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Background: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ., Methods: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors., Results: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma., Conclusion: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: By interacting with bone marrow mesenchymal stem cells (BMSCs) and regulating their function through exosomes, bone macrophages play crucial roles in various bone-related diseases. Research has highlighted a notable increase in the number of M1 macrophages in glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH). Nevertheless, the intricate crosstalk between M1 macrophages and BMSCs in the glucocorticoid-stimulated environment has not been fully elucidated, and the underlying regulatory mechanisms involved in the occurrence of GA-ONFH remain unclear., Methods: We employed in vivo mouse models and clinical samples from GA-ONFH patients to investigate the interactions between M1 macrophages and BMSCs. Immunofluorescence staining was used to assess the colocalization of M1 macrophages and BMSCs. Flow cytometry and transcriptomic analysis were performed to evaluate the impact of exosomes derived from normal (n-M1) and glucocorticoid-stimulated M1 macrophages (GC-M1) on BMSC differentiation. Additionally, miR-1a-3p expression was altered in vitro and in vivo to assess its role in regulating adipogenic differentiation., Results: In vivo, the colocalization of M1 macrophages and BMSCs was observed, and an increase in M1 macrophage numbers and a decrease in bone repair capabilities were further confirmed in both GA-ONFH patients and mouse models. Both n-M1 and GC-M1 were identified as contributors to the inhibition of osteogenic differentiation in BMSCs to a certain extent via exosome secretion. More importantly, exosomes derived from GC-M1 macrophages exhibited a heightened capacity to regulate the adipogenic differentiation of BMSCs, which was mediated by miR-1a-3p. In vivo and in vitro, miR-1a-3p promoted the adipogenic differentiation of BMSCs by targeting Cebpz and played an important role in the onset and progression of GA-ONFH., Conclusion: We demonstrated that exosomes derived from GC-M1 macrophages disrupt the balance between osteogenic and adipogenic differentiation in BMSCs, contributing to the pathogenesis of GA-ONFH. Inhibiting miR-1a-3p expression, both in vitro and in vivo, significantly mitigates the preferential adipogenic differentiation of BMSCs, thus slowing the progression of GA-ONFH. These findings provide new insights into the regulatory mechanisms underlying GA-ONFH and highlight potential therapeutic targets for intervention., (© 2024. The Author(s).)

Due to persistent inflammation and oxidative stress reactions, achieving drug absorption in diabetic wounds is challenging. To overcome this problem, our article presents a composite hydrogel, GelMA-GA/DMOG@GDNP, which consists of gelatin methacryloyl (GelMA) treated with gallic acid (GA) and encapsulating ginseng-derived nanoparticles (GDNPs) loaded with dimethyloxallyl glycine (DMOG). The composite hydrogel demonstrates excellent biocompatibility. In laboratory settings, the hydrogel inhibits the production of nitric oxide synthase 2 (iNOS) in mouse immune cells (RAW264.7 cells), enhances the growth and migration of mouse connective tissue cells (L929 cells) and human endothelial cells (HUVECs), and promotes tube formation in HUVECs. In a rat model of type 1 diabetes-induced wounds, the composite hydrogel attenuates inflammatory reactions, facilitates the formation of fibres and blood vessels, accelerates wound healing, and elucidates specific pathway mechanisms through transcriptome sequencing. Therefore, the GelMA-GA/DMOG@GDNP hydrogel can serve as a safe and efficient wound dressing to regulate the inflammatory response, promote collagen fiber and blood vessel formation, and accelerate wound healing. These findings suggest that utilizing this multifunctional engineered nanoparticle-loaded hydrogel in a clinical setting may be a promising strategy for diabetic wound healing., 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 © 2024 Elsevier B.V. All rights reserved.)

Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8 + T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients., (© 2024. The Author(s).)

Background: Isopropyl 4-(2-chloro-6-(1H-1,2,4-triazol-1-yl)benzamido)benzoate (TPB) was a 1,2,4-triazole benzoyl arylamine derivative with excellent antifungal activity, especially against Gaeumannomyces graminis var. tritici (Ggt). Its mechanism of action was investigated by transmission electron microscopy (TEM) observation, assays of sterol composition, cell membrane permeability, intracellular ATP and mitochondrial membrane potential, and mPTP permeability, ROS measurement, RNA sequencing (RNA-seq) analysis., Results: TPB interfered with ergosterol synthesis, reducing ergosterol content, increasing toxic intermediates, and finally causing biomembrane disruption such as increasing cell membrane permeability and content leakage, and destruction of organelle membranes such as coarse endoplasmic reticulum and vacuole. Moreover, TPB destroyed the function of adenine nucleotide transferase (ANT), leading to ATP transport obstruction in mitochondria, inhibiting mPTP opening, inducing intracellular ROS accumulation and mitochondrial membrane potential loss, finally resulting in mitochondrial damage including mitochondria swelled, mitochondrial membrane dissolved, and cristae destroyed and reduced. RNA-seq analyses showed that TPB increased the expression of ERG11, ERG24, ERG6, ERG5, ERG3 and ERG2 genes in ergosterol synthesis pathway, interfered with the expression of genes (NDUFS5, ATPeV0E, NCA2 and Pam17) related to mitochondrial structure, and inhibited the expression of genes (WrbA and GST) related to anti-oxidative stress., Conclusions: TPB exhibited excellent antifungal activity against Ggt by inhibiting ergosterol synthesis and destroying ANT function. So, TPB was a novel compound with dual-target mechanism of action and can be considered a promising novel fungicide for the control of wheat Take-all. The results provided new guides for the structural design of active compounds and powerful tools for pathogen resistance management. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Three samples whose growth temperatures were 450°C, 500°C, and 560°C for S E S A M 1 , S E S A M 2 , and S E S A M 3 , respectively, were tested by femto-second time-resolved transient absorption spectroscopy. The results indicate that the carrier dynamics of excited state absorption were dominant, and the lifetimes of carriers trapped by defect levels were about tens of pico-seconds. To further study the influence of carrier dynamics and recovery time of samples by ion-implantation, B + ions of 80 and 130 KeV were implanted into the samples with dose of 10 14 / c m 2 . The modified samples showed a dominance of ultra-fast carrier dynamics of ground-state bleaching and direct recombination, which lasted for hundreds of femto-seconds, over excited state absorption. Additionally, carrier fast trapping was observed to be competitive with the excited state absorption process. After ion-implantation, the carrier dynamics of carrier trapping were enhanced, which contributed to forming an ultra-short laser, while the carrier dynamics of absorption of the excited state were suppressed. The conclusion that defect levels were partially eliminated by B + ion-implantation can be drawn.

