteric-coated tilmicosin granule in the treatment and control of artificial infection of App., Methods: Sixty Duroc and Yorkshire crossbred pigs (50 of which were artificially infected) were divided into six groups: BCG (Blank control group), ICG (Infection-only control group), HDG (High-dose enteric-coated tilmicosin granules), MDG (Medium-dose enteric-coated tilmicosin granules), LDG (Low-dose enteric-coated tilmicosin granules) and TPG (Tilmicosin premix drug control group). The cure rate, mortality, clinical respiratory score, body temperature score, weight gain, lung score and so on were recorded., Results: The cure rate of HDG and MDG was as high as 90%, the mortality was 10%, and the clinical signs recovered quickly., Conclusion: The results showed that enteric-coated tilmicosin granules had obvious therapeutic effect on artificial infection, which could reduce the damage caused by the disease and reduce the mortality., (© 2019 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

In chronic infectious diseases caused by gram-negative bacteria, such as osteomyelitis, septic arthritis, and periodontitis, osteoclastic activity is enhanced with elevated inflammation, which disturbs the bone homeostasis and results in osteolysis. Lipopolysaccharide (LPS), as a bacteria product, plays an important role in this process. Recent evidence shows that an antimalarial drug artesunate attenuates LPS-induced osteolysis independent of RANKL. In this study we evaluated the effects of artesunate on LPS-induced osteoclastogenesis in vitro and femur osteolysis in vivo, and explored the mechanisms underlying the effects of artesunate on LPS-induced osteoclast differentiation independent of RANKL. In preosteoclastic RAW264.7 cells, we found that artesunate (1.56-12.5 μM) dose dependently inhibited LPS-induced osteoclast formation accompanied by suppressing LPS-stimulated osteoclast-related gene expression (Fra-2, TRAP, Cathepsin K, β3-integrin, DC-STAMP, and Atp6v0d2). We showed that artesunate (3.125-12.5 µM) inhibited LPS-stimulated nuclear factor of activated T cells c1 (NFATc1) but not NF-κB transcriptional activity; artesunate (6.25, 12.5 μM) significantly inhibited LPS-stimulated NFATc1 protein expression. Furthermore, artesunate treatment markedly suppressed LPS-induced Ca 2+ influx, and decreased the expression of PP2B-Aα (calcineurin) and pPLCγ1 in the cells. In addition, artesunate treatment significantly decreased the expression of upstream signals TLR4 and TRAF6 during LPS-induced osteoclastogenesis. Administration of artesunate (10 mg/kg, ip) for 8 days effectively inhibited serum TNF-α levels and ameliorated LPS (5 mg/kg, ip)-induced inflammatory bone loss in vivo. Taken together, artesunate attenuates LPS-induced inflammatory osteoclastogenesis by inhibiting the expression of TLR4/TRAF6 and the downstream PLCγ1-Ca 2+ -NFATc1 signaling pathway. Artesunate is a valuable choice to treat bone loss induced by gram-negative bacteria infection or inflammation in RANKL-independent pathway.

