Search

Jiulong Li,1 Bing Tian,1 Tao Li,1 Shang Dai,1 Yulan Weng,1 Jianjiang Lu,2 Xiaolin Xu,2 Ye Jin,1 Renjiang Pang,1 Yuejin Hua1 1Key Laboratory for Nuclear-Agricultural Sciences of Chinese Ministry of Agriculture and Zhejiang Province, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, People’s Republic of China; 2Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang, People’s Republic of China Background: Biosynthesis of noble metallic nanoparticles (NPs) has attracted significant interest due to their environmental friendly and biocompatible properties.Methods: In this study, we investigated syntheses of Au, Ag and Au–Ag bimetallic NPs using protein extracts of Deinococcus radiodurans, which demonstrated powerful metal-reducing ability. The obtained NPs were characterized and analyzed by various spectroscopy techniques.Results: The D. radiodurans protein extract-mediated silver nanoparticles (Drp-AgNPs) were preferably monodispersed and stably distributed compared to D. radiodurans protein extract-mediated gold nanoparticles (Drp-AuNPs). Drp-AgNPs and Drp-AuNPs exhibited spherical morphology with average sizes of 37.13±5.97 nm and 51.72±7.38 nm and zeta potential values of -18.31±1.39 mV and -15.17±1.24 mV at pH 7, respectively. The release efficiencies of Drp-AuNPs and Drp-AgNPs measured at 24 h were 3.99% and 18.20%, respectively. During the synthesis process, Au(III) was reduced to Au(I) and further to Au(0) and Ag(I) was reduced to Ag(0) by interactions with the hydroxyl, amine, carboxyl, phospho or sulfhydryl groups of proteins and subsequently stabilized by these groups. Some characteristics of Drp-AuNPs were different from those of Drp-AgNPs, which could be attributed to the interaction of the NPs with different binding groups of proteins. The Drp-AgNPs could be further formed into Au–Ag bimetallic NPs via galvanic replacement reaction. Drp-AuNPs and Au–Ag bimetallic NPs showed low cytotoxicity against MCF-10A cells due to the lower level of intracellular reactive oxygen species (ROS) generation than that of Drp-AgNPs.Conclusions: These results are crucial to understand the biosynthetic mechanism and properties of noble metallic NPs using the protein extracts of bacteria. The biocompatible Au or Au–Ag bimetallic NPs are applicable in biosensing, bioimaging and biomedicine. Keywords: extreme bacterium, green synthesis, noble metallic nanoparticles, reactive oxygen species

m 6 A RNA methylation suppresses the immunostimulatory potential of endogenous RNA. Deficiency of m 6 A provokes inflammatory responses and cell death, but the underlying mechanisms remain elusive. Here we showed that the noncoding RNA 7SK gains immunostimulatory potential upon m 6 A depletion and subsequently activates the RIG-I/MAVS axis to spark interferon (IFN) signaling cascades. Concomitant excess of IFN and m 6 A deficiency synergistically facilitate the formation of RNA G-quadruplexes (rG4) to promote ZBP1-mediated necroptotic cell death. Collectively, our findings delineate a hitherto uncharacterized mechanism that links m 6 A dysregulation with ZBP1 activity in triggering inflammatory cell death.

Objective: To analyze the differential genes and related signaling pathways of microglia subpopulations in Parkinson's disease (PD) -like mouse brains induced by paraquat (PQ) based on single-cell RNA sequencing, and provide clues to elucidate the mechanism of PQ-induced PD-like changes in the brain of animals. Methods: In September 2021, six male 6-week-old C57BL/6 mice were randomly divided into control group and experimental group (three mice in each group) . The mice were injected with saline, 10.0 mg/kg PQ intraperitoneally, once every three days, and 10 consecutive injections were used for modeling. After infection, the brains of mice were taken and 10×Genomics single-cell RNA sequencing was performed. Microglia subpopulations were screened based on gene expression characteristics, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. The differential genes of microglia subpopulations between the experimental group and control group were further screened, and functional enrichment analysis was performed using bioinformatics tools. Mouse microglia (BV2 cells) were treated with 0, 60, 90 μmol/L PQ solution, respectively. And real-time fluorescence quantitative PCR experiments were conducted to validate the expressions of differential genes hexokinase 2 (Hk2) , ATPase H+ Transporting V0 Subunit B (Atp6v0b) and Neuregulin 1 (Nrg1) . Results: Cluster 7 and Cluster 20 were identified as microglia subpopulations based on the signature genes inositol polyphosphate-5-phosphatase d, Inpp5d (Inpp5d) and transforming growth factor beta receptor 1 (Tgfbr1) , and they reflected the microglia-activated M2 phenotype. The bioinformatics analysis showed that the characteristic genes of identified microglia subpopulations were enriched in endocytosis. In terms of molecular function, it mainly enriched in transmembrane receptor protein kinase activity and cytokine binding. The up-regulated genes of Cluster 7 were mainly enriched in lysosomal pathway, endocytosis pathway, and down-regulated genes were mainly enriched in neurodegenerative disease and other signaling pathways. The up-regulated genes of Cluster 20 were mainly enriched in signaling pathways related to PD, and down-regulated genes were mainly enriched in cyclic adenosine 3', 5'-monophosphate (cAMP) signaling pathways, neurological development, synaptic function and other signaling pathways. The results of real-time fluorescence quantitative PCR showed that the expressions of Hk2 mRNA and Atp6v0b mRNA increased and the expression of Nrg1 mRNA decreased in the 90 μmol/L PQ-treated BV2 cells compared with the 0 μmol/L, and the differences were statistically significant ( P <0.05) . Conclusion: Microglia are activated in the PQ-induced PD-like mouse model and polarized toward the M2 phenotype. And their functions are associated with lysosomal (endocytosis) , synaptic functions and the regulation of PD-related pathways.

Increasing evidence reinforces the essential function of RNA modifications in development and diseases, especially in the nervous system. RNA modifications impact various processes in the brain, including neurodevelopment, neurogenesis, neuroplasticity, learning and memory, neural regeneration, neurodegeneration, and brain tumorigenesis, leading to the emergence of a new field termed neuroepitranscriptomics. Deficiency in machineries modulating RNA modifications has been implicated in a range of brain disorders from microcephaly, intellectual disability, seizures, and psychiatric disorders to brain cancers such as glioblastoma. The inaugural NSAS Challenge Workshop on Brain Epitranscriptomics hosted in Crans-Montana, Switzerland in 2023 assembled a group of experts from the field, to discuss the current state of the field and provide novel translational perspectives. A summary of the discussions at the workshop is presented here to simulate broader engagement from the general neuroscience field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Lee, Koo, Carré, Fischer, He, Kumar, Liu, Meyer, Ming, Peng, Roignant, Storkebaum, Sun, De Pietri Tonelli, Wang, Weng, Pulvirenti, Shi, Yoon and Song.)