Bisphosphonates are widely used to treat osteoporosis and malignant tumors due to their effectiveness in increasing bone density and inhibiting bone resorption. However, their association with bisphosphonate-related osteonecrosis of the jaws (BRONJ) following invasive dental procedures poses a significant challenge. This review explores the functions, mechanisms, and side effects of bisphosphonates, emphasizing their impact on dental procedures. Dental patients receiving bisphosphonate treatment are at higher risk of BRONJ, necessitating dentists' awareness of these risks. Topical bisphosphonate applications enhance dental implant success, by promoting osseointegration and preventing osteoclast apoptosis, and is effective in periodontal treatment. Yet, systemic administration (intravenous or intraoral) significantly increases the risk of BRONJ following dental procedures, particularly in inflamed conditions. Prevention and management of BRONJ involve maintaining oral health, considering alternative treatments, and careful pre-operative and post-operative follow-ups. Future research could focus on finding bisphosphonate alternatives with fewer side effects or developing combinations that reduce BRONJ risk. This review underscores the need for further exploration of bisphosphonates and their implications in dental procedures.

Competing Interests: All authors declare no conflicts of interest.

Drug-target interactions (DTIs) are considered a crucial component of drug design and drug discovery. To date, many computational methods were developed for drug-target interactions, but they are insufficiently informative for accurately predicting DTIs due to the lack of experimentally verified negative datasets, inaccurate molecular feature representation, and ineffective DTI classifiers. Therefore, we address the limitations of randomly selecting negative DTI data from unknown drug-target pairs by establishing two experimentally validated datasets and propose a capsule network-based framework called CapBM-DTI to capture hierarchical relationships of drugs and targets, which adopts pre-trained bidirectional encoder representations from transformers (BERT) for contextual sequence feature extraction from target proteins through transfer learning and the message-passing neural network (MPNN) for the 2-D graph feature extraction of compounds to accurately and robustly identify drug-target interactions. We compared the performance of CapBM-DTI with state-of-the-art methods using four experimentally validated DTI datasets of different sizes, including human ( Homo sapiens ) and worm ( Caenorhabditis elegans ) species datasets, as well as three subsets (new compounds, new proteins, and new pairs). Our results demonstrate that the proposed model achieved robust performance and powerful generalization ability in all experiments. The case study on treating COVID-19 demonstrates the applicability of the model in virtual screening.

Background: Overseas screening for tuberculosis (TB) has sought to reduce the burden of active TB in the United States. The duration of time between two unchanged, or stable, chest X-rays (CXRs) taken four to six months apart has been considered clinically useful in the evaluation of suspected pulmonary TB disease, but this relationship has not been previously quantified., Objective: To investigate the association between pre-treatment CXR stability duration and future clinical or culture-confirmed (Class 3) diagnosis of pulmonary TB in San Diego, California, USA., Methods: This retrospective record review included County of San Diego TB clinic patients with abnormal CXR results who were started on treatment between 2012 and 2017; multivariable logistic regression was used to analyze the clinical data., Results: Pre-treatment CXR stability duration of at least four months was not significantly associated with a Class 3 pulmonary TB diagnosis (adjusted odds ratio [AOR], 0.83; 95 % confidence interval [CI], 0.20-3.48), nor was pre-treatment CXR stability duration of at least six months (AOR, 0.97; 95 % CI, 0.30-3.10). Similar results were obtained when four-to-six-month stability was considered (AOR, 0.78; 95 % CI, 0.16-3.89). Patients screened overseas (B1 notification) were less likely to develop Class 3 TB (unadjusted OR, 0.15; 95 % CI 0.05-0.44)., Conclusion: Pre-treatment chest X-ray stability duration was not associated with excluding Class 3 pulmonary TB in this setting, and CXR stability duration cut points may not be as clinically informative as previously understood, but overseas screening is likely an important step in reducing active TB disease burden in the U.S., 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., (© 2022 The Author(s).)

Wheat root diseases can seriously reduce yields and quality of wheat. 1,2,4-Triazole benzoyl arylamine derivatives previously showed good activities against some wheat root fungal pathogens. To further systematically disclose the structure-activity relationship, a series of benzoyl arylamines were designed and prepared. Their structures were characterized and fungicidal activities against Gaeumannomyces graminis var. tritici and Fusarium graminearum were evaluated. The results indicated that the structure of the N-heterocyclic group and the substituted group and their position on the benzamide scaffold had an important influence on the activities, as predicted. Finally, compound 18f was found to show excellent activities against G. graminis var. tritici , F. graminearum , Fusarium culmorum , Fusarium pseudograminearum , and Fusarium moniliforme with half-maximum effective concentrations of 0.002, 0.093, 0.011, 0.881, and 0.287 μg/mL, respectively. These results proposed that compound 18f deserved serious consideration as a novel fungicide candidate for the control of wheat root diseases.

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

The study focused on dissimilar brazing of metallized YSZ (Yttria-Stabilized Zirconia) and Crofer alloy using BAg-8 (72Ag-28Cu, wt%) filler foil. The YSZ substrate was metallized by sequentially sputtering Ti (0.5/1 μm), Cu (1/3 μm), and Ag (1.5/5 μm) layers, and the Crofer substrate was coated with Ag layers with a thickness of 1.5 and 5 μm, respectively. The BAg-8 filler demonstrated excellent wettability on both metallized YSZ and Crofer substrates. The brazed joint primarily consisted of Ag-Cu eutectic. The metallized Ti layer dissolved into the braze melt, and the Ti preferentially reacted with YSZ and Fe from the Crofer substrate. The globular Fe 2 Ti intermetallic compound was observed on the YSZ side of the joint. The interfacial reaction of Ti was increased when the thickness of the metallized Ti layer was increased from 0.5 to 1 μm. Both brazed joints were crack free, and no pressure drop was detected after testing at room temperature for 24 h. In the YSZ/Ti(0.5μ)/Cu(1μ)/Ag(1.5μ)/BAg-8(50μ)/Ag(1.5μ)/Crofer joint tested at 600 °C, the pressure of helium decreased from 2.01 to 1.91 psig. In contrast, the helium pressure of the YSZ/Ti(1μ)/Cu(3μ)/Ag(5μ)/BAg-8(50μ)/Ag(5μ)/Crofer joint slightly decreased from 2.02 to 1.98 psig during the cooling cycle of the test. The greater interfacial reaction between the metallized YSZ and BAg-8 filler due to the thicker metallized Ti layer on the YSZ substrate was responsible for the improved gas-tight performance of the joint.