Aims: Ursodeoxycholic acid (UDCA) has been widely used in the treatment of primary biliary cholangitis (PBC) with chronic liver fibrosis, but its detailed mechanism remains unclear. This study was aimed to determine whether autophagic signaling is involved in the therapeutic effect of UDCA on liver fibrosis., Methods: By using hepatic stellate cell (HSC) line LX2 and CCl 4 -induced fibrotic rat model, autophagy signaling was investigated by western blotting and mRFP-EGFP-LC3 tandem fluorescent tagged plasmid (ptfLC3) transfection technique. Anti-fibrotic profile was determined by western blotting, qRT-PCR, MTT assay, trypan blue, hydroxyproline assay and Masson staining., Key Findings: TGFβ1 treatment decreased P62 accumulation and increased both autophagosomes and autolysosomes in LX2 cells, thereby elevated autophagic flux. Hydroxychloroquine (HCQ), antagonist of autophagy, was found to dramatically inhibit COL1A2 mRNA expression and cell proliferation in a dose-dependent manner. This coincides with the effect of UDCA intervention on collagen aggradation and cell viability. Meanwhile, UDCA inhibited TGFβ1-induced autophagy flux. And rapamycin, agonist of autophagy, was found to impair the anti-fibrotic effect of UDCA. Moreover, study in vivo showed that UDCA alone or in combination with HCQ restored the CCl 4 -induced liver fibrosis in rodent models with autophagy inhibited profile., Significance: Taken together, our study revealed that UDCA displays anti-fibrotic role by protecting HSC against production of collagen and inhibiting cellular viability involving autophagy inhibition and provide a new insight into the pharmacological basis of UDCA treatment for hepatic fibrosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The difficulty of assessment of neoadjuvant chemotherapeutic response preoperatively may hinder personalized-medicine strategies that depend on the results from pathological examination., Methods: A total of 191 patients with high-grade osteosarcoma (HOS) were enrolled retrospectively from November 2013 to November 2017 and received neoadjuvant chemotherapy (NCT). A cutoff time of November 2016 was used to divide the training set and validation set. All patients underwent diagnostic CTs before and after chemotherapy. By quantifying the tumor regions on the CT images before and after NCT, 540 delta-radiomic features were calculated. The interclass correlation coefficients for segmentations of inter/intra-observers and feature pair-wise correlation coefficients (Pearson) were used for robust feature selection. A delta-radiomics signature was constructed using the lasso algorithm based on the training set. Radiomics signatures built from single-phase CT were constructed for comparison purpose. A radiomics nomogram was then developed from the multivariate logistic regression model by combining independent clinical factors and the delta-radiomics signature. The prediction performance was assessed using area under the ROC curve (AUC), calibration curves and decision curve analysis (DCA)., Results: The delta-radiomics signature showed higher AUC than single-CT based radiomics signatures in both training and validation cohorts. The delta-radiomics signature, consisting of 8 selected features, showed significant differences between the pathologic good response (pGR) (necrosis fraction ≥90%) group and the non-pGR (necrosis fraction < 90%) group (P < 0.0001, in both training and validation sets). The delta-radiomics nomogram, which consisted of the delta-radiomics signature and new pulmonary metastasis during chemotherapy showed good calibration and great discrimination capacity with AUC 0.871 (95% CI, 0.804 to 0.923) in the training cohort, and 0.843 (95% CI, 0.718 to 0.927) in the validation cohort. The DCA confirmed the clinical utility of the radiomics model., Conclusion: The delta-radiomics nomogram incorporating the radiomics signature and clinical factors in this study could be used for individualized pathologic response evaluation after chemotherapy preoperatively and help tailor appropriate chemotherapy and further treatment plans.

On February 6, 2020, Xiaogan City became the second most seriously affected city with coronavirus disease 2019 (COVID-19), outside Wuhan district, Hubei Province, China. The objectives are to study the clinical features of COVID-19 patients and assess the relationship between the severity of COVID-19, age, and C-reactive protein (CRP) levels. The retrospective data of 134 COVID-19 patients hospitalized in 3 hospitals of Xiaogan City, between February 1 and March 1, 2020, was collected. This study documented COVID-19 patients. Clinical data in terms of body temperature, history of travel, and direct contact with COVID-19 patients, and incubation period was collected. Out of the 134 patients, only 5 required intensive care. Moreover, 2 patients succumbed during this period. The median age of patients was 45 (33-56) years. The most common symptoms at the onset of disease were fever (66.4%), cough (33, 6%), and sore throat (14.7%). Amongst the medicines used, antiviral agents (92.3%) followed by the traditional Chinese medicine (89.5%) were most commonly used. In both the crude and adjusted (I to III) models, odds ratio and its 95% confidence interval for both age and CRP levels were > 1. Moreover, the smooth curve fitting graph reflected that the severity of COVID-19 was positively correlated with both age and CRP levels (all P value < 0.05). The signs and symptoms of COVID-19 patients were fairly moderate. The health care professionals treating the COVID-19 patients should be aware of the increased likelihood of progression to severe COVID-19 in elderly patients and those with high CRP levels., Competing Interests: Conflict of InterestThe authors declare that they have no conflicts of interest., (© Springer Nature Switzerland AG 2020.)