Effective axonal regeneration in the adult mammalian nervous system requires coordination of elevated intrinsic growth capacity and decreased responses to the inhibitory environment. Intrinsic regenerative capacity largely depends on the gene regulatory network and protein translation machinery. A failure to activate these pathways upon injury is underlying a lack of robust axon regeneration in the mature mammalian central nervous system. Epigenetics and epitranscriptomics are key regulatory mechanisms that shape gene expression and protein translation. Here, we provide an overview of different types of modifications on DNA, histones, and RNA, underpinning the regenerative competence of axons in the mature mammalian peripheral and central nervous systems. We highlight other non-neuronal cells and their epigenetic changes in determining the microenvironment for tissue repair and axon regeneration. We also address advancements of single-cell technology in charting transcriptomic and epigenetic landscapes that may further facilitate the mechanistic understanding of differential regenerative capacity in neuronal subtypes. Finally, as epigenetic and epitranscriptomic processes are commonly affected by brain injuries and psychiatric disorders, understanding their alterations upon brain injury would provide unprecedented mechanistic insights into etiology of injury-associated-psychiatric disorders and facilitate the development of therapeutic interventions to restore brain function., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

RNA-binding proteins (RBPs) have critical roles in N6-methyladenosine (m6A) modification process. We designed a Random Forest (RF) model to systematically analyze the interaction among RBPs and m6A modifications by integrating the binding signals from hundreds of RBPs. Accurate prediction of m6A sites demonstrated significant connections between RBP bindings and m6A modifications. The relative importance of different RBPs from the model provided a quantitative metric to evaluate their interactions with m6A modifications. Redundancy analysis showed that several RBPs may have similar binding patterns with m6A sites. The RF model exhibited fairly high prediction accuracy across cell lines, suggesting a conservative RBP interaction network regulates m6A occupancy. Specific RBPs can engage to the corresponding regional m6A sites and deploy distinct regulatory processes, such as cleavage site selection of the alternative polyadenylation (APA). We also integrated histone modifications into our RF model, which demonstrated H3K36me3 and H3K27me3 as determining features for m6A distribution., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Background: It remains controversial whether the application of chemotherapy has an impact on recurrent nasopharyngeal carcinoma (rNPC) patients with salvage radiotherapy. Here, we aimed to evaluate treatment outcomes of rNPC patients and derive a prognostic model to assess the benefit of chemotherapy in patients with re-radiotherapy. Methods: This study was conducted as a retrospective study. In total, 340 rNPC patients treated with salvage intensity-modulated radiotherapy (IMRT) or radiochemotherapy (RCT) from October 2006 to September 2019 were included in this study. Overall survival (OS) was the primary outcome. Kaplan-Meier method was employed to detect the prognostic difference with Log-rank tests. The Cox regression analysis was performed to explore the potential prognostic factors while the multivariate Cox analysis was used to identify candidate variables for the prognostic model of OS. Results: The 5-year actuarial rates of OS, progression-free survival, loco-regional progression-free survival, and distant metastases-free survival did not show significant difference between the IMRT and RCT groups ( P  > .05). Age at recurrence and rT category were found to be the independent prognostic factors for OS. We found that rNPC patients suffered poor OS in the high-risk group (patients with higher age at recurrence and advanced rT category) (high-risk vs low-risk, HR = 1.87, 95% CI: 1.36-2.57, P  < .001). Salvage RT alone may be superior to RCT for patients in the low-risk group (RCT group vs RT group, HR = 1.89, 95% CI: 1.11-3.20, P  = .038). Conclusion: Salvage RT combined with chemotherapy cannot improve survival outcomes for rNPC. More novel clinical trials should be explored to develop individualized strategies to improve survival and minimize toxicities.

Alloreactive CD4 + T cells play a central role in allograft rejection. However, the post-transcriptional regulation of the effector program in alloreactive CD4 + T cells remains unclear. N 6 -methyladenosine (m 6 A) RNA modification is involved in various physiological and pathological processes. Herein, we investigated whether m 6 A methylation plays a role in the allogeneic T-cell effector program. m 6 A levels of CD4 + T cells from spleens, draining lymph nodes and skin allografts were determined in a skin transplantation model. The effects of a METTL3 inhibitor (STM2457) on CD4 + T-cell characteristics including proliferation, cell cycle, cell apoptosis and effector differentiation were determined after stimulation of polyclonal and alloantigen-specific (TEa; CD4 + T cells specific for I-Eα 52-68 ) CD4 + T cells with α-CD3/α-CD28 monoclonal antibodies and cognate CB6F1 alloantigen, respectively. We found that graft-infiltrating CD4 + T cells expressed high m 6 A levels. Administration of STM2457 reduced m 6 A levels, inhibited T-cell proliferation and suppressed effector differentiation of polyclonal CD4 + T cells. Alloreactive TEa cells challenged with 40 μm STM2457 exhibited deficits in T-cell proliferation and T helper type 1 cell differentiation, a cell cycle arrest in the G0 phase and elevated cell apoptosis. Moreover, these impaired T-cell responses were associated with the diminished expression levels of transcription factors Ki-67, c-Myc and T-bet. Therefore, METTL3 inhibition reduces the expression of several key transcriptional factors for the T-cell effector program and suppresses alloreactive CD4 + T-cell effector function and differentiation. Targeting m 6 A-related enzymes and molecular machinery in CD4 + T cells represents an attractive therapeutic approach to prevent allograft rejection., (© 2022 Australian and New Zealand Society for Immunology, Inc.)

Statistical learning, the process of tracking distributional information and discovering embedded patterns, is traditionally regarded as a form of implicit learning. However, recent studies proposed that both implicit (attention-independent) and explicit (attention-dependent) learning systems are involved in statistical learning. To understand the role of attention in statistical learning, the current study investigates the cortical processing of distributional patterns in speech across local and global contexts. We then ask how these cortical responses relate to statistical learning behavior in a word segmentation task. We found Event-Related Potential (ERP) evidence of pre-attentive processing of both the local (mismatching negativity) and global distributional information (late discriminative negativity). However, as speech elements became less frequent and more surprising, some participants showed an involuntary attentional shift, reflected in a P3a response. Individuals who displayed attentive neural tracking of distributional information showed faster learning in a speech statistical learning task. These results suggest that an involuntary attentional shift might play a facilitatory, but not essential, role in statistical learning., (Published by Elsevier Ltd.)

Magnetic nanoparticles (MNPs) are useful for magnetic targeted drug delivery while ligand-mediated active targeting is another common delivery strategy for cancer therapy. In this work, we intend to prepare magnetic graphene oxide (mGO) by chemical co-precipitation of MNPs on the GO surface, followed by conjugation of the gastrin releasing peptide (GRP) as a targeting ligand, for dual targeted drug/gene delivery in invasive brain glioma treatment. mGO was grafted with chitosan, complexed with shRNA plasmid DNA for stomatin-like protein 2 (SLP2) gene silencing, modified with urocanic acid for plasmid DNA endosomal escape, PEGylated for GRP conjugation, and loaded with the chemotherapeutic drug irinotecan (CPT-11) by π-π interaction for pH-responsive drug release (mGOCUG/CPT-11/shRNA). In addition to the in depth characterization of the physico-chemical and biological properties during each preparation step, we also study the loading/pH-responsive release behavior of CPT-11 and the shRNA plasmid loading/cell transfection efficiency. The targeting and antitumor efficacies of the nanocomposite were studied with U87 human glioblastoma cells in vitro . An in vivo study revealed that intravenous administration followed by magnetic guidance results in the efficient targeted delivery of mGOCUG/CPT-11/shRNA to orthotopic brain tumors in nude mice, and it exhibits excellent antitumor efficacy with a reduced tumor growth rate and prolonged animal survival time. Our work thus highlights a multifunctional mGO-based drug/gene delivery platform for effective combination cancer therapy in glioblastoma treatment.