Lower respiratory tract sampling from endotracheal aspirate (EA) and bronchoalveolar lavage (BAL) are both common methods to identify pathogens in severe pneumonia. However, the difference between these two methods in microbiota profiles remains unclear. We compared the microbiota profiles of pairwise EA and BAL samples in ICU patients with respiratory failure due to severe pneumonia. We prospectively enrolled 50 ICU patients with new onset of pneumonia requiring mechanical ventilation. EA and BAL were performed on the first ICU day, and samples were analyzed for microbial community composition via 16S rRNA metagenomic sequencing. Pathogens were identified in culture medium from BAL samples in 21 (42%) out of 50 patients. No difference was observed in the antibiotic prescription pattern, ICU mortality, or hospital mortality between BAL-positive and BAL-negative patients. The microbiota profiles in the EA and BAL samples are similar with respect to diversity, microbial composition, and microbial community correlations. The antibiotic treatment regimen was rarely changed based on the BAL findings. The samples from BAL did not provide more information than EA in the microbiota profiles. We suggest that EA is more useful than BAL for microbiome identification in mechanically ventilated patients.

Chemoresistance and migration represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients in clinic. In the present study, we report that the compound C1632 is preferentially distributed in the lung after oral administration in vivo with high bioavailability and limited inhibitory effects on CYP450 isoenzymes. We found that C1632 could simultaneously inhibit the expression of LIN28 and block FGFR1 signalling transduction in NSCLC A549 and A549R cells, resulting in significant decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metalloproteinase-9. Consequently, C1632 effectively inhibited the migration and invasion of A549 and A549R cells. Meanwhile, C1632 significantly suppressed the cell viability and the colony formation of A549 and A549R cells by inhibiting DNA replication and inducing G0/G1 cell cycle arrest. Interestingly, compared with A549 cells, C1632 possesses the same or even better anti-migration and anti-proliferation effects on A549R cells, regardless of drug resistance. In addition, C1632 also displayed the capacity to inhibit the growth of A549R xenograft tumours in mice. Altogether, these findings reveal the potential of C1632 as a promising anti-NSCLC agent, especially for chemotherapy-resistant NSCLC treatment., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Insulin resistance promotes the occurrence of liver cancer and decreases its chemosensitivity. Rosiglitazone (ROSI), a thiazolidinedione insulin sensitiser, could be used for diabetes with insulin resistance and has been reported to show anticancer effects on human malignant cells. In this paper, we investigated the combination of ROSI and chemotherapeutics on the growth and metastasis of insulin-resistant hepatoma. In vitro assay, ROSI significantly enhanced the inhibitory effects of adriamycin (ADR) on the proliferation, autophagy and migration of insulin-resistant hepatoma HepG2/IR cells via downregulation of EGFR/ERK and AKT/mTOR signalling pathway. In addition, ROSI promoted the apoptosis of HepG2/IR cells induced by ADR. In vivo assay, high fat and glucose diet and streptozotocin (STZ) induced insulin resistance in mice by increasing the body weight, fasting blood glucose (FBG) level, oral glucose tolerance, fasting insulin level and insulin resistance index. Both the growth of mouse liver cancer hepatoma H22 cells and serum FBG level in insulin resistant mice were significantly inhibited by combination of ROSI and ADR. Thus, ROSI and ADR in combination showed a stronger anti-tumour effect in insulin resistant hepatoma cells accompanying with glucose reduction and might represent an effective therapeutic strategy for liver cancer accompanied with insulin resistant diabetes.

Rationale: Stimulation of the NLRP3 inflammasome by metabolic byproducts is known to result in inflammatory responses and metabolic diseases. However, how the host controls aberrant NLRP3 inflammasome activation remains unclear. PPARγ, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-κB activation and additionally attenuates NLRP3-dependent IL-1β and IL-18 production. Therefore, we hypothesized that PPARγ serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPARγ agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPARγ on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPARγ and the NLRP3 inflammasome. Results: Exposure to the PPARγ agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1β maturation. Moreover, PPARγ interfered with NLRP3 inflammasome formation by decreasing NLRP3-ASC and NLRP3-NLRP3 interactions as well as NLRP3-dependent ASC oligomerization, which is mediated through interaction between the PPARγ DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPARγ was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPARγ ratio was reduced in circulating mononuclear cells of obese patients after weight-loss surgery, which we define as an "NLRP3 accelerating index". Conclusions: These results revealed an additional anti-inflammatory role for PPARγ in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPARγ agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To investigate the immunopathology and immunomodulatory roles of interleukin-12 (IL-12) in periodontal disease., Methods: Ninety-eight patients with chronic periodontitis from January 2016 to January 2019 were enrolled and divided into mild group (30 cases), moderate group (35 cases) and severe group (33 cases) according to the severity of periodontitis; meanwhile, 30 healthy subjects who underwent periodontal examination in our hospital were selected as the control group. Clinical periodontal indicators including probing depth(PD), attachment loss(AL), plaque index(PLI), bleeding index(BI), Th cell expression (Th1, Th2, Th17) in peripheral blood, IL-12 levels in gingival crevicular fluid (GCF) and serum were measured. SPSS 20.0 software package was performed to analyze the correlation between IL-12 levels in GCF and serum and Th1, Th2, Th17, PD, AL, PLI, and BI., Results: The differences of PD, PLI and BI among the groups were statistically significant(P<0.05). The levels of PD, PLI and BI in the mild, moderate and severe group were significantly higher than those in the control group (P<0.05). The difference of AL index among mild, moderate and severe group was statistically significant(P<0.05). The PD, AL, PLI, and BI in the moderate and severe group was significantly higher than those in the mild group(P<0.05), and the severe group was significantly higher than the mild group(P<0.05). Th1, Th2 and Th17 were significantly higher in the mild, moderate and severe group than in the control group(P<0.05); the moderate, severe group was significantly higher than the mild group in terms of Th1, Th2 and Th17 (P<0.05), and the severe group was significantly higher than the moderate group (P<0.05). The IL-12 levels in GCF and serum of the mild, moderate, and severe groups were significantly higher than those of the control group (P<0.05); IL-12 levels in the the moderate and severe groups were significantly higher than those in the mild group (P<0.05), and the IL-12 were significantly higher in the severe group than in the moderate group (P<0.05); IL-12 was positively correlated with PD, AL, PLI, BI, Th1, Th2 and Th17(P<0.05). H-E staining showed there were fewer lymphocytes in the mild group, more lymphocytes in the moderate group, and dense lymphocytes in the severe group with significant hemorrhage in intercellular mesenchyme. The IL-12 protein positive staining results were expressed in gingival tissue lymphocyte pulp with significant brown observed. The positive staining of IL-12 protein in the gingival tissues in the mild, moderate and severe group was significantly higher than in the control group, and the staining was aggravated with mild, moderate and severe inflammatory changes., Conclusions: IL-12 is involved in the immunoregulatory mechanism of periodontal disease and may be a key pro-inflammatory cytokine in the development of periodontitis.