Purpose: The purpose of the present study was to investigate the differences in postoperative thrombosis and flap failure between internal jugular vein (IJV) system anastomosis and external jugular vein (EJV) system anastomosis in free flaps for the reconstruction of head and neck defects., Materials and Methods: We searched PubMed, Web of Science, EMBASE, Chinese BioMedical Literature Database, and other databases until March 2019 for studies that had reported data for anastomosis for the 2 different venous systems in the microvascular free-flap reconstruction of head and neck defects. We assessed thrombosis and flap failure in patients undergoing anastomosis of the IJV system and patients undergoing anastomosis of the EJV system., Results: Nine studies with a total of 2051 patients with venous anastomosis were included in the present meta-analysis. IJV system anastomosis showed a significantly lower incidence of venous thrombosis than did the EJV system (relative risk [RR], 0.55; 95% confidence interval [CI], 0.37 to 0.82). Eight studies were included in the analysis of the flap failure rate, which showed a lower failure rate for the IJV system anastomosis than for the EJV system (RR, 0.59; 95% CI, 0.35 to 1.00)., Conclusions: The incidence of thrombosis and flap failure after venous anastomosis in the IJV system was lower than that in the EJV system. The results from the present study have shown that the IJV system should be the first choice for venous anastomosis in the reconstruction of free flaps., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Acute coronary syndrome (ACS) is characterized by atherosclerotic plaque rupture with a high incidence of recurrent ischemic events. Several microRNAs are found to be aberrantly expressed in atherosclerotic plaques. This study aims to investigate the effects of microRNA-9 (miR-9) on vulnerable atherosclerotic plaque and vascular remodeling in ACS and underlying mechanisms. Microarray-based gene expression profiling was used to identify differentially expressed genes related to ACS and regulatory miRNAs. Oxidized low-density lipoprotein (lectin-like) receptor 1 (OLR1) was identified to be aberrantly activated in ACS and regulated by miR-9. OLR1 was verified as a target gene of miR-9 by bioinformatics prediction and dual luciferase reporter gene assay. The atherosclerotic models were induced in ApoE -/- mice, in which the agomir or antagomir of miR-9, or small interfering RNA (siRNA) against OLR1 were separately introduced. Serum lipid levels and expression of vascular remodeling and inflammatory response-related factors were determined, respectively. On the basis of the obtained results, in the atherosclerosis mice treated with the agomir of miR-9 and siRNA against OLR1, the p38-mitogen-activated protein kinase (p38MAPK) pathway was inhibited; levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol, tumor necrosis factor-α, interleukin-6, and vascular endothelial growth factor were reduced, but the high-density lipoprotein cholesterol level was increased, along with decreased vulnerable atherosclerotic plaque area and enhanced vascular remodeling. Taken together, these findings suggested an inhibitory role miR-9 acts in the formation of vulnerable atherosclerotic plaques in ACS mice, along with a promoted vascular remodeling, via a negative feedback regulation of OLR1-mediated p38MAPK pathway., (© 2018 Wiley Periodicals, Inc.)

Microcarriers are 100- to 300-micron support matrices that permit the growth of adherent cells in bioreactor systems. They have a larger surface area to volume ratio in comparison to single cell monolayers, enabling cost-effective cell production and expansion. Microcarriers are composed of a solid matrix that must be separated from expanded cells during downstream processing stages. The detachment method is chosen on the basis of several factors like cell type, microcarrier surface chemistry, cell confluency and degree of aggregation. The development of microcarriers with a range of physiochemical properties permit controlled cell and protein associations that hold utility for novel therapeutics. In this review, we provide an overview of the recent advances in microcarrier cell culture technology. We also discuss its significance as an ex vivo research tool and the therapeutic potential of newly designed microcarrier systems in vivo.

Dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin-related protein (DC-SIGNR) is a transmembrane receptor primarily involved in pathogen recognition by the innate immune system, with particular importance for viral recognition. DC-SIGNR may also be associated with tumorigenesis. The aim of the present study was to investigate the association between DC-SIGNR expression, development of hepatocellular carcinoma (HCC), and clinicopathological features. Immunohistochemistry was used to assess DC-SIGNR protein expression in HCC and paired non-cancerous tissue samples. DC-SIGNR expression was lower in HCC tissues compared with adjacent non-tumor tissue samples. The expression of DC-SIGNR was associated with small tumor size, low Edmondson grade and high patient long term survival rates. Bioinformatics analyses were performed on several datasets to assess the potential function of DC-SIGNR and related genes; the data revealed that DC-SIGNR mRNA expression was lower in HCC tissues compared with non-cancerous controls, and analyses of ten-year survival rates indicated patients with low DC-SIGNR expression exhibited shorter average survival times. In conclusion, decreased DC-SIGNR expression in HCC tissues may be a relevant predictive biomarker of clinical prognosis, in addition to being a viable therapeutic target for HCC treatment., (Copyright: © Xia et al.)