Allogeneic CD8 + T cells are prominently involved in allograft rejection, but how their effector differentiation and function are regulated at a transcriptional level is not fully understood. Herein, we identified the basic leucine zipper ATF-like transcription factor (BATF) as a key transcription factor that drives the effector program of allogeneic CD8 + T cells. We found that BATF is highly expressed in graft-infiltrating CD8 + T cells, and its ablation in CD8 + T cells significantly prolonged skin allograft survival in a fully MHC-mismatched transplantation model. To investigate how BATF dictates allogeneic CD8 + T cell response, BATF -/- and wild-type (WT) CD8 + T cells were mixed in a 1:1 ratio and adoptively transferred into B6. Rag1 -/- mice 1 day prior to skin transplantation. Compared with WT CD8 + T cells at the peak of rejection response, BATF -/- CD8 + T cells displayed a dysfunctional phenotype, evident by their failure to differentiate into CD127 - KLRG1 + terminal effectors, impaired proliferative capacity and production of pro-inflammatory cytokines/cytotoxic molecules, and diminished capacity to infiltrate allografts. In association with the failure of effector differentiation, BATF -/- CD8 + T cells largely retained TCF1 expression and expressed significantly low levels of T-bet, TOX, and Ki67. At the memory phase, BATF-deficient CD8 + T cells displayed impaired effector differentiation upon allogeneic antigen re-stimulation. Therefore, BATF is a critical transcriptional determinant that governs the terminal differentiation and memory responses of allogeneic CD8 + T cells in the transplantation setting. Targeting BATF in CD8 + T cells may be an attractive therapeutic approach to promote transplant acceptance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zou, Chen, Cheng, Britz, Weng and Liu.)

Background: This paper investigated how second- and third-trimester gestational weight gain relates to perinatal outcomes among normal weight women with twin pregnancies in Fujian, China., Methods: A retrospective study examining the medical records of 931 normal weight twin-pregnant women was conducted in Fujian Maternity and Child Health Hospital from 2014 to 2018.The 2 nd and 3 rd trimester weekly weight gain rates were calculated, and women were categorized as gaining below, within, or above the 2009 Institute of Medicine (IOM) recommended rates. The association between the trimester-specific weight gain rate and perinatal outcome was determined by traditional regression analysis among groups., Results: A total of 25.9%, 19.8% and 54.3% of women had rates of weight gain across the 2 nd and 3 rd trimesters less than, greater than or within the recommended rates respectively. Multivariate logistic regression analysis showed that weight gain greater than the recommended rate in the 2 nd trimester was associated with a decreased risk of preeclampsia (aOR:0.489,95%CI:0.289 ~ 0.974). Weight gain less than the recommended rate of weight gain in the 3 rd trimester was associated with increased risks of premature delivery(aOR:2.079, 95%CI:1.467 ~ 2.968), gestational diabetes mellitus (aOR: 2.048, 95%CI:1.411 ~ 2.971), intrahepatic cholestasis syndrome (aOR:3.015,95%CI: 1.058 ~ 8.587), pre-labour rupture of membrane (aOR: 1.708,95%CI: 1.169 ~ 2.493), average twin birth weight < 2500 g(aOR:1.532,95%CI: 1.125 ~ 2.084) and neonatal respiratory distress syndrome (aOR:4.934,95%CI:1.626 ~ 15.083) and was associated with decreased risks of caesarean section (aOR:0.589,95%CI:0.386 ~ 0.898) and preeclampsia (aOR:0.471, 95%CI:0.274 ~ 0.808). In addition, weight gain greater than the recommended rate of weight gain in the 3 rd trimester was associated with increased risks of premature delivery (aOR:1.589,95%CI:1.428 ~ 2.951) and gestational hypertension (aOR:2.137,95% CI:1.034 ~ 4.415) as well as preeclampsia (aOR:2.246, 95%CI:1.462 ~ 3.452). The stratified analysis of weight gain in the 3 rd trimester showed that there was no significant difference in the incidence of adverse pregnancy outcomes compared to the 2 nd trimester weight gain groups., Conclusions: While this study showed that a gestational weight gain rate above or below the recommendation in the 3 rd trimester was associated with some adverse maternal and neonatal outcomes, further prospective and multicentre studies are required to explore alternate ranges of gestational weight gain rates in twin pregnancies., (© 2022. The Author(s).)

Intracerebral hemorrhage (ICH) remains a common and debilitating form of stroke. This neurological emergency must be diagnosed and treated rapidly yet effectively. In this article, we review the medical, surgical, repair, and regenerative treatment options for managing ICH. Topics of focus include the management of blood pressure, intracranial pressure, coagulopathy, and intraventricular hemorrhage, as well as the role of surgery, regeneration, rehabilitation, and secondary prevention. Results of various phase II and III trials are incorporated. In summary, ICH patients should undergo rapid evaluation with neuroimaging, and early interventions should include systolic blood pressure control in the range of 140 mmHg, correction of coagulopathy if indicated, and assessment for surgical intervention. ICH patients should be managed in dedicated neurosurgical intensive care or stroke units where continuous monitoring of neurological status and evaluation for neurological deterioration is rapidly possible. Extravasation of hematoma may be helpful in patients with intraventricular extension of ICH. The goal of care is to reduce mortality and enable multimodal rehabilitative therapy., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: The prevalence of convenience and beverage stores in Taiwan provides an environment for children to access different beverages. To our knowledge, the relationship between beverage consumption types and anthropometrics in children has not been reported in Taiwan. The aim of this study was to examine the association between the consumption frequency of beverage type and anthropometrics in third-grade children., Methods: This was a cross-sectional study conducted in 10 elementary schools in 12 administrative regions distributed evenly throughout Taipei City from June 2017 to December 2018. Parents of 515 children completed a questionnaire with written instructions, which was designed to collect demographic characteristics, frequency of consumed beverage types, and anthropometrics. This study was novel because beverage types were categorized based on sugar and protein contents, namely nutritious, sugar, nutritious and sugar, and non-nutritious and sugar-free. The differences in height and body weight between intake frequencies within each beverage type were determined using analysis of variance test or nonparametric statistics, depending on the confirmation of normal data distribution., Results: Height and weight of children consuming the most nutritious beverages fell in the highest respective percentile compared with those who did not consume them (P = 0.001 and 0.035, respectively). Consumption of nutritious and sugar and sugar beverages were not associated with height, body weight, or body mass index. Children who consumed more non-nutritious and sugar-free beverages were significantly heavier (P = 0.016) and had a higher body mass index (P = 0.001)., Conclusion: This was the first study conducted on third-grade children in Taiwan showing the beverage consumption type was associated with anthropometrics. Nutritious beverages appear to be a better choice for growth in children. Nevertheless, additional related studies, including an overall assessment of children's calorie and nutrient intakes and related dietary behaviors, are warranted to provide more helpful information for policymakers., (Copyright © 2021. Published by Elsevier Inc.)