Two series of novel 1, 2, 4-triazole benzoyl arylamine derivatives were prepared and screened for their activities against three pathogens of Gaeumannomyces graminis var.tritici, Sclerotinia sclerotiorum and Fusarium graminearum using the mycelium growth inhibition method in vitro. The results indicated that most of the synthesized derivatives displayed antifungal activities. Compounds 6c-d and 6f-g exhibited lower EC 50 s against all the three pathogens. Among of them, the compound 6g displayed the most potent antifungal activities with EC 50 values of 0.01, 0.19 and 0.12 μg mL -1 respectively. The structure and activity relationship showed that election-withdrawing group at pata-position of aniline was favorable for high activities, and the preferred groups were alkoxy carbonyls. These results proposed that the compound 6g can be a lead compound for development of novel fungicide., 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 Masson SAS. All rights reserved.)

Identifying the molecular modules that drive cancer progression can greatly deepen the understanding of cancer mechanisms and provide useful information for targeted therapies. Most methods currently addressing this issue primarily use mutual exclusivity without making full use of the extra layer of module property. In this paper, we propose MCLCluster to identity cancer driver modules, which use somatic mutation data, Cancer Cell Fraction (CCF) data, gene functional interaction network and protein-protein interaction (PPI) network to derive the module property on mutual exclusivity, connectivity in PPI network and functionally similarity of genes. We have taken three effective measures to ensure the effectiveness of our algorithm. First, we use CCF data to choose stronger signals and more confident mutations. Second, the weighted gene functional interaction network is used to quantify the gene functional similarity in PPI. The third, graph clustering method based on Markov is exploited to extract the candidate module. MCLCluster is tested in the two TCGA datasets (GBM and BRCA), and identifies several well-known oncogenes driver modules and some modules with functionally associated driver genes. Besides, we compare it with Multi-Dendrix, FSME Cluster and RME in simulated dataset with background noise and passenger rate, MCLCluster outperforming all of these methods., (Copyright © 2020 Zhang, Zeng, Wang, Liu and Cheng.)

Echinocandin B deacylase (EBDA), from Actinoplanes utahensis ZJB-08196, is capable of cleaving the linoleoyl group from echinocandin B (ECB), forming the echinocandin B nucleus (ECBN), which is a key precursor of semisynthetic antifungal antibiotics. In the present study, molecular evolution of AuEBDA by random mutagenesis combined with site-directed mutagenesis (SDM) and screening was performed. Random mutagenesis on the wild-type (WT) AuEBDA generated two beneficial substitutions of G287Q, R527V. The "best" variant AuEBDA-G287Q/R527V was obtained by combining G287Q with R527V through SDM, which was most active at 35 °C, pH 7.5, with K m and v max values of 0.68 mM and 395.26 U/mg, respectively. Mutation of G287Q/R527V markedly increased the catalytic efficiency k cat /K m by 290% compared with the WT-AuEBDA.

Rationale : Subjects unable to sustain β-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence β-cell compensation in response to metabolic overload. Methods : Mice deficient in EGR-1 ( Egr1 -/- ) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. Results : In response to a high-fat diet, Egr1 -/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1 -/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for β-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of β-cell compensatory genes in the non-diabetic group, but not in the diabetic group. Conclusion : These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of β-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and has a poor prognosis. Circular RNA (circRNA) has been increasingly recognized as a crucial contributor to carcinogenesis. circRNA&#95;0000140 has been aberrantly expressed in OSCC, but its role in tumor growth and metastasis remains largely unclear. Sanger sequencing, actinomycin D, and RNase R treatments were used to confirm head-to-tail junction sequences and the stability of circ&#95;0000140. In vitro cell activities, including proliferation, migration, invasion, and apoptosis, were determined by colony formation, transwell, and flow cytometry assays. The expression levels of circ&#95;0000140, Hippo signaling pathway, and serial epithelial-mesenchymal transition (EMT) markers were measured by quantitative real-time PCR, western blotting, immunofluorescence, and immunohistochemistry. Dual luciferase reporter assays and Argonaute 2-RNA immunoprecipitation assays were performed to explore the interplay among circ&#95;0000140, miR-31, and LATS2. Subcutaneous tumor growth was observed in nude mice, in which in vivo metastasis was observed following tail vein injection of OSCC cells. circ&#95;0000140 is derived from exons 7 to 10 of the KIAA0907 gene. It was down-regulated in OSCC tissues and cell lines, and correlated negatively with poor prognostic outcomes in OSCC patients. Gain-of-function experiments demonstrated that circ&#95;0000140 enhancement suppressed cell proliferation, migration, and invasion, and facilitated cell apoptosis in vitro. In xenograft mouse models, overexpression of circ&#95;0000140 was able to repress tumor growth and lung metastasis. Furthermore, mechanistic studies showed that circ&#95;0000140 could bind with miR-31 and up-regulate its target gene LATS2, thus affecting OSCC cellular EMT. Our findings demonstrated the roles of circ&#95;0000140 in OSCC tumorigenesis as well as in metastasis, and circ&#95;0000140 exerts its tumor-suppressing effect through miR-31/LATS2 axis of Hippo signaling pathway in OSCC.

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H + -K + -ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Our goal was to describe the characteristics and posttreatment outcomes of pediatric patients with central nervous system (CNS) tuberculosis (TB) and to identify factors associated with poor outcome., Methods: We included children aged 0 to 18 years with CNS TB reported to the California TB registry between 1993 and 2011. Demographics, clinical characteristics, severity of disease at presentation (Modified Medical Research Council stage I, II, or III [III is most severe]), treatment, and outcomes during the year after treatment completion were abstracted systematically from the medical and public health records. Patient outcomes were categorized as good or poor on the basis of disability in hearing, vision, language, ambulation, and development and other neurologic deficits., Results: Among 151 pediatric CNS TB cases reported between 1993 and 2011 in California for which records were available, 92 (61%) cases included sufficient information to determine outcome. Overall, 55 (60%) children had a poor outcome. After we adjusted for age (0 to 4 years), children with stage III severity (vs I or II; prevalence rate ratio [PRR], 1.4 [95% confidence interval (CI), 1.1-1.9]), a protein concentration of >100 mg/dL on initial lumbar puncture (PRR, 1.2 [95% CI, 1.03-1.4]), or infarct on neuroimaging (PRR, 1.2 [95% CI, 1.04-1.3]) were at increased risk for a poor outcome. In multivariate analysis, an age of 0 to 4 years (vs >4 years; PRR, 1.4 [95% CI, 1.2-1.7]) and a stage II or III Modified Medical Research Council score (vs stage I; PRR, 1.2 [95% CI, 1.03-1.5]) remained significantly associated with poor outcome., Conclusions: Pediatric patients with CNS TB in California are left with high rates of disabling clinical sequelae after treatment. The identification of modifiable factors is critical for improving outcomes., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: When an object contains a distribution of discrete magnetic inclusions with a constant susceptibility, the MRI signal inside the object may no longer be determined analytically by assuming that the object is uniform or magnetic inclusions are completely random. Through simulations and experiments with spherical particles inside cylinders, this work is to study the signal behavior in the static dephasing regime., Methods: MRI complex images of long cylinders containing spherical particles with different arrangements were simulated and compared to similar experimental phantom data. All experiments were designed for the static dephasing regime so that diffusion was neglected., Results: Several factors can lead to different phase shifts over echo time. These include numbers of particles per image voxel, particle arrangements, and Gibbs ringing effects. Purely random arrangements of particles in simulations can agree with a revised theoretical formula at short echo times, but quasi-random arrangements of particles do not agree with the theory. In addition, close to half of experimental results show deviations from the theory and the quasi-random arrangements of particles can explain those experimental results. Simulated R 2 ' values are about the same for different cylinder orientations but increase when random particle arrangement is restricted toward lattice. Nonetheless, as expected, phase distributions outside and far away from each cylinder are independent of any factor affecting phase inside and behave as if they are from a cylinder with a uniform bulk susceptibility., Conclusion: Phase over echo time inside an object containing discrete spheres can be nonlinear and deviate from current theories in the static dephasing regime. Phase outside the object can be used to accurately determine its magnetic moment and bulk susceptibility without a priori knowledge of the spherical particle distribution inside the object. These results can be extended to the subcortical gray matter and suggest that in vivo susceptibility quantification will need to be re-thought., (Copyright © 2019 Elsevier Inc. All rights reserved.)