Abstract: Population aging and air pollution are global concerns. The purpose of this study is to explore the relationship among particulate matter with a diameter of 2.5 μm or less (PM2.5) knowledge, PM2.5 preventive attitude, and PM2.5 preventive behavioral intention in the elderly.A cross-sectional survey design was applied in this study, including usage intention and snowball sampling. A total of 617 elderly people aged over 65 participated, and the collected data were quantitatively analyzed.The results showed that the mean score of PM2.5 knowledge of the elderly was 10.34 (79.53%) with the standard deviation (SD) of 3.42, the mean score of PM2.5 preventive attitude was 4.58 (91.60%) with SD of 0.49, and the mean score of PM2.5 preventive behavioral intention was 4.72 (94.40%) with SD of 0.40. Elderly people's characteristics regarding PM2.5 knowledge and PM2.5 preventive attitude explained 22% (adjusted R2 = 0.22, F = 30.44, P < .001) of the variance in PM2.5 preventive behavioral intention.It is concluded that we found no difference in PM2.5 knowledge, PM2.5 preventive attitude, or PM2.5 preventive behavioral intention among the elderly with or without chronic diseases. In our opinion, health education regarding the threat of PM2.5 to the health of the elderly should be strengthened, to enhance their knowledge, preventive attitude, and preventive behavioral intention of PM2.5., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Inconsistent results have been reported for the association between alcohol use and pancreatic cancer, particularly at low levels of alcohol consumption. Individuals genetically susceptible to the carcinogenic effect of alcohol might have higher pancreatic cancer risk after drinking alcohol. The current study investigated the association between alcohol use and pancreatic cancer with 419 pancreatic cancer cases and 963 controls recruited by a hospital-based case-control study in Taiwan. Gene-environment interaction between alcohol use and polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on pancreatic risk was evaluated. Our results showed no significant association between alcohol drinking and an increased pancreatic cancer risk, even at high levels of alcohol consumption. Even among those genetically susceptible to the carcinogenic effect of alcohol (carriers of ADH1B*2/*2(fast activity) combined with ALDH2*1/*2(slow activity) or ALDH2*2/*2(almost non-functional)), no significant association between alcohol use and pancreatic cancer was observed. Overall, our results suggested that alcohol drinking is not a significant contributor to the occurrence of pancreatic cancer in Taiwan., (© 2021. The Author(s).)

Human papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital-based case-control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non-OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV-positive OPC., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (M pro ) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 M pro that resulted in hundreds of X-ray crystal structures of ligand-bound M pro complexes in the Protein Data Bank (PDB) describing the interactions of different fragment chemotypes within different sites of the M pro . In this work, we performed rigorous molecular dynamics (MD) simulation of 62 reversible ligand-M pro complexes in the PDB to gain mechanistic insights about their interactions at the atomic level. Using a total of over 3 µs long MD trajectories, we characterized different pockets in the apo M pro structure, and analyzed the dynamic interactions and binding affinity of ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets of M pro . Our analyses unraveled the role of a lateral pocket in the catalytic site in M pro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in the lateral pocket towards ligand binding and affinity against M pro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and M pro dimerization in the ligand association with the target. Thus, comprehensive molecular-level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 M pro .

Background: The antioxidant effects of Bacillus subtilis -fermented red bean (natto-red bean) extract (NRBE) in young (6 weeks old) Sprague-Dawley rats and aged (12 months old) mice had been reported previously., Objective: To evaluate the antioxidant and anti-inflammatory effects of NRBE in the kidneys of streptozocin-induced diabetic rats., Design: Normal control rats and diabetic rats were orally gavaged with saline and low-dose NRBE (100 mg/kg body weight [BW]), medium-dose NRBE (200 mg/kg BW), and high-dose NRBE (500 mg/kg BW), for 12 weeks and then sacrificed. Concentration of fasting glucose, adiponectin, renal function markers, antioxidative markers, and pro-inflammatory markers were measured., Results: Oral administration of 50% ethanolic extract of NRBE with a dosage of 100 mg/kg BW, 200 mg/kg BW, or 500 mg/kg BW could improve the symptoms of kidney enlargement and renal function. Supplementation of NRBE can effectively inhibit the formation of renal reactive oxygen species and advanced-glycation end-products and increase renal glutathione content and serum adiponectin. A low dose of NRBE (100 mg/kg BW) decreased fasting blood sugar and renal interleukin (IL)-6 expression. Serum C-reactive protein, renal tumor necrosis factor-α, and monocyte chemoattractant protein-1 concentrations were decreased, and renal superoxide dismutase activity was increased in the medium-dose NRBE group. Twenty-four hour creatinine clearance and urinary albumin excretion also improved by medium-dose NRBE supplementation. In NRBE, total phenols and flavonoids were 6.3 mg gallic acid equivalent/g and 12.02 mg rutin equivalent/g, respectively, and kampherol was the major active antioxidant compound., Conclusion: This study demonstrated that appropriate amount of NRBE, 200 mg/kg BW in rats, could prevent diabetic nephropathy by improving antioxidant status and inhibiting inflammation in renal tissue., Competing Interests: The authors have not received any funding or benefits from industry or elsewhere to conduct this study., (© 2020 Kung-Chi Chan et al.)

EGFR is an oncogene with a high frequency of activating mutations in nonsmall cell lung cancer (NSCLC). EGFR inhibitors have been FDA-approved for NSCLC and have shown efficacy in patients with certain EGFR mutations. However, only 9% to 26% of these patients achieve objective responses. In our study, we developed an EGFR gene signature based on The Cancer Genome Atlas (TCGA) RNA-seq data of lung adenocarcinoma (LUAD) to direct the preselection of patients for more effective EGFR-targeted therapy. This signature infers baseline EGFR signaling pathway activity (denoted as EGFR score) in tumor samples, which is associated with tumor sensitivity to EGFR inhibitors and other tyrosine kinase inhibitors (TKIs). EGFR score predicted sensitivity of lung cancer cell lines to Erlotinib, Gefitinib and Sorafenib. Importantly, EGFR score calculated from pretreated samples was associated with patient response to Gefitinib and Sorafenib in lung cancer. Additionally, integration of the EGFR signature with TCGA LUAD data showed that it accurately predicted functional effects of different somatic EGFR mutations, and identified other mutations affecting EGFR pathway activity. Finally, using cancer cell line and clinical trial data, the EGFR score was associated with patient response to TKIs in liver cancer and other cancer types. The EGFR signature provides a useful biomarker that can expand the application of EGFR inhibitors or other TKIs and improve their treatment efficacy through patient stratification., (© 2020 UICC.)

Many studies have reported a positive association between lower socioeconomic status (SES) and higher head and neck cancer (HNC) risk. Fewer studies have examined the impact of SES on the association between alcohol or cigarette use and HNC risk. The current case-control study (1104 HNC cases and 1363 controls) investigated the influence of education, a SES indicator, on the association between HNC and the use of alcohol, cigarettes, or betel quids in Taiwan, a country with universal health care. Our results showed a larger increase in HNC risk associated with alcohol among those with lower educational level (odds ratio [OR] = 2.07; 95% confidence interval [CI], 1.53-2.80) than those with higher educational level (OR = 1.38; 95% CI, 1.04-1.85) (heterogeneity-P = .03). Educational level had an influence on the association between alcohol use and HNC risk among those with genetic susceptibility (ALDH2-deficient) to the carcinogenic effect of alcohol. The association between cigarette or betel quid use and HNC risk was similar between the high and low educational groups. National policies and social interventions have led to the decline in the prevalence of cigarette and betel quid users in Taiwan. In contrast, due to the lack of adequate alcohol control policies, alcohol consumption in Taiwan has continued to rise. A higher impact of alcohol on HNC risk among lower SES individuals even with universal health care could be the result of insufficient alcohol control policies in Taiwan., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The present study examined the hypothesis that left hemisphere (LH) equivalent language capabilities in the right hemisphere (RH) are inhibited in neurologically intact individuals by testing healthy young right-handers with a history of familial sinistrality (FS+, i.e. with at least one left handed biological relative), a population documented to show greater variability for RH language processing. Event-Related Potential (ERP) and split visual field presentation techniques were combined to assess LH- and RH- biased responses to syntactic category violations. In addition, a bilateral flanker task was used to measure inter-hemispheric inhibition ability in the same set of participants. Replicating prior findings, in addition to the LH-biased P600 grammaticality effect previously seen for right-handers in general, a fair amount, though not all, of FS + right-handers showed RH-biased P600 responses, leading to a reliable RH P600 grammaticality effect at the group level. Capitalizing on the variability of RH P600 responses, our results further revealed that reduced RH-biased P600 effects were reliably correlated with more effective RH inhibition (indexed by smaller reaction time differences between incongruent and neutral flankers presented to the RH via the left visual field). These results corroborated previous findings that the RH is capable of processing syntactic information in a manner qualitatively similar to that in the LH and further demonstrated that LH-equivalent processing in the RH as indexed by the P600 responses is modulated by RH inhibition, contributing to inter-individual variability in syntactic lateralization., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population., Methods: This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk., Results: Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer., Conclusions: The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.

In addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here, we show that knocking out myosin IIA and IIB (myosin IIA/B) in retinal ganglion cells alone, either before or after optic nerve crush, induces significant optic nerve regeneration. Combined Lin28a overexpression and myosin IIA/B knockout lead to an additive promoting effect and long-distance axon regeneration. Immunostaining, RNA sequencing, and western blot analyses reveal that myosin II deletion does not affect known axon regeneration signaling pathways or the expression of regeneration-associated genes. Instead, it abolishes the retraction bulb formation and significantly enhances the axon extension efficiency. The study provides clear evidence that directly targeting neuronal cytoskeleton is sufficient to induce significant CNS axon regeneration and that combining altered gene expression in the soma and modified cytoskeletal dynamics in the axon is a promising approach for long-distance CNS axon regeneration., Competing Interests: Declaration of Interests The authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background : Patients with either osteoporosis or depression are prone to develop other diseases and require more medical resources than do the general population. However, there are no studies on health-related quality of life (HRQoL) and medical resource use by osteoporosis patients with comorbid depression. We conducted this study for clarifying it. Methods : This cross-sectional study from 2005 to 2010 (6 years) analyzed 9776 National Health and Nutrition Examination Survey (NHANES) patients > 40 years old. Each patient was assigned to one of four groups: osteoporosis-positive (+) and depression-positive (+) (O + /D + ); O + /D - ; O - /D + ; O - /D - . We used multivariate linear and logistic regression model to analyze the HRQoL and medical resource use between groups. Results : The O + /D + group reported more unhealthy days of physical health, more unhealthy days of mental health, and more inactive days during a specified 30 days. The adjusted odds ratios (AORs) of O + /D + patients who had poor general health (7.40, 95% CI = 4.80-11.40), who needed healthcare (3.25, 95% CI = 2.12-5.00), and who had been hospitalized overnight (2.71, 95% CI = 1.89-3.90) were significantly highest. Conclusions : Low HRQoL was significantly more prevalent in D + /O + patients. We found that depression severity more significantly affected HRQoL than did osteoporosis. However, both diseases significantly increased the risk of high medical resource use., Competing Interests: The authors declare no conflicts of interest.

The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N 6 -methyladenosine (m 6 A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in m 6 A modification on numerous transcripts. In vivo conditional inactivation of an essential m 6 A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts postmitotic oligodendrocyte maturation and has distinct effects on OPC and oligodendrocyte transcriptomes. Moreover, the loss of Mettl14 in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts, including those that encode the essential paranodal component neurofascin 155 (NF155). Together, our findings indicate that dynamic RNA methylation plays an important regulatory role in oligodendrocyte development and CNS myelination., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a , with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.

Background: Carriers of the ALDH2*2 allele have impaired alcohol metabolism and are more susceptible to the development of alcohol-related cancers, including head and neck cancer (HNC). Screening for ALDH2*2 allele may identify high-risk individuals for alcohol health education. Although genotyping of ALDH2 is the most accurate way to identify ALDH2 deficiency, it may not be practical due to the cost and requirement for genotyping service., Methods: This study evaluated the accuracy of the alcohol flushing questionnaire to identify ALDH2 deficiency in a case-control study of HNC conducted in Taiwan using data collected from 904 patients with HNC and 1,078 controls., Results: Overall, alcohol flushing questionnaire had a high sensitivity (89%) of identifying ALDH2*2 carriers among the control subjects and a good sensitivity (79%) among the patients with HNC. The sensitivity of the alcohol flushing questionnaire in identifying ALDH2*2 carriers was affected by alcohol use, with a lower sensitivity among individuals who consumed alcohol, particularly among current regular (drinking alcohol once per week or more) alcohol drinkers., Conclusions: The current validation study showed that the alcohol flushing questionnaire may be a reasonable method to identify ALDH2-deficient individuals. However, current regular users of alcohol who reported no alcohol flushing may need to undergo genotyping of ALDH2 for a more accurate assessment of the ALDH2 status., (© 2019 by the Research Society on Alcoholism.)

Poor oral hygiene is an established risk factor of head and neck cancer (HNC); however, its role in the survival of HNC patients is unclear. This study evaluated the association between oral hygiene habits, including regular dental visits, frequency of tooth brushing, and use of dental floss, and the overall survival (OS) of HNC patients using interview data collected from 740 HNC patients. In addition, the interactions between oral hygiene and the polymorphisms of TLR2 and TLR4 on the OS of HNC patients were assessed. The analysis indicated that poor oral hygiene was significantly associated with poorer OS of HNC patients (hazard ratio (HR) = 1.38, 95% confidence interval (CI): 1.03-1.86). This association was modified by a single nucleotide polymorphism, rs11536889, of TLR4. A significant association between poor oral hygiene and worse survival of HNC was observed among those with the CG or CC genotype (HR = 2.32, 95% CI: 1.41-3.82) but not among those with the GG genotype (HR = 0.95, 95% CI: 0.65-1.40). Our results suggested that poor oral hygiene is not only a risk factor but may also be a prognostic factor of HNC., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Although alcohol drinking is an established risk factor of head and neck cancer (HNC), less is known about its role in the prognosis of HNC. The current study investigated the association between pretreatment alcohol consumption and the overall survival (OS) of HNC patients., Methods: Cox proportional hazards models were performed to evaluate the association between prediagnosis alcohol drinking and the OS of HNC patients. In addition, the influence of the polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2 , on this relationship was also evaluated., Results: The results showed a significant positive dose-response relationship between prediagnosis alcohol use and worse OS of HNC patients. This association was more significant for oropharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer than for oral cancer. The association between alcohol use and the poorer OS of HNC patients was mainly through its association with a higher stage of HNC at diagnosis. The worst OS associated with alcohol use was observed among HNC patients with the fast ADH1B and the slow/nonfunctional ALDH2 genotype combination., Conclusions: Our analysis showed a significant positive dose-response relationship between prediagnosis alcohol use and a worse OS of HNC. This association was mainly due to the higher stage of HNC among alcohol drinkers. In addition, the polymorphisms of the ethanol-metabolizing genes, ADH1B and ALDH2 , modified the relationship between prediagnosis alcohol use and the OS of HNC patients., Impact: Prediagnosis alcohol use may be a prognostic indicator of HNC., (©2018 American Association for Cancer Research.)