t-Butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-2) is an important chiral diol synthon of atorvastatin calcium. Previously, we constructed a variant KmAKR-W297H (M1) of Kluyveromyces marxianus aldo-keto reductase (KmAKR, designated as M0), possessing excellent diastereoselectivity but moderate activity towards t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((5R)-1). In this work, KmAKR-W297H/Y296W/K29H (M3) was developed via semi-rational design. It exhibited much improved catalytic efficiency towards (5R)-1. The K m values of M3 for NADPH and (5R)-1 were 0.15 mmol/L and 1.41 mmol/L, and the maximal reaction rate v max was 55.56 μmol/min/mg. Compared with M1, the catalytic efficiency k cat /K m of M3 was increased 2.64-fold. Coupled with Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for nicotinamide adenine dinucleotide phosphate (NADPH) regeneration, M3 took 3.5 h to completely reduce (5R)-1 at up to 100.0 g/L, producing 237.4 mmol/L (3R,5R)-2 in d.e. P value above 99.5%. The space-time yield (STY) of M3-catalyzed (3R,5R)-2 synthesis was 372.8 g/L/d., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: This study aimed to evaluate the effectiveness of neuromuscular electrical stimulation (NMES) therapy for chronic urinary retention (CUR) following traumatic brain injury (TBI)., Methods: This 2-arm randomized controlled trial (RCT) enrolled 86 eligible patients with CUR following TBI. All included patients were randomly allocated to a treatment group (n = 43) or a sham group (n = 43). The administration of NMES or sham NMES, as intervention, was performed for an 8-week period treatment, and 4-week period follow-up. In addition, all subjects were required to undergo indwelling urinary catheter throughout the study period. The primary outcome was assessed by the post-voiding residual urine volume (PV-VRU). The secondary outcomes were evaluated by the voided volume, maximum urinary flow rate (Qmax), and quality of life, as assessed by Barthel Index (BI) scale. In addition, adverse events were also recorded during the study period. All primary and secondary outcomes were measured at baseline, at the end of 8-week treatment, and 4-week follow-up., Results: At the end of 8-week treatment, the patients in the treatment group did not achieve better outcomes in PV-VRU (P = .66), voided volume (P = .59), Qmax (P = .53), and BI scores (P = .67), than patients in the control group. At the end of 4-week follow-up, there were also no significant differences regarding the PV-VRU (P = .42), voided volume (P = .71), Qmax (P = .24), and BI scores (P = .75) between 2 groups. No adverse events occurred in either group., Conclusions: In summary, the findings of this study showed that NMES therapy may not benefit patients with CUR following TBI.

Background: One of the most common and recurrent vaginal infections is bacterial vaginosis (BV). The diagnosis is based on changes to the "normal" vaginal microbiome; however, the normal microbiome appears to differ according to reproductive status and ethnicity, and even among individuals within these groups. The Amsel criteria and Nugent score test are widely used for diagnosing BV; however, these tests are based on different criteria, and so may indicate distinct changes in the vaginal microbial community. Nevertheless, few studies have compared the results of these test against metagenomics analysis., Methods: Vaginal flora samples from 77 participants were classified according to the Amsel criteria and Nugent score test. The microbiota composition was analyzed using 16S ribosome RNA gene amplicon sequencing. Bioinformatics analysis and multivariate statistical analysis were used to evaluate the microbial diversity and function., Results: Only 3 % of the participants diagnosed BV negative using the Amsel criteria (A-) were BV-positive according to the Nugent score test (N+), while over half of the BV-positive patients using the Amsel criteria (A+) were BV-negative according to the Nugent score test (N-). Thirteen genera showed significant differences in distribution among BV status defined by BV tests (e.g., A - N-, A + N- and A + N+). Variations in the four most abundant taxa, Lactobacillus, Gardnerella, Prevotella, and Escherichia, were responsible for most of this dissimilarity. Furthermore, vaginal microbial diversity differed significantly among the three groups classified by the Nugent score test (N-, N+, and intermediate flora), but not between the Amsel criteria groups. Numerous predictive microbial functions, such as bacterial chemotaxis and bacterial invasion of epithelial cells, differed significantly among multiple BV test, but not between the A- and A+ groups., Conclusions: Metagenomics analysis can greatly expand our current understanding of vaginal microbial diversity in health and disease. Metagenomics profiling may also provide more reliable diagnostic criteria for BV testing.