Purpose: Glioblastoma (GBM) is one of the most aggressive and incurable primary brain tumors. Identification of novel therapeutic targets is an urgent priority. Programmed cell death 10 (PDCD10), a ubiquitously expressed apoptotic protein, has shown a dual function in different types of cancers and in chemo-resistance. Recently, we reported that PDCD10 was downregulated in human GBM. The aim of this study was to explore the function of PDCD10 in GBM cells., Methods: PDCD10 was knocked down in three GBM cell lines (U87, T98g and LN229) by lentiviral-mediated shRNA transduction. U87 and T98g transduced cells were used for phenotype study and LN229 and T98g cells were used for apoptosis study. The role of PDCD10 in apoptosis and chemo-resistance was investigated after treatment with staurosporine and temozolomide. A GBM xenograft mouse model was used to confirm the function of PDCD10 in vivo. A protein array was performed in PDCD10-knockdown and control GBM cells., Results: Knockdown of PDCD10 in GBM cells promoted cell proliferation, adhesion, migration, invasion, and inhibited apoptosis and caspase-3 activation. PDCD10-knockdown accelerated tumor growth and increased tumor mass by 2.1-fold and led to a chemo-resistance of mice treated with temozolomide. Immunostaining revealed extensive Ki67-positive cells and less activation of caspase-3 in PDCD10-knockdown tumors. The protein array demonstrated an increased release of multiple growth factors from PDCD10-knockdown GBM cells., Conclusions: Loss of programmed cell death 10 activates tumor cells and leads to temozolomide-resistance in GBM, suggesting PDCD10 as a potential target for GBM therapy.

Two camptothecin derivatives, 10-cyclohexyl-7-methyl-20( S )-camptothecin and 7-methyl-10-morpholino-20( S )-camptothecin, were synthesized and their differences in solubility were investigated using four chosen solvent systems. Based on our results, 10-cyclohexyl-7-methyl-20( S )-camptothecin exhibited higher solubilities than 7-methyl-10-morpholino-20( S )-camptothecin in polar aprotic solvents. However, these two camptothecin derivatives did not exhibit apparent differences in solubility between 5% dimethyl sulfoxide (DMSO)/95% normal saline co-solvent system and 5% dimethylacetamide (DMAC)/95% normal saline co-solvent system. To rationalize their differences in solubility, we also tried to perform a DFT-B3LYP study to investigate their interaction with one water molecule.

N 6 -methyladenosine (m 6 A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m 6 A-specific binding proteins 1-5 . In the nervous system, m 6 A is abundant and modulates various neural functions 6-11 . Whereas m 6 A marks groups of mRNAs for coordinated degradation in various physiological processes 12-15 , the relevance of m 6 A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m 6 A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1-knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3, which encodes the catalytic component of the m 6 A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m 6 A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m 6 A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory.

Poor oral hygiene may lead to overgrowth of pathogenic oral bacteria, which may induce chronic inflammation to promote the oncogenesis of oral squamous cell carcinoma (OSCC). This study investigated the association between oral bacterial profile and OSCC risk in a case-control study of 138 OSCC cases and 151 controls (88 cases and 90 controls for the discovery group and 50 cases and 61 controls for the validation group). Oral bacterial profiles were characterized by targeted sequencing of the 16S rRNA gene. Three species of periodontopathogenic bacteria, Prevotella tannerae, Fusobacterium nucleatum, and Prevotella intermedia, were associated with an increased OSCC risk. This association was modified by the genetic polymorphisms of TLR2 and TLR4. Use of alcohol, betel quids and cigarettes and poor oral hygiene were associated with a higher percentage of oral periodontopathogenic bacteria. The association between alcohol and periodontopathogenic bacteria was modified by the genetic polymorphism of ALDH2, with a stronger positive association observed among the ALDH2-deficient individuals. The percentage of periodontopathogenic bacteria was positively correlated with the level of salivary IL1β, an inflammatory cytokine. Overall, our results showed a positive association between periodontopathogenic bacteria and OSCC risk and this relationship may be influenced by lifestyle and genetic factors. Our results provided further biological support for the established association between poor oral hygiene and OSCC risk. This suggested that improving oral hygiene may reduce OSCC risk and should be part of a public health campaign to prevent the occurrence of OSCC.

N 6 -methyladenosine (m 6 A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m 6 A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m 6 A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m 6 A-CLIP mapping further reveals a dynamic m 6 A landscape in the adult DRG upon injury. Loss of either m 6 A methyltransferase complex component Mettl14 or m 6 A-binding protein Ythdf1 globally attenuates injury-induced protein translation in adult DRGs and reduces functional axon regeneration in the peripheral nervous system in vivo. Furthermore, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult central nervous system is attenuated upon Mettl14 knockdown. Our study reveals a critical epitranscriptomic mechanism in promoting injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Metal nanocrystals (NCs) have been recognized as an important class of nanomaterials by virtue of their unique surface plasmon resonance (SPR) effect and pivotal roles as electron traps in photocatalysis. Nevertheless, it is still challenging to unambiguously unravel and simultaneously harness the dual synergistic roles of metal NCs in a single photocatalytic system for solar-to-chemical energy conversion. Herein, an efficient ligand-triggered electrostatic self-assembly strategy was developed to achieve the spontaneous and monodispersed attachment of Au NCs onto 1D WO 3 nanorods (NRs) via pronounced electrostatic attractive interaction, in which tailor-made positively charged Au NCs were closely integrated with negatively charged WO 3 NRs. The intimate integration of Au NCs with WO 3 NRs at the nanoscale could significantly benefit the extraction, separation, and migration of plasmon-induced energetic hot carriers over Au NCs and promote the separation of photogenerated charge carriers over the WO 3 substrate. Such a cooperative synergy stemming from SPR and the electron-withdrawal effects of the Au NCs resulted in distinctly enhanced photoredox catalytic performances for plasmonic photocatalysis under both simulated solar and visible light irradiation. Our study highlights the significance of utilizing a rational interface design between metal NCs and semiconductors for excavating the multifarious roles of metal NCs in substantial solar energy conversion.

Most studies reporting an inverse association between the consumption of vegetables and fruits and head and neck cancer (HNC) risk were conducted in Western populations and only a few included East Asians. The current case-control study investigated the association between diet and HNC risk using data of 838 HNC cases and 998 controls from a case-control study of HNC conducted in Taiwan. Each participant was asked about their consumption of fresh vegetables, pickled vegetables, fresh fruits, citrus fruits, meat, processed meat, fish, egg, and dairy products. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with each food category, adjusted for sex, age, education, and use of alcohol, betel quid and cigarette. An inverse association was observed between HNC risk and daily intake of fresh vegetables (OR = 0.44, 95% CI: 0.20-0.95, p -trend = 0.002) or fruits (OR = 0.55, 95% CI: 0.43-0.72, p -trend = 0.00001). Individuals who did not consume fresh fruits and vegetables daily had more than double the risk of HNC compared to those with daily intake of vegetables and fruits (OR= 2.24, 95% CI: 1.54-3.25). The results of the current study supported an inverse association between the consumption of fresh vegetables and fruits and HNC risk. In addition to cessation of cigarette smoking and betel quid chewing and reduction of alcohol drinking, a public health campaign for preventing the occurrence of HNC should promote a healthy diet that contains plenty of fresh vegetables and fruits., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Although alcohol is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature in several aspects. We analyzed detailed alcohol consumption data (amount and type of alcoholic beverage) of 811 HNC patients and 940 controls to evaluate the association between alcohol and HNC by HNC sites and by genotypes of ADH1B and ALDH2. Alcohol was associated with an increased HNC risk in a dose-response relationship, with the highest risk observed for hypopharyngeal cancer, followed by oropharyngeal and laryngeal cancers. Liquor showed a stronger positive association with HNC than beer and wine. The highest HNC risk occurred in individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. In our study population, 21.8% of HNCs, 55.7% of oropharyngeal cancers, and 89.1% of hypopharyngeal cancers could be attributed to alcohol. Alcohol accounted for 47.3% of HNCs among individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. The HNC risk associated with alcohol became comparable to that of never/occasional drinkers after ten or more years of cessation from regular alcohol drinking. In conclusion, alcohol use is associated with an increased HNC risk, particularly for individuals with slow ethanol metabolism. HNC incidence may be reduced by alcohol cessation.

Background: Although substantial evidence supports a 20-30% risk reduction of colon cancer, breast cancer, and endometrial cancer by physical activity (PA), the evidence for head and neck cancer (HNC) is limited. Three published studies on the association between PA and HNC have generated inconsistent results. The current study examined the association between recreational PA (RPA) and HNC risk with a more detailed assessment on the intensity, frequency, duration, and total years of RPA., Methods: Data on RPA were collected from 623 HNC cases and 731 controls by in-person interview using a standardized questionnaire. The association between RPA and HNC risk was assessed using unconditional logistic regression, adjusted for sex, age, educational level, use of alcohol, betel quid, and cigarette, and consumption of vegetables and fruits., Results: A significant inverse association between RPA and HNC risk was observed in a logistic regression model that adjusted for sex, age, and education (odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.51-0.82). However, after further adjustment for the use of alcohol, betel quid, and cigarette, and consumption of vegetables and fruits, RPA was no longer associated with HNC risk (OR =0.97, 95% CI: 0.73-1.28). No significant inverse association between RPA and HNC risk was observed in the analysis stratified by HNC sites or by the use of alcohol, betel quid, or cigarette., Conclusion: Results from our study did not support an inverse association between RPA and HNC risk. The major focus of HNC prevention should be on cessation of cigarette smoking and betel chewing, reduction of alcohol drinking, and promotion of healthy diet that contains plenty of fruits and vegetables.

Objective: To investigatethe effection of white matter abnormality to auditory and speech rehabilitation after cochlear implantation in prelingual deafness children. Method: Thirty-five children with white matter abnormality were included in this study. The degree of leukoaraiosis was evaluated by Scheltens scale based on MRI.The hearing and speechrecovery level was rated by auditory behavior grading standards(CAP) and speech intelligibility grading standards(SIR) at 6 months, 12 months, and 24 months post operation. Result: The CAP scores and SIR scores of the children with white matter abnormality were lower than those of the control group at 6 months after operation ( P <0.05).The SIR scores of the children with white matter abnormality at 12 months and 24 months post operation were significantly lower than those of the control group.There was no statistically significant difference between the CAP scores of the two groups at 12 and 24 months after operation( P >0.05).Schelten classification had a greater impact on SIR scores than on CAP scores. Conclusion: The effect of white matter abnormality on auditory and speech rehabilitation after cochlear implantation was related to the degree of leukoencephalopathy. When the lesion of white matter abnormality was larger, the level of hearing and verbal rehabilitation was lower, and the speech rehabilitation was more significantly impacted by white matter lesions degree., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Mature neurons in the adult peripheral nervous system can effectively switch from a dormant state with little axonal growth to robust axon regeneration upon injury. The mechanisms by which injury unlocks mature neurons' intrinsic axonal growth competence are not well understood. Here, we show that peripheral sciatic nerve lesion in adult mice leads to elevated levels of Tet3 and 5-hydroxylmethylcytosine in dorsal root ganglion (DRG) neurons. Functionally, Tet3 is required for robust axon regeneration of DRG neurons and behavioral recovery. Mechanistically, peripheral nerve injury induces DNA demethylation and upregulation of multiple regeneration-associated genes in a Tet3- and thymine DNA glycosylase-dependent fashion in DRG neurons. In addition, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult CNS is attenuated upon Tet1 knockdown. Together, our study suggests an epigenetic barrier that can be removed by active DNA demethylation to permit axon regeneration in the adult mammalian nervous system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Although betel quid (BQ) is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature regarding the dose-response, BQ types, HNC sites, and BQ cessation. The current study was conducted to fill these insufficiencies., Materials and Methods: A hospital-based case-control study was conducted to evaluate the association between BQ and HNC. In-person interview was conducted to collect data on BQ chewing. The current analysis included 487 men newly diagnosed with HNC and 617 male controls who were frequency-matched to the cases by age. The association between BQ and HNC was assessed using multivariable unconditional logistic regression., Results: Ever BQ chewing was associated with an increased HNC risk regardless of the BQ types. A non-linear positive association between BQ and HNC was observed, with a steep rise in HNC risk for the first 5 pack-years or 200,000 minutes of BQ consumption. Every year of BQ cessation was associated with a 2.9% reduction in HNC risk; however, the risk did not reduce to the level of non-BQ chewers even after 20 years of BQ cessation. Eliminating BQ chewing may prevent 51.6% of HNCs, 62.6% of oral cancers, and 41.3% of pharyngeal cancers in Taiwan., Conclusion: Our results supported the positive association between BQ and HNC. BQ cessation is effective in reducing HNC risk and should be encouraged. Because BQ cessation may not reduce the HNC risk to the level of non-BQ chewers, it is important to prevent the initiation of BQ chewing., Competing Interests: The authors have declared that no competing interests exist.

The intrinsic growth capacity of neurons in the CNS declines during neuronal maturation, while neurons in the adult PNS are capable of regeneration. Injured mature PNS neurons require activation of an array of regeneration-associated genes to regain axonal growth competence. Accumulating evidence indicates a pivotal role of epigenetic mechanisms in transcriptional reprogramming and regulation of neuronal growth ability upon injury. In this review, we summarize the latest findings implicating epigenetic mechanisms, including histone and DNA modifications, in axon regeneration and discuss differential epigenomic configurations between neurons in the adult mammalian CNS and PNS.