Purpose: A method of removing the background phase with a reference phantom but without overcorrecting the induced phase from objects of interest is proposed. Several factors during the imaging procedure and post-processing are investigated for their accuracies., Methods: A method using a reference phantom to remove eddy currents as well as using the least squares fit to quantify susceptibility and to remove the background phase is proposed. Phase induced from simulated spheroids was fitted and compared to their true magnetic moments, an important concept for the proposed method. A cylindrical phantom and its simulation, a phantom with straws filled with Gd-DTPA, and a simulated head model were used to study systematic errors due to some confounding factors. The feasibility for in vivo applications was demonstrated from an actual human head. Susceptibility and remaining phase after removing the background phase were measured in all cases., Results: Simulations show that magnetic moments of various spheroids and phantoms can be accurately quantified from images, regardless of the partial volume effect. All measured susceptibility values are within ±0.16 ppm of -9.4 ppm for agarose and 0.05 ppm of 1 ppm for Gd-DTPA. Most residual phase is within ±0.1 rad from the phantom center. Susceptibilities close to -9.4 ppm are also obtained for the simulated and actual head. Correspondingly, the remaining phase has a mean value less than two standard deviations., Conclusion: The proposed method from phantom studies can reliably remove the background phase without overcorrections. The in vivo example demonstrates the feasibility of the method., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sambutoxin, a representative derivative of 4-hydroxy-2-pyridone, was isolated from Hericium alpestre for the first time in this study. The possible correlation between the sambutoxin-induced suppression of tumor growth and its influence on cell-cycle arrest and apoptosis was investigated. The effects of sambutoxin on reactive oxygen species (ROS) production, DNA damage, mitochondrial transmembrane potential, cell apoptosis, and the expression of related proteins were evaluated. An in vitro cell viability study demonstrated that sambutoxin could inhibit the proliferation of various cancer cells. Treatment with sambutoxin induced the production of ROS, which caused DNA damage. Furthermore, the subsequent sambutoxin-induced activation of ATM and Chk2 resulted in G2/M arrest, accompanied by decreased expression of cdc25C, cdc2, and cyclin B1. Sambutoxin induced apoptosis by activating the mitochondrial apoptosis pathway through an increased Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (ΔΨm), cytochrome (Cyt) c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) degradation. The ROS elevation induced the sustained phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125, a JNK inhibitor, nearly completely reversed sambutoxin-induced apoptosis. Accordingly, an in vivo study showed that sambutoxin exhibited potential antitumor activity in a BALB/c nude mouse xenograft model without significant systemic toxicity. Moreover, the expression changes in proteins related to the G2/M phase, DNA damage, and apoptosis in vivo were consistent with those in vitro. Importantly, sambutoxin has remarkable antiproliferative effects and is a promising anticarcinogen candidate for cancer treatment.

Introduction: Chondromyxoid fibrotherma (CMF) is a rare benign cartilage tumor that occurs more frequently in young males at the age of 20 to 30. It occurs more frequently on long bones, but rarely involves craniofacial bones., Case Presentation: This study mainly introduced a 30-year-old male with CMF of zygomatic bone. Single tumor excochleation was conducted initially. However, CMF reoccurred, and then the following steps were adopted: firstly, the tumor was extensively excised; secondly, in vitro tumor excochleation was conducted; thirdly, the excised tumor bone was placed in liquid nitrogen for 3 cycles of cryoablation; finally, the orthotopic transplantation was performed to reconstruct the zygomatic appearance, with satisfactory follow-up efficacy obtained., Conclusions: Orthotopic transplantation after tumorectomy and cryopreservation of tumor bone in liquid nitrogen could lead to excellent therapeutic efficacy and deserves to be widely applied in clinical practice in the treatment of a male patient with CMF of zygomatic bone, because it not only radically eliminates the tumor and kills tumor cells, but also provides bony skeleton for the growth of new bone, thus greatly promoting postoperative aesthetic degree and reducing the occurrence rates of complications.

Rationale: Senile patients with LS complicated with DNM are rarely seen in clinical practice, and extensive cervical incision and drainage plus administration of effective antibiotics are the basis for treatment. Currently, the treatment controversy mainly has focused on whether mediastinal incision and drainage is necessary for patients with type I DNM, and whether anticoagulation therapy is required for jugular venous emboli and distant metastatic emboli induced by LS., Patient Concerns: A female, 76 years old, developed pain of tonsil on right side 5 days ago, and felt that the pain aggravated complicated with dysphagia and swelling pain of neck on both sides since then., Diagnoses: She was diagnosed with LS complicated with type I DNM., Interventions: Tazobactam and Piperacillin 4.5 q8h and Ornidazole 100 ml q6h ivgtt were administered empirically,and secondary extensive cervical incision and drainage was performed under general anesthesia, after which low molecular weight heparin 4250 U q12h SC was administered. G test was performed 3 days later, which showed (1,3)-β-D-glucan >1000 pg/ml. Bridging anticoagulation therapy, low molecular weight heparin 4250 U q12h SC, and Warfarin 2.5 mg qd po were given one week later. Low molecular weight heparin SC was discontinued and only Warfarin po was administered after treatment of bridging therapy for 3 days., Outcomes: CT of head and neck was reexamined on post-admission d24 and revealed that neck infection was improved on both sides, jugular vein distension on right side was restored to normal, abscess and pneumatosis of superior mediastinum were improved, distension of pulmonary artery on both sides was normalized, WBC was 9.94×109/L, neutrophil count was 4.43×109/L, CRP level was 9.8mg/L, D-D level was 0.81mg/L, PCT level was 0.800ng/mL and G test suggested (1,3)-β-D-glucan pf 27.1 pg/mL., Lessons: Concomitant use of anticoagulants on the basis of repeated cervical incision and drainage + administration of effective antibiotics can obtain excellent therapeutic efficacy in the treatment of patient with LS complicated with type I DNM.