Cardiometabolic risk factors or their precursors are observed in childhood and may continue into adulthood. We investigated the effects of parental overweight and cardiometabolic diseases and pediatric lifestyle factors on the clustering of cardiovascular risk factors among adolescents, and examined the mediating and modifying effects of pediatric adiposity on these associations. Representative adolescents (n = 2727; age, 12-16 years) were randomly recruited through multistage stratified sampling from 36 schools in Southern Taiwan. Adolescent and parent surveys were conducted in schools and participant homes, respectively. Their demographic factors, diet patterns, and physical, anthropometric, and clinical parameters were collected and analyzed. Adolescents with 1-2 and ≥3 risk components for pediatric metabolic syndrome (MetS) were defined as potential MetS (pot-MetS) and MetS, respectively. Adolescents whose parents were overweight/obese, or with diabetes and hypertension had a higher prevalence ratio of pot-MetS and MetS (1.5-1.6 and 1.9-4.2-fold, respectively). Low physical activity (<952.4 MET·min/week), long screen time (≥3 h/day) and high sugar-sweetened beverage intake (>500 mL/day) were associated with a 3.3- (95% confidence intervals (CI) = 1.5-7.3), 2.2- (95% CI = 1.1-4.4), and 26.9-fold (95% CI = 3.2-229.0) odds ratio (OR) of MetS, respectively. Pediatric body mass index (BMI) accounted for 18.8%-95.6% and 16.9%-60.3% increased prevalence ratios of these parental and pediatric risk factors for MetS. The OR of pot-MetS + MetS for sugar-sweetened beverage consumption was multiplicatively enhanced among adolescents with overweight/obesity (combined OR, 8.6-fold (95% CI = 4.3-17.3); p for multiplicative interaction, 0.009). The results suggest that parental overweight and cardiometabolic diseases and pediatric sedentary and high sugar-intake lifestyles correlate with the development of adolescent MetS, and an elevated child BMI explains a part of these associations. Pediatric adiposity might be multiplicatively associated with sugar-sweetened beverage consumption for enhancing the MetS prevalence ratio among adolescents., Competing Interests: The authors declare no conflict of interest.

Purpose: Allergy symptoms have been associated with a reduced head and neck cancer (HNC) risk, while elevated blood immunoglobulin E (IgE) levels have been associated with an increased HNC risk. According to the "prophylaxis hypothesis," allergic reaction is the body's way of expelling carcinogens. IgE level may be increased by exposure to environmental carcinogens, including alcohol and cigarette smoke. We hypothesized that individuals with elevated serum IgE without allergy symptoms (i.e., asymptomatic atopic) would have the highest HNC risk., Methods: A case-control study of HNC (576 cases and 740 controls) was conducted to evaluate the association between allergy symptoms or serum total IgE and HNC risk and the effect modification of allergy symptoms on the association between serum total IgE and HNC risk., Results: Elevated serum total IgE was associated with a significantly increased HNC risk [odds ratio (OR) 1.71, 95 % confidence interval (CI) 1.21-2.42]. Having allergy symptoms was associated with a significantly reduced HNC risk (OR 0.56, 95 % CI 0.43-0.73). Compared to subjects with normal serum total IgE and no allergy symptoms, asymptomatic atopic individuals had a significantly increased HNC risk (OR 2.12, 95 % CI 1.33-3.35)., Conclusions: Our results provided further evidence to support the "prophylaxis hypothesis." Further investigations regarding the immune profiles of asymptomatic atopic individuals may provide additional clues for the biological mechanisms underlying the association between allergy symptoms, IgE, and HNC risk.

Objective: To perform laboratory diagnosis for an imported case of human African trypanosomiasis and identify the pathogen., Methods: Clinical and epidemiological information was collected. Blood and cerebrospinal fluid samples were collected, stained with Wright-Giemsa, and microscopically examined. Genomic DNA from the blood samples was amplified with primers specific for Trypanosoma sp. expression site-associated gene (ESAG), Trypanosoma brucei gambiense specific glycoprotein (TgsGP) and 18S rRNA（M18S-Ⅱ-Tb） gene, and Trypanosoma brucei rhodesiense specific serum resistance associated （SRA） gene. Complete blood count, blood chemistry, and CSF examination were also conducted., Results: The patient had a 4-month history of lower extremity weakness and swelling of surface lymph nodes. Physical examination showed somnolence, and occasional emotional abnormalities, accompanied by anemia (hemoglobin 85 g/L), electrolyte disturbance (sodium 124 mmol/L; chlorine 87 mmol/L) and significantly increased nonspecific immune globulin protein （globulin 63 g/L）. Epidemiological survey showed that the patient suffered insect bites and stings for several times during his work in the Republic of Gabon in Africa. Microscopic examination revealed flagella of trypanosome in peripheral blood. PCR amplification produced bands of 286, 308, and 150 bp with primers specific for ESAG, TgsGP and M18S-Ⅱ-Tb, respectively., Conclusion: The patient was diagnosed with Trypanosoma brucei gambiense infection from the clinical information, epidemiological history, etiology and PCR results.

This analysis evaluated the association between serum retinol levels and risk of head and neck cancer (HNC) and whether the association is modulated by the use of alcohol, betel quid, or cigarette. In addition, we also examined the association between HNC risk and 2 single nucleotide polymorphisms, TTR rs1667255 and RBP4 rs10882272, that have been associated with serum retinol levels. Unconditional logistic regression was performed to evaluate the association between serum retinol levels and HNC risk among 160 HNC cases and 198 controls. The associations between TTR rs1667255 and RBP4 rs10882272 and serum retinol levels or HNC risk were evaluated by linear regression and unconditional logistic regression, respectively, for 418 HNC cases and 497 controls. The results showed that HNC cases had a lower mean serum retinol level compared with controls (845.3 μg/L vs 914.8 μg/L, P = 0.03). An inverse association between serum retinol levels and HNC risk occurred among never/occasional alcohol drinkers but not among regular drinkers. TTR rs1667255 was associated with serum retinol levels; however, neither TTR rs1667255 nor RBP4 rs10882272 was associated with HNC risk. In summary, this study showed an inverse association between serum retinol levels and HNC risk, specifically among never/occasional alcohol drinkers. More studies are needed to establish the underlying biologic mechanisms for the inverse association between serum retinol levels and HNC risk and the modulation of this relationship by alcohol drinking.

Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.

Objective: Previous studies examining the association between genetic variations in prostaglandin pathway and risk of head and neck cancer (HNC) have only included polymorphisms in the PTGS2 (COX2) gene. This study investigated the association between genetic polymorphisms of six prostaglandin pathway genes (PGDS, PTGDS, PTGES, PTGIS, PTGS1 and PTGS2), and risk of HNC., Methods: Interviews regarding the consumption of alcohol, betel quid, and cigarette were conducted with 222 HNC cases and 214 controls. Genotyping was performed for 48 tag and functional single-nucleotide polymorphisms (SNPs)., Results: Two tag SNPs of PTGIS showed a significant association with HNC risk [rs522962: log-additive odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.01-1.99 and dominant OR = 1.58, 95% CI: 1.02-2.47; rs6125671: log-additive OR = 1.49, 95% CI: 1.08-2.05 and dominant OR = 1.96, 95% CI: 1.16-3.32]. In addition, a region in PTGIS tagged by rs927068 and rs6019902 was significantly associated with risk of HNC (global P = 0.007). Finally, several SNPs interacted with betel quid and cigarette to influence the risk of HNC., Conclusions: Genetic variations in prostaglandin pathway genes are associated with risk of HNC and may modify the relationship between use of betel quid or cigarette and development of HNC., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)