Taiwan Blue Magpie ( Urocissa caerulea ) is endemic to Taiwan and listed as threatened species protected by law. In this study, we first determined and described the complete mitochondrial genome of Taiwan Blue Magpie. The circle genome is 16,928 bp in length, and contains 13 protein coding, 22 tRNA, two rRNA genes, and one non-coding control region (CR). The overall base composition of the mitochondrial DNA is 30.99% for A, 24.69% for T, 30.07% for C, and 14.25% for G. The percentage of G + C content is 44.32%. This work provides fundamental molecular data which will be useful for evolution and phylogeny studies on Corvidae in the future., Competing Interests: No potential conflict of interest was reported by the authors., (© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Modeling MRI signal behaviors in the presence of discrete magnetic particles is important, as magnetic particles appear in nanoparticle labeled cells, contrast agents, and other biological forms of iron. Currently, many models that take into account the discrete particle nature in a system have been used to predict magnitude signal decays in the form of R2* or R2' from one single voxel. Little work has been done for predicting phase signals. In addition, most calculations of phase signals rely on the assumption that a system containing discrete particles behaves as a continuous medium. In this work, numerical simulations are used to investigate MRI magnitude and phase signals from discrete particles, without diffusion effects. Factors such as particle size, number density, susceptibility, volume fraction, particle arrangements for their randomness, and field of view have been considered in simulations. The results are compared to either a ground truth model, theoretical work based on continuous mediums, or previous literature. Suitable parameters used to model particles in several voxels that lead to acceptable magnetic field distributions around particle surfaces and accurate MR signals are identified. The phase values as a function of echo time from a central voxel filled by particles can be significantly different from those of a continuous cubic medium. However, a completely random distribution of particles can lead to an R2' value which agrees with the prediction from the static dephasing theory. A sphere with a radius of at least 4 grid points used in simulations is found to be acceptable to generate MR signals equivalent from a larger sphere. Increasing number of particles with a fixed volume fraction in simulations reduces the resulting variance in the phase behavior, and converges to almost the same phase value for different particle numbers at each echo time. The variance of phase values is also reduced when increasing the number of particles in a fixed voxel. These results indicate that MRI signals from voxels containing discrete particles, even with a sufficient number of particles per voxel, cannot be properly modeled by a continuous medium with an equivalent susceptibility value in the voxel., (Copyright © 2017 Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are small non-coding RNAs of ∼ 22 nucleotides that are involved in negative regulation of mRNA at the post-transcriptional level. Previously, we developed miRTarBase which provides information about experimentally validated miRNA-target interactions (MTIs). Here, we describe an updated database containing 422 517 curated MTIs from 4076 miRNAs and 23 054 target genes collected from over 8500 articles. The number of MTIs curated by strong evidence has increased ∼1.4-fold since the last update in 2016. In this updated version, target sites validated by reporter assay that are available in the literature can be downloaded. The target site sequence can extract new features for analysis via a machine learning approach which can help to evaluate the performance of miRNA-target prediction tools. Furthermore, different ways of browsing enhance user browsing specific MTIs. With these improvements, miRTarBase serves as more comprehensively annotated, experimentally validated miRNA-target interactions databases in the field of miRNA related research. miRTarBase is available at http://miRTarBase.mbc.nctu.edu.tw/., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Hepatocellular carcinoma (HCC) has poor prognosis due to the advanced disease stages by the time it is diagnosed, high recurrence rates and metastasis. In the present study, we investigated the effects of metformin (a safe anti-diabetic drug) and curcumin (a turmeric polyphenol extracted from rhizome of Curcuma longa Linn.) on proliferation, apoptosis, invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. It was found that co-treatment of metformin and curcumin could not only induce tumor cells into apoptosis through activating the mitochondria pathways, but also suppress the invasion, metastasis of HCC cells and angiogenesis of HUVECs. These effects were associated with downregulation of the expression of MMP2/9, VEGF, and VEGFR-2, up-regulation of PTEN, P53 and suppression of PI3K/Akt/mTOR/NF-κB and EGFR/STAT3 signaling. Co-administration of metformin and curcumin significantly inhibited HCC tumor growth than administration with metformin or curcumin alone in a xenograft mouse model. Thus, metformin and curcumin in combination showed a better anti-tumor effects in hepatoma cells than either metformin or curcumin presence alone and might represent an effective therapeutic strategy for HCC treatment., (© 2017 Wiley Periodicals, Inc.)

Multidrug resistance (MDR) is one of major obstacles to effective chemotherapeutic treatment of cancer. This study showed that DHPAC, 2-(6-ethoxy-3-(3-ethoxyphenylamino) -1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy) acetamide, a novel compound that binds to the same site on microtubules as colchicine, has high anti-tumour activity in vincristine-resistant oral epidermoid carcinoma (KB/V) cells. It found that the presence of DHPAC strongly inhibited KB/V cell growth in vivo and in mice xenograft. The inhibitory effect of DHPAC is much stronger than that by colchicine in these KB/V cells (IC 50 : 64.4nM and 458.0nM respectively). Treatment of the cells with DHPAC induced cell apoptosis by reducing mitochondrial membrane potential and altered the expression of several apoptosis-related proteins such as Bcl-2, Bax, Caspase-9, Cytochrome c and PARP. DHPAC treatment also caused cell rest in G2/M phase by regulating of the expression of a number of cell cycle-related proteins (e.g. Cyclin B1, Cdc2, Cdc25b, Cdc25c, RSK2). Furthermore, DHPAC presence inhibits PTEN phosphorylation and PTEN/Akt/NF-κB signalling. Thus, DHPAC has potent anti-cancer activity in MDR tumuors and may be a potential therapeutic agent for the treatment of vincristine-resistant human oral epidermoid carcinoma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Asian hornet, Vespa velutina, is an invasive, globally-distributed predator of European honey bees and other insects. To better under its reproductive biology and to find a specific, effective, and low-impact control method for this species, we identified and tested the key compounds in V. velutina sex pheromone. Virgin gynes (reproductive females) produced this sex pheromone in the sixth intersegmental sternal glands of their abdomens. The active compounds were 4-oxo-octanoic acid (4-OOA, 10.4 μg bee -1 ) and 4-oxo-decanoic acid (4-ODA, 13.3 μg bee -1 ) at a 0.78 ratio of 4-OOA/4-ODA. We synthesized these compounds and showed that male antennae were highly sensitive to them. Moreover, males were only strongly attracted to a 4-OOA/4-ODA blend at the natural ratio produced by gynes. These results provide the first demonstration of an effective way to lure V. velutina males, and the first chemical identification of a sex pheromone in the eusocial hornets.

Scope: Although the previous trials of inflammation have indicated that morin hydrate (MO) hold considerable promise, understanding the distinct mechanism of MO against inflammation remains a challenge., Methods and Results: This study investigated the effect of MO in atherosclerosis in ApoE -/- mice and underlying cell signaling of MO effect in inflammation in human umbilical vein endothelial cells (HUVECs). Administration of MO significantly reduced serum lipid level, inflammatory cytokines (TNF-α and ICAM-1), and atherosclerotic plaque formation in vivo. MO presence attenuated the expression of TNF-α-induced inflammatory cytokines (ICAM-1, COX-2, and MMP-9), and remarkably enhanced microtubule associated protein 1 light chain 3 beta 2 (MAP1LC3B2) expression and sequestosome 1 (SQSTM1/p62) degradation in HUVECs. These MO effects were significantly prevented by the presence of autophagic inhibitors, 3-methyladenine (3-MA), or chloroquine (CQ), as well as siRNA suppression of ATG5 and BECN1. MO increased intracellular cAMP levels and activated cAMP-PKA-AMPK-SIRT1 signaling in vivo and in vitro. These changes resulted in increased expression of autophagy-related protein MAP1LC3B2 and decreased secretion of inflammatory cytokines (ICAM-1, COX-2, and MMP-9)., Conclusion: Our results suggest that anti-AS and anti-inflammatory effects of MO are largely associated with its induction of autophagy through stimulation of cAMP-PKA-AMPK-SIRT1 signaling pathway., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Esophageal carcinoma (EC) is a malignancy with high metastatic potential. Chromosomal helicase/ATPase DNA binding protein 1-like (CHD1L) gene is a newly identified oncogene located at Chr1q21, and it is amplified in many solid tumors. However, the status of CHD1L protein expression in EC and its clinical significance is uncertain. This study was designed to investigate the significance of CHD1L expression in human EC and its biological function in EC cells. The expression of CHD1L was examined by immunohistochemistry in 191 surgically resected ECs. The associations between CHD1L expression and clinical pathological parameters and the prognostic value of CHD1L were analyzed. Western blot analysis showed that CHD1L was overexpressed in EC cell lines. In addition, positive CHD1L expression was strongly related to advanced clinical stage ( P <0.01), and lymph node metastasis ( P <0.01) of EC. The Kaplan-Meier curve indicated that high expression of CHD1L may result in poor prognosis of EC patients ( P <0.01), and multivariate analysis showed that CHD1L overexpression was an independent predictor of overall survival. Furthermore, suppression of CHD1L in EC cells increased apoptosis and decreased cell proliferation invasion ability. Our results suggest that CHD1L is a target oncogene with the potential to serve as a novel prognostic biomarker in EC pathogenesis., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest in this work.

Cerebral microbleeds (CMBs) are small brain hemorrhages caused by the break down or structural abnormalities of small vessels of the brain. Owing to the paramagnetic properties of blood degradation products, CMBs can be detected in vivo using susceptibility-weighted imaging (SWI). SWI can be used not only to detect iron changes and CMBs, but also to differentiate them from calcifications, both of which may be important MR-based biomarkers for neurodegenerative diseases. Moreover, SWI can be used to quantify the iron in CMBs. SWI and gradient echo (GE) imaging are the two most common methods for the detection of iron deposition and CMBs. This study provides a comprehensive analysis of the number of voxels detected in the presence of a CMB on GE magnitude, phase and SWI composite images as a function of resolution, signal-to-noise ratio (SNR), TE, field strength and susceptibility using in silico experiments. Susceptibility maps were used to quantify the bias in the effective susceptibility value and to determine the optimal TE for CMB quantification. We observed a non-linear trend with susceptibility for CMB detection from the magnitude images, but a linear trend with susceptibility for CMB detection from the phase and SWI composite images. The optimal TE values for CMB quantification were found to be 3 ms at 7 T, 7 ms at 3 T and 14 ms at 1.5 T for a CMB of one voxel in diameter with an SNR of 20: 1. The simulations of signal loss and detectability were used to generate theoretical formulae for predictions. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

In colonial organisms, alarm pheromones can provide a key fitness advantage by enhancing colony defence and warning of danger. Learning which species use alarm pheromone and the key compounds involved therefore enhances our understanding of how this important signal has evolved. However, our knowledge of alarm pheromones is more limited in the social wasps and hornets compared with the social bees and ants. Vespa velutina is an economically important and widespread hornet predator that attacks honey bees and humans. This species is native to Asia and has now invaded Europe. Despite growing interest in V. velutina , it was unknown whether it possessed an alarm pheromone. We show that these hornets use sting venom as an alarm pheromone. Sting venom volatiles were strongly attractive to hornet workers and triggered attacks. Two major venom fractions, consisting of monoketones and diketones, also elicited attack. We used gas chromatography coupled to electroantennographic detection (GC-EAD) to isolate 13 known and 3 unknown aliphatic ketones and alcohols in venom that elicited conspicuous hornet antennal activity. Two of the unknown compounds may be an undecen-2-one and an undecene-2,10-dinone. Three major compounds (heptan-2-one, nonan-2-one and undecan-2-one) triggered attacks, but only nonan-2-one did so at biologically relevant levels (10 hornet equivalents). Nonan-2-one thus deserves particular attention. However, the key alarm releasers for V. velutina remain to be identified. Such identification will help to illuminate the evolution and function of alarm compounds in hornets., (© 2017. Published by The Company of Biologists Ltd.)

Objective: To screen genes related to familial non-medullary thyroid carcinoma (FNMTC) using next-generation sequencing (NGS). Methods: A panel of NGS was designed and sequencing was performed for DNA samples extracted from peripheral blood leukocytes of FNMTC patients and sporadic non-medullary thyroid carcinoma (SNMTC) cases, respectively, and gene mutations were screened. In addition, the clinicopathological characteristics, including tumor size, extension of surgery, lymph node metastasis and extra-thyroidal extension, were compared between patients with or without mutations. Results: In 63 NMTC samples, 45 mutations were detected on 13 genes. 37 germline mutations were detected in 47 FNMTC patients, while 8 germline mutations were detected in 16 SNMTC patients. In 8 FNMTC family lineages, the same mutations were carried by FNMTC patients from the same pedigree. The number of carriers of mutations was 29 in the 47 FNMTC patients and 6 in the 16 SNMTC patients, with a non-significant difference ( P = 0.092). Among the FNMTC patients, there were 22 patients with central lymph node metastasis in the 29 mutation-positive patients, significantly more than 7 in the 16 mutation-negative cases ( P = 0.031). As for the parentage, there were 3 patients with central lymph node involvement among the 7 patients of parent generation, while all the 9 patients of offspring generation had central lymph node metastasis ( P =0.019). Conclusions: This panel of NGS can be used to screen mutant susceptibility gene of FNMTC patients, and the findings may be helpful for early detection of FNMTC patients and predicting the disease risk to familial members of FNMTC patients.

Cells labeled by super paramagnetic iron-oxide (SPIO) nanoparticles are more easily seen in gradient echo MR images, but it has not been shown that the amount of nanoparticles or the number of cells can be directly quantified from MR images. This work utilizes a previously developed and improved Complex Image Summation around a Spherical or Cylindrical Object (CISSCO) method to quantify the magnetic moments of several clusters of SPIO nanoparticle labeled cells from archived rat brain images. With the knowledge of mass magnetization of the cell labeling agent and cell iron uptake, the number of cells in each nanoparticle cluster can be determined. Using a high pass filter with a reasonable size has little effect on each measured magnetic moment from the CISSCO method. These procedures and quantitative results may help improve the efficacy of cell-based treatments in vivo., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To introduce a method of increasing the width of alveolar bone. The patient, who needed dental implantation and had narrow alveolar bone, was selected. The preparation of mucosa-periosteal bone flap included two surgeries. The first surgery was corticotomy, which made a square cortex cut on narrow alveolar bone region. The second surgery was performed four weeks after the first one, which split the alveolar bone and inserted implants. Artificial bone and/or autologous bone was filled between inner and outer bone plate, and collagen membrane and platelet-rich fibrin membrane were used to cover the wound. This technique maintained the blood supply of labial(buccal) alveolar bone completely. Artificial bone and/or autologous bone graft contacted with cancellous bone directly and led to better bone growth and bone formation. Alveolar bone mucosa-periosteal bone flap can maintain the labial(buccal) alveolar bone effectively and avoid bone resorption.